Date post: | 30-Jul-2015 |
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Emetics and antiemetics
Emesis (vomiting)
• Act of forceful expulsion of gastric contents through the mouth• Often preceded by nausea
Emesis
• Rational (valuable) reflex• prevention of ingestion of noxious substances (sight, smell,
taste, texture)• local gut reflexes stimulate vomiting e.g. toxins
• Irrational reflexes• labyrinth• pregnancy
Neurotransmitters Involved
• Histamine via H1 receptors
• Serotonin via 5HT3 receptors
• Acetylcholine via M receptors
• Dopamine via D2 receptors
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Emetic Centre
CTZHormonesAzotaemiaDiabetes
VestibularSightsSmellTaste
Vomiting Gut
OpioidsChemotherapyAnaesthetics
BBB
HypotensionHypoxaemia
Vomiting Centre (medulla)
Cerebral cortex
Anticipatory emesisSmellSight
Thought
Vestibular nucleiMotion
sickness
Pharynx & GIT
Chemo & radio therapy Gastroenteritis
Chemoreceptor Trigger Zone
(CTZ)(Outside BBB)
Cancer chemotherapyOpioids
Muscarinic, 5 HT3 & Histaminic H1
5 HT3 receptors
Dopamine D2
5 HT3,,
Opioid Receptors
Muscarinic Histaminic H1
Pathophysiology of Emesis
Emetics
They are required when an undesirable substance has been ingested
Emetic Drugs - Uses
• Acute cases of poisoning (except in corrosive substances poisoning or if patient is not fully conscious)
• Alcoholic intoxication• Removal of foreign bodies from the oesophagus• Certain cases of paroxysmal tachycardia
Emetic Drugs - Contraindications
• Hernias• Aneurysm• Severe heart diseases• Peptic ulcer• Pulmonary TB• Prolapse of rectum or uterus• Threatened abortion• Weak / debilitated persons
Emetic Drugs
• Centrally acting: Apomorphine • directly stimulate the CTZ or VC
• Reflexly acting: Ipecacuanha • stimulate the VC by irritating gastric & duodenal mucosa which
stimulate afferent fibres of vagus nerve
• Locally acting: Aluminum, Sodium Chloride (Concentrated Solution)
• Other Drugs as Adverse Effect: Morphine, Digitalis, Emetine, Aspirin, Quinine & Anticancer drugs
Emetic drugs
• Apomorphine
• Ipecacuanha
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Apomorphine
• Semi synthetic derivative of morphine• Given IM or SC, act centrally; local effect on GIT not required. • Dose is 6 mg (2-8mg)• Induces vomiting in 5 -10 min• CNS depressant contraindicated in respiratory depression•
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Ipecacuanha
• Contains two alkaloids- emetine & cephaeline• Used as syrup ipecac.• Produces effect in 15 min.• Acts by irritating gastric mucosa & through CTZ centre.• Dose = 5ml in infants
= 10-15ml in children= 15-20ml in adults
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Contraindications• Corrosive poisoning
• Kerosene poisoning
• Unconscious patients
• Morphine poisoning
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Anti-emetics
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Introduction - Anti-emetics
• Two centres: vomiting centre (VC) and chemoreceptor trigger zone (CTZ)
• Both near the floor of the fourth ventricle, close to the vital centres
• VC is within the blood brain barrier (BBB)• CTZ outside in the area postrema• They are connected together
ANTIEMETIC DRUGS
A group of drugs which are used to control nausea and vomiting
Provide symptomatic relief
Removal of causative factor to have ultimate relief
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Vomiting Centre (medulla)
Cerebral cortex
Anticipatory emesisSmellSight
Thought
Vestibular nucleiMotion
sickness
Pharynx & GIT
Chemo & radio therapy Gastroenteritis
Chemoreceptor Trigger Zone
(CTZ)(Outside BBB)
Cancer chemotherapyOpioids
Muscarinic, 5 HT3 & Histaminic H1
5 HT3 receptors
Dopamine D2
5 HT3,
Opioid Receptors
Muscarinic Histaminic H1
Pathophysiology of Emesis
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Classification - Antiemetic drugs
1. H1antihistamines Meclizine, Cinnarizine, Cyclizine,
Dimenhydrinate & Diphenhydramine.
2. Muscarinic Antagonist
Hyoscine (Scopolamine).
3. Selective 5-HT3 Antagonists
Ondansetron, Granisetron, Palonosetron & Dolasetron.
4. D2 Antagonists a. Substituted Benzamides
Metoclopramide, Trimethobenzamide b. Butyrophenones
Domperidone , Droperidol c. Phenothiazines
Prochlorperazine, Promethazine & Thiethylperazine.5. Cannabinoids
Dronabinol , Nabilone6. Glucocorticoids
Dexamethasone, Methylprednisolone7. Benzodiazepines
Diazepam , Lorazepam8. Neurokinin-I Antagonist
Aprepitant (oral formulation), Fosaprepitant (IV formulation)
D2 Antagonists
a. Substituted Benzamides Metoclopramide, Trimethobenzamide
b. Butyrophenones Domperidone , Droperidol
c. Phenothiazines Prochlorperazine, Promethazine & Thiethylperazine.
Metoclopramide
Chemistry: Substituted Benzamide
MOA: Dopamine D2 receptors antagonist
It is potent Antiemetic & Prokinetic agent
As Antiemetic • It has potent Antiemetic & antinausea effect.
• Blocks D2 receptors in CTZ of the medulla (area postrema)
As Prokinetic agent • It can selectively stimulate gut motor function.
• Blocks D2 receptor in GIT & blocks the normal inhibitory effect of Dopamine on cholinergic smooth muscle stimulation--- ↑ motility.
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The Uses - Metroclopramide
Potent antiemetic controls / reduces vomiting due to • Uremia • Radiation • Viral gastro enteritis, hepatic-biliary disease • Anticancer drugs • Migraine• Post operatively & pre-operatively
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Metroclopramide…
Pharmacokinetics• Rapidly absorbed from GIT after oral administration.• Undergoes a high degree first pass metabolism.• It is excreted in the urine as free and as metabolites.• It is also excreted in the breast milk.• DOSE: 10-20mg orally or IV every 6 hrs
Adverse Effects - Metroclopramide
• Extrapyramidal reactions with facial and skeletal muscle spasms- Restlessness, Dystonias , Parkinsonian symptoms.
-----More common in young and very old. Usually occur shortly after staring treatment and subside with in 24 hours of stopping the drug.• Bowel upsets, Diarrhea• Drowsiness and fatigue, dizziness, restlessness and anxiety.• Galactorrhoea, Gynecomastia, impotence and menstrual
disorders – due to increased prolactin levels
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Trimethobenzamide
Substituted Benzamide
Antiemetic like Metoclopramide.
D2 Antagonist & mild anti- histaminic activity
DOSE: 250mg orally, 200mg rectally, 200mg IM
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Phenothiazines
Phenothiazines
Prochlorperazine, Promethazine & Thiethylperazine
Phenothiazines are antipsychotics with potent antiemetic property due to D2 antagonism and anti-maucarinic properties
Sedative property due to anti-histaminic property
Mainly used as anti-emetic in severe N& V
Main A/E: EPS , sedation , postural hypotension
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Butyrophenones
Antipsychotic drugs , D2 antagonists
DroperidolCentral D2 antagonist
Main A/E: EPS , postural hypotension
QT prolongation may occur
Domperidone • Does not cross BBB. Only blocks D2 in CTZ where BBB is leaky.
• May be used in N&V due to Levodopa, without affecting its efficacy.
• No EPS. • Used as antiemetic , prokinetic agent & for post partum lactation
stimulation.
Selective 5-HT3 Antagonists Ondansetron, Granisetron , Dolasetron & Palonosetron
MOA Act as anti-emetic by Selectively blocking central 5HT3 receptors in Vomiting center & CTZ & Mainly by blocking Periphery 5HT3 receptors on intestinal vagal and spinal afferent fibers
Antiemetic action is restricted to emesis caused by vagal stimulation (e..g post operative) & chemotherapyPalonosetron: newer with greater affinity for 5-HT3 receptor & comparatively longer half life
No effect on Dopamine / muscarinic receptors
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Ph. K - Selective 5-HT3 Antagonists
• High first pass metabolism
• t1/2 : 4-9 hrs (Ondansetron, Granisetron & Dolasetron)
40 hrs (Palonosetron)• Given once or twice daily – orally or intravenously• Excreted by liver & kidney• No dose reduction in renal insufficiency but needed in
hepatic insufficiency (Ondansetron)
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The Uses - Selective 5-HT3 Antagonists
• Chemotherapy- Induced Nausea & vomiting• Primary Agents - prevention of acute chemotherapy induced
Nausea & vomitingEffective alone in most of the cases. Efficacy is enhanced
in combination. Can be given I/V 1/2 hr before chemotherapy• To prevent Delayed Nausea & vomiting occurring after 24 hrs
of Cancer chemotherapy in combination with Dexamethasone & NK1 receptor
antagonist.• To prevent & treat post operative & post radiation
Nausea & vomiting
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A/Es - Selective 5-HT3 Antagonists
• Excellent safety profile• Headache, Dizziness & constipation• All three drugs cause prolongation of QT interval, but
more pronounced with dolasetron.
DIs Hepatic clearance may decrease by enzyme inhibitors
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H1antihistamines & Muscarinic Antagonists
H1antihistamines Meclizine, Cinnarizine, Cyclizine & Diphenhydramine
& its salt Dimenhydrinate. • They have anticholinergic & H1 antagonist sedating properties
(1st generation).• They produce specific depression of conduction in
vestibulocerebellar pathway.
MuscarinicAntagonistHyoscine (Scopolamine).
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H1antihistamines & Muscarinic Antagonists…
Theraputic Uses• Vestibular system is important in motion sickness via
cranial nerve VIII - rich in Cholinergic M1 & Histamine H1receptors
• Most effective drugs for motion sickness
• Effective for nausea & vomiting associated with motion sickness.
• Vestibular disorders ( Meniere’s disease)
• (hyoscine) – used as transdermal patch for motion sickness• Meclozine is long acting so useful in sea sickness• Cinnarizine also has antivertigo effect. Act by inhibiting
influx of calcium to vestibular sensory cells from endolymph
Cannabinoids (Dronabinol , Nabilone)
Dronabinol
Tetrahydrocannabinol (THC) main psychoactive chemical in marijuana
Pharmacokinetics: complete absorption on oral administration, significant 1st pass effect, metabolites excreted slowly over days to weeks in faeces & urine
• MOA: Act as antiemetic & appetite stimulant in addition to psychoactive action. MOA not clear.
• Cancer chemotherapy induced Nausea & vomiting with Phenothiazines – synergistic effect but AEs are added – not used as better drugs are available
• Nabilone• closely related THC analog
Glucocorticoids Dexamethasone , Methylprednisolone
Antiemetic MOA not clear
Enhance action of 5HT3 antagonists in Cancer chemotherapy induced Nausea & vomiting
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Benzodiazepines
Diazepam, Lorazepam
• Used prior to Cancer chemotherapy to reduce anticipatory vomiting
• Vomiting caused by anxiety
Neurokinin-1 (NK1 )Antagonists Aprepitant, Fosaprepitant
Given orally BA = 65% , Crosses BBB.t ½ : 11 hrs, Metabolized by hepatic CYP3A4.
MOAAct as Antiemetic: Selectively block NK1 receptor in area postrema. No effect on Serotonin , Dopamine or Corticoid receptors.
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Aprepitant
• Non peptide, selective, Neurokinin type 1 (NK 1) receptors antagonist
• Block substance P from binding to NK1 receptor• Broader spectrum and activity in delayed emesis (In
Preclinical studies)• Augment the antiemetic activity of 5HT3 receptor
antagonists and dexamethasone• Inhibit both acute and delayed CINV
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Neurokinin-1 (NK1 )Antagonists
Uses
Used in combination with 5HT3 antagonists & Corticosteroids for prevention of acute & chronic nausea and vomiting from Cancer chemotherapy
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Neurokinin-1 (NK1 )Antagonists
A/Es • Fatigue, dizziness & diarrhoea. • Enzyme inhibition
• Metabolized by CYP3A4 & may inhibit metabolism of many anticancer drugs (Docetaxel, Paclitaxel, Etoposide, Vinblastine, Imatinib) ---- ↑ levels --- toxicity.
• Metabolism of Aprepitant may be inhibited by Ketoconazole, Ciprofloxacin, Clarithromycin, Nafazodone, Ritonavir, Nelfinavir, Verapamil & Quinidine)
• Aprepitant ↓ INR in patients taking warfarin.
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Therapeutic Uses of Anti-emetics
• Motion sickness: Hyoscine• Vestibular disorders( Menieres, disease): Cinnerazine• Vomiting due to Uremia, Radiation, Viral gastro enteritis,
Liver disease, Migraine, Prochlorperazine , Metroclopramide
• Vomiting due to pregnancy ( hyperemesis gravidarum), Meclizine with vit. B6 (Navidoxine)
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• Vomiting due to Cytotoxic Anticancer drugs: 5HT3 Antagonists Metroclopramide, Cannabinoids, corticosteroids , Aprepitant
• Anticipatory Vomiting due to Cytotoxic Anticancer drugs. Benzodiazepines (Diazepam)
• Post Operative Vomiting: Metoclopramide , Prochlorperazine , Dimenhydrinate, 5HT3 Antagonists (Ondensetron)
Manikandan 47Thank You
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