Antinauseants and

Antiemetic Agents By

M.H.Farjoo M.D. , Ph.D.Shahid Beheshti University of Medical Science

M.H.Farjoo MD, Ph.D

Nausea and Vomiting The pathologic process is coordinated by a central

emesis center. It is in the mid-brainstem adjacent to the

chemoreceptor trigger zone (CTZ) and the solitary tract nucleus (STN) of the vagus nerve.

The lack of a blood-brain barrier allows the CTZ to monitor blood and cerebrospinal fluid constantly for toxic substances.

It relays information to the emesis center to trigger nausea and vomiting.

M.H.Farjoo MD, Ph.D

Nausea and Vomiting

The emesis center also receives information from the gut, principally by the vagus nerve

Two other important inputs to the emesis center come from: the cerebral cortex in anticipatory nausea or

vomiting which responds better to anxiolytic therapy than to antiemetics.

the vestibular apparatus (in motion sickness)

M.H.Farjoo MD, Ph.D

Nausea and Vomiting

The CTZ has high concentrations of receptors for serotonin (5-HT3), dopamine (D2), and opioids

the STN is rich in receptors for enkephalin, histamine, and ACh, and 5-HT3

A variety of these neurotransmitters are involved in nausea and vomiting

For treatment of the emesis associated with cancer chemotherapy, several antiemetic agents from different classes are used.

Figure 37-4. Pharmacologist's view of emetic stimuli.

Myriad signaling pathways lead from the periphery to the emetic center. Stimulants of these pathways are noted in italics. These pathways involve specific neurotransmitters and their receptors (bold type). Receptors are shown for dopamine (D2), acetylcholine (muscarinic, M), histamine (H1), and 5-hydroxytryptamine (5-HT3). Some of these receptors also may mediate signaling in the emetic center.

M.H.Farjoo MD, Ph.D

Nausea and Vomiting

Drugs evoking vomiting include: Analgesics

Erythromycin

Digoxin

Opiates

anti-Parkinsonian drugs

OCPs

M.H.Farjoo MD, Ph.D

5-HT3 Receptor Antagonists Ondansetron is the prototypical 5-HT3 Receptor

Antagonist. Another agent is granisetron. There is evidence that effects at peripheral and central

sites contribute to the efficacy of these agents. Optimal antiemetic effects often are obtained with a

5-HT3 antagonist combined with a glucocorticoid. Serotonin is released by the enterochromaffin cells of

the small intestine in response to chemotherapeutic agents.

M.H.Farjoo MD, Ph.D

5-HT3 Receptor Antagonists this stimulates vagal afferents (via 5-HT3 receptors)

to initiate the vomiting reflex. These agents are most effective in treating

chemotherapy-induced nausea and in treating nausea secondary to upper abdominal irradiation.

They are effective against hyperemesis of pregnancy, and to a lesser degree, postoperative nausea.

They have no effect against motion sickness. the most common adverse effects is constipation or

diarrhea, headache, and light-headedness.

M.H.Farjoo MD, Ph.D

Dopamine-Receptor Antagonists

Dopamine antagonists cross the blood-brain barrier and cause anxiety, dystonic reactions, galactorrhea, sexual dysfunction, and tardive dyskinesia.

Phenothiazines such as chlorpromazine are among the most commonly used "general purpose" antiemetics.

their principal mechanism of action is dopamine D2 receptor antagonism at the CTZ.

they do not appear to be as uniformly effective in cancer chemotherapy-induced emesis.

M.H.Farjoo MD, Ph.D

Dopamine-Receptor Antagonists

Metoclopramide and domperidone are dopamine D2 receptor antagonists.

Within the gastrointestinal tract activation of dopamine receptors inhibits cholinergic smooth muscle stimulation

blockade of this effect is believed to be the primary prokinetic mechanism of action of these agents.

They increase esophageal peristaltic amplitude, increase lower esophageal sphincter pressure, and enhance gastric emptying.

M.H.Farjoo MD, Ph.D

Dopamine-Receptor Antagonists

They have no effect on small intestine or colonic motility.

Metoclopramide and domperidone also block dopamine D2 receptors in the chemoreceptor trigger zone

this results in potent antinausea and antiemetic action.

High-dose metoclopramide also exhibits efficacy in chemotherapy-evoked emesis

M.H.Farjoo MD, Ph.D

Antihistamines

H1-receptor antagonists act on vestibular afferents

They are useful for motion sickness and postoperative emesis.

Cyclizine, hydroxyzine, promethazine, and diphenhydramine are examples of this class.

Cyclizine has additional anticholinergic effects that may be useful for patients with abdominal cancer.

M.H.Farjoo MD, Ph.D

Anticholinergic Agents

The most commonly used muscarinic receptor antagonist is scopolamine (hyoscine).

Its principal application is in motion sickness.

it has some activity in postoperative nausea and vomiting, as well.

In general, anticholinergic agents have no role in chemotherapy-induced nausea.

M.H.Farjoo MD, Ph.D

Dronabinol

Dronabinol is a cannabinoid that is extracted from Cannabis sativa.

The exact mechanism of the antiemetic action of dronabinol is unknown

It probably stimulates the CB1 cannabinoid receptors on neurons of the vomiting center.

its onset of action occurs within an hour, and peak levels are achieved within 2 to 4 hours.

Cannabis crop in Afghanistan

cannabis plant

cannabis plant

Cannabis female flowers close-up

Male Cannabis pollen sacs.

M.H.Farjoo MD, Ph.D

Dronabinol Dronabinol is a useful prophylactic agent in patients receiving

cancer chemotherapy when other antiemetic medications are not effective.

It also can stimulate appetite and has been used in patients with acquired immunodeficiency syndrome (AIDS) and anorexia.

Dronabinol causes central sympathomimetic activity which leads to palpitations, tachycardia, and conjunctival injection (bloodshot eyes).

marijuana-like "highs" (e.g., euphoria, somnolence, detachment, dizziness, anxiety, nervousness, panic, etc.) can occur.

M.H.Farjoo MD, Ph.D

Dronabinol

abrupt withdrawal causes irritability, insomnia, and restlessness.

Dronabinol should be prescribed with great caution to persons with a history of substance abuse (it may be abused by them)

M.H.Farjoo MD, Ph.D

Antiinflammatory Agents

Glucocorticoids such as dexamethasone can be useful adjuncts for nausea in cancer.

They suppress peritumoral inflammation and prostaglandin production.

A similar mechanism explains NSAIDs efficacy for vomiting induced by systemic irradiation

M.H.Farjoo MD, Ph.D

Benzodiazepines

lorazepam and alprazolam, by themselves are not very effective antiemetics

their sedative, amnesic, and anti-anxiety effects can be helpful in anticipatory vomiting.

M.H.Farjoo MD, Ph.D

Substance P Receptor Antagonists

The nausea and vomiting associated with cisplatin has two components: an acute phase that universally is experienced (within 24

hours after chemotherapy) a delayed phase that affects only some patients (on days 2

to 5).

Acute emesis is mediated by 5-HT3 pathways, whereas delayed emesis is 5-HT3-independent.

5-HT receptor antagonists are not very effective against delayed emesis.

M.H.Farjoo MD, Ph.D

Substance P Receptor Antagonists

Substance P is in vagal afferent fibers innervating the STN and area postrema.

Antagonists of the NK1 receptors for substance P, such as aprepitant, have antiemetic effects in delayed nausea.

they improve the efficacy of antiemetic regimens in patients receiving multiple cycles of chemotherapy.

M.H.Farjoo MD, Ph.D

Vomiting and Pregnancy

Pregnancy is the most prevalent endocrinologic cause of nausea

It occurs in 70% of women in the first trimester. Hyperemesis gravidarum is a severe form of

nausea of pregnancy. It can produce significant fluid loss and

electrolyte disturbances.

M.H.Farjoo MD, Ph.D

Vomiting and Pregnancy

The clinician should be cautious in managing the pregnant patient with nausea.

meclizine (antihistamine) and prochlorperazine (antidopaminergic) arebetter than placebo.

Some obstetricians offer other therapies such as pyridoxine, acupressure, or ginger.

M.H.Farjoo MD, Ph.D

Metabolic causes of emesis

Uremia, ketoacidosis, and adrenal insufficiency, as well as parathyroid and thyroid disease, are other.

Ethanol intoxication is a common toxic etiology of nausea and vomiting.

M.H.Farjoo MD, Ph.D

Summary of Antiemetic Medications

Most current drug regimens produce greater reductions in vomiting than in nausea.

The most commonly used antiemetic agents act on sites within the central nervous system

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Thank youAny question?