Anti-emetics and pro kinetics

Dr. Syed Md. Basheeruddin Asdaq

Learning outcomes At the end of lecture, students should be able to:

• Enlist the agents used as antiemetic and pro kinetic• Discuss the clinical uses, mechanism of action and

adverse effects of 5HT3 Antagonist, D2 Antagonists, Neurokinin Antagonists, Glucocorticoids H1 and Muscarinic Antagonists

• Describe the pharmacology of Prokinetic Drugs

• An antiemetic is a drug that is effective against vomiting and nausea.

• Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer.

• Anti-emetics are also used for morning sickness

1. 5-HT3 receptor antagonists

• Drugs-Ondansetron, granisetron, dolasetron, palonosetron, ramosetron, are the drugs on the market.

Mechanism of action: • Competitive blockade of 5-HT receptors located on:

A. Nucleus of tractus solitarius (likely the main site of action)

B. Chemoreceptor trigger zoneC. Visceral afferent nerves. It is likely that they can

prevent both peripheral and central stimulation of the vomiting center.

Adverse effects: • Headache (up to 10%), light-handedness and

constipation

Clinical uses:• Chemotherapy-induced nausea and vomiting

(drugs of first choice)• Postoperative nausea and vomiting• They are also effective against pregnancy-induced

emesis but not against motion sickness

2. Neurokinin receptor antagonists• Aprepitant is the only drug on the market.Mechanism of action:• Blockade of substance P/neurokinin-1 receptors located on

A. Nucleus of tractus solitarius (likely the main site of action)

B. Visceral afferent nerves- In this way it is likely that it can prevent both peripheral and central stimulation of the vomiting center.

• Neurokinin-1 [NK1] receptors mediate most of central and peripheral effects of substance P).

Adverse effects• Sleepiness (20%), diarrhea (10%).

Therapeutic uses• Chemotherapy-induced nausea and vomiting

(drug of first choice)• Postoperative nausea and vomiting.

3. Dopamine D2 receptor antagonists

Mechanism of action: • Most neuroleptics have antiemetic action by

blocking D2 receptors in the CTZ. • Prochlorperazine is the phenothiazine most

commonly used as antiemetic.• Metoclopramide is both a prokinetic and an

antiemetic agent. The antiemetic effect is most likely related to blockade of both D2 and 5-HT3 receptors.

Adverse effects: • hypotension, extrapyramidal effects.Clinical uses: • D2 antagonists are commonly used antiemetics for

nausea and vomiting, but they are less effective than 5-HT3 antagonists in chemotherapy-induced emesis.

• Pure D2 antagonists are ineffective in motion sickness.

• Neuroleptics are also used to treat vestibular disorders and motion sickness, but this is likely a result of their antimuscarinic activity.

4. First generation H1-antagonists

• Drugs: meclizine, diphenhydramine and dimenhydrinate are the main drugs used as antiemetics.

Mechanism of action: • Competitive blockade of H1 (and M1) receptors on the

vestibular nuclei and on nucleus of tractus solitarius. • Diphenhydramine and one of its salts, dimenhydrinate

(Dramamine), are first-generation histamine H1 antagonists that also have significant anticholinergic properties.

• Because of its sedating properties, diphenhydramine is also commonly used in conjunction with other antiemetics for treatment of emesis due to chemotherapy.

• Meclizine is an H1 antihistaminic agent with minimal anticholinergic properties that also causes less sedation.

Clinical uses: • Mainly to prevent (and, less effectively, to treat)

nausea and vomiting due to motion sickness. • They have minimal efficacy in other types of

nausea and vomiting.

5. Antimuscarinic drugs• ScopolamineMechanism of action: • Most likely through competitive blockade of M receptors in

the vestibular nuclei (blockade of M receptors in nucleus of tractus solitarius, CTZ, and vomiting center can also play a role).

Adverse effects: • Are common to those of the antimuscarinic class. Clinical uses: • Mainly to prevent (and, less effectively, to treat) nausea and

vomiting due to motion sickness. • The drug is of limited value in other types of nausea and

vomiting.

• Dronabinol-The drug is the Ä9-tetrahydrocannabinol, the most active cannabinoid of cannabis.

• Mechanism of action: is not known but the drug likely activates specific cannabinoid receptors in the vomiting center, which results in decreased excitability of target neurons.

• Adverse effects: - Prominent central sympathomimetic activity (which can lead to tachycardia).

• Marijuana-like effects (changes in mood, paranoid reactions) when given at high doses.

• Clinical uses: -Prevention of chemotherapy-induced emesis (when other antiemetics are not effective)

• As an appetite stimulant in AIDS patients.

Glucocorticoids

• High-dose glucocorticoids can have pronounced antiemetic action but the mechanism is unknown.

• They are used in combination with other antiemetic agents, mainly in chemotherapy-induced emesis.

Prokinetic Drugs

• A gastroprokinetic agent, gastrokinetic, or prokinetic, is a type of drug which enhances gastrointestinal motility by increasing the frequency of contractions in the small intestine or making them stronger, but without disrupting their rhythm.

• They are used to relieve gastrointestinal symptoms such as abdominal discomfort, bloating, constipation, heart burn, nausea, and vomiting.

• They are used to treat a number of gastrointestinal disorders, including irritable bowel syndrome, gastritis, acid reflux disease, gastroparesis, and functional dyspepsia.

CHOLINOMIMETIC AGENTS• Not commonly used• Cholinomimetic agonists such as bethanechol stimulate

muscarinic M3 receptors on smooth muscle cells and at myenteric plexus synapses.

• Due to multiple cholinergic effects and the advent of less toxic agents, it is now seldom used.

• The acetylcholinesterase inhibitor neostigmine can enhance gastric, small intestine, and colonic emptying.

• Intravenous neostigmine is in clinical usage for the treatment of hospitalized patients with acute large bowel distention (known as acute colonic pseudo-obstruction).

• Cholinergic effects include excessive salivation, nausea, vomiting, diarrhea, and bradycardia.

METOCLOPRAMIDE

Mechanism of action• Metoclopramide and domperidone are dopamine D2

receptor antagonists. • Within the gastrointestinal tract activation of D2

receptors block cholinergic smooth muscle stimulation.

• Blocking D2 will unblock the cholinergic smooth muscle stimulation.

• These agents increase esophageal peristaltic amplitude, increase lower esophageal sphincter pressure, and enhance gastric emptying but have no effect upon small intestine or colonic motility.

• Metoclopramide and domperidone also block dopamine D2 receptors in the chemoreceptor trigger zone of the medulla (area postrema), resulting in potent antinausea and antiemetic action.

Therapeutic UsesImpaired Gastric Emptying• These agents are widely used in the treatment of patients

with delayed gastric emptying due to postsurgical disorders (vagotomy, antrectomy) and diabetic gastroparesis.

• Prevention of Vomiting Due to their potent antiemetic action, metoclopramide is used for the prevention and treatment of emesis.

Gastroesophageal Reflux Disease (GERD)• Metoclopramide is available for clinical use in the USA

(domperidone is available in many other countries). • Metoclopramide is used mainly in combination with acid

suppressors in patients with regurgitation or refractory heartburn.

Nonulcer Dyspepsia• These agents lead to symptomatic improvement in a

small number of patients with chronic dyspepsia.

Adverse Effects• The most common adverse effects of metoclopramide

involve the central nervous system. Restlessness, drowsiness, insomnia, anxiety, and agitation occur in 10-20% of patients, especially the elderly.

• Extrapyramidal effects (dystonias, akathisia, parkinsonian features) due to central dopamine receptor blockade occur acutely in 25% of patients given high doses and in 5% of patients receiving long-term therapy.

• Tardive dyskinesia, sometimes irreversible, has developed in patients treated for a prolonged period with metoclopramide. For this reason, longterm use should be avoided unless absolutely necessary, especially in the elderly.

• Elevated prolactin levels (caused by both metoclopramide and domperidone) can cause galactorrhea, gynecomastia, impotence, and menstrual disorders.

• Domperidone is extremely well tolerated. Because it does not cross the blood-brain barrier to a significant degree, neuropsychiatric and extrapyramidal effects are rare.

MACROLIDES

• Macrolide antibiotics such as erythromycin directly stimulate motilin receptors on gastrointestinal smooth muscle and promote gastric peristalsis, however, tolerance rapidly develops.

• It may be used in patients with acute upper gastrointestinal hemorrhage to promote gastric emptying of blood prior to endoscopy.

Questions?

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