Antimalarial Drugs

5/28/2018 Antimalarial Drugs

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ANTIMALARIAL DRUGS


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INTRODUCTION TO MALARIA

Malaria is one of the most common infectious diseases and an

enormous public health problem. There are five species of the plasmodium parasite that can

infect humans, These are :

Plasmodium falciparum (Most Fatal)

Plasmodium vivax (Mild Fatal)

Plasmodium ovale (Mild Fatal)

Plasmodium malariae (Mild Fatal) and

Plasmodium knowlesi: causes malaria in macaques ( a type

of monkey ) but can also infect humans.

Although all of the species may cause significant illness,

Plasmodium falciparum is responsible for the majority of

serious complications and deaths


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HISTORY

In India the National Malaria Eradication Programme (NMEP)

, started in 1958. There was a target for complete disappearance of this disease

upto 1960s. However to the development of insecticidal

resistance among mosquitoes and other factors, it was

conceding that eradication of malaria is not possible. Therefore NMEP has been renamed National Antimalarial

Programme.

In 2001 NAMP has reported > 2 million malaria cases, out of

which approx. 48% were due to Plasmodium falciparum with1003 confirmed deaths.

WHO estimates that actual number of malaria cases in India is

6 times more, i.e. 12-15 million.


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THE LIFE CYCLE OF MALARIAL

PARASITE


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PATHOGENESIS OF MALARIA


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CLASSIFICATION OF ANTIMALARIAL

DRUGS

1. 4-Aminoquinolines : Chloroquine,Amodiaquine2. Quinoline-methanol : Mefloquine.

3. Cinchona alkaloid : Quinine, Quinidine

4. Biguanides : Proguanil(Chloroguanide)

5. Diaminopyrimidines : Pyrimethamine6. 8-Aminoquinoline : Primaquine, Bulaquine

7. Sulfonamides and sulfone :Dapsone

8. Tetracyclines : Tetracycline, Doxycycline

9. Sesquiterpine lactones : Artesunate,

10. Naphthoquinone : Atovaquone

11. Mannich base : Pyronaridine


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ANTIMALARIAL DRUGS AND THEIR

SITE OF ACTIONS


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CHLOROQUINE

The 4-aminoquinoline chloroquine dates from the 1940s.

It is still widely used as a blood schizonticidal agent ,effective

against the erythrocytic forms of all four plasmodial species,

but it does not have any effect on sporozoites, hypnozoites or

gametocytes.


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COMPLICATIONS1. After oral doses for Acute attack of Malaria:

Pruritis (primarily in Africans)sometimes with Urticaria. Nausea, vomiting ,Abdominal Pain, Anorexia.

Blurring of vision

2. Chronic use of high daily doses in Rheumatoid diseases:-

Discoloration of nail beds and mucus membranes Bleaching of hair & Alopecia

Irreversible Ototoxicity , Retinopathymyopathy & PeripheralNeuropathy.

It can exacerbate dermatitis produced by gold /phenylbutazonetherapy.

3. Large I/M or Rapid I/V administration:

Excessive hypotension.

Respiratory & cardiac arrest.


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TREATMENT OF P. VI VAX

MALARIA: A FLOW CHART


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HERBAL ANTIMALARIAL DRUGS

CINCHONA

Synonym:Jesuitsbark,Peruvian barkBiological source : Cinchona calisaya, C.officinalis

Parts used : Barks

Chemical constituents:

Quinine,quinidine,cinchonine,cinchonidineMechanism of action:

Uses : Antimalarial action bitter stomachics & antipyretic


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ARTIMISIA

Synonym: Wormwood,quinghao.

Biological source : Artemisia annua.

Parts used : Unexpanded flower heads.

Chemical constituents:

Artimisinin, artemether, artether, artemisinic acid

Mechanism of action :

The endoperoxide bridge in its molecule appears to interactwith heme in the parasite.

Iron mediated cleavage of the bridge releases a highly reactivefree radical species that binds to membrane proteins,causes

lipid peroxidation,damages endoplasmic reticulum, inhibitsprotein synthesis & altemately lysis of parasite.

Uses :Artemisinin shows antimalarial effects by its rapid bloodschizonticidal activity.

Recent research : Artemisia is the most potent drug for

treating cerebral malaria


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SITE OF ACTION OF ARTIMISIA


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PLUMBAGO BENESIS

Biological source : Plumbago benesis.

Family : Euphorbiaceae.

Parts used : Flowers.

Chemical constituents: Plumbagin , 3,3plumbagin , 8,8

plumbagin.

Uses :Have in-vitro activities against P.falciparum andepimastigotes of T.cruzi & also show antileishmaniasis activity.


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TINOSPORA CARDIFOLIA (GILOYA)

Family-Menispermaceae .

Chemical constituents-The active glycoside is giloin .Uses-

It is used in jaundice,diabetes, gynacological & joint disorders.

Also having antiviral,antibacterial, & hypoglycemic activity.

The fine powder of dried stem prescribed (10gm BD for 5

days) for the treatment of malarial fever.


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ANTIMALARIAL DRUG DISCOVERY

PATH


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ANTIMALARIAL SCREENING

IN VITRO SCREENING TESTS

The test is carried in a 96 flat-bottomed wells in microtitre

plates.

Extract is dissolved or micronised in ethanol & a series of 6conc. prepared by 10 fold dilutions in RPMI 1640 medium.

The ethanol conc. of dilutions for testing is kept below 0.1%.

Aliquots(50l) of culture medium is then added to each well.

Human blood(50l) containing 1% parasitaemia is added toeach well


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Two series of controls are set up

1. with parasitised blood without addition of extract

2. with uninfected red blood cells. After incubation in 3% O2 ,4% CO2 & 93% N2gas phase for

18h at 37C,50l of G-[3 H] hypoxanthine is added to each

well.

Incubation continued at 37C for a further 18-24h.

RBCsare harvested with a Titertek Cell Harvester washing

out the wells with normal saline & filtering through glass fibre

membrane.


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Membranes are dried , placed in scintillation fluid &

incorporation of [3H] hypoxanthine determined by scintillation

counting.EVALUATION:

The % inhibition of incorporation & IC50 values are

determined.


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INVIVO SCREENING TESTS

1. PETERSTEST Male mice(swiss albino) weighing 202 g are maintained at

22C in batches of 5 & fed on std diet.

Blood from donor mouse with rising parasitaemia is diluted

in tissue culture medium so that each 0.2ml contains 107

infected red cells.

Each mouse receives 0.2ml i.v via the tail on day zero.

Extract is either suspended or dissolved by trituration or

sonication after the addition of 0.2% solution of Tween 80 or0.5 DMSO.


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Initial aq. conc. of doses ranging b/w 1 and 100 mg/kg are

administered daily from initial day of infection for 4

successive days either by s.c or oral routes. On the 5 th day samples are taken from tail blood &

stained with a suitable stain(eg.Giemsa)

EVALUATION:

Parasitised red cells are recorded as a percentage of total

ED50 values(i.e 50% suppression of parasites when

compared with controls)


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2.THE RANE TEST

The basis of the test is to compare the effect of a std inoculum

of P.berghei,which kills mice within 6 days with extension of

survival time to 12 days by a single dose of test compound.

An inoculum of 106 infected donor cells is given i.p on day 1 .

Test compound is suspended in arachis oil are given s.c at an

initial dose range of 640,320,160 & 80 mg/kg on day 4.

EVALUATION:

The minimum effective dose(MED) is obtained & compared

with the maximum tolerated dose(MTD) that produces no

more than one in five toxic deaths.


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CONCLUSION

..And


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REFERENCES

KD Tripathi. Essentials of medical pharmacology;5thEdn.

2004,Jaypee brothers publication, New Delhi :587-598.

Rang & Dale's, Pharmacology 7thedition.

N.S Parmar & Shiv prakash. ,Screening Methods in

Pharmacology

H.Gerhard Vogel ,Drug Discovery And Evaluation,

Pharmacology Bioassay


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