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 occursVomiting occurs in gastroenteritis, motion sickness, in gastroenteritis, motion sickness,

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

several drugs mostly drugs used for cancer several drugs mostly drugs used for cancer

chemotherapy.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 Neurologic pathways involved in nausea & vomitingnausea & vomiting

Class Drug

5-HT3 – R antagonists Ondansetron, Granisetron

Dopamine antagonists Metoclopramide, Domperidone

Antimuscarinics Scopolamine (l-hyoscine)

Anti-histamines Cyclizine, Promethazine, Doxylamine

Cannabinoids Nabilone, Dronabinol

Antacids Magnesium hydroxide, aluminium hydroxide either alone or in combination

H2 receptor antagonis Ranitinidine, famotidine etc.

Miscellaneous Dexamethasone, Diazepam, antipsychotic (droperidol)

Classification of Anti-emetic drugs

Site of action of Antiemetics

H1, M1, DA2 antagonists Nabilone

Benzodiazepines

5HT anta.

Prokinetic agents

Motion sickness

Hyoscine

Antihistamines

H1, M1, DA2 antagonists, Nabilone

Benzodiazepines

5HT anta.

Prokinetic 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 & DomperidoneMetoclopramide & 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 vomitingMotion 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 - pediatric gastroenteritis - rehydration rehydration

measures. Children receiving chemotherapy a measures. Children receiving chemotherapy a corticosteroidcorticosteroid plus plus

5-HT 5-HT 33 receptor receptor antagonist may be preferred.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…..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 it’s serious adverse

effects like prolongation of QT interval and ventricular

arrhythmia

Miscellaneous Prokinetic agents 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

EmeticsEmetics

The drugs that produce vomitingThe drugs that produce vomiting

Mustard and common salt – Peripherally acting by irritation of Mustard and common salt – Peripherally acting by irritation of

stomach and used as household emeticsstomach and used as household emetics

Morphine & apomorphine – centrally acting by stimulating CTZMorphine & apomorphine – centrally acting by stimulating CTZ

Syrup epecac - acts both centrally and peripherally & safe Syrup epecac - acts both centrally and peripherally & safe

emeticemetic

Emetics are indicated in certain cases of poisoningEmetics 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 outcomesAt 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

Benzodiazepines

5HT anta.

Prokinetic agents

Motion sickness

A Benzodiazepines

Prokinetic agents

A A

B

C

D