54
MANAGEMENT OF CHLOROQUINE RESISTANT MALARIA Dr.HARMANJIT SINGH JR- PHARMACOLOGY
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MANAGEMENT OF CHLOROQUINE RESISTANT MALARIA
DrHARMANJIT SINGH
JR- PHARMACOLOGY
GMC PATIALA
2
CONTENTS
Introduction
Life cycle
Anti malarial drugs
Treatment (Chloroquine sensitive amp Resistant both)
Anti malarial vaccine
Summary
MALARIA bull Malaria was once considered to arise from marshy
land (hence the name mal aria-bad or poisonous air)
bull Caused by Plasmodiumbull Four species Pvivaxbull Pfalciparum bull Povale
Pmalariae
The insect vector female Anopheles mosquitobull Breeds in stagnant water
MALARIA bull Malaria remains the worldrsquos most devastating
human parasitic infection afflicting more than 500 million people and causing from 17 million to 25 million deaths each year
bull In 2010 more than 100 countries were considered malarious
bull Malaria kills more than 1 million children a year in the developing world
In malaria endemic areas - Children under age of 5 years - greater risk of dying
Chloroquine resistant-PF Chloroquine sensitive-PF
Malaria Endemic Areas
Mexico Central America west of Panama canalCarribean South America middle east
Resistant PVIndonesiaPapua New Guinea Burma
7
DRUG RESISTANT MALARIA
Definition Drug resistance is the ability of the parasite species to survive andor multiply despite the administration and absorption of a drug given in doses equal to or higher than those usually recommended but within the limit of tolerance
MDR Malaria Resistance to 3 or more anti-malarials of different
chemical classes of which two are
4-aminoquinolines and diaminopyrimidinerdquo
8
Resistance occurs most commonly due to improper treatment and inadequate dosage of antimalarials
The important factors that are associated with resistance are
1 Longer half-life 2 Single mutation for resistance 3 Poor compliance 4 Host immunity 5 Number of people using these drugs
Although chloroquine resistant strains of P vivax have been described drug resistance poses a serious clinical problem only with P falciparum gt70 of cases
9
Global Scenario of Drug Resistant Malaria
P falciparum resistance 1048698 Chloroquine resistant strains are found now in
nearly all areas of chloroquine use including South America Central America east of the Panama Canal the Western Pacific East Asia
P vivax resistance 1048698 Recent reports from Indonesia (Irian Jaya
Sumatra) and Papua New Guinea indicate high levels of P vivax schizonts resistant to chloroquine Decreased susceptibility may also be appearing in the Solomon Islands Myanmar Brazil Colombia
P ovale and P malariae resistance 1048698 P ovale and P malariae forms have not shown
resistance to chloroquine
10
MECHANISM Resistant strains are able to efflux the drug by an
active pump mechanism and thereby rendering the drug ineffective
Resistant strains concentrate chloroquine less in vacuoles
Crt-Chloroquine resistant transporter and Pfmdr transporters mutations
There is an increase in the surface area of the resistant parasites permitting more efficient pinocytosis
Binding of chloroquine with haemoglobin breakdown product to form toxic complexes is also prevented
Nonspecific pump inhibitors like calcium channel blockers or antagonists of calmodulin (eg verapamil) have not shown any benefit
11
Types of Drug Resistance 1048698 In defining criteria for resistance to the
aminoquinoline antimalarial drugs the WHO has described three grades of resistance following treatment
1048698 (Low grade) R1 Recrudescence of infection between 7 and 28 days of completing treatment following initial resolution of symptoms and parasite clearance
1048698 (High grade) R2 Reduction of parasitaemia by gt 75 at 48 hours but failure to clear parasites
within 7 days 1048698 R3 Parasitaemia does not fall by gt75 within 48
hours
Indian Scenario of Drug Resistant Malaria
P falciparum gtgt P vivax Incidence being 5 to full dose chloroquine The first confirmed report of chloroquine resistance in
P falciparum was reported in Diphu area of Karbianglong district of Assam in 1973
Resurgence of P falciparum resistant to chloroquine has been noticed in several regions of India more in North Eastern parts of the country
KEM hospital in Mumbai confirmed the existence of chloroquine resistance in P falciparum cases in Mumbai
However for all practical purposes drug resistant malaria in the Indian context means malaria caused by strains of P falciparum which are resistant to chloroquine 12
13
Clinical features
Cold Stagebull Feeling of Intense Coldbull Vigorous Shivering Rigorbull Lasts 15-60 Min
Hot Stagebull Intense Heatbull Dry Burning Skinbull Throbbing Headachebull Lasts 2-6 Hours
Sweating Stagebull Profuse Sweatingbull Declining Temperaturebull Exhausted Weak bull Lasts 2-4 Hours
Why PF Serious
PPalciparum
Produces
Leads to
Binds-RBCs all ages Alters surface Grows in low o2
Micro-vascular blocks Cytokine release Endotoxin release
High parasitemia Cerebral malaria Hypoglycemia Shock Multi organ failure Death
15
Thick Smear Rapid Diagnosis Thin Species identification
Rapid diagnostic test
Antibody detection test
- RIA
- ELISA
Diagnosis
16
1 Chemical classification 4-aminoquinolines
- Chloroquine amodiaquine Piperaquine
8-aminoquinolines - Primaquine Bulaquine
Folate synthesis inhibitors - Sulphonamides like Sulphadoxine Dapsone
- Biguanides like proguanil and chloroproguanil
- Diaminopyrimidine like pyrimethamine
CINCHONA ALKALOIDS Quinine Quinidine
AMINO ALCOHOLS - Lumefantrine Halofantrine
-
17
Antimicrobials Tetracycline doxycycline clindamycin azithromycin
fluoroquinolones FOSMIDOMYCIN
Peroxides Artemisinin (Qinghaosu) derivatives and analogues -
artemether arteether artesunate artelinic acid
Naphthoquinones Atovaquone
Iron chelating agents Desferrioxamine
Chemical classification
2 According To Mode Of Action FOR CAUSAL
PROPHYLAXIS MODE Pre-erythorcytic
Schizonticides ( kill schizonts in the liver )
DRUGS
- Primaquine
- Proguanil
- Tetracycline
FOR THE TREATMENT OF ACUTE ATTACK
MODE Erythrocytic Schizonticides (kill schizonts in the Blood)
DRUGS - Rapidly acting -
Chloroquine quinine atovaquone artemisinin derivatives mefloquine
- Slow acting - - Proguanil sulphonamides
tetracyclines pyrimethamine
According To Mode Of Action FOR PREVENTION OF
TRNSMISSION MODE GAMETOCIDES
( kill Gametes ) DRUGS
- Primaquine for all
species
- Artemisinin for all
- Quinine For vivax
- Chloroquine for
vivax
FOR RADICAL CURE MODE Exo-erythrocytic
Schizonticides (kill Exo-erythrocytic forms ie Hypnozoites)
DRUGS
- Primaquine
20
Site of action
21
CHLOROQUINE
Erythrocytic schizontocide all plasmodial species
Gametocytic not Pfalciparum
No effect on sporozoites hypnozoites
MOA Concentrates in parasite food vacuoles uarrpH
Disruption of polymerization of Heme to Hemozoin
Heme damage plasmodium membrane
Well absorbed oral IM SC 60 PPB
Metabolized by liver t12 3-10 days
Excreted by kidney
22
ADRsNausea vomiting Blurring of
vision Headache Confusion seizures
ndash Hemolysis G6PD individuals Impaired hearing
ndash Hypotension ECG changes
ndash High dose Irreversible ototoxicity retinopathy
myopathy Peripheral neuropathy Chloroquine sulphate (Tab)136 mg = 100 mg Base Chloroquine phosphate (Tab) 250mg=150mg Base
Dose 600 mg stat 300 mg after 8 hours and then
for next two days
Chloroquine
23
Faster acting MOA amp resistance similar to chloroquine ADRs
ndash Toxic hepatitisndash Agranulocytosis
Dose 25-35 mgkg over 3 days Chloroquine resistant combine Artesunate
Amodiaquine
24
Mefloquine Erythrocytic schizontocide Rapidly control fever eliminate circulating parasite Effective Chloroquine resistant plasmodium MOA- Inhibits heme polymerization
- Forms toxic complexes with free heme Oral absorbed Highly protein bound Extensive
tissues distribution
ADRs Nauses Vomiting Diarrhoea Neuropsychiatric Arrythmias Haematological Hepatic toxicity
Dose1250 mg 750 mg 500mg 12 hrly
25
Derived from bark of cinchona tree
Effective blood schizonticidal
Gametocidal P vivax
Chloroquine resistant MDR FP MOA same as of chloroquine Oral absorption rapid amp complete Bound to α1 acid
glycoprotein Metabolized by CYP3A4 Excreted in urine t12 10-12 hrs
Quinine
26
QuinineADRs Cinchonism tinnitusdysphoria headache
Nausea vomiting dizziness flushing amp visual
disturbances
GIT nausea vomiting diarrhoeaabdominal pain Hypoglycemia CVS hypotension dysrhythmias VT fibrillation Hemolysis (G6PD deficiency) Blackwater fever hemolysis hemoglobinemia
hemoglobinuria Dose
ndash Quinine 600 mg 8 hrly
27
Pyrimethamine
Erythrocytic schizontocide
Resistance develops rapidly if used alone
MOA DHFRase inhibitor Oral absorption good slow Concentrated liver spleen kidneys Metabolized liver Excreted renal amp t12 4 days ADRs Nausea Rashes Folate deficiency Dose sulphadoxine 1500 mg
+
pyrimethamine 75 mg
28
Proguanil
Erythrocyte schizontocide
Cyclic triazine metabolite cycloguanil
MOA DHFRase Inhibitor
Slowly adequately absorbed Partly metabolized
Excreted in urine amp t12 is 20 hrs
ADRs Vomiting Abdominal pain Haematuria
Dose 200-300 mgday for 4wks
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
2
CONTENTS
Introduction
Life cycle
Anti malarial drugs
Treatment (Chloroquine sensitive amp Resistant both)
Anti malarial vaccine
Summary
MALARIA bull Malaria was once considered to arise from marshy
land (hence the name mal aria-bad or poisonous air)
bull Caused by Plasmodiumbull Four species Pvivaxbull Pfalciparum bull Povale
Pmalariae
The insect vector female Anopheles mosquitobull Breeds in stagnant water
MALARIA bull Malaria remains the worldrsquos most devastating
human parasitic infection afflicting more than 500 million people and causing from 17 million to 25 million deaths each year
bull In 2010 more than 100 countries were considered malarious
bull Malaria kills more than 1 million children a year in the developing world
In malaria endemic areas - Children under age of 5 years - greater risk of dying
Chloroquine resistant-PF Chloroquine sensitive-PF
Malaria Endemic Areas
Mexico Central America west of Panama canalCarribean South America middle east
Resistant PVIndonesiaPapua New Guinea Burma
7
DRUG RESISTANT MALARIA
Definition Drug resistance is the ability of the parasite species to survive andor multiply despite the administration and absorption of a drug given in doses equal to or higher than those usually recommended but within the limit of tolerance
MDR Malaria Resistance to 3 or more anti-malarials of different
chemical classes of which two are
4-aminoquinolines and diaminopyrimidinerdquo
8
Resistance occurs most commonly due to improper treatment and inadequate dosage of antimalarials
The important factors that are associated with resistance are
1 Longer half-life 2 Single mutation for resistance 3 Poor compliance 4 Host immunity 5 Number of people using these drugs
Although chloroquine resistant strains of P vivax have been described drug resistance poses a serious clinical problem only with P falciparum gt70 of cases
9
Global Scenario of Drug Resistant Malaria
P falciparum resistance 1048698 Chloroquine resistant strains are found now in
nearly all areas of chloroquine use including South America Central America east of the Panama Canal the Western Pacific East Asia
P vivax resistance 1048698 Recent reports from Indonesia (Irian Jaya
Sumatra) and Papua New Guinea indicate high levels of P vivax schizonts resistant to chloroquine Decreased susceptibility may also be appearing in the Solomon Islands Myanmar Brazil Colombia
P ovale and P malariae resistance 1048698 P ovale and P malariae forms have not shown
resistance to chloroquine
10
MECHANISM Resistant strains are able to efflux the drug by an
active pump mechanism and thereby rendering the drug ineffective
Resistant strains concentrate chloroquine less in vacuoles
Crt-Chloroquine resistant transporter and Pfmdr transporters mutations
There is an increase in the surface area of the resistant parasites permitting more efficient pinocytosis
Binding of chloroquine with haemoglobin breakdown product to form toxic complexes is also prevented
Nonspecific pump inhibitors like calcium channel blockers or antagonists of calmodulin (eg verapamil) have not shown any benefit
11
Types of Drug Resistance 1048698 In defining criteria for resistance to the
aminoquinoline antimalarial drugs the WHO has described three grades of resistance following treatment
1048698 (Low grade) R1 Recrudescence of infection between 7 and 28 days of completing treatment following initial resolution of symptoms and parasite clearance
1048698 (High grade) R2 Reduction of parasitaemia by gt 75 at 48 hours but failure to clear parasites
within 7 days 1048698 R3 Parasitaemia does not fall by gt75 within 48
hours
Indian Scenario of Drug Resistant Malaria
P falciparum gtgt P vivax Incidence being 5 to full dose chloroquine The first confirmed report of chloroquine resistance in
P falciparum was reported in Diphu area of Karbianglong district of Assam in 1973
Resurgence of P falciparum resistant to chloroquine has been noticed in several regions of India more in North Eastern parts of the country
KEM hospital in Mumbai confirmed the existence of chloroquine resistance in P falciparum cases in Mumbai
However for all practical purposes drug resistant malaria in the Indian context means malaria caused by strains of P falciparum which are resistant to chloroquine 12
13
Clinical features
Cold Stagebull Feeling of Intense Coldbull Vigorous Shivering Rigorbull Lasts 15-60 Min
Hot Stagebull Intense Heatbull Dry Burning Skinbull Throbbing Headachebull Lasts 2-6 Hours
Sweating Stagebull Profuse Sweatingbull Declining Temperaturebull Exhausted Weak bull Lasts 2-4 Hours
Why PF Serious
PPalciparum
Produces
Leads to
Binds-RBCs all ages Alters surface Grows in low o2
Micro-vascular blocks Cytokine release Endotoxin release
High parasitemia Cerebral malaria Hypoglycemia Shock Multi organ failure Death
15
Thick Smear Rapid Diagnosis Thin Species identification
Rapid diagnostic test
Antibody detection test
- RIA
- ELISA
Diagnosis
16
1 Chemical classification 4-aminoquinolines
- Chloroquine amodiaquine Piperaquine
8-aminoquinolines - Primaquine Bulaquine
Folate synthesis inhibitors - Sulphonamides like Sulphadoxine Dapsone
- Biguanides like proguanil and chloroproguanil
- Diaminopyrimidine like pyrimethamine
CINCHONA ALKALOIDS Quinine Quinidine
AMINO ALCOHOLS - Lumefantrine Halofantrine
-
17
Antimicrobials Tetracycline doxycycline clindamycin azithromycin
fluoroquinolones FOSMIDOMYCIN
Peroxides Artemisinin (Qinghaosu) derivatives and analogues -
artemether arteether artesunate artelinic acid
Naphthoquinones Atovaquone
Iron chelating agents Desferrioxamine
Chemical classification
2 According To Mode Of Action FOR CAUSAL
PROPHYLAXIS MODE Pre-erythorcytic
Schizonticides ( kill schizonts in the liver )
DRUGS
- Primaquine
- Proguanil
- Tetracycline
FOR THE TREATMENT OF ACUTE ATTACK
MODE Erythrocytic Schizonticides (kill schizonts in the Blood)
DRUGS - Rapidly acting -
Chloroquine quinine atovaquone artemisinin derivatives mefloquine
- Slow acting - - Proguanil sulphonamides
tetracyclines pyrimethamine
According To Mode Of Action FOR PREVENTION OF
TRNSMISSION MODE GAMETOCIDES
( kill Gametes ) DRUGS
- Primaquine for all
species
- Artemisinin for all
- Quinine For vivax
- Chloroquine for
vivax
FOR RADICAL CURE MODE Exo-erythrocytic
Schizonticides (kill Exo-erythrocytic forms ie Hypnozoites)
DRUGS
- Primaquine
20
Site of action
21
CHLOROQUINE
Erythrocytic schizontocide all plasmodial species
Gametocytic not Pfalciparum
No effect on sporozoites hypnozoites
MOA Concentrates in parasite food vacuoles uarrpH
Disruption of polymerization of Heme to Hemozoin
Heme damage plasmodium membrane
Well absorbed oral IM SC 60 PPB
Metabolized by liver t12 3-10 days
Excreted by kidney
22
ADRsNausea vomiting Blurring of
vision Headache Confusion seizures
ndash Hemolysis G6PD individuals Impaired hearing
ndash Hypotension ECG changes
ndash High dose Irreversible ototoxicity retinopathy
myopathy Peripheral neuropathy Chloroquine sulphate (Tab)136 mg = 100 mg Base Chloroquine phosphate (Tab) 250mg=150mg Base
Dose 600 mg stat 300 mg after 8 hours and then
for next two days
Chloroquine
23
Faster acting MOA amp resistance similar to chloroquine ADRs
ndash Toxic hepatitisndash Agranulocytosis
Dose 25-35 mgkg over 3 days Chloroquine resistant combine Artesunate
Amodiaquine
24
Mefloquine Erythrocytic schizontocide Rapidly control fever eliminate circulating parasite Effective Chloroquine resistant plasmodium MOA- Inhibits heme polymerization
- Forms toxic complexes with free heme Oral absorbed Highly protein bound Extensive
tissues distribution
ADRs Nauses Vomiting Diarrhoea Neuropsychiatric Arrythmias Haematological Hepatic toxicity
Dose1250 mg 750 mg 500mg 12 hrly
25
Derived from bark of cinchona tree
Effective blood schizonticidal
Gametocidal P vivax
Chloroquine resistant MDR FP MOA same as of chloroquine Oral absorption rapid amp complete Bound to α1 acid
glycoprotein Metabolized by CYP3A4 Excreted in urine t12 10-12 hrs
Quinine
26
QuinineADRs Cinchonism tinnitusdysphoria headache
Nausea vomiting dizziness flushing amp visual
disturbances
GIT nausea vomiting diarrhoeaabdominal pain Hypoglycemia CVS hypotension dysrhythmias VT fibrillation Hemolysis (G6PD deficiency) Blackwater fever hemolysis hemoglobinemia
hemoglobinuria Dose
ndash Quinine 600 mg 8 hrly
27
Pyrimethamine
Erythrocytic schizontocide
Resistance develops rapidly if used alone
MOA DHFRase inhibitor Oral absorption good slow Concentrated liver spleen kidneys Metabolized liver Excreted renal amp t12 4 days ADRs Nausea Rashes Folate deficiency Dose sulphadoxine 1500 mg
+
pyrimethamine 75 mg
28
Proguanil
Erythrocyte schizontocide
Cyclic triazine metabolite cycloguanil
MOA DHFRase Inhibitor
Slowly adequately absorbed Partly metabolized
Excreted in urine amp t12 is 20 hrs
ADRs Vomiting Abdominal pain Haematuria
Dose 200-300 mgday for 4wks
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
MALARIA bull Malaria was once considered to arise from marshy
land (hence the name mal aria-bad or poisonous air)
bull Caused by Plasmodiumbull Four species Pvivaxbull Pfalciparum bull Povale
Pmalariae
The insect vector female Anopheles mosquitobull Breeds in stagnant water
MALARIA bull Malaria remains the worldrsquos most devastating
human parasitic infection afflicting more than 500 million people and causing from 17 million to 25 million deaths each year
bull In 2010 more than 100 countries were considered malarious
bull Malaria kills more than 1 million children a year in the developing world
In malaria endemic areas - Children under age of 5 years - greater risk of dying
Chloroquine resistant-PF Chloroquine sensitive-PF
Malaria Endemic Areas
Mexico Central America west of Panama canalCarribean South America middle east
Resistant PVIndonesiaPapua New Guinea Burma
7
DRUG RESISTANT MALARIA
Definition Drug resistance is the ability of the parasite species to survive andor multiply despite the administration and absorption of a drug given in doses equal to or higher than those usually recommended but within the limit of tolerance
MDR Malaria Resistance to 3 or more anti-malarials of different
chemical classes of which two are
4-aminoquinolines and diaminopyrimidinerdquo
8
Resistance occurs most commonly due to improper treatment and inadequate dosage of antimalarials
The important factors that are associated with resistance are
1 Longer half-life 2 Single mutation for resistance 3 Poor compliance 4 Host immunity 5 Number of people using these drugs
Although chloroquine resistant strains of P vivax have been described drug resistance poses a serious clinical problem only with P falciparum gt70 of cases
9
Global Scenario of Drug Resistant Malaria
P falciparum resistance 1048698 Chloroquine resistant strains are found now in
nearly all areas of chloroquine use including South America Central America east of the Panama Canal the Western Pacific East Asia
P vivax resistance 1048698 Recent reports from Indonesia (Irian Jaya
Sumatra) and Papua New Guinea indicate high levels of P vivax schizonts resistant to chloroquine Decreased susceptibility may also be appearing in the Solomon Islands Myanmar Brazil Colombia
P ovale and P malariae resistance 1048698 P ovale and P malariae forms have not shown
resistance to chloroquine
10
MECHANISM Resistant strains are able to efflux the drug by an
active pump mechanism and thereby rendering the drug ineffective
Resistant strains concentrate chloroquine less in vacuoles
Crt-Chloroquine resistant transporter and Pfmdr transporters mutations
There is an increase in the surface area of the resistant parasites permitting more efficient pinocytosis
Binding of chloroquine with haemoglobin breakdown product to form toxic complexes is also prevented
Nonspecific pump inhibitors like calcium channel blockers or antagonists of calmodulin (eg verapamil) have not shown any benefit
11
Types of Drug Resistance 1048698 In defining criteria for resistance to the
aminoquinoline antimalarial drugs the WHO has described three grades of resistance following treatment
1048698 (Low grade) R1 Recrudescence of infection between 7 and 28 days of completing treatment following initial resolution of symptoms and parasite clearance
1048698 (High grade) R2 Reduction of parasitaemia by gt 75 at 48 hours but failure to clear parasites
within 7 days 1048698 R3 Parasitaemia does not fall by gt75 within 48
hours
Indian Scenario of Drug Resistant Malaria
P falciparum gtgt P vivax Incidence being 5 to full dose chloroquine The first confirmed report of chloroquine resistance in
P falciparum was reported in Diphu area of Karbianglong district of Assam in 1973
Resurgence of P falciparum resistant to chloroquine has been noticed in several regions of India more in North Eastern parts of the country
KEM hospital in Mumbai confirmed the existence of chloroquine resistance in P falciparum cases in Mumbai
However for all practical purposes drug resistant malaria in the Indian context means malaria caused by strains of P falciparum which are resistant to chloroquine 12
13
Clinical features
Cold Stagebull Feeling of Intense Coldbull Vigorous Shivering Rigorbull Lasts 15-60 Min
Hot Stagebull Intense Heatbull Dry Burning Skinbull Throbbing Headachebull Lasts 2-6 Hours
Sweating Stagebull Profuse Sweatingbull Declining Temperaturebull Exhausted Weak bull Lasts 2-4 Hours
Why PF Serious
PPalciparum
Produces
Leads to
Binds-RBCs all ages Alters surface Grows in low o2
Micro-vascular blocks Cytokine release Endotoxin release
High parasitemia Cerebral malaria Hypoglycemia Shock Multi organ failure Death
15
Thick Smear Rapid Diagnosis Thin Species identification
Rapid diagnostic test
Antibody detection test
- RIA
- ELISA
Diagnosis
16
1 Chemical classification 4-aminoquinolines
- Chloroquine amodiaquine Piperaquine
8-aminoquinolines - Primaquine Bulaquine
Folate synthesis inhibitors - Sulphonamides like Sulphadoxine Dapsone
- Biguanides like proguanil and chloroproguanil
- Diaminopyrimidine like pyrimethamine
CINCHONA ALKALOIDS Quinine Quinidine
AMINO ALCOHOLS - Lumefantrine Halofantrine
-
17
Antimicrobials Tetracycline doxycycline clindamycin azithromycin
fluoroquinolones FOSMIDOMYCIN
Peroxides Artemisinin (Qinghaosu) derivatives and analogues -
artemether arteether artesunate artelinic acid
Naphthoquinones Atovaquone
Iron chelating agents Desferrioxamine
Chemical classification
2 According To Mode Of Action FOR CAUSAL
PROPHYLAXIS MODE Pre-erythorcytic
Schizonticides ( kill schizonts in the liver )
DRUGS
- Primaquine
- Proguanil
- Tetracycline
FOR THE TREATMENT OF ACUTE ATTACK
MODE Erythrocytic Schizonticides (kill schizonts in the Blood)
DRUGS - Rapidly acting -
Chloroquine quinine atovaquone artemisinin derivatives mefloquine
- Slow acting - - Proguanil sulphonamides
tetracyclines pyrimethamine
According To Mode Of Action FOR PREVENTION OF
TRNSMISSION MODE GAMETOCIDES
( kill Gametes ) DRUGS
- Primaquine for all
species
- Artemisinin for all
- Quinine For vivax
- Chloroquine for
vivax
FOR RADICAL CURE MODE Exo-erythrocytic
Schizonticides (kill Exo-erythrocytic forms ie Hypnozoites)
DRUGS
- Primaquine
20
Site of action
21
CHLOROQUINE
Erythrocytic schizontocide all plasmodial species
Gametocytic not Pfalciparum
No effect on sporozoites hypnozoites
MOA Concentrates in parasite food vacuoles uarrpH
Disruption of polymerization of Heme to Hemozoin
Heme damage plasmodium membrane
Well absorbed oral IM SC 60 PPB
Metabolized by liver t12 3-10 days
Excreted by kidney
22
ADRsNausea vomiting Blurring of
vision Headache Confusion seizures
ndash Hemolysis G6PD individuals Impaired hearing
ndash Hypotension ECG changes
ndash High dose Irreversible ototoxicity retinopathy
myopathy Peripheral neuropathy Chloroquine sulphate (Tab)136 mg = 100 mg Base Chloroquine phosphate (Tab) 250mg=150mg Base
Dose 600 mg stat 300 mg after 8 hours and then
for next two days
Chloroquine
23
Faster acting MOA amp resistance similar to chloroquine ADRs
ndash Toxic hepatitisndash Agranulocytosis
Dose 25-35 mgkg over 3 days Chloroquine resistant combine Artesunate
Amodiaquine
24
Mefloquine Erythrocytic schizontocide Rapidly control fever eliminate circulating parasite Effective Chloroquine resistant plasmodium MOA- Inhibits heme polymerization
- Forms toxic complexes with free heme Oral absorbed Highly protein bound Extensive
tissues distribution
ADRs Nauses Vomiting Diarrhoea Neuropsychiatric Arrythmias Haematological Hepatic toxicity
Dose1250 mg 750 mg 500mg 12 hrly
25
Derived from bark of cinchona tree
Effective blood schizonticidal
Gametocidal P vivax
Chloroquine resistant MDR FP MOA same as of chloroquine Oral absorption rapid amp complete Bound to α1 acid
glycoprotein Metabolized by CYP3A4 Excreted in urine t12 10-12 hrs
Quinine
26
QuinineADRs Cinchonism tinnitusdysphoria headache
Nausea vomiting dizziness flushing amp visual
disturbances
GIT nausea vomiting diarrhoeaabdominal pain Hypoglycemia CVS hypotension dysrhythmias VT fibrillation Hemolysis (G6PD deficiency) Blackwater fever hemolysis hemoglobinemia
hemoglobinuria Dose
ndash Quinine 600 mg 8 hrly
27
Pyrimethamine
Erythrocytic schizontocide
Resistance develops rapidly if used alone
MOA DHFRase inhibitor Oral absorption good slow Concentrated liver spleen kidneys Metabolized liver Excreted renal amp t12 4 days ADRs Nausea Rashes Folate deficiency Dose sulphadoxine 1500 mg
+
pyrimethamine 75 mg
28
Proguanil
Erythrocyte schizontocide
Cyclic triazine metabolite cycloguanil
MOA DHFRase Inhibitor
Slowly adequately absorbed Partly metabolized
Excreted in urine amp t12 is 20 hrs
ADRs Vomiting Abdominal pain Haematuria
Dose 200-300 mgday for 4wks
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
MALARIA bull Malaria remains the worldrsquos most devastating
human parasitic infection afflicting more than 500 million people and causing from 17 million to 25 million deaths each year
bull In 2010 more than 100 countries were considered malarious
bull Malaria kills more than 1 million children a year in the developing world
In malaria endemic areas - Children under age of 5 years - greater risk of dying
Chloroquine resistant-PF Chloroquine sensitive-PF
Malaria Endemic Areas
Mexico Central America west of Panama canalCarribean South America middle east
Resistant PVIndonesiaPapua New Guinea Burma
7
DRUG RESISTANT MALARIA
Definition Drug resistance is the ability of the parasite species to survive andor multiply despite the administration and absorption of a drug given in doses equal to or higher than those usually recommended but within the limit of tolerance
MDR Malaria Resistance to 3 or more anti-malarials of different
chemical classes of which two are
4-aminoquinolines and diaminopyrimidinerdquo
8
Resistance occurs most commonly due to improper treatment and inadequate dosage of antimalarials
The important factors that are associated with resistance are
1 Longer half-life 2 Single mutation for resistance 3 Poor compliance 4 Host immunity 5 Number of people using these drugs
Although chloroquine resistant strains of P vivax have been described drug resistance poses a serious clinical problem only with P falciparum gt70 of cases
9
Global Scenario of Drug Resistant Malaria
P falciparum resistance 1048698 Chloroquine resistant strains are found now in
nearly all areas of chloroquine use including South America Central America east of the Panama Canal the Western Pacific East Asia
P vivax resistance 1048698 Recent reports from Indonesia (Irian Jaya
Sumatra) and Papua New Guinea indicate high levels of P vivax schizonts resistant to chloroquine Decreased susceptibility may also be appearing in the Solomon Islands Myanmar Brazil Colombia
P ovale and P malariae resistance 1048698 P ovale and P malariae forms have not shown
resistance to chloroquine
10
MECHANISM Resistant strains are able to efflux the drug by an
active pump mechanism and thereby rendering the drug ineffective
Resistant strains concentrate chloroquine less in vacuoles
Crt-Chloroquine resistant transporter and Pfmdr transporters mutations
There is an increase in the surface area of the resistant parasites permitting more efficient pinocytosis
Binding of chloroquine with haemoglobin breakdown product to form toxic complexes is also prevented
Nonspecific pump inhibitors like calcium channel blockers or antagonists of calmodulin (eg verapamil) have not shown any benefit
11
Types of Drug Resistance 1048698 In defining criteria for resistance to the
aminoquinoline antimalarial drugs the WHO has described three grades of resistance following treatment
1048698 (Low grade) R1 Recrudescence of infection between 7 and 28 days of completing treatment following initial resolution of symptoms and parasite clearance
1048698 (High grade) R2 Reduction of parasitaemia by gt 75 at 48 hours but failure to clear parasites
within 7 days 1048698 R3 Parasitaemia does not fall by gt75 within 48
hours
Indian Scenario of Drug Resistant Malaria
P falciparum gtgt P vivax Incidence being 5 to full dose chloroquine The first confirmed report of chloroquine resistance in
P falciparum was reported in Diphu area of Karbianglong district of Assam in 1973
Resurgence of P falciparum resistant to chloroquine has been noticed in several regions of India more in North Eastern parts of the country
KEM hospital in Mumbai confirmed the existence of chloroquine resistance in P falciparum cases in Mumbai
However for all practical purposes drug resistant malaria in the Indian context means malaria caused by strains of P falciparum which are resistant to chloroquine 12
13
Clinical features
Cold Stagebull Feeling of Intense Coldbull Vigorous Shivering Rigorbull Lasts 15-60 Min
Hot Stagebull Intense Heatbull Dry Burning Skinbull Throbbing Headachebull Lasts 2-6 Hours
Sweating Stagebull Profuse Sweatingbull Declining Temperaturebull Exhausted Weak bull Lasts 2-4 Hours
Why PF Serious
PPalciparum
Produces
Leads to
Binds-RBCs all ages Alters surface Grows in low o2
Micro-vascular blocks Cytokine release Endotoxin release
High parasitemia Cerebral malaria Hypoglycemia Shock Multi organ failure Death
15
Thick Smear Rapid Diagnosis Thin Species identification
Rapid diagnostic test
Antibody detection test
- RIA
- ELISA
Diagnosis
16
1 Chemical classification 4-aminoquinolines
- Chloroquine amodiaquine Piperaquine
8-aminoquinolines - Primaquine Bulaquine
Folate synthesis inhibitors - Sulphonamides like Sulphadoxine Dapsone
- Biguanides like proguanil and chloroproguanil
- Diaminopyrimidine like pyrimethamine
CINCHONA ALKALOIDS Quinine Quinidine
AMINO ALCOHOLS - Lumefantrine Halofantrine
-
17
Antimicrobials Tetracycline doxycycline clindamycin azithromycin
fluoroquinolones FOSMIDOMYCIN
Peroxides Artemisinin (Qinghaosu) derivatives and analogues -
artemether arteether artesunate artelinic acid
Naphthoquinones Atovaquone
Iron chelating agents Desferrioxamine
Chemical classification
2 According To Mode Of Action FOR CAUSAL
PROPHYLAXIS MODE Pre-erythorcytic
Schizonticides ( kill schizonts in the liver )
DRUGS
- Primaquine
- Proguanil
- Tetracycline
FOR THE TREATMENT OF ACUTE ATTACK
MODE Erythrocytic Schizonticides (kill schizonts in the Blood)
DRUGS - Rapidly acting -
Chloroquine quinine atovaquone artemisinin derivatives mefloquine
- Slow acting - - Proguanil sulphonamides
tetracyclines pyrimethamine
According To Mode Of Action FOR PREVENTION OF
TRNSMISSION MODE GAMETOCIDES
( kill Gametes ) DRUGS
- Primaquine for all
species
- Artemisinin for all
- Quinine For vivax
- Chloroquine for
vivax
FOR RADICAL CURE MODE Exo-erythrocytic
Schizonticides (kill Exo-erythrocytic forms ie Hypnozoites)
DRUGS
- Primaquine
20
Site of action
21
CHLOROQUINE
Erythrocytic schizontocide all plasmodial species
Gametocytic not Pfalciparum
No effect on sporozoites hypnozoites
MOA Concentrates in parasite food vacuoles uarrpH
Disruption of polymerization of Heme to Hemozoin
Heme damage plasmodium membrane
Well absorbed oral IM SC 60 PPB
Metabolized by liver t12 3-10 days
Excreted by kidney
22
ADRsNausea vomiting Blurring of
vision Headache Confusion seizures
ndash Hemolysis G6PD individuals Impaired hearing
ndash Hypotension ECG changes
ndash High dose Irreversible ototoxicity retinopathy
myopathy Peripheral neuropathy Chloroquine sulphate (Tab)136 mg = 100 mg Base Chloroquine phosphate (Tab) 250mg=150mg Base
Dose 600 mg stat 300 mg after 8 hours and then
for next two days
Chloroquine
23
Faster acting MOA amp resistance similar to chloroquine ADRs
ndash Toxic hepatitisndash Agranulocytosis
Dose 25-35 mgkg over 3 days Chloroquine resistant combine Artesunate
Amodiaquine
24
Mefloquine Erythrocytic schizontocide Rapidly control fever eliminate circulating parasite Effective Chloroquine resistant plasmodium MOA- Inhibits heme polymerization
- Forms toxic complexes with free heme Oral absorbed Highly protein bound Extensive
tissues distribution
ADRs Nauses Vomiting Diarrhoea Neuropsychiatric Arrythmias Haematological Hepatic toxicity
Dose1250 mg 750 mg 500mg 12 hrly
25
Derived from bark of cinchona tree
Effective blood schizonticidal
Gametocidal P vivax
Chloroquine resistant MDR FP MOA same as of chloroquine Oral absorption rapid amp complete Bound to α1 acid
glycoprotein Metabolized by CYP3A4 Excreted in urine t12 10-12 hrs
Quinine
26
QuinineADRs Cinchonism tinnitusdysphoria headache
Nausea vomiting dizziness flushing amp visual
disturbances
GIT nausea vomiting diarrhoeaabdominal pain Hypoglycemia CVS hypotension dysrhythmias VT fibrillation Hemolysis (G6PD deficiency) Blackwater fever hemolysis hemoglobinemia
hemoglobinuria Dose
ndash Quinine 600 mg 8 hrly
27
Pyrimethamine
Erythrocytic schizontocide
Resistance develops rapidly if used alone
MOA DHFRase inhibitor Oral absorption good slow Concentrated liver spleen kidneys Metabolized liver Excreted renal amp t12 4 days ADRs Nausea Rashes Folate deficiency Dose sulphadoxine 1500 mg
+
pyrimethamine 75 mg
28
Proguanil
Erythrocyte schizontocide
Cyclic triazine metabolite cycloguanil
MOA DHFRase Inhibitor
Slowly adequately absorbed Partly metabolized
Excreted in urine amp t12 is 20 hrs
ADRs Vomiting Abdominal pain Haematuria
Dose 200-300 mgday for 4wks
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
Chloroquine resistant-PF Chloroquine sensitive-PF
Malaria Endemic Areas
Mexico Central America west of Panama canalCarribean South America middle east
Resistant PVIndonesiaPapua New Guinea Burma
7
DRUG RESISTANT MALARIA
Definition Drug resistance is the ability of the parasite species to survive andor multiply despite the administration and absorption of a drug given in doses equal to or higher than those usually recommended but within the limit of tolerance
MDR Malaria Resistance to 3 or more anti-malarials of different
chemical classes of which two are
4-aminoquinolines and diaminopyrimidinerdquo
8
Resistance occurs most commonly due to improper treatment and inadequate dosage of antimalarials
The important factors that are associated with resistance are
1 Longer half-life 2 Single mutation for resistance 3 Poor compliance 4 Host immunity 5 Number of people using these drugs
Although chloroquine resistant strains of P vivax have been described drug resistance poses a serious clinical problem only with P falciparum gt70 of cases
9
Global Scenario of Drug Resistant Malaria
P falciparum resistance 1048698 Chloroquine resistant strains are found now in
nearly all areas of chloroquine use including South America Central America east of the Panama Canal the Western Pacific East Asia
P vivax resistance 1048698 Recent reports from Indonesia (Irian Jaya
Sumatra) and Papua New Guinea indicate high levels of P vivax schizonts resistant to chloroquine Decreased susceptibility may also be appearing in the Solomon Islands Myanmar Brazil Colombia
P ovale and P malariae resistance 1048698 P ovale and P malariae forms have not shown
resistance to chloroquine
10
MECHANISM Resistant strains are able to efflux the drug by an
active pump mechanism and thereby rendering the drug ineffective
Resistant strains concentrate chloroquine less in vacuoles
Crt-Chloroquine resistant transporter and Pfmdr transporters mutations
There is an increase in the surface area of the resistant parasites permitting more efficient pinocytosis
Binding of chloroquine with haemoglobin breakdown product to form toxic complexes is also prevented
Nonspecific pump inhibitors like calcium channel blockers or antagonists of calmodulin (eg verapamil) have not shown any benefit
11
Types of Drug Resistance 1048698 In defining criteria for resistance to the
aminoquinoline antimalarial drugs the WHO has described three grades of resistance following treatment
1048698 (Low grade) R1 Recrudescence of infection between 7 and 28 days of completing treatment following initial resolution of symptoms and parasite clearance
1048698 (High grade) R2 Reduction of parasitaemia by gt 75 at 48 hours but failure to clear parasites
within 7 days 1048698 R3 Parasitaemia does not fall by gt75 within 48
hours
Indian Scenario of Drug Resistant Malaria
P falciparum gtgt P vivax Incidence being 5 to full dose chloroquine The first confirmed report of chloroquine resistance in
P falciparum was reported in Diphu area of Karbianglong district of Assam in 1973
Resurgence of P falciparum resistant to chloroquine has been noticed in several regions of India more in North Eastern parts of the country
KEM hospital in Mumbai confirmed the existence of chloroquine resistance in P falciparum cases in Mumbai
However for all practical purposes drug resistant malaria in the Indian context means malaria caused by strains of P falciparum which are resistant to chloroquine 12
13
Clinical features
Cold Stagebull Feeling of Intense Coldbull Vigorous Shivering Rigorbull Lasts 15-60 Min
Hot Stagebull Intense Heatbull Dry Burning Skinbull Throbbing Headachebull Lasts 2-6 Hours
Sweating Stagebull Profuse Sweatingbull Declining Temperaturebull Exhausted Weak bull Lasts 2-4 Hours
Why PF Serious
PPalciparum
Produces
Leads to
Binds-RBCs all ages Alters surface Grows in low o2
Micro-vascular blocks Cytokine release Endotoxin release
High parasitemia Cerebral malaria Hypoglycemia Shock Multi organ failure Death
15
Thick Smear Rapid Diagnosis Thin Species identification
Rapid diagnostic test
Antibody detection test
- RIA
- ELISA
Diagnosis
16
1 Chemical classification 4-aminoquinolines
- Chloroquine amodiaquine Piperaquine
8-aminoquinolines - Primaquine Bulaquine
Folate synthesis inhibitors - Sulphonamides like Sulphadoxine Dapsone
- Biguanides like proguanil and chloroproguanil
- Diaminopyrimidine like pyrimethamine
CINCHONA ALKALOIDS Quinine Quinidine
AMINO ALCOHOLS - Lumefantrine Halofantrine
-
17
Antimicrobials Tetracycline doxycycline clindamycin azithromycin
fluoroquinolones FOSMIDOMYCIN
Peroxides Artemisinin (Qinghaosu) derivatives and analogues -
artemether arteether artesunate artelinic acid
Naphthoquinones Atovaquone
Iron chelating agents Desferrioxamine
Chemical classification
2 According To Mode Of Action FOR CAUSAL
PROPHYLAXIS MODE Pre-erythorcytic
Schizonticides ( kill schizonts in the liver )
DRUGS
- Primaquine
- Proguanil
- Tetracycline
FOR THE TREATMENT OF ACUTE ATTACK
MODE Erythrocytic Schizonticides (kill schizonts in the Blood)
DRUGS - Rapidly acting -
Chloroquine quinine atovaquone artemisinin derivatives mefloquine
- Slow acting - - Proguanil sulphonamides
tetracyclines pyrimethamine
According To Mode Of Action FOR PREVENTION OF
TRNSMISSION MODE GAMETOCIDES
( kill Gametes ) DRUGS
- Primaquine for all
species
- Artemisinin for all
- Quinine For vivax
- Chloroquine for
vivax
FOR RADICAL CURE MODE Exo-erythrocytic
Schizonticides (kill Exo-erythrocytic forms ie Hypnozoites)
DRUGS
- Primaquine
20
Site of action
21
CHLOROQUINE
Erythrocytic schizontocide all plasmodial species
Gametocytic not Pfalciparum
No effect on sporozoites hypnozoites
MOA Concentrates in parasite food vacuoles uarrpH
Disruption of polymerization of Heme to Hemozoin
Heme damage plasmodium membrane
Well absorbed oral IM SC 60 PPB
Metabolized by liver t12 3-10 days
Excreted by kidney
22
ADRsNausea vomiting Blurring of
vision Headache Confusion seizures
ndash Hemolysis G6PD individuals Impaired hearing
ndash Hypotension ECG changes
ndash High dose Irreversible ototoxicity retinopathy
myopathy Peripheral neuropathy Chloroquine sulphate (Tab)136 mg = 100 mg Base Chloroquine phosphate (Tab) 250mg=150mg Base
Dose 600 mg stat 300 mg after 8 hours and then
for next two days
Chloroquine
23
Faster acting MOA amp resistance similar to chloroquine ADRs
ndash Toxic hepatitisndash Agranulocytosis
Dose 25-35 mgkg over 3 days Chloroquine resistant combine Artesunate
Amodiaquine
24
Mefloquine Erythrocytic schizontocide Rapidly control fever eliminate circulating parasite Effective Chloroquine resistant plasmodium MOA- Inhibits heme polymerization
- Forms toxic complexes with free heme Oral absorbed Highly protein bound Extensive
tissues distribution
ADRs Nauses Vomiting Diarrhoea Neuropsychiatric Arrythmias Haematological Hepatic toxicity
Dose1250 mg 750 mg 500mg 12 hrly
25
Derived from bark of cinchona tree
Effective blood schizonticidal
Gametocidal P vivax
Chloroquine resistant MDR FP MOA same as of chloroquine Oral absorption rapid amp complete Bound to α1 acid
glycoprotein Metabolized by CYP3A4 Excreted in urine t12 10-12 hrs
Quinine
26
QuinineADRs Cinchonism tinnitusdysphoria headache
Nausea vomiting dizziness flushing amp visual
disturbances
GIT nausea vomiting diarrhoeaabdominal pain Hypoglycemia CVS hypotension dysrhythmias VT fibrillation Hemolysis (G6PD deficiency) Blackwater fever hemolysis hemoglobinemia
hemoglobinuria Dose
ndash Quinine 600 mg 8 hrly
27
Pyrimethamine
Erythrocytic schizontocide
Resistance develops rapidly if used alone
MOA DHFRase inhibitor Oral absorption good slow Concentrated liver spleen kidneys Metabolized liver Excreted renal amp t12 4 days ADRs Nausea Rashes Folate deficiency Dose sulphadoxine 1500 mg
+
pyrimethamine 75 mg
28
Proguanil
Erythrocyte schizontocide
Cyclic triazine metabolite cycloguanil
MOA DHFRase Inhibitor
Slowly adequately absorbed Partly metabolized
Excreted in urine amp t12 is 20 hrs
ADRs Vomiting Abdominal pain Haematuria
Dose 200-300 mgday for 4wks
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
7
DRUG RESISTANT MALARIA
Definition Drug resistance is the ability of the parasite species to survive andor multiply despite the administration and absorption of a drug given in doses equal to or higher than those usually recommended but within the limit of tolerance
MDR Malaria Resistance to 3 or more anti-malarials of different
chemical classes of which two are
4-aminoquinolines and diaminopyrimidinerdquo
8
Resistance occurs most commonly due to improper treatment and inadequate dosage of antimalarials
The important factors that are associated with resistance are
1 Longer half-life 2 Single mutation for resistance 3 Poor compliance 4 Host immunity 5 Number of people using these drugs
Although chloroquine resistant strains of P vivax have been described drug resistance poses a serious clinical problem only with P falciparum gt70 of cases
9
Global Scenario of Drug Resistant Malaria
P falciparum resistance 1048698 Chloroquine resistant strains are found now in
nearly all areas of chloroquine use including South America Central America east of the Panama Canal the Western Pacific East Asia
P vivax resistance 1048698 Recent reports from Indonesia (Irian Jaya
Sumatra) and Papua New Guinea indicate high levels of P vivax schizonts resistant to chloroquine Decreased susceptibility may also be appearing in the Solomon Islands Myanmar Brazil Colombia
P ovale and P malariae resistance 1048698 P ovale and P malariae forms have not shown
resistance to chloroquine
10
MECHANISM Resistant strains are able to efflux the drug by an
active pump mechanism and thereby rendering the drug ineffective
Resistant strains concentrate chloroquine less in vacuoles
Crt-Chloroquine resistant transporter and Pfmdr transporters mutations
There is an increase in the surface area of the resistant parasites permitting more efficient pinocytosis
Binding of chloroquine with haemoglobin breakdown product to form toxic complexes is also prevented
Nonspecific pump inhibitors like calcium channel blockers or antagonists of calmodulin (eg verapamil) have not shown any benefit
11
Types of Drug Resistance 1048698 In defining criteria for resistance to the
aminoquinoline antimalarial drugs the WHO has described three grades of resistance following treatment
1048698 (Low grade) R1 Recrudescence of infection between 7 and 28 days of completing treatment following initial resolution of symptoms and parasite clearance
1048698 (High grade) R2 Reduction of parasitaemia by gt 75 at 48 hours but failure to clear parasites
within 7 days 1048698 R3 Parasitaemia does not fall by gt75 within 48
hours
Indian Scenario of Drug Resistant Malaria
P falciparum gtgt P vivax Incidence being 5 to full dose chloroquine The first confirmed report of chloroquine resistance in
P falciparum was reported in Diphu area of Karbianglong district of Assam in 1973
Resurgence of P falciparum resistant to chloroquine has been noticed in several regions of India more in North Eastern parts of the country
KEM hospital in Mumbai confirmed the existence of chloroquine resistance in P falciparum cases in Mumbai
However for all practical purposes drug resistant malaria in the Indian context means malaria caused by strains of P falciparum which are resistant to chloroquine 12
13
Clinical features
Cold Stagebull Feeling of Intense Coldbull Vigorous Shivering Rigorbull Lasts 15-60 Min
Hot Stagebull Intense Heatbull Dry Burning Skinbull Throbbing Headachebull Lasts 2-6 Hours
Sweating Stagebull Profuse Sweatingbull Declining Temperaturebull Exhausted Weak bull Lasts 2-4 Hours
Why PF Serious
PPalciparum
Produces
Leads to
Binds-RBCs all ages Alters surface Grows in low o2
Micro-vascular blocks Cytokine release Endotoxin release
High parasitemia Cerebral malaria Hypoglycemia Shock Multi organ failure Death
15
Thick Smear Rapid Diagnosis Thin Species identification
Rapid diagnostic test
Antibody detection test
- RIA
- ELISA
Diagnosis
16
1 Chemical classification 4-aminoquinolines
- Chloroquine amodiaquine Piperaquine
8-aminoquinolines - Primaquine Bulaquine
Folate synthesis inhibitors - Sulphonamides like Sulphadoxine Dapsone
- Biguanides like proguanil and chloroproguanil
- Diaminopyrimidine like pyrimethamine
CINCHONA ALKALOIDS Quinine Quinidine
AMINO ALCOHOLS - Lumefantrine Halofantrine
-
17
Antimicrobials Tetracycline doxycycline clindamycin azithromycin
fluoroquinolones FOSMIDOMYCIN
Peroxides Artemisinin (Qinghaosu) derivatives and analogues -
artemether arteether artesunate artelinic acid
Naphthoquinones Atovaquone
Iron chelating agents Desferrioxamine
Chemical classification
2 According To Mode Of Action FOR CAUSAL
PROPHYLAXIS MODE Pre-erythorcytic
Schizonticides ( kill schizonts in the liver )
DRUGS
- Primaquine
- Proguanil
- Tetracycline
FOR THE TREATMENT OF ACUTE ATTACK
MODE Erythrocytic Schizonticides (kill schizonts in the Blood)
DRUGS - Rapidly acting -
Chloroquine quinine atovaquone artemisinin derivatives mefloquine
- Slow acting - - Proguanil sulphonamides
tetracyclines pyrimethamine
According To Mode Of Action FOR PREVENTION OF
TRNSMISSION MODE GAMETOCIDES
( kill Gametes ) DRUGS
- Primaquine for all
species
- Artemisinin for all
- Quinine For vivax
- Chloroquine for
vivax
FOR RADICAL CURE MODE Exo-erythrocytic
Schizonticides (kill Exo-erythrocytic forms ie Hypnozoites)
DRUGS
- Primaquine
20
Site of action
21
CHLOROQUINE
Erythrocytic schizontocide all plasmodial species
Gametocytic not Pfalciparum
No effect on sporozoites hypnozoites
MOA Concentrates in parasite food vacuoles uarrpH
Disruption of polymerization of Heme to Hemozoin
Heme damage plasmodium membrane
Well absorbed oral IM SC 60 PPB
Metabolized by liver t12 3-10 days
Excreted by kidney
22
ADRsNausea vomiting Blurring of
vision Headache Confusion seizures
ndash Hemolysis G6PD individuals Impaired hearing
ndash Hypotension ECG changes
ndash High dose Irreversible ototoxicity retinopathy
myopathy Peripheral neuropathy Chloroquine sulphate (Tab)136 mg = 100 mg Base Chloroquine phosphate (Tab) 250mg=150mg Base
Dose 600 mg stat 300 mg after 8 hours and then
for next two days
Chloroquine
23
Faster acting MOA amp resistance similar to chloroquine ADRs
ndash Toxic hepatitisndash Agranulocytosis
Dose 25-35 mgkg over 3 days Chloroquine resistant combine Artesunate
Amodiaquine
24
Mefloquine Erythrocytic schizontocide Rapidly control fever eliminate circulating parasite Effective Chloroquine resistant plasmodium MOA- Inhibits heme polymerization
- Forms toxic complexes with free heme Oral absorbed Highly protein bound Extensive
tissues distribution
ADRs Nauses Vomiting Diarrhoea Neuropsychiatric Arrythmias Haematological Hepatic toxicity
Dose1250 mg 750 mg 500mg 12 hrly
25
Derived from bark of cinchona tree
Effective blood schizonticidal
Gametocidal P vivax
Chloroquine resistant MDR FP MOA same as of chloroquine Oral absorption rapid amp complete Bound to α1 acid
glycoprotein Metabolized by CYP3A4 Excreted in urine t12 10-12 hrs
Quinine
26
QuinineADRs Cinchonism tinnitusdysphoria headache
Nausea vomiting dizziness flushing amp visual
disturbances
GIT nausea vomiting diarrhoeaabdominal pain Hypoglycemia CVS hypotension dysrhythmias VT fibrillation Hemolysis (G6PD deficiency) Blackwater fever hemolysis hemoglobinemia
hemoglobinuria Dose
ndash Quinine 600 mg 8 hrly
27
Pyrimethamine
Erythrocytic schizontocide
Resistance develops rapidly if used alone
MOA DHFRase inhibitor Oral absorption good slow Concentrated liver spleen kidneys Metabolized liver Excreted renal amp t12 4 days ADRs Nausea Rashes Folate deficiency Dose sulphadoxine 1500 mg
+
pyrimethamine 75 mg
28
Proguanil
Erythrocyte schizontocide
Cyclic triazine metabolite cycloguanil
MOA DHFRase Inhibitor
Slowly adequately absorbed Partly metabolized
Excreted in urine amp t12 is 20 hrs
ADRs Vomiting Abdominal pain Haematuria
Dose 200-300 mgday for 4wks
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
8
Resistance occurs most commonly due to improper treatment and inadequate dosage of antimalarials
The important factors that are associated with resistance are
1 Longer half-life 2 Single mutation for resistance 3 Poor compliance 4 Host immunity 5 Number of people using these drugs
Although chloroquine resistant strains of P vivax have been described drug resistance poses a serious clinical problem only with P falciparum gt70 of cases
9
Global Scenario of Drug Resistant Malaria
P falciparum resistance 1048698 Chloroquine resistant strains are found now in
nearly all areas of chloroquine use including South America Central America east of the Panama Canal the Western Pacific East Asia
P vivax resistance 1048698 Recent reports from Indonesia (Irian Jaya
Sumatra) and Papua New Guinea indicate high levels of P vivax schizonts resistant to chloroquine Decreased susceptibility may also be appearing in the Solomon Islands Myanmar Brazil Colombia
P ovale and P malariae resistance 1048698 P ovale and P malariae forms have not shown
resistance to chloroquine
10
MECHANISM Resistant strains are able to efflux the drug by an
active pump mechanism and thereby rendering the drug ineffective
Resistant strains concentrate chloroquine less in vacuoles
Crt-Chloroquine resistant transporter and Pfmdr transporters mutations
There is an increase in the surface area of the resistant parasites permitting more efficient pinocytosis
Binding of chloroquine with haemoglobin breakdown product to form toxic complexes is also prevented
Nonspecific pump inhibitors like calcium channel blockers or antagonists of calmodulin (eg verapamil) have not shown any benefit
11
Types of Drug Resistance 1048698 In defining criteria for resistance to the
aminoquinoline antimalarial drugs the WHO has described three grades of resistance following treatment
1048698 (Low grade) R1 Recrudescence of infection between 7 and 28 days of completing treatment following initial resolution of symptoms and parasite clearance
1048698 (High grade) R2 Reduction of parasitaemia by gt 75 at 48 hours but failure to clear parasites
within 7 days 1048698 R3 Parasitaemia does not fall by gt75 within 48
hours
Indian Scenario of Drug Resistant Malaria
P falciparum gtgt P vivax Incidence being 5 to full dose chloroquine The first confirmed report of chloroquine resistance in
P falciparum was reported in Diphu area of Karbianglong district of Assam in 1973
Resurgence of P falciparum resistant to chloroquine has been noticed in several regions of India more in North Eastern parts of the country
KEM hospital in Mumbai confirmed the existence of chloroquine resistance in P falciparum cases in Mumbai
However for all practical purposes drug resistant malaria in the Indian context means malaria caused by strains of P falciparum which are resistant to chloroquine 12
13
Clinical features
Cold Stagebull Feeling of Intense Coldbull Vigorous Shivering Rigorbull Lasts 15-60 Min
Hot Stagebull Intense Heatbull Dry Burning Skinbull Throbbing Headachebull Lasts 2-6 Hours
Sweating Stagebull Profuse Sweatingbull Declining Temperaturebull Exhausted Weak bull Lasts 2-4 Hours
Why PF Serious
PPalciparum
Produces
Leads to
Binds-RBCs all ages Alters surface Grows in low o2
Micro-vascular blocks Cytokine release Endotoxin release
High parasitemia Cerebral malaria Hypoglycemia Shock Multi organ failure Death
15
Thick Smear Rapid Diagnosis Thin Species identification
Rapid diagnostic test
Antibody detection test
- RIA
- ELISA
Diagnosis
16
1 Chemical classification 4-aminoquinolines
- Chloroquine amodiaquine Piperaquine
8-aminoquinolines - Primaquine Bulaquine
Folate synthesis inhibitors - Sulphonamides like Sulphadoxine Dapsone
- Biguanides like proguanil and chloroproguanil
- Diaminopyrimidine like pyrimethamine
CINCHONA ALKALOIDS Quinine Quinidine
AMINO ALCOHOLS - Lumefantrine Halofantrine
-
17
Antimicrobials Tetracycline doxycycline clindamycin azithromycin
fluoroquinolones FOSMIDOMYCIN
Peroxides Artemisinin (Qinghaosu) derivatives and analogues -
artemether arteether artesunate artelinic acid
Naphthoquinones Atovaquone
Iron chelating agents Desferrioxamine
Chemical classification
2 According To Mode Of Action FOR CAUSAL
PROPHYLAXIS MODE Pre-erythorcytic
Schizonticides ( kill schizonts in the liver )
DRUGS
- Primaquine
- Proguanil
- Tetracycline
FOR THE TREATMENT OF ACUTE ATTACK
MODE Erythrocytic Schizonticides (kill schizonts in the Blood)
DRUGS - Rapidly acting -
Chloroquine quinine atovaquone artemisinin derivatives mefloquine
- Slow acting - - Proguanil sulphonamides
tetracyclines pyrimethamine
According To Mode Of Action FOR PREVENTION OF
TRNSMISSION MODE GAMETOCIDES
( kill Gametes ) DRUGS
- Primaquine for all
species
- Artemisinin for all
- Quinine For vivax
- Chloroquine for
vivax
FOR RADICAL CURE MODE Exo-erythrocytic
Schizonticides (kill Exo-erythrocytic forms ie Hypnozoites)
DRUGS
- Primaquine
20
Site of action
21
CHLOROQUINE
Erythrocytic schizontocide all plasmodial species
Gametocytic not Pfalciparum
No effect on sporozoites hypnozoites
MOA Concentrates in parasite food vacuoles uarrpH
Disruption of polymerization of Heme to Hemozoin
Heme damage plasmodium membrane
Well absorbed oral IM SC 60 PPB
Metabolized by liver t12 3-10 days
Excreted by kidney
22
ADRsNausea vomiting Blurring of
vision Headache Confusion seizures
ndash Hemolysis G6PD individuals Impaired hearing
ndash Hypotension ECG changes
ndash High dose Irreversible ototoxicity retinopathy
myopathy Peripheral neuropathy Chloroquine sulphate (Tab)136 mg = 100 mg Base Chloroquine phosphate (Tab) 250mg=150mg Base
Dose 600 mg stat 300 mg after 8 hours and then
for next two days
Chloroquine
23
Faster acting MOA amp resistance similar to chloroquine ADRs
ndash Toxic hepatitisndash Agranulocytosis
Dose 25-35 mgkg over 3 days Chloroquine resistant combine Artesunate
Amodiaquine
24
Mefloquine Erythrocytic schizontocide Rapidly control fever eliminate circulating parasite Effective Chloroquine resistant plasmodium MOA- Inhibits heme polymerization
- Forms toxic complexes with free heme Oral absorbed Highly protein bound Extensive
tissues distribution
ADRs Nauses Vomiting Diarrhoea Neuropsychiatric Arrythmias Haematological Hepatic toxicity
Dose1250 mg 750 mg 500mg 12 hrly
25
Derived from bark of cinchona tree
Effective blood schizonticidal
Gametocidal P vivax
Chloroquine resistant MDR FP MOA same as of chloroquine Oral absorption rapid amp complete Bound to α1 acid
glycoprotein Metabolized by CYP3A4 Excreted in urine t12 10-12 hrs
Quinine
26
QuinineADRs Cinchonism tinnitusdysphoria headache
Nausea vomiting dizziness flushing amp visual
disturbances
GIT nausea vomiting diarrhoeaabdominal pain Hypoglycemia CVS hypotension dysrhythmias VT fibrillation Hemolysis (G6PD deficiency) Blackwater fever hemolysis hemoglobinemia
hemoglobinuria Dose
ndash Quinine 600 mg 8 hrly
27
Pyrimethamine
Erythrocytic schizontocide
Resistance develops rapidly if used alone
MOA DHFRase inhibitor Oral absorption good slow Concentrated liver spleen kidneys Metabolized liver Excreted renal amp t12 4 days ADRs Nausea Rashes Folate deficiency Dose sulphadoxine 1500 mg
+
pyrimethamine 75 mg
28
Proguanil
Erythrocyte schizontocide
Cyclic triazine metabolite cycloguanil
MOA DHFRase Inhibitor
Slowly adequately absorbed Partly metabolized
Excreted in urine amp t12 is 20 hrs
ADRs Vomiting Abdominal pain Haematuria
Dose 200-300 mgday for 4wks
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
9
Global Scenario of Drug Resistant Malaria
P falciparum resistance 1048698 Chloroquine resistant strains are found now in
nearly all areas of chloroquine use including South America Central America east of the Panama Canal the Western Pacific East Asia
P vivax resistance 1048698 Recent reports from Indonesia (Irian Jaya
Sumatra) and Papua New Guinea indicate high levels of P vivax schizonts resistant to chloroquine Decreased susceptibility may also be appearing in the Solomon Islands Myanmar Brazil Colombia
P ovale and P malariae resistance 1048698 P ovale and P malariae forms have not shown
resistance to chloroquine
10
MECHANISM Resistant strains are able to efflux the drug by an
active pump mechanism and thereby rendering the drug ineffective
Resistant strains concentrate chloroquine less in vacuoles
Crt-Chloroquine resistant transporter and Pfmdr transporters mutations
There is an increase in the surface area of the resistant parasites permitting more efficient pinocytosis
Binding of chloroquine with haemoglobin breakdown product to form toxic complexes is also prevented
Nonspecific pump inhibitors like calcium channel blockers or antagonists of calmodulin (eg verapamil) have not shown any benefit
11
Types of Drug Resistance 1048698 In defining criteria for resistance to the
aminoquinoline antimalarial drugs the WHO has described three grades of resistance following treatment
1048698 (Low grade) R1 Recrudescence of infection between 7 and 28 days of completing treatment following initial resolution of symptoms and parasite clearance
1048698 (High grade) R2 Reduction of parasitaemia by gt 75 at 48 hours but failure to clear parasites
within 7 days 1048698 R3 Parasitaemia does not fall by gt75 within 48
hours
Indian Scenario of Drug Resistant Malaria
P falciparum gtgt P vivax Incidence being 5 to full dose chloroquine The first confirmed report of chloroquine resistance in
P falciparum was reported in Diphu area of Karbianglong district of Assam in 1973
Resurgence of P falciparum resistant to chloroquine has been noticed in several regions of India more in North Eastern parts of the country
KEM hospital in Mumbai confirmed the existence of chloroquine resistance in P falciparum cases in Mumbai
However for all practical purposes drug resistant malaria in the Indian context means malaria caused by strains of P falciparum which are resistant to chloroquine 12
13
Clinical features
Cold Stagebull Feeling of Intense Coldbull Vigorous Shivering Rigorbull Lasts 15-60 Min
Hot Stagebull Intense Heatbull Dry Burning Skinbull Throbbing Headachebull Lasts 2-6 Hours
Sweating Stagebull Profuse Sweatingbull Declining Temperaturebull Exhausted Weak bull Lasts 2-4 Hours
Why PF Serious
PPalciparum
Produces
Leads to
Binds-RBCs all ages Alters surface Grows in low o2
Micro-vascular blocks Cytokine release Endotoxin release
High parasitemia Cerebral malaria Hypoglycemia Shock Multi organ failure Death
15
Thick Smear Rapid Diagnosis Thin Species identification
Rapid diagnostic test
Antibody detection test
- RIA
- ELISA
Diagnosis
16
1 Chemical classification 4-aminoquinolines
- Chloroquine amodiaquine Piperaquine
8-aminoquinolines - Primaquine Bulaquine
Folate synthesis inhibitors - Sulphonamides like Sulphadoxine Dapsone
- Biguanides like proguanil and chloroproguanil
- Diaminopyrimidine like pyrimethamine
CINCHONA ALKALOIDS Quinine Quinidine
AMINO ALCOHOLS - Lumefantrine Halofantrine
-
17
Antimicrobials Tetracycline doxycycline clindamycin azithromycin
fluoroquinolones FOSMIDOMYCIN
Peroxides Artemisinin (Qinghaosu) derivatives and analogues -
artemether arteether artesunate artelinic acid
Naphthoquinones Atovaquone
Iron chelating agents Desferrioxamine
Chemical classification
2 According To Mode Of Action FOR CAUSAL
PROPHYLAXIS MODE Pre-erythorcytic
Schizonticides ( kill schizonts in the liver )
DRUGS
- Primaquine
- Proguanil
- Tetracycline
FOR THE TREATMENT OF ACUTE ATTACK
MODE Erythrocytic Schizonticides (kill schizonts in the Blood)
DRUGS - Rapidly acting -
Chloroquine quinine atovaquone artemisinin derivatives mefloquine
- Slow acting - - Proguanil sulphonamides
tetracyclines pyrimethamine
According To Mode Of Action FOR PREVENTION OF
TRNSMISSION MODE GAMETOCIDES
( kill Gametes ) DRUGS
- Primaquine for all
species
- Artemisinin for all
- Quinine For vivax
- Chloroquine for
vivax
FOR RADICAL CURE MODE Exo-erythrocytic
Schizonticides (kill Exo-erythrocytic forms ie Hypnozoites)
DRUGS
- Primaquine
20
Site of action
21
CHLOROQUINE
Erythrocytic schizontocide all plasmodial species
Gametocytic not Pfalciparum
No effect on sporozoites hypnozoites
MOA Concentrates in parasite food vacuoles uarrpH
Disruption of polymerization of Heme to Hemozoin
Heme damage plasmodium membrane
Well absorbed oral IM SC 60 PPB
Metabolized by liver t12 3-10 days
Excreted by kidney
22
ADRsNausea vomiting Blurring of
vision Headache Confusion seizures
ndash Hemolysis G6PD individuals Impaired hearing
ndash Hypotension ECG changes
ndash High dose Irreversible ototoxicity retinopathy
myopathy Peripheral neuropathy Chloroquine sulphate (Tab)136 mg = 100 mg Base Chloroquine phosphate (Tab) 250mg=150mg Base
Dose 600 mg stat 300 mg after 8 hours and then
for next two days
Chloroquine
23
Faster acting MOA amp resistance similar to chloroquine ADRs
ndash Toxic hepatitisndash Agranulocytosis
Dose 25-35 mgkg over 3 days Chloroquine resistant combine Artesunate
Amodiaquine
24
Mefloquine Erythrocytic schizontocide Rapidly control fever eliminate circulating parasite Effective Chloroquine resistant plasmodium MOA- Inhibits heme polymerization
- Forms toxic complexes with free heme Oral absorbed Highly protein bound Extensive
tissues distribution
ADRs Nauses Vomiting Diarrhoea Neuropsychiatric Arrythmias Haematological Hepatic toxicity
Dose1250 mg 750 mg 500mg 12 hrly
25
Derived from bark of cinchona tree
Effective blood schizonticidal
Gametocidal P vivax
Chloroquine resistant MDR FP MOA same as of chloroquine Oral absorption rapid amp complete Bound to α1 acid
glycoprotein Metabolized by CYP3A4 Excreted in urine t12 10-12 hrs
Quinine
26
QuinineADRs Cinchonism tinnitusdysphoria headache
Nausea vomiting dizziness flushing amp visual
disturbances
GIT nausea vomiting diarrhoeaabdominal pain Hypoglycemia CVS hypotension dysrhythmias VT fibrillation Hemolysis (G6PD deficiency) Blackwater fever hemolysis hemoglobinemia
hemoglobinuria Dose
ndash Quinine 600 mg 8 hrly
27
Pyrimethamine
Erythrocytic schizontocide
Resistance develops rapidly if used alone
MOA DHFRase inhibitor Oral absorption good slow Concentrated liver spleen kidneys Metabolized liver Excreted renal amp t12 4 days ADRs Nausea Rashes Folate deficiency Dose sulphadoxine 1500 mg
+
pyrimethamine 75 mg
28
Proguanil
Erythrocyte schizontocide
Cyclic triazine metabolite cycloguanil
MOA DHFRase Inhibitor
Slowly adequately absorbed Partly metabolized
Excreted in urine amp t12 is 20 hrs
ADRs Vomiting Abdominal pain Haematuria
Dose 200-300 mgday for 4wks
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
10
MECHANISM Resistant strains are able to efflux the drug by an
active pump mechanism and thereby rendering the drug ineffective
Resistant strains concentrate chloroquine less in vacuoles
Crt-Chloroquine resistant transporter and Pfmdr transporters mutations
There is an increase in the surface area of the resistant parasites permitting more efficient pinocytosis
Binding of chloroquine with haemoglobin breakdown product to form toxic complexes is also prevented
Nonspecific pump inhibitors like calcium channel blockers or antagonists of calmodulin (eg verapamil) have not shown any benefit
11
Types of Drug Resistance 1048698 In defining criteria for resistance to the
aminoquinoline antimalarial drugs the WHO has described three grades of resistance following treatment
1048698 (Low grade) R1 Recrudescence of infection between 7 and 28 days of completing treatment following initial resolution of symptoms and parasite clearance
1048698 (High grade) R2 Reduction of parasitaemia by gt 75 at 48 hours but failure to clear parasites
within 7 days 1048698 R3 Parasitaemia does not fall by gt75 within 48
hours
Indian Scenario of Drug Resistant Malaria
P falciparum gtgt P vivax Incidence being 5 to full dose chloroquine The first confirmed report of chloroquine resistance in
P falciparum was reported in Diphu area of Karbianglong district of Assam in 1973
Resurgence of P falciparum resistant to chloroquine has been noticed in several regions of India more in North Eastern parts of the country
KEM hospital in Mumbai confirmed the existence of chloroquine resistance in P falciparum cases in Mumbai
However for all practical purposes drug resistant malaria in the Indian context means malaria caused by strains of P falciparum which are resistant to chloroquine 12
13
Clinical features
Cold Stagebull Feeling of Intense Coldbull Vigorous Shivering Rigorbull Lasts 15-60 Min
Hot Stagebull Intense Heatbull Dry Burning Skinbull Throbbing Headachebull Lasts 2-6 Hours
Sweating Stagebull Profuse Sweatingbull Declining Temperaturebull Exhausted Weak bull Lasts 2-4 Hours
Why PF Serious
PPalciparum
Produces
Leads to
Binds-RBCs all ages Alters surface Grows in low o2
Micro-vascular blocks Cytokine release Endotoxin release
High parasitemia Cerebral malaria Hypoglycemia Shock Multi organ failure Death
15
Thick Smear Rapid Diagnosis Thin Species identification
Rapid diagnostic test
Antibody detection test
- RIA
- ELISA
Diagnosis
16
1 Chemical classification 4-aminoquinolines
- Chloroquine amodiaquine Piperaquine
8-aminoquinolines - Primaquine Bulaquine
Folate synthesis inhibitors - Sulphonamides like Sulphadoxine Dapsone
- Biguanides like proguanil and chloroproguanil
- Diaminopyrimidine like pyrimethamine
CINCHONA ALKALOIDS Quinine Quinidine
AMINO ALCOHOLS - Lumefantrine Halofantrine
-
17
Antimicrobials Tetracycline doxycycline clindamycin azithromycin
fluoroquinolones FOSMIDOMYCIN
Peroxides Artemisinin (Qinghaosu) derivatives and analogues -
artemether arteether artesunate artelinic acid
Naphthoquinones Atovaquone
Iron chelating agents Desferrioxamine
Chemical classification
2 According To Mode Of Action FOR CAUSAL
PROPHYLAXIS MODE Pre-erythorcytic
Schizonticides ( kill schizonts in the liver )
DRUGS
- Primaquine
- Proguanil
- Tetracycline
FOR THE TREATMENT OF ACUTE ATTACK
MODE Erythrocytic Schizonticides (kill schizonts in the Blood)
DRUGS - Rapidly acting -
Chloroquine quinine atovaquone artemisinin derivatives mefloquine
- Slow acting - - Proguanil sulphonamides
tetracyclines pyrimethamine
According To Mode Of Action FOR PREVENTION OF
TRNSMISSION MODE GAMETOCIDES
( kill Gametes ) DRUGS
- Primaquine for all
species
- Artemisinin for all
- Quinine For vivax
- Chloroquine for
vivax
FOR RADICAL CURE MODE Exo-erythrocytic
Schizonticides (kill Exo-erythrocytic forms ie Hypnozoites)
DRUGS
- Primaquine
20
Site of action
21
CHLOROQUINE
Erythrocytic schizontocide all plasmodial species
Gametocytic not Pfalciparum
No effect on sporozoites hypnozoites
MOA Concentrates in parasite food vacuoles uarrpH
Disruption of polymerization of Heme to Hemozoin
Heme damage plasmodium membrane
Well absorbed oral IM SC 60 PPB
Metabolized by liver t12 3-10 days
Excreted by kidney
22
ADRsNausea vomiting Blurring of
vision Headache Confusion seizures
ndash Hemolysis G6PD individuals Impaired hearing
ndash Hypotension ECG changes
ndash High dose Irreversible ototoxicity retinopathy
myopathy Peripheral neuropathy Chloroquine sulphate (Tab)136 mg = 100 mg Base Chloroquine phosphate (Tab) 250mg=150mg Base
Dose 600 mg stat 300 mg after 8 hours and then
for next two days
Chloroquine
23
Faster acting MOA amp resistance similar to chloroquine ADRs
ndash Toxic hepatitisndash Agranulocytosis
Dose 25-35 mgkg over 3 days Chloroquine resistant combine Artesunate
Amodiaquine
24
Mefloquine Erythrocytic schizontocide Rapidly control fever eliminate circulating parasite Effective Chloroquine resistant plasmodium MOA- Inhibits heme polymerization
- Forms toxic complexes with free heme Oral absorbed Highly protein bound Extensive
tissues distribution
ADRs Nauses Vomiting Diarrhoea Neuropsychiatric Arrythmias Haematological Hepatic toxicity
Dose1250 mg 750 mg 500mg 12 hrly
25
Derived from bark of cinchona tree
Effective blood schizonticidal
Gametocidal P vivax
Chloroquine resistant MDR FP MOA same as of chloroquine Oral absorption rapid amp complete Bound to α1 acid
glycoprotein Metabolized by CYP3A4 Excreted in urine t12 10-12 hrs
Quinine
26
QuinineADRs Cinchonism tinnitusdysphoria headache
Nausea vomiting dizziness flushing amp visual
disturbances
GIT nausea vomiting diarrhoeaabdominal pain Hypoglycemia CVS hypotension dysrhythmias VT fibrillation Hemolysis (G6PD deficiency) Blackwater fever hemolysis hemoglobinemia
hemoglobinuria Dose
ndash Quinine 600 mg 8 hrly
27
Pyrimethamine
Erythrocytic schizontocide
Resistance develops rapidly if used alone
MOA DHFRase inhibitor Oral absorption good slow Concentrated liver spleen kidneys Metabolized liver Excreted renal amp t12 4 days ADRs Nausea Rashes Folate deficiency Dose sulphadoxine 1500 mg
+
pyrimethamine 75 mg
28
Proguanil
Erythrocyte schizontocide
Cyclic triazine metabolite cycloguanil
MOA DHFRase Inhibitor
Slowly adequately absorbed Partly metabolized
Excreted in urine amp t12 is 20 hrs
ADRs Vomiting Abdominal pain Haematuria
Dose 200-300 mgday for 4wks
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
11
Types of Drug Resistance 1048698 In defining criteria for resistance to the
aminoquinoline antimalarial drugs the WHO has described three grades of resistance following treatment
1048698 (Low grade) R1 Recrudescence of infection between 7 and 28 days of completing treatment following initial resolution of symptoms and parasite clearance
1048698 (High grade) R2 Reduction of parasitaemia by gt 75 at 48 hours but failure to clear parasites
within 7 days 1048698 R3 Parasitaemia does not fall by gt75 within 48
hours
Indian Scenario of Drug Resistant Malaria
P falciparum gtgt P vivax Incidence being 5 to full dose chloroquine The first confirmed report of chloroquine resistance in
P falciparum was reported in Diphu area of Karbianglong district of Assam in 1973
Resurgence of P falciparum resistant to chloroquine has been noticed in several regions of India more in North Eastern parts of the country
KEM hospital in Mumbai confirmed the existence of chloroquine resistance in P falciparum cases in Mumbai
However for all practical purposes drug resistant malaria in the Indian context means malaria caused by strains of P falciparum which are resistant to chloroquine 12
13
Clinical features
Cold Stagebull Feeling of Intense Coldbull Vigorous Shivering Rigorbull Lasts 15-60 Min
Hot Stagebull Intense Heatbull Dry Burning Skinbull Throbbing Headachebull Lasts 2-6 Hours
Sweating Stagebull Profuse Sweatingbull Declining Temperaturebull Exhausted Weak bull Lasts 2-4 Hours
Why PF Serious
PPalciparum
Produces
Leads to
Binds-RBCs all ages Alters surface Grows in low o2
Micro-vascular blocks Cytokine release Endotoxin release
High parasitemia Cerebral malaria Hypoglycemia Shock Multi organ failure Death
15
Thick Smear Rapid Diagnosis Thin Species identification
Rapid diagnostic test
Antibody detection test
- RIA
- ELISA
Diagnosis
16
1 Chemical classification 4-aminoquinolines
- Chloroquine amodiaquine Piperaquine
8-aminoquinolines - Primaquine Bulaquine
Folate synthesis inhibitors - Sulphonamides like Sulphadoxine Dapsone
- Biguanides like proguanil and chloroproguanil
- Diaminopyrimidine like pyrimethamine
CINCHONA ALKALOIDS Quinine Quinidine
AMINO ALCOHOLS - Lumefantrine Halofantrine
-
17
Antimicrobials Tetracycline doxycycline clindamycin azithromycin
fluoroquinolones FOSMIDOMYCIN
Peroxides Artemisinin (Qinghaosu) derivatives and analogues -
artemether arteether artesunate artelinic acid
Naphthoquinones Atovaquone
Iron chelating agents Desferrioxamine
Chemical classification
2 According To Mode Of Action FOR CAUSAL
PROPHYLAXIS MODE Pre-erythorcytic
Schizonticides ( kill schizonts in the liver )
DRUGS
- Primaquine
- Proguanil
- Tetracycline
FOR THE TREATMENT OF ACUTE ATTACK
MODE Erythrocytic Schizonticides (kill schizonts in the Blood)
DRUGS - Rapidly acting -
Chloroquine quinine atovaquone artemisinin derivatives mefloquine
- Slow acting - - Proguanil sulphonamides
tetracyclines pyrimethamine
According To Mode Of Action FOR PREVENTION OF
TRNSMISSION MODE GAMETOCIDES
( kill Gametes ) DRUGS
- Primaquine for all
species
- Artemisinin for all
- Quinine For vivax
- Chloroquine for
vivax
FOR RADICAL CURE MODE Exo-erythrocytic
Schizonticides (kill Exo-erythrocytic forms ie Hypnozoites)
DRUGS
- Primaquine
20
Site of action
21
CHLOROQUINE
Erythrocytic schizontocide all plasmodial species
Gametocytic not Pfalciparum
No effect on sporozoites hypnozoites
MOA Concentrates in parasite food vacuoles uarrpH
Disruption of polymerization of Heme to Hemozoin
Heme damage plasmodium membrane
Well absorbed oral IM SC 60 PPB
Metabolized by liver t12 3-10 days
Excreted by kidney
22
ADRsNausea vomiting Blurring of
vision Headache Confusion seizures
ndash Hemolysis G6PD individuals Impaired hearing
ndash Hypotension ECG changes
ndash High dose Irreversible ototoxicity retinopathy
myopathy Peripheral neuropathy Chloroquine sulphate (Tab)136 mg = 100 mg Base Chloroquine phosphate (Tab) 250mg=150mg Base
Dose 600 mg stat 300 mg after 8 hours and then
for next two days
Chloroquine
23
Faster acting MOA amp resistance similar to chloroquine ADRs
ndash Toxic hepatitisndash Agranulocytosis
Dose 25-35 mgkg over 3 days Chloroquine resistant combine Artesunate
Amodiaquine
24
Mefloquine Erythrocytic schizontocide Rapidly control fever eliminate circulating parasite Effective Chloroquine resistant plasmodium MOA- Inhibits heme polymerization
- Forms toxic complexes with free heme Oral absorbed Highly protein bound Extensive
tissues distribution
ADRs Nauses Vomiting Diarrhoea Neuropsychiatric Arrythmias Haematological Hepatic toxicity
Dose1250 mg 750 mg 500mg 12 hrly
25
Derived from bark of cinchona tree
Effective blood schizonticidal
Gametocidal P vivax
Chloroquine resistant MDR FP MOA same as of chloroquine Oral absorption rapid amp complete Bound to α1 acid
glycoprotein Metabolized by CYP3A4 Excreted in urine t12 10-12 hrs
Quinine
26
QuinineADRs Cinchonism tinnitusdysphoria headache
Nausea vomiting dizziness flushing amp visual
disturbances
GIT nausea vomiting diarrhoeaabdominal pain Hypoglycemia CVS hypotension dysrhythmias VT fibrillation Hemolysis (G6PD deficiency) Blackwater fever hemolysis hemoglobinemia
hemoglobinuria Dose
ndash Quinine 600 mg 8 hrly
27
Pyrimethamine
Erythrocytic schizontocide
Resistance develops rapidly if used alone
MOA DHFRase inhibitor Oral absorption good slow Concentrated liver spleen kidneys Metabolized liver Excreted renal amp t12 4 days ADRs Nausea Rashes Folate deficiency Dose sulphadoxine 1500 mg
+
pyrimethamine 75 mg
28
Proguanil
Erythrocyte schizontocide
Cyclic triazine metabolite cycloguanil
MOA DHFRase Inhibitor
Slowly adequately absorbed Partly metabolized
Excreted in urine amp t12 is 20 hrs
ADRs Vomiting Abdominal pain Haematuria
Dose 200-300 mgday for 4wks
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
Indian Scenario of Drug Resistant Malaria
P falciparum gtgt P vivax Incidence being 5 to full dose chloroquine The first confirmed report of chloroquine resistance in
P falciparum was reported in Diphu area of Karbianglong district of Assam in 1973
Resurgence of P falciparum resistant to chloroquine has been noticed in several regions of India more in North Eastern parts of the country
KEM hospital in Mumbai confirmed the existence of chloroquine resistance in P falciparum cases in Mumbai
However for all practical purposes drug resistant malaria in the Indian context means malaria caused by strains of P falciparum which are resistant to chloroquine 12
13
Clinical features
Cold Stagebull Feeling of Intense Coldbull Vigorous Shivering Rigorbull Lasts 15-60 Min
Hot Stagebull Intense Heatbull Dry Burning Skinbull Throbbing Headachebull Lasts 2-6 Hours
Sweating Stagebull Profuse Sweatingbull Declining Temperaturebull Exhausted Weak bull Lasts 2-4 Hours
Why PF Serious
PPalciparum
Produces
Leads to
Binds-RBCs all ages Alters surface Grows in low o2
Micro-vascular blocks Cytokine release Endotoxin release
High parasitemia Cerebral malaria Hypoglycemia Shock Multi organ failure Death
15
Thick Smear Rapid Diagnosis Thin Species identification
Rapid diagnostic test
Antibody detection test
- RIA
- ELISA
Diagnosis
16
1 Chemical classification 4-aminoquinolines
- Chloroquine amodiaquine Piperaquine
8-aminoquinolines - Primaquine Bulaquine
Folate synthesis inhibitors - Sulphonamides like Sulphadoxine Dapsone
- Biguanides like proguanil and chloroproguanil
- Diaminopyrimidine like pyrimethamine
CINCHONA ALKALOIDS Quinine Quinidine
AMINO ALCOHOLS - Lumefantrine Halofantrine
-
17
Antimicrobials Tetracycline doxycycline clindamycin azithromycin
fluoroquinolones FOSMIDOMYCIN
Peroxides Artemisinin (Qinghaosu) derivatives and analogues -
artemether arteether artesunate artelinic acid
Naphthoquinones Atovaquone
Iron chelating agents Desferrioxamine
Chemical classification
2 According To Mode Of Action FOR CAUSAL
PROPHYLAXIS MODE Pre-erythorcytic
Schizonticides ( kill schizonts in the liver )
DRUGS
- Primaquine
- Proguanil
- Tetracycline
FOR THE TREATMENT OF ACUTE ATTACK
MODE Erythrocytic Schizonticides (kill schizonts in the Blood)
DRUGS - Rapidly acting -
Chloroquine quinine atovaquone artemisinin derivatives mefloquine
- Slow acting - - Proguanil sulphonamides
tetracyclines pyrimethamine
According To Mode Of Action FOR PREVENTION OF
TRNSMISSION MODE GAMETOCIDES
( kill Gametes ) DRUGS
- Primaquine for all
species
- Artemisinin for all
- Quinine For vivax
- Chloroquine for
vivax
FOR RADICAL CURE MODE Exo-erythrocytic
Schizonticides (kill Exo-erythrocytic forms ie Hypnozoites)
DRUGS
- Primaquine
20
Site of action
21
CHLOROQUINE
Erythrocytic schizontocide all plasmodial species
Gametocytic not Pfalciparum
No effect on sporozoites hypnozoites
MOA Concentrates in parasite food vacuoles uarrpH
Disruption of polymerization of Heme to Hemozoin
Heme damage plasmodium membrane
Well absorbed oral IM SC 60 PPB
Metabolized by liver t12 3-10 days
Excreted by kidney
22
ADRsNausea vomiting Blurring of
vision Headache Confusion seizures
ndash Hemolysis G6PD individuals Impaired hearing
ndash Hypotension ECG changes
ndash High dose Irreversible ototoxicity retinopathy
myopathy Peripheral neuropathy Chloroquine sulphate (Tab)136 mg = 100 mg Base Chloroquine phosphate (Tab) 250mg=150mg Base
Dose 600 mg stat 300 mg after 8 hours and then
for next two days
Chloroquine
23
Faster acting MOA amp resistance similar to chloroquine ADRs
ndash Toxic hepatitisndash Agranulocytosis
Dose 25-35 mgkg over 3 days Chloroquine resistant combine Artesunate
Amodiaquine
24
Mefloquine Erythrocytic schizontocide Rapidly control fever eliminate circulating parasite Effective Chloroquine resistant plasmodium MOA- Inhibits heme polymerization
- Forms toxic complexes with free heme Oral absorbed Highly protein bound Extensive
tissues distribution
ADRs Nauses Vomiting Diarrhoea Neuropsychiatric Arrythmias Haematological Hepatic toxicity
Dose1250 mg 750 mg 500mg 12 hrly
25
Derived from bark of cinchona tree
Effective blood schizonticidal
Gametocidal P vivax
Chloroquine resistant MDR FP MOA same as of chloroquine Oral absorption rapid amp complete Bound to α1 acid
glycoprotein Metabolized by CYP3A4 Excreted in urine t12 10-12 hrs
Quinine
26
QuinineADRs Cinchonism tinnitusdysphoria headache
Nausea vomiting dizziness flushing amp visual
disturbances
GIT nausea vomiting diarrhoeaabdominal pain Hypoglycemia CVS hypotension dysrhythmias VT fibrillation Hemolysis (G6PD deficiency) Blackwater fever hemolysis hemoglobinemia
hemoglobinuria Dose
ndash Quinine 600 mg 8 hrly
27
Pyrimethamine
Erythrocytic schizontocide
Resistance develops rapidly if used alone
MOA DHFRase inhibitor Oral absorption good slow Concentrated liver spleen kidneys Metabolized liver Excreted renal amp t12 4 days ADRs Nausea Rashes Folate deficiency Dose sulphadoxine 1500 mg
+
pyrimethamine 75 mg
28
Proguanil
Erythrocyte schizontocide
Cyclic triazine metabolite cycloguanil
MOA DHFRase Inhibitor
Slowly adequately absorbed Partly metabolized
Excreted in urine amp t12 is 20 hrs
ADRs Vomiting Abdominal pain Haematuria
Dose 200-300 mgday for 4wks
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
13
Clinical features
Cold Stagebull Feeling of Intense Coldbull Vigorous Shivering Rigorbull Lasts 15-60 Min
Hot Stagebull Intense Heatbull Dry Burning Skinbull Throbbing Headachebull Lasts 2-6 Hours
Sweating Stagebull Profuse Sweatingbull Declining Temperaturebull Exhausted Weak bull Lasts 2-4 Hours
Why PF Serious
PPalciparum
Produces
Leads to
Binds-RBCs all ages Alters surface Grows in low o2
Micro-vascular blocks Cytokine release Endotoxin release
High parasitemia Cerebral malaria Hypoglycemia Shock Multi organ failure Death
15
Thick Smear Rapid Diagnosis Thin Species identification
Rapid diagnostic test
Antibody detection test
- RIA
- ELISA
Diagnosis
16
1 Chemical classification 4-aminoquinolines
- Chloroquine amodiaquine Piperaquine
8-aminoquinolines - Primaquine Bulaquine
Folate synthesis inhibitors - Sulphonamides like Sulphadoxine Dapsone
- Biguanides like proguanil and chloroproguanil
- Diaminopyrimidine like pyrimethamine
CINCHONA ALKALOIDS Quinine Quinidine
AMINO ALCOHOLS - Lumefantrine Halofantrine
-
17
Antimicrobials Tetracycline doxycycline clindamycin azithromycin
fluoroquinolones FOSMIDOMYCIN
Peroxides Artemisinin (Qinghaosu) derivatives and analogues -
artemether arteether artesunate artelinic acid
Naphthoquinones Atovaquone
Iron chelating agents Desferrioxamine
Chemical classification
2 According To Mode Of Action FOR CAUSAL
PROPHYLAXIS MODE Pre-erythorcytic
Schizonticides ( kill schizonts in the liver )
DRUGS
- Primaquine
- Proguanil
- Tetracycline
FOR THE TREATMENT OF ACUTE ATTACK
MODE Erythrocytic Schizonticides (kill schizonts in the Blood)
DRUGS - Rapidly acting -
Chloroquine quinine atovaquone artemisinin derivatives mefloquine
- Slow acting - - Proguanil sulphonamides
tetracyclines pyrimethamine
According To Mode Of Action FOR PREVENTION OF
TRNSMISSION MODE GAMETOCIDES
( kill Gametes ) DRUGS
- Primaquine for all
species
- Artemisinin for all
- Quinine For vivax
- Chloroquine for
vivax
FOR RADICAL CURE MODE Exo-erythrocytic
Schizonticides (kill Exo-erythrocytic forms ie Hypnozoites)
DRUGS
- Primaquine
20
Site of action
21
CHLOROQUINE
Erythrocytic schizontocide all plasmodial species
Gametocytic not Pfalciparum
No effect on sporozoites hypnozoites
MOA Concentrates in parasite food vacuoles uarrpH
Disruption of polymerization of Heme to Hemozoin
Heme damage plasmodium membrane
Well absorbed oral IM SC 60 PPB
Metabolized by liver t12 3-10 days
Excreted by kidney
22
ADRsNausea vomiting Blurring of
vision Headache Confusion seizures
ndash Hemolysis G6PD individuals Impaired hearing
ndash Hypotension ECG changes
ndash High dose Irreversible ototoxicity retinopathy
myopathy Peripheral neuropathy Chloroquine sulphate (Tab)136 mg = 100 mg Base Chloroquine phosphate (Tab) 250mg=150mg Base
Dose 600 mg stat 300 mg after 8 hours and then
for next two days
Chloroquine
23
Faster acting MOA amp resistance similar to chloroquine ADRs
ndash Toxic hepatitisndash Agranulocytosis
Dose 25-35 mgkg over 3 days Chloroquine resistant combine Artesunate
Amodiaquine
24
Mefloquine Erythrocytic schizontocide Rapidly control fever eliminate circulating parasite Effective Chloroquine resistant plasmodium MOA- Inhibits heme polymerization
- Forms toxic complexes with free heme Oral absorbed Highly protein bound Extensive
tissues distribution
ADRs Nauses Vomiting Diarrhoea Neuropsychiatric Arrythmias Haematological Hepatic toxicity
Dose1250 mg 750 mg 500mg 12 hrly
25
Derived from bark of cinchona tree
Effective blood schizonticidal
Gametocidal P vivax
Chloroquine resistant MDR FP MOA same as of chloroquine Oral absorption rapid amp complete Bound to α1 acid
glycoprotein Metabolized by CYP3A4 Excreted in urine t12 10-12 hrs
Quinine
26
QuinineADRs Cinchonism tinnitusdysphoria headache
Nausea vomiting dizziness flushing amp visual
disturbances
GIT nausea vomiting diarrhoeaabdominal pain Hypoglycemia CVS hypotension dysrhythmias VT fibrillation Hemolysis (G6PD deficiency) Blackwater fever hemolysis hemoglobinemia
hemoglobinuria Dose
ndash Quinine 600 mg 8 hrly
27
Pyrimethamine
Erythrocytic schizontocide
Resistance develops rapidly if used alone
MOA DHFRase inhibitor Oral absorption good slow Concentrated liver spleen kidneys Metabolized liver Excreted renal amp t12 4 days ADRs Nausea Rashes Folate deficiency Dose sulphadoxine 1500 mg
+
pyrimethamine 75 mg
28
Proguanil
Erythrocyte schizontocide
Cyclic triazine metabolite cycloguanil
MOA DHFRase Inhibitor
Slowly adequately absorbed Partly metabolized
Excreted in urine amp t12 is 20 hrs
ADRs Vomiting Abdominal pain Haematuria
Dose 200-300 mgday for 4wks
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
Why PF Serious
PPalciparum
Produces
Leads to
Binds-RBCs all ages Alters surface Grows in low o2
Micro-vascular blocks Cytokine release Endotoxin release
High parasitemia Cerebral malaria Hypoglycemia Shock Multi organ failure Death
15
Thick Smear Rapid Diagnosis Thin Species identification
Rapid diagnostic test
Antibody detection test
- RIA
- ELISA
Diagnosis
16
1 Chemical classification 4-aminoquinolines
- Chloroquine amodiaquine Piperaquine
8-aminoquinolines - Primaquine Bulaquine
Folate synthesis inhibitors - Sulphonamides like Sulphadoxine Dapsone
- Biguanides like proguanil and chloroproguanil
- Diaminopyrimidine like pyrimethamine
CINCHONA ALKALOIDS Quinine Quinidine
AMINO ALCOHOLS - Lumefantrine Halofantrine
-
17
Antimicrobials Tetracycline doxycycline clindamycin azithromycin
fluoroquinolones FOSMIDOMYCIN
Peroxides Artemisinin (Qinghaosu) derivatives and analogues -
artemether arteether artesunate artelinic acid
Naphthoquinones Atovaquone
Iron chelating agents Desferrioxamine
Chemical classification
2 According To Mode Of Action FOR CAUSAL
PROPHYLAXIS MODE Pre-erythorcytic
Schizonticides ( kill schizonts in the liver )
DRUGS
- Primaquine
- Proguanil
- Tetracycline
FOR THE TREATMENT OF ACUTE ATTACK
MODE Erythrocytic Schizonticides (kill schizonts in the Blood)
DRUGS - Rapidly acting -
Chloroquine quinine atovaquone artemisinin derivatives mefloquine
- Slow acting - - Proguanil sulphonamides
tetracyclines pyrimethamine
According To Mode Of Action FOR PREVENTION OF
TRNSMISSION MODE GAMETOCIDES
( kill Gametes ) DRUGS
- Primaquine for all
species
- Artemisinin for all
- Quinine For vivax
- Chloroquine for
vivax
FOR RADICAL CURE MODE Exo-erythrocytic
Schizonticides (kill Exo-erythrocytic forms ie Hypnozoites)
DRUGS
- Primaquine
20
Site of action
21
CHLOROQUINE
Erythrocytic schizontocide all plasmodial species
Gametocytic not Pfalciparum
No effect on sporozoites hypnozoites
MOA Concentrates in parasite food vacuoles uarrpH
Disruption of polymerization of Heme to Hemozoin
Heme damage plasmodium membrane
Well absorbed oral IM SC 60 PPB
Metabolized by liver t12 3-10 days
Excreted by kidney
22
ADRsNausea vomiting Blurring of
vision Headache Confusion seizures
ndash Hemolysis G6PD individuals Impaired hearing
ndash Hypotension ECG changes
ndash High dose Irreversible ototoxicity retinopathy
myopathy Peripheral neuropathy Chloroquine sulphate (Tab)136 mg = 100 mg Base Chloroquine phosphate (Tab) 250mg=150mg Base
Dose 600 mg stat 300 mg after 8 hours and then
for next two days
Chloroquine
23
Faster acting MOA amp resistance similar to chloroquine ADRs
ndash Toxic hepatitisndash Agranulocytosis
Dose 25-35 mgkg over 3 days Chloroquine resistant combine Artesunate
Amodiaquine
24
Mefloquine Erythrocytic schizontocide Rapidly control fever eliminate circulating parasite Effective Chloroquine resistant plasmodium MOA- Inhibits heme polymerization
- Forms toxic complexes with free heme Oral absorbed Highly protein bound Extensive
tissues distribution
ADRs Nauses Vomiting Diarrhoea Neuropsychiatric Arrythmias Haematological Hepatic toxicity
Dose1250 mg 750 mg 500mg 12 hrly
25
Derived from bark of cinchona tree
Effective blood schizonticidal
Gametocidal P vivax
Chloroquine resistant MDR FP MOA same as of chloroquine Oral absorption rapid amp complete Bound to α1 acid
glycoprotein Metabolized by CYP3A4 Excreted in urine t12 10-12 hrs
Quinine
26
QuinineADRs Cinchonism tinnitusdysphoria headache
Nausea vomiting dizziness flushing amp visual
disturbances
GIT nausea vomiting diarrhoeaabdominal pain Hypoglycemia CVS hypotension dysrhythmias VT fibrillation Hemolysis (G6PD deficiency) Blackwater fever hemolysis hemoglobinemia
hemoglobinuria Dose
ndash Quinine 600 mg 8 hrly
27
Pyrimethamine
Erythrocytic schizontocide
Resistance develops rapidly if used alone
MOA DHFRase inhibitor Oral absorption good slow Concentrated liver spleen kidneys Metabolized liver Excreted renal amp t12 4 days ADRs Nausea Rashes Folate deficiency Dose sulphadoxine 1500 mg
+
pyrimethamine 75 mg
28
Proguanil
Erythrocyte schizontocide
Cyclic triazine metabolite cycloguanil
MOA DHFRase Inhibitor
Slowly adequately absorbed Partly metabolized
Excreted in urine amp t12 is 20 hrs
ADRs Vomiting Abdominal pain Haematuria
Dose 200-300 mgday for 4wks
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
15
Thick Smear Rapid Diagnosis Thin Species identification
Rapid diagnostic test
Antibody detection test
- RIA
- ELISA
Diagnosis
16
1 Chemical classification 4-aminoquinolines
- Chloroquine amodiaquine Piperaquine
8-aminoquinolines - Primaquine Bulaquine
Folate synthesis inhibitors - Sulphonamides like Sulphadoxine Dapsone
- Biguanides like proguanil and chloroproguanil
- Diaminopyrimidine like pyrimethamine
CINCHONA ALKALOIDS Quinine Quinidine
AMINO ALCOHOLS - Lumefantrine Halofantrine
-
17
Antimicrobials Tetracycline doxycycline clindamycin azithromycin
fluoroquinolones FOSMIDOMYCIN
Peroxides Artemisinin (Qinghaosu) derivatives and analogues -
artemether arteether artesunate artelinic acid
Naphthoquinones Atovaquone
Iron chelating agents Desferrioxamine
Chemical classification
2 According To Mode Of Action FOR CAUSAL
PROPHYLAXIS MODE Pre-erythorcytic
Schizonticides ( kill schizonts in the liver )
DRUGS
- Primaquine
- Proguanil
- Tetracycline
FOR THE TREATMENT OF ACUTE ATTACK
MODE Erythrocytic Schizonticides (kill schizonts in the Blood)
DRUGS - Rapidly acting -
Chloroquine quinine atovaquone artemisinin derivatives mefloquine
- Slow acting - - Proguanil sulphonamides
tetracyclines pyrimethamine
According To Mode Of Action FOR PREVENTION OF
TRNSMISSION MODE GAMETOCIDES
( kill Gametes ) DRUGS
- Primaquine for all
species
- Artemisinin for all
- Quinine For vivax
- Chloroquine for
vivax
FOR RADICAL CURE MODE Exo-erythrocytic
Schizonticides (kill Exo-erythrocytic forms ie Hypnozoites)
DRUGS
- Primaquine
20
Site of action
21
CHLOROQUINE
Erythrocytic schizontocide all plasmodial species
Gametocytic not Pfalciparum
No effect on sporozoites hypnozoites
MOA Concentrates in parasite food vacuoles uarrpH
Disruption of polymerization of Heme to Hemozoin
Heme damage plasmodium membrane
Well absorbed oral IM SC 60 PPB
Metabolized by liver t12 3-10 days
Excreted by kidney
22
ADRsNausea vomiting Blurring of
vision Headache Confusion seizures
ndash Hemolysis G6PD individuals Impaired hearing
ndash Hypotension ECG changes
ndash High dose Irreversible ototoxicity retinopathy
myopathy Peripheral neuropathy Chloroquine sulphate (Tab)136 mg = 100 mg Base Chloroquine phosphate (Tab) 250mg=150mg Base
Dose 600 mg stat 300 mg after 8 hours and then
for next two days
Chloroquine
23
Faster acting MOA amp resistance similar to chloroquine ADRs
ndash Toxic hepatitisndash Agranulocytosis
Dose 25-35 mgkg over 3 days Chloroquine resistant combine Artesunate
Amodiaquine
24
Mefloquine Erythrocytic schizontocide Rapidly control fever eliminate circulating parasite Effective Chloroquine resistant plasmodium MOA- Inhibits heme polymerization
- Forms toxic complexes with free heme Oral absorbed Highly protein bound Extensive
tissues distribution
ADRs Nauses Vomiting Diarrhoea Neuropsychiatric Arrythmias Haematological Hepatic toxicity
Dose1250 mg 750 mg 500mg 12 hrly
25
Derived from bark of cinchona tree
Effective blood schizonticidal
Gametocidal P vivax
Chloroquine resistant MDR FP MOA same as of chloroquine Oral absorption rapid amp complete Bound to α1 acid
glycoprotein Metabolized by CYP3A4 Excreted in urine t12 10-12 hrs
Quinine
26
QuinineADRs Cinchonism tinnitusdysphoria headache
Nausea vomiting dizziness flushing amp visual
disturbances
GIT nausea vomiting diarrhoeaabdominal pain Hypoglycemia CVS hypotension dysrhythmias VT fibrillation Hemolysis (G6PD deficiency) Blackwater fever hemolysis hemoglobinemia
hemoglobinuria Dose
ndash Quinine 600 mg 8 hrly
27
Pyrimethamine
Erythrocytic schizontocide
Resistance develops rapidly if used alone
MOA DHFRase inhibitor Oral absorption good slow Concentrated liver spleen kidneys Metabolized liver Excreted renal amp t12 4 days ADRs Nausea Rashes Folate deficiency Dose sulphadoxine 1500 mg
+
pyrimethamine 75 mg
28
Proguanil
Erythrocyte schizontocide
Cyclic triazine metabolite cycloguanil
MOA DHFRase Inhibitor
Slowly adequately absorbed Partly metabolized
Excreted in urine amp t12 is 20 hrs
ADRs Vomiting Abdominal pain Haematuria
Dose 200-300 mgday for 4wks
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
16
1 Chemical classification 4-aminoquinolines
- Chloroquine amodiaquine Piperaquine
8-aminoquinolines - Primaquine Bulaquine
Folate synthesis inhibitors - Sulphonamides like Sulphadoxine Dapsone
- Biguanides like proguanil and chloroproguanil
- Diaminopyrimidine like pyrimethamine
CINCHONA ALKALOIDS Quinine Quinidine
AMINO ALCOHOLS - Lumefantrine Halofantrine
-
17
Antimicrobials Tetracycline doxycycline clindamycin azithromycin
fluoroquinolones FOSMIDOMYCIN
Peroxides Artemisinin (Qinghaosu) derivatives and analogues -
artemether arteether artesunate artelinic acid
Naphthoquinones Atovaquone
Iron chelating agents Desferrioxamine
Chemical classification
2 According To Mode Of Action FOR CAUSAL
PROPHYLAXIS MODE Pre-erythorcytic
Schizonticides ( kill schizonts in the liver )
DRUGS
- Primaquine
- Proguanil
- Tetracycline
FOR THE TREATMENT OF ACUTE ATTACK
MODE Erythrocytic Schizonticides (kill schizonts in the Blood)
DRUGS - Rapidly acting -
Chloroquine quinine atovaquone artemisinin derivatives mefloquine
- Slow acting - - Proguanil sulphonamides
tetracyclines pyrimethamine
According To Mode Of Action FOR PREVENTION OF
TRNSMISSION MODE GAMETOCIDES
( kill Gametes ) DRUGS
- Primaquine for all
species
- Artemisinin for all
- Quinine For vivax
- Chloroquine for
vivax
FOR RADICAL CURE MODE Exo-erythrocytic
Schizonticides (kill Exo-erythrocytic forms ie Hypnozoites)
DRUGS
- Primaquine
20
Site of action
21
CHLOROQUINE
Erythrocytic schizontocide all plasmodial species
Gametocytic not Pfalciparum
No effect on sporozoites hypnozoites
MOA Concentrates in parasite food vacuoles uarrpH
Disruption of polymerization of Heme to Hemozoin
Heme damage plasmodium membrane
Well absorbed oral IM SC 60 PPB
Metabolized by liver t12 3-10 days
Excreted by kidney
22
ADRsNausea vomiting Blurring of
vision Headache Confusion seizures
ndash Hemolysis G6PD individuals Impaired hearing
ndash Hypotension ECG changes
ndash High dose Irreversible ototoxicity retinopathy
myopathy Peripheral neuropathy Chloroquine sulphate (Tab)136 mg = 100 mg Base Chloroquine phosphate (Tab) 250mg=150mg Base
Dose 600 mg stat 300 mg after 8 hours and then
for next two days
Chloroquine
23
Faster acting MOA amp resistance similar to chloroquine ADRs
ndash Toxic hepatitisndash Agranulocytosis
Dose 25-35 mgkg over 3 days Chloroquine resistant combine Artesunate
Amodiaquine
24
Mefloquine Erythrocytic schizontocide Rapidly control fever eliminate circulating parasite Effective Chloroquine resistant plasmodium MOA- Inhibits heme polymerization
- Forms toxic complexes with free heme Oral absorbed Highly protein bound Extensive
tissues distribution
ADRs Nauses Vomiting Diarrhoea Neuropsychiatric Arrythmias Haematological Hepatic toxicity
Dose1250 mg 750 mg 500mg 12 hrly
25
Derived from bark of cinchona tree
Effective blood schizonticidal
Gametocidal P vivax
Chloroquine resistant MDR FP MOA same as of chloroquine Oral absorption rapid amp complete Bound to α1 acid
glycoprotein Metabolized by CYP3A4 Excreted in urine t12 10-12 hrs
Quinine
26
QuinineADRs Cinchonism tinnitusdysphoria headache
Nausea vomiting dizziness flushing amp visual
disturbances
GIT nausea vomiting diarrhoeaabdominal pain Hypoglycemia CVS hypotension dysrhythmias VT fibrillation Hemolysis (G6PD deficiency) Blackwater fever hemolysis hemoglobinemia
hemoglobinuria Dose
ndash Quinine 600 mg 8 hrly
27
Pyrimethamine
Erythrocytic schizontocide
Resistance develops rapidly if used alone
MOA DHFRase inhibitor Oral absorption good slow Concentrated liver spleen kidneys Metabolized liver Excreted renal amp t12 4 days ADRs Nausea Rashes Folate deficiency Dose sulphadoxine 1500 mg
+
pyrimethamine 75 mg
28
Proguanil
Erythrocyte schizontocide
Cyclic triazine metabolite cycloguanil
MOA DHFRase Inhibitor
Slowly adequately absorbed Partly metabolized
Excreted in urine amp t12 is 20 hrs
ADRs Vomiting Abdominal pain Haematuria
Dose 200-300 mgday for 4wks
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
17
Antimicrobials Tetracycline doxycycline clindamycin azithromycin
fluoroquinolones FOSMIDOMYCIN
Peroxides Artemisinin (Qinghaosu) derivatives and analogues -
artemether arteether artesunate artelinic acid
Naphthoquinones Atovaquone
Iron chelating agents Desferrioxamine
Chemical classification
2 According To Mode Of Action FOR CAUSAL
PROPHYLAXIS MODE Pre-erythorcytic
Schizonticides ( kill schizonts in the liver )
DRUGS
- Primaquine
- Proguanil
- Tetracycline
FOR THE TREATMENT OF ACUTE ATTACK
MODE Erythrocytic Schizonticides (kill schizonts in the Blood)
DRUGS - Rapidly acting -
Chloroquine quinine atovaquone artemisinin derivatives mefloquine
- Slow acting - - Proguanil sulphonamides
tetracyclines pyrimethamine
According To Mode Of Action FOR PREVENTION OF
TRNSMISSION MODE GAMETOCIDES
( kill Gametes ) DRUGS
- Primaquine for all
species
- Artemisinin for all
- Quinine For vivax
- Chloroquine for
vivax
FOR RADICAL CURE MODE Exo-erythrocytic
Schizonticides (kill Exo-erythrocytic forms ie Hypnozoites)
DRUGS
- Primaquine
20
Site of action
21
CHLOROQUINE
Erythrocytic schizontocide all plasmodial species
Gametocytic not Pfalciparum
No effect on sporozoites hypnozoites
MOA Concentrates in parasite food vacuoles uarrpH
Disruption of polymerization of Heme to Hemozoin
Heme damage plasmodium membrane
Well absorbed oral IM SC 60 PPB
Metabolized by liver t12 3-10 days
Excreted by kidney
22
ADRsNausea vomiting Blurring of
vision Headache Confusion seizures
ndash Hemolysis G6PD individuals Impaired hearing
ndash Hypotension ECG changes
ndash High dose Irreversible ototoxicity retinopathy
myopathy Peripheral neuropathy Chloroquine sulphate (Tab)136 mg = 100 mg Base Chloroquine phosphate (Tab) 250mg=150mg Base
Dose 600 mg stat 300 mg after 8 hours and then
for next two days
Chloroquine
23
Faster acting MOA amp resistance similar to chloroquine ADRs
ndash Toxic hepatitisndash Agranulocytosis
Dose 25-35 mgkg over 3 days Chloroquine resistant combine Artesunate
Amodiaquine
24
Mefloquine Erythrocytic schizontocide Rapidly control fever eliminate circulating parasite Effective Chloroquine resistant plasmodium MOA- Inhibits heme polymerization
- Forms toxic complexes with free heme Oral absorbed Highly protein bound Extensive
tissues distribution
ADRs Nauses Vomiting Diarrhoea Neuropsychiatric Arrythmias Haematological Hepatic toxicity
Dose1250 mg 750 mg 500mg 12 hrly
25
Derived from bark of cinchona tree
Effective blood schizonticidal
Gametocidal P vivax
Chloroquine resistant MDR FP MOA same as of chloroquine Oral absorption rapid amp complete Bound to α1 acid
glycoprotein Metabolized by CYP3A4 Excreted in urine t12 10-12 hrs
Quinine
26
QuinineADRs Cinchonism tinnitusdysphoria headache
Nausea vomiting dizziness flushing amp visual
disturbances
GIT nausea vomiting diarrhoeaabdominal pain Hypoglycemia CVS hypotension dysrhythmias VT fibrillation Hemolysis (G6PD deficiency) Blackwater fever hemolysis hemoglobinemia
hemoglobinuria Dose
ndash Quinine 600 mg 8 hrly
27
Pyrimethamine
Erythrocytic schizontocide
Resistance develops rapidly if used alone
MOA DHFRase inhibitor Oral absorption good slow Concentrated liver spleen kidneys Metabolized liver Excreted renal amp t12 4 days ADRs Nausea Rashes Folate deficiency Dose sulphadoxine 1500 mg
+
pyrimethamine 75 mg
28
Proguanil
Erythrocyte schizontocide
Cyclic triazine metabolite cycloguanil
MOA DHFRase Inhibitor
Slowly adequately absorbed Partly metabolized
Excreted in urine amp t12 is 20 hrs
ADRs Vomiting Abdominal pain Haematuria
Dose 200-300 mgday for 4wks
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
2 According To Mode Of Action FOR CAUSAL
PROPHYLAXIS MODE Pre-erythorcytic
Schizonticides ( kill schizonts in the liver )
DRUGS
- Primaquine
- Proguanil
- Tetracycline
FOR THE TREATMENT OF ACUTE ATTACK
MODE Erythrocytic Schizonticides (kill schizonts in the Blood)
DRUGS - Rapidly acting -
Chloroquine quinine atovaquone artemisinin derivatives mefloquine
- Slow acting - - Proguanil sulphonamides
tetracyclines pyrimethamine
According To Mode Of Action FOR PREVENTION OF
TRNSMISSION MODE GAMETOCIDES
( kill Gametes ) DRUGS
- Primaquine for all
species
- Artemisinin for all
- Quinine For vivax
- Chloroquine for
vivax
FOR RADICAL CURE MODE Exo-erythrocytic
Schizonticides (kill Exo-erythrocytic forms ie Hypnozoites)
DRUGS
- Primaquine
20
Site of action
21
CHLOROQUINE
Erythrocytic schizontocide all plasmodial species
Gametocytic not Pfalciparum
No effect on sporozoites hypnozoites
MOA Concentrates in parasite food vacuoles uarrpH
Disruption of polymerization of Heme to Hemozoin
Heme damage plasmodium membrane
Well absorbed oral IM SC 60 PPB
Metabolized by liver t12 3-10 days
Excreted by kidney
22
ADRsNausea vomiting Blurring of
vision Headache Confusion seizures
ndash Hemolysis G6PD individuals Impaired hearing
ndash Hypotension ECG changes
ndash High dose Irreversible ototoxicity retinopathy
myopathy Peripheral neuropathy Chloroquine sulphate (Tab)136 mg = 100 mg Base Chloroquine phosphate (Tab) 250mg=150mg Base
Dose 600 mg stat 300 mg after 8 hours and then
for next two days
Chloroquine
23
Faster acting MOA amp resistance similar to chloroquine ADRs
ndash Toxic hepatitisndash Agranulocytosis
Dose 25-35 mgkg over 3 days Chloroquine resistant combine Artesunate
Amodiaquine
24
Mefloquine Erythrocytic schizontocide Rapidly control fever eliminate circulating parasite Effective Chloroquine resistant plasmodium MOA- Inhibits heme polymerization
- Forms toxic complexes with free heme Oral absorbed Highly protein bound Extensive
tissues distribution
ADRs Nauses Vomiting Diarrhoea Neuropsychiatric Arrythmias Haematological Hepatic toxicity
Dose1250 mg 750 mg 500mg 12 hrly
25
Derived from bark of cinchona tree
Effective blood schizonticidal
Gametocidal P vivax
Chloroquine resistant MDR FP MOA same as of chloroquine Oral absorption rapid amp complete Bound to α1 acid
glycoprotein Metabolized by CYP3A4 Excreted in urine t12 10-12 hrs
Quinine
26
QuinineADRs Cinchonism tinnitusdysphoria headache
Nausea vomiting dizziness flushing amp visual
disturbances
GIT nausea vomiting diarrhoeaabdominal pain Hypoglycemia CVS hypotension dysrhythmias VT fibrillation Hemolysis (G6PD deficiency) Blackwater fever hemolysis hemoglobinemia
hemoglobinuria Dose
ndash Quinine 600 mg 8 hrly
27
Pyrimethamine
Erythrocytic schizontocide
Resistance develops rapidly if used alone
MOA DHFRase inhibitor Oral absorption good slow Concentrated liver spleen kidneys Metabolized liver Excreted renal amp t12 4 days ADRs Nausea Rashes Folate deficiency Dose sulphadoxine 1500 mg
+
pyrimethamine 75 mg
28
Proguanil
Erythrocyte schizontocide
Cyclic triazine metabolite cycloguanil
MOA DHFRase Inhibitor
Slowly adequately absorbed Partly metabolized
Excreted in urine amp t12 is 20 hrs
ADRs Vomiting Abdominal pain Haematuria
Dose 200-300 mgday for 4wks
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
According To Mode Of Action FOR PREVENTION OF
TRNSMISSION MODE GAMETOCIDES
( kill Gametes ) DRUGS
- Primaquine for all
species
- Artemisinin for all
- Quinine For vivax
- Chloroquine for
vivax
FOR RADICAL CURE MODE Exo-erythrocytic
Schizonticides (kill Exo-erythrocytic forms ie Hypnozoites)
DRUGS
- Primaquine
20
Site of action
21
CHLOROQUINE
Erythrocytic schizontocide all plasmodial species
Gametocytic not Pfalciparum
No effect on sporozoites hypnozoites
MOA Concentrates in parasite food vacuoles uarrpH
Disruption of polymerization of Heme to Hemozoin
Heme damage plasmodium membrane
Well absorbed oral IM SC 60 PPB
Metabolized by liver t12 3-10 days
Excreted by kidney
22
ADRsNausea vomiting Blurring of
vision Headache Confusion seizures
ndash Hemolysis G6PD individuals Impaired hearing
ndash Hypotension ECG changes
ndash High dose Irreversible ototoxicity retinopathy
myopathy Peripheral neuropathy Chloroquine sulphate (Tab)136 mg = 100 mg Base Chloroquine phosphate (Tab) 250mg=150mg Base
Dose 600 mg stat 300 mg after 8 hours and then
for next two days
Chloroquine
23
Faster acting MOA amp resistance similar to chloroquine ADRs
ndash Toxic hepatitisndash Agranulocytosis
Dose 25-35 mgkg over 3 days Chloroquine resistant combine Artesunate
Amodiaquine
24
Mefloquine Erythrocytic schizontocide Rapidly control fever eliminate circulating parasite Effective Chloroquine resistant plasmodium MOA- Inhibits heme polymerization
- Forms toxic complexes with free heme Oral absorbed Highly protein bound Extensive
tissues distribution
ADRs Nauses Vomiting Diarrhoea Neuropsychiatric Arrythmias Haematological Hepatic toxicity
Dose1250 mg 750 mg 500mg 12 hrly
25
Derived from bark of cinchona tree
Effective blood schizonticidal
Gametocidal P vivax
Chloroquine resistant MDR FP MOA same as of chloroquine Oral absorption rapid amp complete Bound to α1 acid
glycoprotein Metabolized by CYP3A4 Excreted in urine t12 10-12 hrs
Quinine
26
QuinineADRs Cinchonism tinnitusdysphoria headache
Nausea vomiting dizziness flushing amp visual
disturbances
GIT nausea vomiting diarrhoeaabdominal pain Hypoglycemia CVS hypotension dysrhythmias VT fibrillation Hemolysis (G6PD deficiency) Blackwater fever hemolysis hemoglobinemia
hemoglobinuria Dose
ndash Quinine 600 mg 8 hrly
27
Pyrimethamine
Erythrocytic schizontocide
Resistance develops rapidly if used alone
MOA DHFRase inhibitor Oral absorption good slow Concentrated liver spleen kidneys Metabolized liver Excreted renal amp t12 4 days ADRs Nausea Rashes Folate deficiency Dose sulphadoxine 1500 mg
+
pyrimethamine 75 mg
28
Proguanil
Erythrocyte schizontocide
Cyclic triazine metabolite cycloguanil
MOA DHFRase Inhibitor
Slowly adequately absorbed Partly metabolized
Excreted in urine amp t12 is 20 hrs
ADRs Vomiting Abdominal pain Haematuria
Dose 200-300 mgday for 4wks
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
20
Site of action
21
CHLOROQUINE
Erythrocytic schizontocide all plasmodial species
Gametocytic not Pfalciparum
No effect on sporozoites hypnozoites
MOA Concentrates in parasite food vacuoles uarrpH
Disruption of polymerization of Heme to Hemozoin
Heme damage plasmodium membrane
Well absorbed oral IM SC 60 PPB
Metabolized by liver t12 3-10 days
Excreted by kidney
22
ADRsNausea vomiting Blurring of
vision Headache Confusion seizures
ndash Hemolysis G6PD individuals Impaired hearing
ndash Hypotension ECG changes
ndash High dose Irreversible ototoxicity retinopathy
myopathy Peripheral neuropathy Chloroquine sulphate (Tab)136 mg = 100 mg Base Chloroquine phosphate (Tab) 250mg=150mg Base
Dose 600 mg stat 300 mg after 8 hours and then
for next two days
Chloroquine
23
Faster acting MOA amp resistance similar to chloroquine ADRs
ndash Toxic hepatitisndash Agranulocytosis
Dose 25-35 mgkg over 3 days Chloroquine resistant combine Artesunate
Amodiaquine
24
Mefloquine Erythrocytic schizontocide Rapidly control fever eliminate circulating parasite Effective Chloroquine resistant plasmodium MOA- Inhibits heme polymerization
- Forms toxic complexes with free heme Oral absorbed Highly protein bound Extensive
tissues distribution
ADRs Nauses Vomiting Diarrhoea Neuropsychiatric Arrythmias Haematological Hepatic toxicity
Dose1250 mg 750 mg 500mg 12 hrly
25
Derived from bark of cinchona tree
Effective blood schizonticidal
Gametocidal P vivax
Chloroquine resistant MDR FP MOA same as of chloroquine Oral absorption rapid amp complete Bound to α1 acid
glycoprotein Metabolized by CYP3A4 Excreted in urine t12 10-12 hrs
Quinine
26
QuinineADRs Cinchonism tinnitusdysphoria headache
Nausea vomiting dizziness flushing amp visual
disturbances
GIT nausea vomiting diarrhoeaabdominal pain Hypoglycemia CVS hypotension dysrhythmias VT fibrillation Hemolysis (G6PD deficiency) Blackwater fever hemolysis hemoglobinemia
hemoglobinuria Dose
ndash Quinine 600 mg 8 hrly
27
Pyrimethamine
Erythrocytic schizontocide
Resistance develops rapidly if used alone
MOA DHFRase inhibitor Oral absorption good slow Concentrated liver spleen kidneys Metabolized liver Excreted renal amp t12 4 days ADRs Nausea Rashes Folate deficiency Dose sulphadoxine 1500 mg
+
pyrimethamine 75 mg
28
Proguanil
Erythrocyte schizontocide
Cyclic triazine metabolite cycloguanil
MOA DHFRase Inhibitor
Slowly adequately absorbed Partly metabolized
Excreted in urine amp t12 is 20 hrs
ADRs Vomiting Abdominal pain Haematuria
Dose 200-300 mgday for 4wks
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
21
CHLOROQUINE
Erythrocytic schizontocide all plasmodial species
Gametocytic not Pfalciparum
No effect on sporozoites hypnozoites
MOA Concentrates in parasite food vacuoles uarrpH
Disruption of polymerization of Heme to Hemozoin
Heme damage plasmodium membrane
Well absorbed oral IM SC 60 PPB
Metabolized by liver t12 3-10 days
Excreted by kidney
22
ADRsNausea vomiting Blurring of
vision Headache Confusion seizures
ndash Hemolysis G6PD individuals Impaired hearing
ndash Hypotension ECG changes
ndash High dose Irreversible ototoxicity retinopathy
myopathy Peripheral neuropathy Chloroquine sulphate (Tab)136 mg = 100 mg Base Chloroquine phosphate (Tab) 250mg=150mg Base
Dose 600 mg stat 300 mg after 8 hours and then
for next two days
Chloroquine
23
Faster acting MOA amp resistance similar to chloroquine ADRs
ndash Toxic hepatitisndash Agranulocytosis
Dose 25-35 mgkg over 3 days Chloroquine resistant combine Artesunate
Amodiaquine
24
Mefloquine Erythrocytic schizontocide Rapidly control fever eliminate circulating parasite Effective Chloroquine resistant plasmodium MOA- Inhibits heme polymerization
- Forms toxic complexes with free heme Oral absorbed Highly protein bound Extensive
tissues distribution
ADRs Nauses Vomiting Diarrhoea Neuropsychiatric Arrythmias Haematological Hepatic toxicity
Dose1250 mg 750 mg 500mg 12 hrly
25
Derived from bark of cinchona tree
Effective blood schizonticidal
Gametocidal P vivax
Chloroquine resistant MDR FP MOA same as of chloroquine Oral absorption rapid amp complete Bound to α1 acid
glycoprotein Metabolized by CYP3A4 Excreted in urine t12 10-12 hrs
Quinine
26
QuinineADRs Cinchonism tinnitusdysphoria headache
Nausea vomiting dizziness flushing amp visual
disturbances
GIT nausea vomiting diarrhoeaabdominal pain Hypoglycemia CVS hypotension dysrhythmias VT fibrillation Hemolysis (G6PD deficiency) Blackwater fever hemolysis hemoglobinemia
hemoglobinuria Dose
ndash Quinine 600 mg 8 hrly
27
Pyrimethamine
Erythrocytic schizontocide
Resistance develops rapidly if used alone
MOA DHFRase inhibitor Oral absorption good slow Concentrated liver spleen kidneys Metabolized liver Excreted renal amp t12 4 days ADRs Nausea Rashes Folate deficiency Dose sulphadoxine 1500 mg
+
pyrimethamine 75 mg
28
Proguanil
Erythrocyte schizontocide
Cyclic triazine metabolite cycloguanil
MOA DHFRase Inhibitor
Slowly adequately absorbed Partly metabolized
Excreted in urine amp t12 is 20 hrs
ADRs Vomiting Abdominal pain Haematuria
Dose 200-300 mgday for 4wks
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
22
ADRsNausea vomiting Blurring of
vision Headache Confusion seizures
ndash Hemolysis G6PD individuals Impaired hearing
ndash Hypotension ECG changes
ndash High dose Irreversible ototoxicity retinopathy
myopathy Peripheral neuropathy Chloroquine sulphate (Tab)136 mg = 100 mg Base Chloroquine phosphate (Tab) 250mg=150mg Base
Dose 600 mg stat 300 mg after 8 hours and then
for next two days
Chloroquine
23
Faster acting MOA amp resistance similar to chloroquine ADRs
ndash Toxic hepatitisndash Agranulocytosis
Dose 25-35 mgkg over 3 days Chloroquine resistant combine Artesunate
Amodiaquine
24
Mefloquine Erythrocytic schizontocide Rapidly control fever eliminate circulating parasite Effective Chloroquine resistant plasmodium MOA- Inhibits heme polymerization
- Forms toxic complexes with free heme Oral absorbed Highly protein bound Extensive
tissues distribution
ADRs Nauses Vomiting Diarrhoea Neuropsychiatric Arrythmias Haematological Hepatic toxicity
Dose1250 mg 750 mg 500mg 12 hrly
25
Derived from bark of cinchona tree
Effective blood schizonticidal
Gametocidal P vivax
Chloroquine resistant MDR FP MOA same as of chloroquine Oral absorption rapid amp complete Bound to α1 acid
glycoprotein Metabolized by CYP3A4 Excreted in urine t12 10-12 hrs
Quinine
26
QuinineADRs Cinchonism tinnitusdysphoria headache
Nausea vomiting dizziness flushing amp visual
disturbances
GIT nausea vomiting diarrhoeaabdominal pain Hypoglycemia CVS hypotension dysrhythmias VT fibrillation Hemolysis (G6PD deficiency) Blackwater fever hemolysis hemoglobinemia
hemoglobinuria Dose
ndash Quinine 600 mg 8 hrly
27
Pyrimethamine
Erythrocytic schizontocide
Resistance develops rapidly if used alone
MOA DHFRase inhibitor Oral absorption good slow Concentrated liver spleen kidneys Metabolized liver Excreted renal amp t12 4 days ADRs Nausea Rashes Folate deficiency Dose sulphadoxine 1500 mg
+
pyrimethamine 75 mg
28
Proguanil
Erythrocyte schizontocide
Cyclic triazine metabolite cycloguanil
MOA DHFRase Inhibitor
Slowly adequately absorbed Partly metabolized
Excreted in urine amp t12 is 20 hrs
ADRs Vomiting Abdominal pain Haematuria
Dose 200-300 mgday for 4wks
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
23
Faster acting MOA amp resistance similar to chloroquine ADRs
ndash Toxic hepatitisndash Agranulocytosis
Dose 25-35 mgkg over 3 days Chloroquine resistant combine Artesunate
Amodiaquine
24
Mefloquine Erythrocytic schizontocide Rapidly control fever eliminate circulating parasite Effective Chloroquine resistant plasmodium MOA- Inhibits heme polymerization
- Forms toxic complexes with free heme Oral absorbed Highly protein bound Extensive
tissues distribution
ADRs Nauses Vomiting Diarrhoea Neuropsychiatric Arrythmias Haematological Hepatic toxicity
Dose1250 mg 750 mg 500mg 12 hrly
25
Derived from bark of cinchona tree
Effective blood schizonticidal
Gametocidal P vivax
Chloroquine resistant MDR FP MOA same as of chloroquine Oral absorption rapid amp complete Bound to α1 acid
glycoprotein Metabolized by CYP3A4 Excreted in urine t12 10-12 hrs
Quinine
26
QuinineADRs Cinchonism tinnitusdysphoria headache
Nausea vomiting dizziness flushing amp visual
disturbances
GIT nausea vomiting diarrhoeaabdominal pain Hypoglycemia CVS hypotension dysrhythmias VT fibrillation Hemolysis (G6PD deficiency) Blackwater fever hemolysis hemoglobinemia
hemoglobinuria Dose
ndash Quinine 600 mg 8 hrly
27
Pyrimethamine
Erythrocytic schizontocide
Resistance develops rapidly if used alone
MOA DHFRase inhibitor Oral absorption good slow Concentrated liver spleen kidneys Metabolized liver Excreted renal amp t12 4 days ADRs Nausea Rashes Folate deficiency Dose sulphadoxine 1500 mg
+
pyrimethamine 75 mg
28
Proguanil
Erythrocyte schizontocide
Cyclic triazine metabolite cycloguanil
MOA DHFRase Inhibitor
Slowly adequately absorbed Partly metabolized
Excreted in urine amp t12 is 20 hrs
ADRs Vomiting Abdominal pain Haematuria
Dose 200-300 mgday for 4wks
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
24
Mefloquine Erythrocytic schizontocide Rapidly control fever eliminate circulating parasite Effective Chloroquine resistant plasmodium MOA- Inhibits heme polymerization
- Forms toxic complexes with free heme Oral absorbed Highly protein bound Extensive
tissues distribution
ADRs Nauses Vomiting Diarrhoea Neuropsychiatric Arrythmias Haematological Hepatic toxicity
Dose1250 mg 750 mg 500mg 12 hrly
25
Derived from bark of cinchona tree
Effective blood schizonticidal
Gametocidal P vivax
Chloroquine resistant MDR FP MOA same as of chloroquine Oral absorption rapid amp complete Bound to α1 acid
glycoprotein Metabolized by CYP3A4 Excreted in urine t12 10-12 hrs
Quinine
26
QuinineADRs Cinchonism tinnitusdysphoria headache
Nausea vomiting dizziness flushing amp visual
disturbances
GIT nausea vomiting diarrhoeaabdominal pain Hypoglycemia CVS hypotension dysrhythmias VT fibrillation Hemolysis (G6PD deficiency) Blackwater fever hemolysis hemoglobinemia
hemoglobinuria Dose
ndash Quinine 600 mg 8 hrly
27
Pyrimethamine
Erythrocytic schizontocide
Resistance develops rapidly if used alone
MOA DHFRase inhibitor Oral absorption good slow Concentrated liver spleen kidneys Metabolized liver Excreted renal amp t12 4 days ADRs Nausea Rashes Folate deficiency Dose sulphadoxine 1500 mg
+
pyrimethamine 75 mg
28
Proguanil
Erythrocyte schizontocide
Cyclic triazine metabolite cycloguanil
MOA DHFRase Inhibitor
Slowly adequately absorbed Partly metabolized
Excreted in urine amp t12 is 20 hrs
ADRs Vomiting Abdominal pain Haematuria
Dose 200-300 mgday for 4wks
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
25
Derived from bark of cinchona tree
Effective blood schizonticidal
Gametocidal P vivax
Chloroquine resistant MDR FP MOA same as of chloroquine Oral absorption rapid amp complete Bound to α1 acid
glycoprotein Metabolized by CYP3A4 Excreted in urine t12 10-12 hrs
Quinine
26
QuinineADRs Cinchonism tinnitusdysphoria headache
Nausea vomiting dizziness flushing amp visual
disturbances
GIT nausea vomiting diarrhoeaabdominal pain Hypoglycemia CVS hypotension dysrhythmias VT fibrillation Hemolysis (G6PD deficiency) Blackwater fever hemolysis hemoglobinemia
hemoglobinuria Dose
ndash Quinine 600 mg 8 hrly
27
Pyrimethamine
Erythrocytic schizontocide
Resistance develops rapidly if used alone
MOA DHFRase inhibitor Oral absorption good slow Concentrated liver spleen kidneys Metabolized liver Excreted renal amp t12 4 days ADRs Nausea Rashes Folate deficiency Dose sulphadoxine 1500 mg
+
pyrimethamine 75 mg
28
Proguanil
Erythrocyte schizontocide
Cyclic triazine metabolite cycloguanil
MOA DHFRase Inhibitor
Slowly adequately absorbed Partly metabolized
Excreted in urine amp t12 is 20 hrs
ADRs Vomiting Abdominal pain Haematuria
Dose 200-300 mgday for 4wks
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
26
QuinineADRs Cinchonism tinnitusdysphoria headache
Nausea vomiting dizziness flushing amp visual
disturbances
GIT nausea vomiting diarrhoeaabdominal pain Hypoglycemia CVS hypotension dysrhythmias VT fibrillation Hemolysis (G6PD deficiency) Blackwater fever hemolysis hemoglobinemia
hemoglobinuria Dose
ndash Quinine 600 mg 8 hrly
27
Pyrimethamine
Erythrocytic schizontocide
Resistance develops rapidly if used alone
MOA DHFRase inhibitor Oral absorption good slow Concentrated liver spleen kidneys Metabolized liver Excreted renal amp t12 4 days ADRs Nausea Rashes Folate deficiency Dose sulphadoxine 1500 mg
+
pyrimethamine 75 mg
28
Proguanil
Erythrocyte schizontocide
Cyclic triazine metabolite cycloguanil
MOA DHFRase Inhibitor
Slowly adequately absorbed Partly metabolized
Excreted in urine amp t12 is 20 hrs
ADRs Vomiting Abdominal pain Haematuria
Dose 200-300 mgday for 4wks
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
27
Pyrimethamine
Erythrocytic schizontocide
Resistance develops rapidly if used alone
MOA DHFRase inhibitor Oral absorption good slow Concentrated liver spleen kidneys Metabolized liver Excreted renal amp t12 4 days ADRs Nausea Rashes Folate deficiency Dose sulphadoxine 1500 mg
+
pyrimethamine 75 mg
28
Proguanil
Erythrocyte schizontocide
Cyclic triazine metabolite cycloguanil
MOA DHFRase Inhibitor
Slowly adequately absorbed Partly metabolized
Excreted in urine amp t12 is 20 hrs
ADRs Vomiting Abdominal pain Haematuria
Dose 200-300 mgday for 4wks
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
28
Proguanil
Erythrocyte schizontocide
Cyclic triazine metabolite cycloguanil
MOA DHFRase Inhibitor
Slowly adequately absorbed Partly metabolized
Excreted in urine amp t12 is 20 hrs
ADRs Vomiting Abdominal pain Haematuria
Dose 200-300 mgday for 4wks
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
29
Radical cure of relapsing cases
Preerythrocytic Gametocytes amp hypnozoites
MOA - Interferes electron transport of parasite
Readily absorbed orally oxidized in liver
t12 3-6 hrs excreted in urine
ADRs Abdominal pain GI upset Hemolysis in G6PD
deficiency methaemoglobinaemia
Dose 15 mgday for 2wks
Primaquine
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
30
Sulphonamides
Blood schizonticides
Given in combination
MOA inhibit folate synthetase
Oral Rapidly absorbed Metabolized by acetylation in
liver Excreted by kidneys
Dose (Chloroquine resistant Pfalciparum)
sulphadoxine 1500 mg + pyrimethamine 75 mg
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
31
Tetracyclines
Week erythrocytic schizonticidal
Use with Quinine SP
Multidrug resistant cases
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
32
FOSMIDOMYCIN Potent inhibitor of 1-deoxy-D-xylulose 5-phosphate
reductoisomerase an essential enzyme of the nonmevalonate pathway
fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P falciparum
In contrast isoprenoids are derived from an alternative pathway known as the mevalonate pathway in mammals
Hence fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of isoprenoids which are essential for cellular function
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
33
Artemether Artesunate Arteether
Blood schizonticidal
Duration of action short recrudescence rate
high
Combine with a long acting drug
Artemisinin derivatives
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
34
MOA Endoperoxide bridge interact haeme of
parasite Release highly reactive free radicals Damage membrane protein Inhibits protein synthesis Lysis of parasite
Artemisinin derivatives
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
35
PKs Artesunate Artemether Arteether
solubility Water soluble Lipid soluble Lipid soluble
Route oral IM IV oral IM IM
Metabolite DHA DHA DHA
t12 2-4 hrs 3-10 hrs 23 hrs
Dose24 mgkg iv 12 amp 24 hrly then once a dayFor 3 days
32 mgkg im on admission 16 mgkgday for 3 days
150 mg daily im for 3 days
Artemisinin derivatives
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
36
ADRs
Nausea Vomiting
Abnormal bleeding
ST segment changes QT prolongation
Artemisinin derivatives
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
37
Artesunate-mefloquinendash 100 mg BD for 3 days + 750 mg 1st day 500 mg
2nd day Aretemether-lumefantrine
ndash 80 mg + 480 mg BD for 3 days Artesunate-sulfadoxine+pyrimethamine
ndash 100 mg BD for 3 day + 1500 mg amp 75 mg single dose
ACT regimens for uncomplicated falciparum malaria
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
38
Halofantrine
Blood schizontocide Effective chloroquine amp SP resistant PKs
ndash Oral absorption lowndash t 12 of active metabolite 3 day
ADRsndash Cardiovascular toxicity
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
39
Atovaquone Erythrocytic schizontocide MOA Mitochondrial electron transport
ndash Interferes ATP production
PKs Lipid soluble absorption slowndash 99 bound plasma proteinsndash Enterohepatic circulation
t12 15-3 days Dose Atovaquone 250 mg amp Proguanil 100mg for 3
days ADRs
ndash Vomiting diarrhoeandash Maculopapular rash
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
Chemoprophylaxis Indications
Special risk groups
1 Non-immune travellers
2 Non-immune persons living in endemic areas
3 Pregnancy- After 1st trimester (Chloroquine Proguanil Quinine)
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
ChemoprophylaxisType Drug Before
EnteringAfterLeaving
ChloroquineSensitive
Chloroquinepo4 300mg once a week
1-2weeks 4 weeksLast dose 25mgkg over 3 days alongwith Primaquine 15 mgday x 14 days
Resistant strains
Mefloquine 250mgweek
1-2 weeks 4 weeks
Doxycycline 100mg od
1 day before 4 weeks
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
Prophylaxis in Pregnancy Travellers
1 Avoid travel[Pregnant or likely to become pregnant]
2 Chlo or Proguanil+FA
3 Or Meflo in II III trimester
4 Doxy Atova Prima C I5 Mosquito net
Intermittent Preventive Treatment [IPT]
6 Pregnant in endemic areas
7 Pyr+Sulfa
8 2-3 doses
9 I dose after quickening-II trimester
10 Further at 1 month intervals
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
43
Sulfadoxine-pyrimethamine (SP) effective
drug for IPT
SP
ndash 500 mg of sulfadoxine
ndash 25 mg of pyrimethamine
Malaria During Pregnancy
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
Treatment-Chloroquine sensitivePV
Chloroquine po4 1 Tab=250mg salt or 150mg base
Clinical cure- 0h - 4Tab stat
6h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs
Radical cure Primaquine 15mgd X 14 days Primaquine CI in G6PD def
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
Treatment-Chloroquine ResistantPV[Rare] Quinine 600mg 8th hrly X 7 days + Doxy 100mg daily X 7 days + Primaquine 15 mg x 14 days
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
Treatment-ChloroquineSensitiveFP
Chloroquine Phoshphate [250mg] = 150mg Base
0h - 4Tab stat
8h - 2 Tabs
24h - 2 Tabs
48h - 2 Tabs + Primaquine 45 mg single dose[gametocidal] OR SulfadoxinePyrrimethamine 3 Tab +
Primaquine[Chlo not tolerated]
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
Treatment-Chloroquine ResistantFP1 Artesunate 100mg BDx3days +
SulfadoxinePyrimethamine 150075 mg (3 tab single dose)
OR Mefloquine 750mg on 2nd day-500mg on 3rd day
2 Artemether 80mg + Lumefantrine 480mg BD x 3 days
3 Quinine 600mg 8th hrly x 7 days + Doxycycline 100mg daily x 7 days
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
Severe malaria Cerebral malaria Severe anemia Renal failure Pulmonary edema Shock Metabolic acidosis Hemoglobinuria jaundice Hyperpyrexia Hyperparasitemia
The single most important step in the management of severe malaria is IMMEDIATE INITIATION OF APPROPRIATE PARENTERAL TREATMENT
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
Severe and complicated FPMalaria Artesunate 24mgKg iv or im raquo 12 hrs raquo 24 hrs raquo
OD x 7days [Change to oral ACTx3days if possible] Or Artemether 32mgKgim on 1st day and then
16mgKg x 7days [change to oral ACTx3days if possible ]
Or Arteether Same as above But 4 days Or Quinine diHCL20mgKg in 10mlKg of 5 dextrose
infused 4hrs raquo 10mgKg for 4hrs every 8hrs raquo Oral quinine10mgkg tds x7days
+ doxy 100mg od oral or 3day oral ACT or pyrimethamineSulfadoxine
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
51
PREVENTION OF RESISTANCE Selection of drugs - Use conventional drugs first in
uncomplicated cases Greater the exposure higher will be the emergence of resistance
Avoid drugs with longer half-life if possible Avoid basic antimalarials for non-malarial indications
(eg Chloroquine for rheumatoid arthritis in a malarial endemic area)
Ensure compliance Monitoring for resistance and early treatment of these
cases to prevent their spread Clear policy of using newer antimalarials Use of combinations to inhibit emergence of
resistance
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
Malaria Vaccine
Reduce severity and complications of malaria Tried in children less than 5yrs in Africa Reduces mortality and morbidity RTSSAS01 Phase III Potential targets of the vaccine
ndash pre-erythrocyticndash erythrocyticndash merozoitendash gametocyte
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
53
Newer regimens under development
1 Dihydroartemisinin-Piperaquinendash 120 mg + 960 mg daily for 3 days
2 Artesunate-amodiaquinendash 200 mg + 600 mg daily for 3 days
3 Astesunate-pyronaridinendash 200 mg + 600 mg daily for 3 days
4 Arterolane (RBx 11160)-piperaquine
5 Artesunate-chlorproguanil + Dapsone
6 Fosmidomycin + Clindamycin
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
54
SUMMARY Drug resistant malaria is a serious problem
worldwide Pfalciparum should be treated with artemisinin
derivatives
Chemoprophylaxis should be followed wherever appropriate
Use of Personal protection measures should be encouraged for pregnant women and other vulnerable groups eg travelers
For Severe Malaria cases Parenteral therapy should be given
Drug combinations should be used
55
THANK YOU
55
THANK YOU
