Lecture 6: Anti-Nausea and Anti-Emetics

Serotonin (5-HT3)

Dopamine (D2)

Histamine (H1)

Neurokinin (NK1)

Cannabinoid (CB1)

Muscarinic (M1)

receptors involved in emesis

• Antibiotics

• Antivirals

• Opioids

• Iron

• Antidepressants

• Antiparkinson medications

medications that most commonly induce N/V

-Ondansetron

-Granisetron

-Dolasetron

-Palonosetron

-Serotonin 5-HT3 antagonists

-Antiemetics agents

-Prochlorperazine

-Thiethylperazine

-Chlorpromazin

-Metoclopramide

-Trimethobenzamide

-Antiemetics agents

-Dopamine D2 antagonists

-Aprepitant

-Rolapitant

-Fosaprepitant

-Substance P /NK1 antagonists

-Antiemetics agents

-Dimenhydrinate

-Meclizine

-Promethazine

-Histamine H1 antagonists

-Antiemetics agents

Scopolamine

-Muscarinic M1 antagonist

-Antiemetics agent

Serotonin 5-HT3 Antagonists

-Selective 5-HT3 antagonists in/on STN, CTZ, GI tract

• Inhibits activation of vomiting reflex pathway

Serotonin 5-HT3 Antagonists

Indications - n/v prophylaxis:

• Postoperative (PONV)

• Radiation-induced

• Chemotherapy-induced

• Poorly control other emetic stimuli

(e.g., motion sickness)

Serotonin 5-HT3 Antagonists

Adverse effects

• Generally, well tolerated

• Most common (Headache, Dizziness, Constipation)

• Small but stat sig ↑QT interval (dose related) esp. when given I.V.,

• Dolasetron >> Ondansetron >> Granisetron >>>>> Palonosetron

Contraindications: When used in conjunction with other QT interval

prolonging agents, there is the risk of arrhythmia development.

Phenothiazines

• Block D2 receptors in STN & CTZ (primary)

• Block H1 receptors in vestibular system & STN

• Indications - Nausea and vomiting

Phenothiazines

Adverse effects

• Hypotension

• Extrapyramidal effects (dystonia, akathisia, parkinsonism)

• Tardive dyskinesia

• QT prolongation (chlorpromazine greatest risk)

• Increased risk of death in elderly w/ dementia (BBW for prochlorperazine and chlorpromazine)

• Anticholinergic effects - caution in elderly

CIs: CNS depression or hypotension

• Metoclopramide

• Trimethobenzamide

-Dopamine (D2) antagonists

• In CTZ & STN → potent antinausea & antiemetic action

• In GI tract → prevents inhibition of cholinergic smooth muscle stimulation → ↑esophageal peristaltic amplitude, ↑LES pressure, and ↑gastric emptying

• Block 5-HT3 at increased dose (weak)

• Metoclopramide

• Trimethobenzamide

Indications

• Nausea/vomiting

(chemotherapy-induced, postoperative)

• GERD (metoclopramide)

• Diabetic gastroparesis (metoclopramide)

• Metoclopramide

• Trimethobenzamide

Adverse effects

• Somnolence or insomnia

• Dystonias, akathisia, parkinsonism

• Tardive dyskinesia (BBW for metoclopramide)

• Elevated prolactin levels → galactorrhea, gynecomastia, impotence, menstrual disorders

Contraindications

• Epilepsy

• GI hemorrhage, mechanical obstruction, or perforation

• Pheochromocytoma (↑ risk of hypertensive crisis)

Droperidol

-Block D2 receptors in CTZ & STN

Indication

• Limited to prophylactic use for n/v in surgical/diagnostic procedures (given IV or IM)

-CIs: antiarrhythmic agents, fluoroquinolones antibiotics

Droperidol

Adverse effects

• Hypotension, tachycardia, sedation

-Dystonia, akathisia, parkinsonism

BBW: QT prolongation

Promethazine

• Blocks H1 receptors in vestibular system & STN

• Also blocks cholinergic and alpha-adrenergic receptors

-Antihistamines

Promethazine

Indications

• Nausea & vomiting

• Motion sickness

• Sedation

• Analgesic administration, prophylaxis

• Postoperative pain, adjunct

• Allergic condition

Promethazine

Contraindications

• Comatose state

• BBW: Children

• *Dimenhydrinate

• *Meclizine

• Doxylamine

1st Generation Antihistamines

• *Dimenhydrinate

• *Meclizine

• Doxylamine

-Block H1 receptors in vestibular system & STN

Indications:

- Prophylaxis/treatment of motion sickness

• Vertigo (meclizine)

• N/V in pregnancy (doxylamine + pyridoxine (Vit B6))

• *Dimenhydrinate

• *Meclizine

• Doxylamine

• Contraindication - Hypersensitivity to

diphenhydramine (dimenhydrinate only)

• Adverse effects - Anticholinergic effects

• Increased risk in elderly (Beers List)

Scopolamine

-Blocks M1 receptors in vestibular system & STN

Indications

• Motion sickness (primary use)

• Postoperative n/v, prophylaxis

Scopolamine

Contraindications

• Chronic lung disease

• Hypersensitivity to

elladonna alkaloids, anticholinergics, barbiturates

• Narrow angle glaucoma

• Hepatic impairment

• Renal impairment

• Pyloric obstruction

• Prostatic hypertrophy

• Aprepitant

• Fosaprepitant

• Rolapitant

-Nk1 Receptor Antagonist

-Substance P antagonist

Indication: Chemotherapy-induced n/v (CINV) prophylaxis

• For highly or moderately emetogenic chemo' regimens

• Often used with 5-HT3 antagonists &/or corticosteroids

• Aprepitant

• Fosaprepitant

• Rolapitant

Adverse effects

• Fatigue, dizziness

• Diarrhea

• Rolapitant (given IV) - Increased risk of hypersensitivity reactions (anaphylaxis, anaphylactic shock)

• Contraindicated if hypersensitivity to soybean oil

• Dronabinol

• Nabilone

Synthetic Analogs of THC Products

• Dronabinol

• Nabilone

-Act on vomiting center and/or CTZ

-activate activating CB1/CB2 receptors

Indications

• CINV in patients who have failed to respond adequately to conventional antiemetic

treatment.

• Dronabinol

• Nabilone

Adverse effects

• Anxiety/confusion

• Euphoria/dysphoria

• GI upset (n/v/pain)

• Somnolence

• Xerostomia

• Increased appetite

• Dexamethasone

• Methylprednisolone

-Corticosteroids

-blockade of prostaglandins

Commonly used for management of:

• CINV: Cisplatin induced acute and delayed

• PONV (Postoperative Nausea & vomiting)

• Usually used in combination w/ other antiemetic agents

• Effective alone in mild-to-moderate emetogenic chemotherapy

• Dexamethasone

• Methylprednisolone

• Appear to enhance efficacy of 5-HT3 antagonists (e.g., ondansetron) in chemotherapy induced n/v

• Effective for delayed n/v with chemotherapy

NSAIDs

• Beneficial effects in radiation induced n/v during chemotherapy

• Maybe used in PONV in exchange of opioid analgesics.

• Mechanism (proposed) - decreased prostaglandin production

Benzodiazepines (Lorazepam and Alprazolam)

• May reduce anticipatory n/v

• Generally, not effective antiemetics alone

⁻ Lorazepam,

⁻ Methylprednisolone

⁻ Prochlorperazine

⁻ Promethazine

⁻ Metoclopramide,

⁻ Dronabinol

Treatment of breakthrough NV

during/after chemotherapy

Amisulpride

-Intravenous D2/D3 receptor antagonist-

-approved by FDA for prevention and treatment of postoperative nausea and vomiting (PONV) in adults.

Scopolamine

-for post-operative n/v (PONV)

-should be administered the evening prior to surgery or 2 hours prior to surgery.