GI System - Drugs for Nausea and Vomiting

What is vomiting?

A symptom characterized by a forceful expulsion of stomach contents and contents of the proximal small intestine

What are causes of vomiting?

1. Obstruction of GI tract (gastroenteritis, constipation, obstruction)

2. Cortical (Hydrocephalus, brain tumor, pain)

3. Pain from peripheral trigger areas (severe chest pain, kidney stones)

4. Systemic disease (cancer)

5. Vestibular (middle ear infections, vertigo)

6. Medications (Chemo, alcohol withdrawal)

7. Pregnancy (Morning sickness)

8. Upper GI disease (GERD, peptic ulcer disease, gastric cancer)

9. Metabolic cause (uremia - urine in blood, diabetes)

10. Psychogenic causes (feeling of disgust)

What are the three steps of vomiting?

1. Nausea (psychic experience of unease and discomfort)

2. Retching

3. Vomiting

What is regurgitation?

Involuntary return of previously swallowed food or secretions in the mouth (when you burp a bit too hard)

Not vomiting

What is rumination?

Voluntary repetitive, effortless regurgitation of recently ingested food in the mouth, followed by rechewing and reswallowing -> usually attention seeking

Not vomiting

What is nausea?

Psychic sensation of unease and discomfort caused by decreased gastric motility, increased small intestinal tone, and reversal of proximal small intestinal peristalsis (food going opposite direction)

Usually precedes vomiting

What occurs physiologically during vomiting?

-> The glottis closes (prevents stomach contents entering airway) and the larynx is raised to open the upper esophageal sphincter (allowing food contents out of the stomach)

->The soft palate is elevated to close off the posterior nares (to prevent stomach contents from entering the nose)

->The diaphragm is contracted to move downwards, applying pressure on the stomach to force out its contents

->>The muscles of the abdominal walls contract, to further apply pressure at push out stomach contents

What two forces physiologically "push out" stomach contents during vomiting?

Sharp downwards contraction of the diaphragm

Contraction of the abdominal walls in the stomach

What part of the brain is responsible for controlling the vomiting process?

In the brainstem, 3 distinct areas

1. Vomiting Center (Initiates process of vomiting)

2. Nucleus tractus solitarius (Varied sensory information)

3. Chemoreceptor Trigger Zone (Chemicals in blood)

What is the role of the vomiting centers in the vomiting process?

Gathers information from a variety of sources, and through electrical stimulation, initiates the process of vomiting

Gathers signals from

-> CTZ + NTS

->Visceral afferents from GI tract

->Visceral afferents from outside the GI tract

->Afferents from extramedullary centers in the brain

Upon stimulation, causes increased respirations, HR, and salivation, eventually leading to contraction of abdominal muscles and the diaphragm - leading to vomiting

What signals does the vomiting centers receive which initiates the vomiting process?

->CTZ + NTS

(Sensory + Chemical)

->Visceral afferents from GI tract

(Vagus + sympathetic input, can be caused by GI distention or mucosal irritation)

->Visceral afferents from outside GI tract

(Bile duct, peritoneum, heart, other organs)

->Afferents from extramedullary centers in the brain

(Psychic information -> fear + odors, vestibular disturbances -> motion sickness, Cerebral trauma)

What is the role of the chemoreceptor trigger zone in the vomiting process?

Located very close to the fourth ventricle, able to detect chemicals in the blood - acting as a chemical chemoreceptor, and signals the vomiting center to initiate the vomiting process

Many antiemetic drugs impact the CTZ to stop vomiting

Which four neurotransmitter receptors are stimulated by chemotherapy, leading to vomiting?

Serotonin (most significant via enterochromaffin cell damage)

Dopamine

Histamine

Neurokinin Nk1 receptors

How does chemotherapy cause vomiting?

-> Chemotherapeutic drugs directly stimulate the CTZ - perceives the drug as a toxic - to signal the vomiting center and initiate vomiting

-> Chemotherapy can damage enterochromaffin cells, stimulating them to release serotonin, which activates vagus afferent nerves and sends signals directly to the vomiting center. It also activates the NTS and CTZ, which sends signals to the vomiting center to initiate vomiting

->Chemotherapy can stimulate dopamine, histamine and NK1 receptors, which signals the CTZ and NTS to initiate vomiting

->Anticipatory nausea can be caused by classical conditioning via the cortex, causing stimulation of the vomiting center

What is anticipatory nausea and vomiting in chemotherapy?

Classical conditioning caused by previous experience of chemotherapy causes nausea and vomiting during or even before initiation of chemotherapy

Usually it is triggered by specific odors, tastes, or objects that a patient associated with chemotherapy treatment

When does acute nausea + vomiting occur in chemotherapy treatment?

Usually within 24 hours after cancer treatment

Caused by direct activation of CTZ by presence of chemotherapeutic drugs

When does delayed nausea + vomiting occur in chemotherapy treatment?

Usually more than 24 hours after cancer treatment and may persist for several days

Caused by damage of chemotherapy drugs to enterochromaffin cells, leading to serotonin release

What are anticholinergic drugs as an antiemetic?

Use

Used to reduce nausea and vomiting, especially effective for the treatment of motion sickness and vestibular issues

Mechanism of Action

Acts as a muscarinic receptor antagonist in the NTS and CTZ

Adverse Effects

Dry mouth

Constipation

Urinary retention

^Associated with parasym inhibition^

Mild memory loss

Includes scopolamine

What is the use of anticholinergic drugs as an antiemetic?

Used to reduce nausea and vomiting, especially effective for the treatment of motion sickness and vestibular issues

What is the mechanism of action of anticholinergic drugs as an antiemetic?

Acts as a muscarinic receptor antagonist in the NTS and CTZ

What are the adverse effects of anticholinergic drugs as an antiemetic?

Dry mouth

Constipation

Urinary retention

^Associated with parasym inhibition^

Mild memory loss

What are antihistamines as an antiemetic? (Use, Mechanism of Action, Adverse Effects)

Use

Used to treat nausea and vomiting

Mechanism of Action

Acts as a histamine receptor antagonist in the NTS and CTZ

Adverse Effects

Sedation -> high abuse for seniors living alone or with mood disorders

What is the mechanism of action of antihistamines as an antiemetic?

Acts as a histamine receptor antagonist in the NTS and CTZ

What are the adverse effects of antihistamines as an antiemetic?

Sedation -> high abuse for seniors living alone or with mood disorders

What are cannabinoids as an antiemetic? (Use, Mechanism of Action)

Use

Not particularly effective in treating nausea and vomiting, more potent in increasing appetite to return nutrition lost by vomiting

Mechanism of Action

Acts as an agonist at CB1 receptors in the cortex and vomiting center

What is the use of cannabinoids as an antiemetic?

Not particularly effective in treating nausea and vomiting, more potent in increasing appetite to return nutrition lost by vomiting

What is the mechanism of action of cannabinoids as an antiemetic?

Acts as an agonist at CB1 receptors in the cortex and vomiting center

What is Olanzapine, an atypical antipsychotic, as an antiemetic? (Use, Mechanism of action, Adverse Effects)

Use

Reduces nausea and vomiting

Prescribed alongside serotonin antagonists, glucocorticoids, and NK1 antagonists to reduce vomiting associated with chemotherapy

Mechanism of Action

Acts as an antagonist at D2 dopamine receptors in the CTZ and the NTS

Adverse Effects

Sedation

Blurred Vision

Dry Mouth

Constipation

Urinary Retention

What is metoclopramide as an antiemetic? (Use, Mechanism of Action)

Use

Reduces nausea and vomiting

Mechanism of Action

1. Acts as an antagonist at D2 dopamine receptors in the CTZ and the NTS

2. Acts as a prokinetic, inhibiting reversal of gut peristalsis in the vomiting process

3. Acts as an antagonist at serotonin receptors

What is the mechanism of action of metoclopramide as an antiemetic?

1. Acts as an antagonist at D2 dopamine receptors in the CTZ and the NTS

2. Acts as a prokinetic, inhibiting reversal of gut peristalsis in the vomiting process

3. Acts as an antagonist at serotonin receptors

What is Domeperidone as an antiemetic? (Use, Mechanism of Action, Adverse Effects)

Use

Reduces nausea and vomiting

Mechanism of Action

1. Acts as an antagonist at D2 dopamine receptors in the CTZ and the NTS

2. Acts as a prokinetic, inhibiting reversal of gut peristalsis in the vomiting process

Adverse Effects

Sedation

Diarrhea

Galactorrhea

Extrapyramidal signs

What is the mechanism of action of domperidone as an antiemetic?

1. Acts as an antagonist at D2 dopamine receptors in the CTZ and the NTS

2. Acts as a prokinetic, inhibiting reversal of gut peristalsis in the vomiting process

What is haloperidol and prochlorperazine, typical antipsychotics, an antiemetics? (Use, Mechanism of Action, Adverse Effects)

Use

Reduces nausea and vomiting

Mechanism of Action

Acts as an antagonist at D2 dopamine receptors in the CTZ and the NTS

Adverse Effects

Sedation

Hypotension

Extrapyramidal signs

What is the overall goal of antiemetic therapy?

Identify the cause of the nausea and vomiting and treat the cause (via pharmacological or nonpharmacological approaches)

What is the mechanism of action of haloperidol and prochlorperazine, typical antipsychotics, an antiemetics?

Acts as an antagonist at D2 dopamine receptors in the CTZ and the NTS

What are serotonin antagonists as antiemetics? (Use, Mechanism of Action, Adverse Effects, Cautions)

Use

Reduces nausea and vomiting

Prescribed alongside Olanzapine, NK1 receptor antagonists, and glucocorticoids to reduce vomiting associated with chemotherapy

Mechanism of Action

Acts as an antagonist at serotonin receptors in the CTZ and the NTS

Adverse Effects

Ondansetron -> QT prolongation and cardiac arrhythmias via IV

Palonosetron -> Headaches, malaise, constipation (no cardiac symptoms, safer for pt with cardiac conditions

Caution

Ondansetron -> Hx of MI, Atrial fibrillation, and other cardiac conditions

What is the mechanism of action of serotonin antagonists as antiemetics?

Acts as an antagonist at serotonin receptors in the CTZ and the NTS

What are the adverse effects of serotonin antagonists as antiemetics?

Ondansetron -> QT prolongation and cardiac arrhythmias via IV

Palonosetron -> Headaches, malaise, constipation (no cardiac symptoms, safer for pt with cardiac conditions

What are cautions of serotonin antagonists as antiemetics?

Ondansetron -> Hx of MI, Atrial fibrillation, and other cardiac conditions

Therefore, should prescribe Palonosetron for these patients

What are glucocorticoids as antiemetics? (Use, Mechanism of Action)

Use

Reduces nausea and vomiting

Prescribed alongside serotonin antagonists, Nk1 antagonists, and Olanzapine to reduce vomiting associated with chemotherapy

Mechanism of Action

1. Inhibits serotonergic tone by decreasing serotonin release and receptor density

2. Inhibits vagus nerve signaling to the vomiting center

3. Reverses chemotherapy induced HPA hypofunction

4. Acts directly upon the NTS to inhibit signaling to the vomiting center

What is the mechanism of action of glucocorticoids as antiemetics?

1. Inhibits serotonergic tone by decreasing serotonin release and receptor density

2. Inhibits vagus nerve signaling to the vomiting center

3. Reverses chemotherapy induced HPA hypofunction

4. Acts directly upon the NTS to inhibit signaling to the vomiting center

What are NK1 receptor antagonists as antiemetics? (Use, Mechanism of Action, Drug-Drug interactions)

Use

Reduces nausea and vomiting

Prescribed alongside Olanzapine, serotonin antagonists, and glucocorticoids to reduce vomiting associated with chemotherapy

Mechanism of Action

Acts as an antagonist at Nk1 receptors in the CTZ and NTS and blocks binding of substance P to Nk1 receptors as well

Drug-Drug Interactions

Inhibits CYP3A4 enzymes, therefore, glucocorticoid dose should be reduced if coadministered with Nk1 receptor antagonists

What is the mechanism of action of NK1 receptor antagonists as antiemetics?

Acts as an antagonist at Nk1 receptors in the CTZ and NTS and blocks binding of substance P to Nk1 receptors as well

What are drug-drug interactions of NK1 receptor antagonists as antiemetics?

Inhibits CYP3A4 enzymes, therefore, glucocorticoid dose should be reduced if coadministered with Nk1 receptor antagonists

What 4 drug classes are commonly prescribed as prophylaxis treatment for patients undergoing chemotherapy?

1. Dopamine receptor antagonist (Olanzapine)

2. Serotonin receptor antagonist (Ondansetron, Palonosetron)

3. Nk1 receptor antagonist (Aprepitant, Rolapitant)

4. Glucocorticoids (Dexamethasone)