DRUGS ACTING ON GIT

Antiemetics &
Prokinetics Dr. Basant K. Mohanty

Unit of Pharmacology
UniKL RCMP

Objectives
To know the mechanism of vomiting including neurotransmitters involved To classify the various drugs that are used as antiemetics To know the mechanism of action, specific uses and common side effects of commonly used antiemetics and their use in specific conditions To know the mechanism of action, therapeutic uses and adverse effects of prokinetics To know the common emetics used in clinical practice and contraindications to their use

Nausea - A feeling of impending vomiting

Vomiting Forceful expulsion of gastric contents through

the mouth.
Nausea & Vomiting are protective reflexes and the major physiological function of emesis (vomiting) is to remove toxic or harmful substances from the body. Vomiting occurs in gastroenteritis, motion sickness,

surgery, pregnancy, poisoning, radiation & as an ADR of

several drugs mostly drugs used for cancer chemotherapy.

Central Neural Regulation of vomiting

Central Neural Regulation of vomiting: Vomiting centre coordinates motor mechanisms of vomiting. Receives impulses from: Chemoreceptor trigger zone (CTZ) Higher cortical centres Peripheral tissues (GIT)

Vestibular apparatus (motion sickness)

CTZ is stimulated by drugs and by chemicals & toxins produced in uremia, infections etc. Antiemetics act by blocking either histamine & or serotonin & or dopamine & or cholinergic receptors.

Opioids Chemothe. Anaesthecia

Chemothe. Radiothe.

Motion sickness

Neurologic pathways involved in nausea & vomiting

Classification of Anti-emetic drugs

Class 5-HT3 R antagonists Antimuscarinics Anti-histamines Cannabinoids
Antacids

Drug Ondansetron, Granisetron Scopolamine (l-hyoscine) Cyclizine, Promethazine, Doxylamine Nabilone, Dronabinol
Magnesium hydroxide, aluminium hydroxide either alone or in combination Ranitinidine, famotidine etc.

Dopamine antagonists Metoclopramide, Domperidone

H2 receptor antagonis

Miscellaneous

Dexamethasone, Diazepam, antipsychotic (droperidol)

Site of action of Antiemetics

H1, M1, DA2 antagonists H1, M1, DA2 Nabilone antagonists, Nabilone

Benzodiazepines Benzodiazepines

5HT anta. 5HT anta.

Motion sickness Hyoscine

Antihistamines

Prokinetic Prokinetic agents agents

Mechanism of action of 5-HT3 antagonists

5 HT3 antagonists Ondansetron & Granisetron

Mechanism: Block serotonergic (5-HT3) receptors in the centre & periphery - gut. ADR: well tolerated but can cause headache, constipation & in some patients QT prolongation. Route: Oral, IV (slow injection or infusion)

Uses: For prevention & treatment of vomiting due to anticancer agents, radiation & postoperative vomiting.
Status: Most effective antiemetic in anticancer agent induced vomiting. Corticosteroids & diazepam enhance its activity.

Metoclopramide & Domperidone

Mechanism: Block DA2 receptors in CTZ

Cholinomimetic action - GI motility Rapid transit of

food through the upper GI tract

Route: Oral, im, iv

ADR: Hyperprolactinemia, Extra pyramidal syndrome

(EPS) only with metoclopramide. (Domperidone does

not cross BBB & hence, no EPS)

Mechanism of action of metoclopramide and domperidone

Metoclopramide & Domperidone ..

Uses: Anti-emetics (not for motion sickness) Gastro-esophageal reflux disorder (GERD) by prokinetic action they hasten gastric emptying & prevent aspiration of gastric contents into lungs. Hence, used in the preoperative preparation of patients for emergency general anaesthecia.

Hyoscine (scopolamine) Mechanism: Block muscarinic (M1) R in vestibular apparatus

ADR: drowsiness, dryness of mouth,

blurred vision & other atropine like side effects Uses: for prevention and treatment of motion sickness, sea sickness

etc.
Hyoscine transdermal patch placed behind the ear works for 3 days.

Antihistamines Cyclizine, promethazine etc.

Block H1 & M1 (atropine like action) receptors.

ADR & uses similar to hyoscine Nabilone & Dronabinol: Synthetic cannabinoids Mechanism: prevents stimulation of CTZ ADR: Mood changes, drowsiness, psychotic reactions,& drug dependence Uses: Reserved drug for anticancer drug induced

vomiting and radiation sickness

Antacids: Magnesium hydroxide &/or aluminium hydroxide Mechanism: from first to last gastric acid neutralization Uses: 15 to 30ml doses of single or multiple agents may provide relief from simple nausea and vomiting associated

with heart burn and gastroesophageal reflux Histamine ( H2 ) receptor antagonists: Ranitidine, famotidine etc. May be used in low doses to manage simple nausea and vomiting associated with heartburn or gastroesophageal reflux.

Corticosteroids: Dexamethasone.

Mechanism not known.

May inhibit prostaglandin synthesis. Uses: synergistic with other antiemetics in anticancer drug induced vomiting Diazepam, Lorazepam: May control anticipatory vomiting by sedative & antianxiety action. Uses: synergistic with other antiemetics in anticancer drug induced vomiting

Treatment of vomiting
Motion sickness is caused by stimulation of vestibular apparatus. As prevention is better, the drug is to be taken 1 hour before the journey Hyoscine, Cyclizine Anticancer agents induced vomiting 5-HT plays a major role.
Ondansetron, Metoclopramide, Corticosteroids Postoperative vomiting & vomiting due to other causes Metoclopramide, Ondansetron Vomiting in pregnancy Reassurance. Pyridoxine alone or Promethazine + Pyridoxine or pyridoxine + doxylamine only if absolutely necessary Vomiting in children- pediatric gastroenteritis - rehydration measures. Children receiving chemotherapy a corticosteroid plus 5-HT 3 receptor antagonist may be preferred.

Prokinetic agents
The drugs that enhance the coordinated activity among various segments of the gut to propel the luminal contents. Drugs that increase lower esophageal sphincter pressure (hence useful for GERD); drugs that speed up gastric emptying (hence used for gastroparesis); agents that stimulate small intestine (hence useful for postoperative paralytic ileus and colonic pseudo-obstruction; and finally agents that enhance colonic transit (hence useful for treatment of constipation)

Prokinetic agents cont.. Metoclopramide, Domperidone in addition to being antiemetics, they are also prokinetic agents. Cisapride, mosapride and renzapride 5HT 4 agonists They are prokinetic agents and enhance the action of acetylcholine on upper GIT, having no antiemetic actions and used for GERD, non-ulcer dyspepsia, impaired gastric emptying and constipation Cisapride is no longer used due to its serious adverse effects like prolongation of QT interval and ventricular arrhythmia

Miscellaneous Prokinetic agents

Levosulpiride A newer D2 receptor antagonist which is being developed

Tegaserod and prukalopride Recent additions of 5HT4 agonists and safe and exhibit full prokinetic effects and useful for constipation dominant irritable bowel syndrome
Loxiglumide A CCK1 receptor antagonist recently developed to improve and speed up gastric emptying and GI motility

Effects of metoclopramide and domperidone

Emetics
The drugs that produce vomiting Mustard and common salt Peripherally acting by irritation of stomach and used as household emetics Morphine & apomorphine centrally acting by

stimulating CTZ
Syrup epecac - acts both centrally and peripherally & safe emetic Emetics are indicated in certain cases of poisoning

Contraindications of use of emetics

Hypertension, peptic ulcer, pulmonary tuberculosis, uremia, and pregnancy Corrosive poisoning because increase in intragastric pressure may lead to perforation

Poisoning due to petroleum products because of danger of producing lipoid aspiration pneumonia

Lecture outcomes
At the end of the lecture the student should be able describe: The mechanism of vomiting The various drugs that are used as antiemetics with their mechanism of action, specific uses and adverse effects The meaning of prokinetics and the various drugs used as prokinetics in clinical practice with their mechanism of action, specific uses and adverse effects Common emetics used for poisoning and the contraindications to their use

Thank you

Sites of action of Antiemetics

H1, M1, DA2 antagonists Nabilone A

Benzodiazepines Benzodiazepines

A
5HT anta.

Motion sickness

B
Prokinetic Prokinetic agents agents