Antiemetics and Laxatives

Core

Introduction

Nausea, vomiting, diarrhoea and constipation are amongst the commonest symptoms a UK doctor manages. Understanding the underlying neurophysiology, particularly which receptors trigger vomiting in which clinical context; is the key to choosing an effective antiemetic. The corresponding article on the gastrointestinal physiology is in Anatomy and Physiology of the Midgut.

The Physiology of Vomiting

Vomiting is the forceful expulsion of gastric contents through the mouth (distinct from the passive regurgitation of oesophageal disease). It is coordinated by the vomiting centre in the medulla, which receives four major inputs:

• The chemoreceptor trigger zone (CTZ) in the area postrema. Sits outside the blood-brain barrier, sensing circulating drugs, toxins and hormones. The dominant receptors here are D₂, 5-HT₃ and NK₁. Triggered by chemotherapy, opioids, anaesthetics, uraemia, hypercalcaemia and pregnancy hormones.
• The vestibular system (semicircular canals, vestibular nuclei). Responsible for motion sickness and vertigo. Dominant receptors are M (muscarinic) and H₁.
• Higher centres (cortex, limbic system). Carry the response to anticipation, anxiety, smells and unpleasant sights.
• Visceral and somatic afferents from the gut (vagus nerve). Triggered by gut distension, irritation, infection and chemotherapy-induced enterochromaffin cell release of serotonin (5-HT). Dominant receptor is 5-HT₃.

The output of the vomiting centre coordinates the motor sequence: nausea, salivation and sweating → retrograde peristalsis → deep inspiration with closure of the glottis → abdominal contraction → lower oesophageal sphincter relaxation → expulsion.

Diagram: The four inputs to the vomiting centre and the dominant receptor at each, mapped to the antiemetic drug classes.

The Antiemetic Drug Classes

Antimuscarinics

Hyoscine hydrobromide (the more lipophilic of the hyoscines, crosses into the brain) blocks muscarinic receptors at the vestibular nuclei and the CTZ. It is the standard treatment for motion sickness, available as oral tablets or transdermal patches.

Side effects are the typical antimuscarinic profile: dry mouth, blurred vision, urinary retention, constipation, drowsiness, confusion (especially in older people). Avoid in glaucoma and prostatic hyperplasia.

(Hyoscine butylbromide, "Buscopan", is a quaternary derivative that does not cross the blood-brain barrier and is used for visceral cramping rather than as an antiemetic.)

H₁ Antihistamines

Sedating H₁ antihistamines act on the vestibular nuclei and the vomiting centre:

• Cyclizine: the standard inpatient antiemetic; useful for opioid-induced nausea, vestibular causes, and in palliative care.
• Promethazine: longer-acting; standard in nausea and vomiting of pregnancy (along with cyclizine).
• Cinnarizine: preferred for motion sickness when sedation is undesirable.

Side effects are the typical sedating-antihistamine profile: drowsiness, dry mouth, urinary retention, blurred vision, occasional paradoxical excitation in children and older people.

5-HT₃ Receptor Antagonists

Ondansetron (and granisetron, palonosetron) block 5-HT₃ receptors on vagal afferents in the gut and at the CTZ. Around 95% of body serotonin is held in enterochromaffin cells: specialised serotonin-secreting cells of the gut epithelium. Chemotherapy and radiation cause these cells to release massive amounts of 5-HT, the dominant trigger of acute chemo-induced vomiting.

Indications:

• Chemotherapy- and radiotherapy-induced nausea and vomiting (CINV/RINV): first-line.
• Post-operative nausea and vomiting.
• Hyperemesis gravidarum (third-line, after MHRA caution about a small association with cleft palate in first trimester).

Side effects are mild: constipation (clinically important when given regularly), headache, mild flushing. QT prolongation is the main caveat: relevant in patients taking other QT-prolonging drugs.

D₂ Receptor Antagonists

Three drugs in this group are commonly tested:

• Metoclopramide: blocks D₂ at the CTZ (anti-emetic effect) and increases gastric emptying via cholinergic action on gut smooth muscle (prokinetic effect). Useful in gastroparesis, GORD, and post-operative nausea. Crosses the blood-brain barrier and can cause extrapyramidal side effects (acute dystonia, particularly in young women) and tardive dyskinesia with prolonged use; the MHRA restricts duration to 5 days.
• Domperidone: same D₂ mechanism as metoclopramide but does not cross the blood-brain barrier well, so extrapyramidal effects are rare. The principal MHRA concern is QT prolongation and sudden cardiac death, which restricts it to short-term use at the lowest effective dose.
• Prochlorperazine (a phenothiazine antipsychotic): D₂ blockade at CTZ. Used for vestibular causes of nausea (vertigo, Ménière's disease) and for some pregnancy-related nausea. Causes sedation, hypotension and extrapyramidal symptoms.
• Haloperidol (a butyrophenone antipsychotic, also a D₂ antagonist) is used in low doses for nausea in palliative care.

NK₁ Receptor Antagonists

Aprepitant and fosaprepitant block neurokinin-1 (NK₁) receptors at the CTZ, where the endogenous ligand is substance P. They are used as adjuncts to 5-HT₃ antagonists and dexamethasone for highly emetogenic chemotherapy regimens, where they substantially reduce the rate of delayed (24+ hour) nausea and vomiting.

Corticosteroids

Dexamethasone is a powerful antiemetic in the chemotherapy and post-operative setting. The mechanism is not entirely understood but probably involves reduction of inflammation around the CTZ, plus inhibition of prostaglandin synthesis. Always used short-term in this context to avoid the chronic side effects of steroids.

Cannabinoids

Nabilone is a synthetic cannabinoid licensed for chemotherapy-induced nausea unresponsive to standard antiemetics. Side effects (drowsiness, dizziness, dysphoria, postural hypotension) limit its use.

Choosing an Antiemetic by Indication

The most useful framework at pre-clinical level is to match the cause of the nausea to the dominant receptor:

• Motion sickness or vestibular cause: muscarinic (hyoscine) or H₁ (cyclizine, cinnarizine).
• Pregnancy nausea: cyclizine or promethazine first, then prochlorperazine or metoclopramide, then ondansetron (used cautiously after first trimester).
• Chemotherapy-induced: dexamethasone + ondansetron, with aprepitant added for highly emetogenic regimens.
• Post-operative nausea and vomiting: ondansetron and/or dexamethasone, with cyclizine as an alternative.
• Opioid-induced nausea: cyclizine, ondansetron or haloperidol.
• Gastric stasis or GORD: metoclopramide or domperidone (prokinetic action).
• Palliative care nausea: haloperidol and cyclizine are first-line; levomepromazine for refractory cases.

A practical safety rule: do not use prokinetic antiemetics (metoclopramide, domperidone) in suspected bowel obstruction: stimulating peristalsis against an obstruction risks perforation.

Antidiarrhoeal Drugs

Acute diarrhoea is most often infective and usually self-limiting. Rehydration and electrolyte replacement are the priority. Pharmacological agents are reserved for symptomatic relief in non-infective diarrhoea, or in stable patients without features suggesting invasive infection.

• Loperamide: a peripheral μ-opioid receptor agonist that does not cross the blood-brain barrier (so no analgesic or addictive effect). Reduces gut peristalsis and increases anal sphincter tone. The standard antidiarrhoeal.
• Codeine: a centrally acting μ-opioid agonist with similar antidiarrhoeal action; useful when pain relief is also needed.
• Bismuth subsalicylate (Pepto-Bismol): over-the-counter, useful for traveller's diarrhoea.
• Octreotide: a somatostatin analogue used in carcinoid syndrome, high-output stoma and other refractory secretory diarrhoea.

Avoid antidiarrhoeals if there is bloody stool, high fever, suspected C. difficile infection, severe abdominal pain, or in children with acute gastroenteritis: in all of these, slowing transit risks worse outcomes.

Constipation and Laxatives

Constipation can be functional, drug-induced (opioids, anticholinergics, calcium channel blockers, iron, ondansetron), endocrine (hypothyroidism, hypercalcaemia), neurological, or obstructive. Lifestyle measures (fluid, fibre, exercise, regular toilet routine) come first; laxatives are added by class in roughly the following order.

Bulk-Forming Laxatives

Ispaghula husk (Fybogel), methylcellulose, sterculia: soluble dietary fibres that absorb water in the gut, increasing stool bulk and stimulating peristalsis. Take 2-3 days to work. Must be taken with adequate fluid; not suitable in suspected obstruction.

Osmotic Laxatives

Retain water in the bowel lumen by osmotic action.

• Lactulose: a non-absorbable disaccharide. Also reduces gut ammonia absorption (used in hepatic encephalopathy). Side effect: flatulence.
• Macrogols (polyethylene glycol): e.g. Movicol, Laxido. Inert, retain the water given with them. The first-line osmotic laxative in NICE guidance.
• Magnesium salts (magnesium hydroxide, magnesium sulfate): faster onset, also used for bowel preparation.
• Phosphate enemas: used for impaction.

Stimulant Laxatives

Increase intestinal motility and electrolyte secretion. Onset 6-12 hours. Used short-term or for opioid-induced constipation.

• Senna: an anthraquinone glycoside. Gentle stimulant.
• Bisacodyl: oral or rectal.
• Sodium picosulfate: also used in bowel preparation.
• Glycerol suppositories: mild stimulant action.

Long-term stimulant use can cause hypokalaemia and theoretical concerns about an "atonic colon", although the modern evidence is weak.

Stool Softeners

Docusate sodium (also has stimulant action), arachis oil enema, liquid paraffin (rarely used now: risk of lipoid pneumonia and anal seepage).

Newer Agents

For chronic refractory constipation, several newer drugs are licensed:

• Linaclotide: guanylate cyclase-C agonist, increases intestinal fluid secretion. Used in chronic constipation and IBS-C.
• Prucalopride: selective 5-HT₄ receptor agonist; prokinetic. Used in chronic constipation when other laxatives fail.
• Naloxegol: peripherally acting μ-opioid receptor antagonist. Specifically for opioid-induced constipation, without reversing analgesia.

Opioid-induced constipation is so predictable that any patient on regular opioids should be co-prescribed a stimulant + osmotic laxative as standard.

Summary

• The vomiting centre receives four inputs: CTZ, vestibular, higher centres, gut afferents. Match the antiemetic to the dominant receptor.
• Antimuscarinics (hyoscine) and H₁ antihistamines (cyclizine, promethazine, cinnarizine) target vestibular causes and motion sickness.
• 5-HT₃ antagonists (ondansetron) target gut afferents and CTZ: first-line for chemotherapy- and post-operative nausea.
• D₂ antagonists (metoclopramide, domperidone, prochlorperazine) target the CTZ; metoclopramide is also prokinetic.
• NK₁ antagonists (aprepitant) and dexamethasone are added in highly emetogenic chemotherapy.
• Loperamide is the standard antidiarrhoeal: avoid in bloody, febrile or suspected C. difficile diarrhoea.
• Constipation ladder: bulk-forming → osmotic (macrogol) → stimulant → stool softener; newer agents (linaclotide, prucalopride, naloxegol) for refractory cases.
• Patients on regular opioids need prophylactic laxatives.

Drug Summary Table

Antiemetics (by receptor) and laxatives (by mechanism), plus key antidiarrhoeals.

Reviewed by: Dr. Marcus Judge

Quiz

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