PP-Anti-emetic Agents

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Drugs used in treatment of Nausea and vomiting

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ANTIEMETICS:

ANTIEMETICS DRPATKI

VOMITING:

VOMITING The act of vomiting and the sensation of nausea that accompanies it are protective reflexes that serve to rid the stomach and intestine of toxic substances and prevent their further ingestion LOYA, KANKER MABUK

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Vomiting Reflex

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Manikandan 5 Vomiting Centre (medulla) Cerebral cortex Anticipatory emesis Smell Sight Thought Vestibular nuclei Motion sickness Pharynx & GIT Chemo & radio therapy Gastroenteritis Chemoreceptor Trigger Zone (CTZ) (Outside BBB) Cancer chemotherapy Opioids Muscarinic, 5 HT 3 & Histaminic H 1 5 HT 3 receptors Dopamine D 2 5 HT 3, ,Opioid Receptors Muscarinic Histaminic H 1 Pathophysiology of Emesis

Cerebral Centers Affecting Vomiting:

Cerebral Centers Affecting Vomiting

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Area Type of receptors Stimulus Chemoreceptor trigger zone (CTZ) Dopamine D2 5HT3 Opioid Cancer chemotherapy Opioids Vestibular nuclei Muscarinic Histamine H1 Motion sickness Pharynx and GIT 5HT3 Cancer chemotherapy Radio therapy Gastroenteritis Cerebral cortex Smell Sight Thought Anticipatory emesis

Various neurotransmitters involved:

Various neurotransmitters involved Histamine via H1 receptors Serotonin via 5HT3 receptors Acetylcholine via M receptors Dopamine via D2 receptors

EMETIC DRUGS:

EMETIC DRUGS Apomorphine (Acts on CTZ) Ipecacuanha ( Acts reflexly & on CTZ) Copper sulphate (not used)

APOMORPHINE:

APOMORPHINE Semi synthetic derivative of morphine Given i.m. or s.c. Dose is 6 mg Dose required is high so not given orally Induces vomiting in 5 min CNS depressant contraindicated in respiratory depression

IPECACUANHA:

IPECACUANHA Used as syrup ipecac. Produces effect in 15min. Acts by irritating gastric mucosa & also through CTZ center. Dose : 5ml in infants, 10-15ml in children, 15-20ml in adults

CONTRAINDICATIONS:

CONTRAINDICATIONS Corrosive poisoning CNS stimulant drug poisoning Kerosene poisoning Unconscious patients Morphine poisoning

ANTIEMETIC DRUGS - Classification:

ANTIEMETIC DRUGS - Classification Antimuscarinics Hyoscine-0.4 mg Dicyclomine-10-20 mg Antihistaminics Promethazine-25 mg, avomine, Diphenhydramine- Dimenhydrinate Cyclizine-10 mg Meclozine

ANTIEMETIC DRUGS - Classification:

ANTIEMETIC DRUGS - Classification Neuroleptics Chlorpromazine Prochlorperazine Haloperidol Prokinetic agents Metocloperamide Domperidone Cisapride Mosapride

ANTIEMETIC DRUGS - Classification:

ANTIEMETIC DRUGS - Classification 5HT3 receptor antagonist Ondansetrone Granisetrone Topisetrone Dolasetrone Adjuvant antiemetics Corticosteroids Cannabinoids Benzodiazepines

ANTICHOLINERGICS:

ANTICHOLINERGICS Act by blocking cholinergic link from vestibular apparatus to vomiting center Used in motion sickness Produces sedation Anticholinergic side effects

Properties of Individual Agents:

Properties of Individual Agents HYOSCINE Oral, IM, transdermal patch (0.2 -0.4 mg) Used for motion (travel) sickness Applied as transdermal patch DICYCLOMINE Used for morning sickness motion sickness

ANTIHISTAMINICS:

ANTIHISTAMINICS Used for motion & morning sickness Block the extrapyramidal side effects of metoclopramide Afford protection for 4-6hrs Given ½-1hr before journey Meclozine is longer acting so useful in sea sickness Cinnarizine also has antivertigo effect. Act by inhibiting influx of calcium to vestibular sensory cells from endolymph

NEUROLEPTICS:

NEUROLEPTICS Broad spectrum antiemetics Acts by blocking D2 receptor in CTZ Useful for - drug induced - disease induced - malignancy associated - radiation induced vomiting Avoided in morning sickness except hyperemesis gravidarum

NEUROLEPTICS:

NEUROLEPTICS SIDE EFFECTS :- Significant degree of sedation Acute muscle dystonia Extrapyramidal effects NOT EFFECTIVE FOR :- Motion sickness as vestibular pathway does not involve dopaminergic pathway Prochlorperazine :- labyrinthine suppressant (antivertigo & antiemetic actions)

INDICATIONS OF ANTIEMETICS:

INDICATIONS OF ANTIEMETICS 1- Chemotherapy-induced vomiting 2- Post irradiation vomiting 3- Postoperative vomiting 4- Vomiting of pregnancy 5- Motion sickness

5HT3 ANTAGONIST:

5HT3 ANTAGONIST Ondansetron Granisetron Dolasetron Palonosteron Romosetrone. EXAMPLES

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Drugs Available Ondansetron 32 mg / day Granisetron 10 m g / kg / day Dolasetron 1.8 mg / kg / day Indications Chemotherapy induced nausea & vomiting – given 30 min. before chemotherapy. Postoperative & postradiation nausea & vomiting

5HT3 ANTAGONIST :

5HT3 ANTAGONIST Blocks the depolarising action of Peripheral 5-HT3 receptor on intestinal vagal afferents Central 5-HT3 receptor in the vomiting center and chemoreceptor trigger zone MECHANISM

5HT3 ANTAGONIST:

5HT3 ANTAGONIST Cytotoxic drug induced radiation induced inflammation induced vomiting THERAPEUTIC USES

5HT3 ANTAGONIST:

5HT3 ANTAGONIST First pass metabolism No dose reduction in renal insufficiency but needed in hepatic insufficiency Well tolerated with minor side effects. 1- Headache and dizziness 2- Constipation or diarrhoea KINETICS SIDE EFFECTS

CORTICOSTEROID:

CORTICOSTEROID Mechanism of action : Possibly by suppressing peritumoral inflammation and prostaglandin production. Use : To enhance efficacy of 5HT3 receptor antagonists in the treatment of chemotherapy induced vomiting.

BENZODIAZEPINES:

BENZODIAZEPINES Benzodiazepines such as diazepam are used prior to the initiation of chemotherapy to reduce anticipatory vomiting or vomiting caused by anxiety

Cannabinoids: (Dronabinol):

Cannabinoids: (Dronabinol) Not known . Readily absorbed after oral administration Undergoes extensive first-pass metabolism with Limited systemic bioavailability after single doses Metabolites are excreted primarily via the biliary-fecal route MECHANISM KINETICS

Cannabinoids: (Dronabinol):

Cannabinoids: (Dronabinol) ADVERSE EFFECTS Euphoria or dysphoria, sedation and hallucinations Abrupt withdrawal leads to withdrawal syndrome (restless, insomnia and irritability) Autonomic effects (sympathetic) in the form of tachycardia, palpitation, conjunctival injection, and orthostatic hypotension. USE For the prevention of chemotherapy-induced nausea and vomiting

PROKINETIC DRUGS:

PROKINETIC DRUGS Increase gastric peristalsis Relaxes pylorus & first part of duodenum Hastens gastric emptying Lower esophageal sphincter tone is increased Gastro esophageal reflux is opposed

METOCLOPRAMIDE:

METOCLOPRAMIDE Acts through D 2 , 5HT 4 & 5HT 3 receptors D 2 antagonism leads to - increased gastric emptying - enhances lower esophageal tone Central D 2 antagonism leads to - extrapyramidal effects - hyperprolactinemia

METOCLOPRAMIDE:

METOCLOPRAMIDE 5HT 3 antagonism leads to - minor increase in Ach release * Central action appears only in large doses 5HT 4 antagonism leads to increased release of Ach leading to - gastric hurrying - Lower esophageal tonic effects

METOCLOPRAMIDE:

METOCLOPRAMIDE Rapidly absorbed orally Enter brain, crosses placenta, secreted in milk so leads to - Sedation - Dizziness - Parkinsonism - Galactorrhea - Gynecomastia Loose motions, dystonia & myoclonus in suckling infants

USES OF METOCLOPRAMIDE:

USES OF METOCLOPRAMIDE Antiemetic Gastrokinetic - in emergency - post vagotomy or diabetes associated gastric stasis - to facilitate duodenal intubation Dyspepsia Gastroesophageal reflux

DOMPERIDONE:

DOMPERIDONE D 2 antagonist with low antiemetic & prokinetic actions Poorly crosses BBB Rare extrapyramidal effects Hyperprolactinemia can occur Absorbed orally Low bioavailability due to first pass metabolism

CISAPRIDE:

CISAPRIDE Mainly has 5HT 4 activity Acts by releasing Ach Also has 5HT 3 antagonistic effects No effects on D 2 receptors; no extra pyramidal symptoms or hyper prolactinemia Restores & facilitate motility throughout GIT including colon therefore used for chronic constipation

CISAPRIDE:

CISAPRIDE Uses - non-ulcer dyspepsia - impaired gastric emptying - chronic constipation Serious drug interaction with CYP3A4 inhibitors (antifungals, macrolide antibiotics, etc.) leads to ventricular arrhythmias & death Withdrawn in USA and other countries MOSAPRIDE same as Cisapride but serious drug interaction not seen. Itopride .

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Now answer this question Which is a better antiemetic – Metoclopramide or Domperidone ? As CTZ is outside BBB both have antiemetic effects. But as metoclopramide crosses BBB it has adverse effects like extrapyramidal side effects. . Domperidone is well tolerated.

New combinations:

New combinations Ondansetrone and Dexa. Dexa, Diphenhydramne, Meoclopramide Lorazepam , Dexa, Metoclopramide.

Motionsickness:

Motionsickness Anticholinegic and Anihistaminics. Morning sickness- No drug is best. Hyperemesis gravidrum- Antihistaminics.

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Now answer this question A physician prescribed Tab.Ondansetron for prophylaxis of motion sickness. Even though ondansetron is a potent antiemetic it didn’t produce any effect in this patient. Can you explain why ?

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Explanation : Vestibular nuclei has only muscarinic and H 1 histaminic receptors.

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Even though both atropine and scopolamine are antimuscarinic, only scopolamine is used in the treatment of motion sickness. Why ? Generally transdermal patches are applied over the arm or chest. But scopolamine transdermal patch is applied behind the ear. Why?

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Thanks

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