Antiemetics and Laxatives

1. Introduction
2. The Physiology of Vomiting
3. The Antiemetic Drug Classes
   • Antimuscarinics
   • H₁ Antihistamines
   • 5-HT₃ Receptor Antagonists
   • D₂ Receptor Antagonists
   • NK₁ Receptor Antagonists
   • Corticosteroids
   • Cannabinoids
4. Choosing an Antiemetic by Indication
5. Antidiarrhoeal Drugs
6. Constipation and Laxatives
   • Bulk-Forming Laxatives
   • Osmotic Laxatives
   • Stimulant Laxatives
   • Stool Softeners
   • Newer Agents
7. Summary
8. Drug Summary Table
9. Quiz

• The vomiting centre in the medulla (the lowest part of the brainstem) integrates four inputs. The first is the chemoreceptor trigger zone (CTZ), which senses drugs and toxins in the blood. The others are the vestibular system (the balance organs of the inner ear and their nerve connections), higher centres in the brain, and gut afferents (sensory nerves carrying signals from the gut to the brain). Antiemetics (drugs that prevent or relieve nausea and vomiting) are best chosen by matching the drug's target receptor to the dominant input.
• The principal receptor targets are muscarinic (M) acetylcholine receptors (the type that hyoscine blocks), histamine H₁, dopamine D₂, serotonin 5-HT₃, and neurokinin NK₁ (the receptor for substance P, a signalling molecule). Each maps to characteristic indications.
• Constipation in adults is treated with laxatives step by step: bulk-forming → osmotic (macrogol first) → add a stimulant if stools are soft but still hard to pass. In opioid-induced constipation (constipation caused by morphine-like painkillers), use an osmotic plus a stimulant and avoid bulk-forming laxatives. Newer drugs are kept for cases that have not responded to laxatives. Linaclotide, a secretagogue (it increases gut fluid secretion), is for irritable bowel syndrome with constipation. Prucalopride, a prokinetic (it speeds up gut movement), is for chronic constipation, and NICE recommends it only for women. Naloxegol is for opioid-induced constipation.
• Acute diarrhoea is mostly self-limiting (it gets better by itself). Pharmacological (drug) treatment uses loperamide (or codeine). Avoid these drugs if the stool is bloody or there is a fever, because these suggest infection or inflammation of the gut wall.

Introduction

Nausea, vomiting, diarrhoea and constipation are amongst the commonest symptoms a UK doctor manages. Understanding the underlying neurophysiology (how nerves and the brain control these functions), 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 (a small area of the brainstem). It sits outside the blood-brain barrier, so it can sense drugs, toxins and hormones circulating in the blood. (The blood-brain barrier is the tight lining of brain blood vessels that keeps most substances in the blood out of the brain.) The dominant receptors here are D₂, 5-HT₃ and NK₁. Because it samples the blood, it is triggered by chemotherapy (anti-cancer drugs), opioids (morphine-like painkillers), anaesthetics, uraemia (a build-up of waste products in kidney failure), hypercalcaemia (a high blood calcium level) and pregnancy hormones.
• The vestibular system (the semicircular canals, which are balance organs in the inner ear, and the vestibular nuclei, which process balance signals in the brainstem). Responsible for motion sickness and vertigo (a false feeling that you or your surroundings are spinning). Dominant receptors are M (muscarinic) and H₁.
• Higher centres (cortex, limbic system: the brain areas involved in emotion and memory). They trigger nausea and vomiting in response to anticipation, anxiety, smells and unpleasant sights.
• Visceral and somatic afferents from the gut (sensory nerves from the gut, mainly in the vagus nerve). Triggered by gut distension, irritation and infection, and by serotonin (5-HT) released from enterochromaffin cells (serotonin-secreting cells in the gut lining) in response to chemotherapy. Dominant receptor is 5-HT₃.

The output of the vomiting centre coordinates the motor sequence: nausea, salivation and sweating → retrograde peristalsis (contractions that push gut contents backwards, towards the mouth) → deep inspiration with closure of the glottis (the opening between the vocal cords, which closes to protect the airway) → 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 (lipophilic, or fat-soluble, so it crosses into the brain; the other hyoscine, hyoscine butylbromide, is described below) blocks muscarinic receptors at the vestibular nuclei and the CTZ. It is the standard treatment for motion sickness. It is available as oral tablets or as transdermal patches (skin patches that release the drug through the skin).

Side effects are the typical antimuscarinic profile: dry mouth, blurred vision, urinary retention (difficulty emptying the bladder), constipation, drowsiness, confusion (especially in older people). Avoid in angle-closure glaucoma (an eye condition in which the pressure inside the eye can rise suddenly), because the drug can trigger such a rise. Avoid in urinary retention, and use with caution in prostatic hyperplasia (an enlarged prostate), because blocking muscarinic receptors in the bladder makes it harder to pass urine.

(Hyoscine butylbromide, "Buscopan", is a quaternary derivative (it carries a permanent electrical charge, so it does not cross cell membranes easily). It does not cross the blood-brain barrier and is used for visceral cramping (painful spasm of the gut or other internal organs) rather than as an antiemetic.)

H₁ Antihistamines

These older H₁ antihistamines enter the brain and act on the vestibular nuclei and the vomiting centre. All of them can cause drowsiness, but some are less sedating than others:

• Cyclizine: effective against nausea and vomiting from many causes; useful for opioid-induced nausea, vestibular causes, and in palliative care. Use with caution in severe heart failure, because it can lower cardiac output (the amount of blood the heart pumps each minute).
• Promethazine: longer-acting and more sedating; standard in nausea and vomiting of pregnancy (along with cyclizine).
• Cinnarizine: used for motion sickness. Like cyclizine, it is one of the less sedating antihistamines, but drowsiness is still common and can affect driving and other skilled tasks.

Side effects are the typical sedating-antihistamine profile: drowsiness, dry mouth, urinary retention, blurred vision, occasional paradoxical excitation (restlessness and agitation instead of drowsiness) 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. About 90% of the body's serotonin is made by 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 (the usual first choice).
• Post-operative nausea and vomiting.
• Nausea and vomiting in pregnancy, including hyperemesis gravidarum (severe, persistent vomiting in pregnancy): a second-line option, used outside its licence. The MHRA (the UK medicines regulator) warns that use in the first 12 weeks of pregnancy is linked to a small increased risk of cleft lip or palate (a split in the upper lip or the roof of the mouth) in the baby. This is about 3 extra cases per 10,000 births.

Side effects are mild: constipation (clinically important when given regularly), headache, mild flushing. QT prolongation is the main caveat. This is a delay in the heart's electrical recovery after each beat, seen as a longer QT interval on the ECG, and it can trigger dangerous heart rhythms. It matters most in patients taking other drugs that prolong the QT interval.

D₂ Receptor Antagonists

Four drugs in this group are commonly tested:

• Metoclopramide: blocks D₂ at the CTZ (antiemetic effect). It also increases gastric emptying via cholinergic action on gut smooth muscle, meaning it boosts the acetylcholine signals that make the gut contract (prokinetic effect). In adults it should now be used only short-term, in these settings: to prevent nausea and vomiting after surgery or radiotherapy; to prevent delayed (not acute) chemotherapy-induced nausea and vomiting; and to treat nausea and vomiting, including in acute migraine. It should no longer be used for long-term conditions such as gastroparesis (slow stomach emptying) or GORD (gastro-oesophageal reflux disease). It crosses the blood-brain barrier and can cause extrapyramidal side effects (movement disorders caused by blocking dopamine in the brain). These include acute dystonia (sudden, sustained muscle spasms, for example of the neck, jaw or eyes). It is more common in the young (especially girls and young women) and the very old. Prolonged use can cause tardive dyskinesia (involuntary, sometimes permanent movements, usually of the face and mouth). The MHRA restricts treatment to a maximum of 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. It is now restricted to relieving nausea and vomiting, at the lowest effective dose for the shortest possible time (usually no more than 1 week).
• Prochlorperazine (an antipsychotic, meaning a drug used for psychosis such as schizophrenia, from the phenothiazine drug family): D₂ blockade at CTZ. Used for vestibular causes of nausea, such as vertigo and Ménière's disease (an inner-ear disorder causing attacks of vertigo, hearing loss and ringing in the ear). It is also a first-line option for nausea and vomiting in pregnancy. Causes sedation, hypotension and extrapyramidal symptoms.
• Haloperidol (an antipsychotic from a different drug family, the butyrophenones, and 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 (the body's own chemical messenger for that receptor) is substance P. They are used as adjuncts (add-on drugs) to 5-HT₃ antagonists and dexamethasone for moderately and highly emetogenic chemotherapy regimens (chemotherapy likely to cause vomiting). They reduce nausea and vomiting in both the first 24 hours (acute) and the later, delayed phase.

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 (prostaglandins are local chemical signals involved in inflammation). Always used short-term in this context to avoid the chronic side effects of steroids.

Cannabinoids

Nabilone is a synthetic cannabinoid (a manufactured drug that acts like the active compounds in cannabis). It is licensed for chemotherapy-induced nausea that has not responded to standard antiemetics. Side effects limit its use: drowsiness, dizziness, dysphoria (a feeling of unease or low mood) and postural hypotension (a fall in blood pressure on standing up).

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).
• Nausea and vomiting in pregnancy: first-line options include cyclizine, promethazine or prochlorperazine. Second-line options include metoclopramide, domperidone or ondansetron. Ondansetron in the first trimester (first 12 weeks) carries a small increased risk of cleft lip or palate in the baby.
• 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: opioids act on the CTZ, so haloperidol or metoclopramide (D₂ antagonists) are suitable options. Levomepromazine is a third option in NICE CKS palliative care guidance, and cyclizine is also an option (it is licensed for postoperative nausea and vomiting caused by opioids). Ondansetron is not a usual choice here, because it commonly causes constipation, which opioids already cause.
• Gastric stasis (slow stomach emptying) in palliative care: metoclopramide (prokinetic action). Outside palliative care, metoclopramide is no longer used for long-term gastric stasis or GORD, and domperidone is licensed only to relieve nausea and vomiting.
• Palliative care nausea: choose by cause. Haloperidol is used for drug-induced or other chemical causes, including opioids. Cyclizine is used for vestibular causes, disease inside the skull and bowel obstruction, with haloperidol added if needed. Metoclopramide is used for gastric stasis (slow stomach emptying). The 5-day limit does not apply to this unlicensed palliative use. Levomepromazine acts on many receptors, so it is the drug of choice when the cause is unknown or there are several causes.

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

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