Anti-emetics and pro kinetics - PowerPoint Presentation

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Anti-emetics and pro kinetics

Dr. Syed Md.

Basheeruddin

Asdaq

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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

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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

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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:

Nucleus

of

tractus

solitarius

(likely the main site of action)

Chemoreceptor

trigger zone

Visceral

afferent nerves

. It

is likely that they can prevent both peripheral and

central stimulation

of the vomiting center.

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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

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2. Neurokinin receptor antagonists

Aprepitant

is the only drug on the

market.

Mechanism

of action

:

Blockade

of substance P/neurokinin-1 receptors located on

Nucleus

of

tractus

solitarius

(likely the main site of action)

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).

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Adverse effectsSleepiness

(20%), diarrhea (10%).

Therapeutic

uses

Chemotherapy-induced

nausea and vomiting (drug of first choice

)

Postoperative

nausea and vomiting.

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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

.

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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.

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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.

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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.

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5. Antimuscarinic

drugs

Scopolamine

Mechanism 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.

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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.

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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.

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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.

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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.

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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.

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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

.

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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.

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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.

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Therapeutic Uses

Impaired 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.

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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.

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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.

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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.

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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.

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Questions?

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Thank You