What you should already have
About 80 minutes
Plus the time it takes to redraw this lesson’s figures from memory, which is the fastest way to find out what you have not understood.
Where this shows up
Every drug here is described by three things: the receptor it acts on, the direction of that action, and the site — central at the trigger zone or the vomiting centre, peripheral, or vestibular. Hold those three and the disadvantages of any one drug as a sole agent follow from the same receptor being present elsewhere in the body. That is a far smaller thing to carry than a list of side effects per drug, and it is the difference between choosing an antiemetic and reciting one.
Learning outcomes
By the end of this lesson you should be able to:
- Describe the 5-HT3 receptor as an excitatory ligand-gated cation channel, say where its density is highest, and explain how one antagonist blocks both the peripheral trigger and the central relay.
- Give ondansetron's structure, presentation, uses, kinetics and adverse effects, state what it does not work for, and quote the number needed to treat and to harm.
- Distinguish tropisetron, granisetron, dolasetron and palonosetron from ondansetron by half-life, potency and binding behaviour.
- Derive the extrapyramidal, prolactin, QT and sedative consequences of D2 blockade from where the receptor sits, rather than memorising them per drug.
- Classify the phenothiazines by side chain, and relate each subgroup to its sedative, anticholinergic and extrapyramidal profile.
- Give droperidol's dose, mechanism and effects, and put its QT warning in the context of the doses the warning was based on.
- Name metoclopramide's three receptor actions with the direction of each, separate its antiemetic from its prokinetic mechanism, and list the disadvantages that keep it off first line.
- Explain why domperidone shares metoclopramide's mechanism without its extrapyramidal effects.
- Explain the antiemetic action of the H1 antagonists, including the anticholinergic contribution, and say which are used for what.
- Contrast hyoscine, atropine and glycopyrrolate on antiemetic potency, central effects and blood-brain barrier penetration, and describe the central anticholinergic syndrome and its specific treatment.
Together these settle one syllabus objective: The receptor antagonists: 5-HT3, dopamine, histamine and muscarinic. Tick it on the Pharmacology objective list once you can do all of the above without notes.
Orientation
Rapid review
- The 5-HT3 receptor is a ligand-gated ion channel, not a G-protein coupled receptor — the odd one out among the antiemetic targets.
- One 5-HT3 antagonist blocks both ends of the same reflex: the peripheral trigger in the gut and the central relay in the area postrema.
- Every extrapyramidal effect, and the raised prolactin, is D2 blockade happening somewhere other than the trigger zone. Nothing about it is specific to a particular dopamine antagonist.
- Metoclopramide has three receptor actions, not one — D2 antagonism, 5-HT3 antagonism and 5-HT4 agonism — and only the first is the antiemetic one.
- Domperidone is metoclopramide’s mechanism without its central effects, because it does not cross the blood-brain barrier.
- The antiemetic antihistamines are all partly anticholinergic, which is where their vestibular efficacy and their dry mouth and drowsiness both come from.
Current first-line prophylaxis
The 5-HT3 receptor, and why one drug covers both ends of the reflex
Chemotherapy and radiotherapy release serotonin from enterochromaffin cells of the small intestine. Peripheral 5-HT3 receptors in the gut are activated and stimulate vagal afferents, which reach the vomiting centre — again through 5-HT3 receptors. One antagonist therefore blocks the reflex at both the peripheral trigger and the central relay, which is a genuinely unusual property and worth saying out loud in an answer.
The transmitter, and the molecule built to sit where it sits
Serotonin is 5-hydroxytryptamine: an indole — a benzene ring fused to a five-membered nitrogen ring — with a hydroxyl on the benzene and a short aminoethyl tail. Ondansetron is a carbazole, structurally related to serotonin, and the two depictions show exactly what that means: ondansetron carries the same fused benzene-and-pyrrole core, with a third ring built onto it and a basic imidazole in place of the aminoethyl tail. The aromatic core is what occupies the serotonin site; the basic nitrogen at the far end is what every drug in this class carries. Because the fit is specific to the 5-HT3 subtype, ondansetron does nothing at dopamine, histamine, adrenergic or cholinergic receptors — which is the reason it has no extrapyramidal effects, and the reason the class displaced the older drugs.
What the class is for, and what it is not for
The 5-HT3 antagonists are effective in the prophylaxis and treatment of chemotherapy- and radiotherapy-induced nausea and vomiting, and are equally effective in the prevention and treatment of the postoperative kind. They are not effective against nausea and vomiting caused by vestibular stimulation, and they are likewise ineffective against vomiting induced by dopamine agonists — for either of those, a drug acting at a different receptor is needed. Read that straight off the map: neither afferent runs through a 5-HT3 receptor.
Because the safety and therapeutic profiles are so similar, these kinetics do not drive the choice between members of the class when they are used alone. The one property that does separate them clinically is half-life, and that matters for the patient who is going home rather than for the patient in recovery.
The one to know completely
Ondansetron
At a glance
Ondansetron
- Class and structure
- Carbazole (described as a carbazalone derivative), structurally related to serotonin
- Receptor and mechanism
- Specific 5-HT3 antagonist, peripherally at the vagal afferents in the gut and centrally at the area postrema. No action at dopamine, histamine, adrenergic or cholinergic receptors.
- Dose
- 4 mg intravenously is the standard prophylactic dose; 4 to 8 mg given over 2 to 5 minutes is described for a susceptible population. Tablets and an orodispersible lyophilisate at 4 to 8 mg, a 16 mg suppository, and a 2 mg/mL solution for slow intravenous injection. In preadolescent children, 0.15 mg/kg orally or 0.05 to 0.15 mg/kg intravenously. Licensed above 2 years of age.
- Kinetics
- Oral bioavailability about 60%, with therapeutic blood concentrations 30 to 60 minutes after administration. About 75% protein bound. Hepatic metabolism by hydroxylation then glucuronide conjugation to inactive metabolites. Elimination half-time 3 to 4 hours.
- Adverse effects
- Headache, flushing, constipation, diarrhoea, and bradycardia after rapid intravenous administration. Slight QTc prolongation — a property of the whole class. Transient rises in liver transaminases, seen only in patients receiving chemotherapy and possibly attributable to it. Arrhythmias and atrioventricular conduction disturbance have been reported after intravenous coadministration with metoclopramide.
- Cautions and contraindications
- Reduce the dose in hepatic impairment. No extrapyramidal effects, which is the positive counterpart of a contraindication and the point most often missed.
- What separates it from its neighbours
- It is the reference drug of the class, and the one with the fullest numerical evidence attached. Its specificity for the 5-HT3 subtype is why it is free of the neurological adverse effects common to droperidol and metoclopramide.
The numbers worth quoting
| Outcome | Figure | Read as |
|---|---|---|
| Vomiting prevented | About 20 patients per 100 treated | Twenty of every hundred given the drug will not vomit who otherwise would have — a number needed to treat of about 5 |
| Vomiting, stated separately | Number needed to treat 4 | Its effect is more marked on vomiting than on nausea |
| Nausea, stated separately | Number needed to treat 7 | The same evidence broken out by outcome rather than combined |
| Headache caused | About 3 patients per 100 treated; number needed to harm 36 | Three of every hundred will get a headache they would not otherwise have had |
| Raised liver enzymes | Number needed to harm 31 | Transient, and reported in the chemotherapy setting |
The two sets of figures are not competing: the first is the combined outcome expressed per hundred patients, the second is the same evidence base with vomiting and nausea separated. Quote either, but say which you are quoting.
One further comparison is worth carrying. Propofol used for induction and maintenance is almost as effective as ondansetron at preventing sickness — 19% against 26% relative risk reduction — and ondansetron continues to work when given on top of a propofol-based anaesthetic. The two are additive rather than redundant.
The rest of the class
Tropisetron, granisetron, dolasetron and palonosetron
Four more setrons, and the one that is not built like the rest
Three of these four are the same idea assembled from different parts: an aromatic heterocycle — indazole in granisetron, indole in dolasetron and tropisetron — joined to a bridged bicyclic amine. Tropisetron makes the point best: it is an indole ester of tropine, the same bicyclic ring atropine is built on, which is why a 5-HT3 antagonist and an antimuscarinic can share a skeleton and share nothing else. Palonosetron is the outlier, and visibly so: a quinuclidine on a fused tricyclic isoquinolinone, with no ester and no indole. It is the one member of the class whose binding is described not as simple competitive block but as driving the receptor into the cell, and it has by far the longest half-life. The structure and the behaviour diverge from the rest together.
Six members of the class are in clinical use: dolasetron, granisetron, ondansetron, palonosetron, ramosetron and tropisetron. Four are set out below alongside ondansetron. Ramosetron is named for completeness; it is not in general use outside a small number of countries.
| Drug | Structure and potency | Half-life | What distinguishes it |
|---|---|---|---|
| Ondansetron | Carbazole; the reference compound | 3 to 4 hours | The most fully characterised, and the one every comparison is quoted against |
| Tropisetron | Indoleacetic acid ester of tropine; highly selective | 7.3 hours, against ondansetron's 3.5 | Effective at 2 to 5 mg intravenously before induction; also effective for carcinoid-syndrome symptoms and may have gastrokinetic properties. It did not prevent sickness associated with epidural morphine, where dexamethasone 5 mg intravenously did. Not approved for use in the United States. |
| Granisetron | More selective for 5-HT3 than ondansetron | 9 to 10 hours — about two and a half times ondansetron's | Effective from as little as 0.02 to 0.04 mg/kg intravenously, and a single dose may cover 24 hours, which is useful where sickness tends to occur on the way home. Concomitant dexamethasone significantly improves acute efficacy. Hepatic metabolism, only about 10% excreted unchanged. Side effects mild: headache, sedation, diarrhoea. |
| Dolasetron | A prodrug: rapidly converted to hydrodolasetron, about 100 times more potent as a serotonin antagonist than the parent | About 8 hours, for the active metabolite | 1.8 mg intravenously is equivalent to ondansetron 32 mg and granisetron 3 mg for chemotherapy-induced sickness. Established postoperative sickness is blunted by 12.5 mg intravenously; oral 25 to 50 mg works as prophylaxis. Not effective against postoperative shivering despite serotonergic pathways being implicated in it. In 2010 the US regulator advised against intravenous dolasetron for chemotherapy-induced sickness because of QT prolongation and torsades de pointes, but it remains usable for the postoperative indication at the lower doses used there. |
| Palonosetron | A quinuclidine on a fused tricyclic core, structurally unlike the rest of the class; binds in a way that leads to internalisation of the receptor rather than simple competitive block | About 40 hours — by far the longest | That combination may give better protection against symptoms after discharge, which is the setting it is specifically highlighted for. Cost is a real barrier for the newer, non-generic members of the class. |
Derive the side effects, do not memorise them
What blocking D2 costs
This one figure is most of what a question about the disadvantages of a dopamine antagonist is asking for. Work left to right along the bottom row and the answer builds itself: the wanted antiemetic effect, then the extrapyramidal effects from the nigrostriatal pathway, then hyperprolactinaemia because dopamine is the prolactin release-inhibiting factor, then the effects of everything else these molecules bind — α-adrenoceptors, muscarinic and H1 receptors, and cardiac repolarisation.
Antipsychotics with a limited antiemetic role
Phenothiazines
One nucleus, and a side chain that decides everything
All three carry the same phenothiazine nucleus: two benzene rings bridged by a sulphur and a nitrogen, a flat tricyclic plate. The nitrogen at the centre of that plate carries the side chain, and the side chain is the whole classification. Chlorpromazine has a plain three-carbon propylamine chain ending in a dimethylamine — the propylamine group. Prochlorperazine is the same molecule with the same ring chlorine, and differs only in that the chain ends in a methylpiperazine ring instead. Perphenazine is the piperazine again with a hydroxyethyl on the far nitrogen. That single substitution is what carries the pharmacology with it: the propylamine compound is the sedative, broadly acting one with moderate anticholinergic effect, and the piperazines are the ones whose extrapyramidal effects dominate. A reader who can see the side chain can predict the profile without the table.
| Group | Drug | What the group tends to bring |
|---|---|---|
| Propylamine | Chlorpromazine | Marked sedation, moderate anticholinergic effect, moderate extrapyramidal effect |
| Piperidine | Thioridazine | Not used as an antiemetic |
| Piperazine | Prochlorperazine, perphenazine | Extrapyramidal effects predominate; less sedation than chlorpromazine |
At a glance
Chlorpromazine
- Class and structure
- Phenothiazine, propylamine group — tricyclic nucleus with a straight three-carbon dimethylaminopropyl side chain
- Receptor and mechanism
- Antagonises D2, muscarinic, α1 and α2 adrenergic, H1 and 5-HT receptors. It also has membrane-stabilising properties and prevents noradrenaline uptake into sympathetic nerves. A genuinely broad profile, which is the source of both its efficacy and its side-effect burden.
- Dose
- Typical therapeutic dosing of 10 to 25 mg orally, or 25 to 50 mg intramuscularly or intravenously
- Kinetics
- Gut absorption is good, but large hepatic first-pass metabolism limits oral bioavailability to about 30%, so it is often given parenterally. Many hepatic metabolites, excreted in urine or bile; a small, variable fraction unchanged in the urine.
- Adverse effects
- Extrapyramidal effects from central D2 antagonism; rarely the neuroleptic malignant syndrome. Reduced growth hormone and raised prolactin. Altered temperature regulation, which may cause hypothermia. α-adrenoceptor antagonism causing vasodilatation, hypotension and increased heat loss. Increased appetite and weight gain. Cholestatic jaundice, agranulocytosis, leucopenia, leucocytosis and haemolytic anaemia are all recognised.
- Cautions and contraindications
- Contact sensitisation — direct contact with the drug should be avoided by anyone not themselves taking it. Care is needed with orthostatic hypotension.
- What separates it from its neighbours
- Its proprietary name hints at the breadth of its effects, and that breadth is the point: it is an adequate antiemetic whose other actions are what limit the role. Effective for preventing postoperative sickness, and occasionally used to control vomiting or pain in terminal care, or hiccup.
At a glance
Prochlorperazine
- Class and structure
- Phenothiazine, piperazine group — the same nucleus and the same ring chlorine as chlorpromazine, differing only in the side chain
- Receptor and mechanism
- Dopamine D2 antagonism at the trigger zone, with the phenothiazine class profile behind it
- Dose
- 5 to 10 mg intravenously
- Kinetics
- Oral absorption is erratic and oral bioavailability very low, from extensive hepatic first-pass metabolism. It may be given by suppository, or intravenously or intramuscularly.
- Adverse effects
- Extrapyramidal effects are seen more commonly than with chlorpromazine, and acute dystonias and akathisia are the most common — children and young adults are the most affected. Only mild sedation perioperatively; it may prolong recovery time, but not markedly. Cholestatic jaundice, haematological abnormality, skin sensitisation, hyperprolactinaemia and, rarely, neuroleptic malignant syndrome.
- What separates it from its neighbours
- Effective in the prevention and treatment of postoperative sickness and of vertigo, which the other phenothiazines are not specifically credited with. It is also one of the second-line options for a patient still vomiting after first-line rescue.
Perphenazine has similar indications and kinetics to prochlorperazine and is likewise effective in the prevention and treatment of postoperative sickness. It is associated with a higher incidence of extrapyramidal effects and more postoperative sedation than prochlorperazine. It appears alongside prochlorperazine in the second-line list for persistent symptoms.
One drug, one warning, one correction
Butyrophenones
The butyrophenone itself, shared by both drugs
Look at the left-hand end of each molecule: a 4-fluorophenyl ring attached to a ketone, with a four-carbon chain running from it to a nitrogen. That fragment is the butyrophenone, and it is identical in the two drugs — it is what the class is named for. Everything to the right of it differs: droperidol carries a benzimidazolone on a partly unsaturated pyridine ring, haloperidol a chlorophenyl piperidinol. Both antagonise D2 in the chemoreceptor trigger zone, and both carry the class caution about the QT interval. Droperidol is the one used in anaesthetic practice; haloperidol appears at low dose, where sedation does not occur.
At a glance
Droperidol
- Class and structure
- Butyrophenone — a 4-fluorophenyl ketone on a four-carbon chain, carrying a benzimidazolone
- Receptor and mechanism
- Antagonises central dopamine D2 receptors at the trigger zone. Like the rest of the first-generation antipsychotics it also has antinoradrenergic, anticholinergic and antihistaminergic activity.
- Dose
- Effective from 0.25 to 5 mg, though side effects rise with dose. The prophylactic and rescue range in current use is 0.625 to 1.25 mg intravenously, and that is also the range for which it regained a UK licence. Doses used for this indication are typically 1.25 mg or less.
- Kinetics
- Usually intravenous, though readily absorbed after intramuscular injection. Highly plasma protein bound at about 90%, extensively metabolised in the liver, with only about 1% excreted unchanged.
- Adverse effects
- More pronounced sedation than the phenothiazines. The true incidence of extrapyramidal effects is unknown but rises with dose; they may appear more than 12 hours after administration, and up to 25% of patients experience anxiety for up to 48 hours afterwards. Akathisia is the effect that most limits its use in some countries; one study of ambulatory gynaecological laparoscopy reported akathisia in 29% of women given 10 µg/kg. Hyperprolactinaemia. Hypotension from peripheral α-adrenoceptor blockade. QT prolongation. In sufficient dose it induces neurolepsis.
- Cautions and contraindications
- Where the QT interval is a concern, an electrocardiogram before administration and monitoring for 2 to 3 hours afterwards are described. Dopamine antagonism itself is the contraindication in a patient with a movement disorder.
- What separates it from its neighbours
- It is as effective as dexamethasone or ondansetron at the low doses used for this indication, and it is the drug whose reputation and whose evidence have diverged most sharply.
Haloperidol also has antiemetic properties at low doses — 0.5 to 2 mg intravenously or intramuscularly — at which sedation does not occur. It shares the butyrophenone structure and the class caution.
The most used, and the least first-line
Benzamides
Why one of these reaches the brain and the other does not
Metoclopramide is a substituted benzamide: one benzene ring carrying an amide, an amine, a chlorine and a methoxy group, with a short diethylaminoethyl tail. It is small — a molecular weight of about 300 — and lipophilic, and it crosses the blood-brain barrier freely. That is the source of its antiemetic action at the trigger zone and of every one of its central adverse effects.
Domperidone is grouped with the benzamides by use rather than by structure, because the structure is a different thing altogether: two benzimidazolone rings — the same ring droperidol carries — joined through a piperidine, at a molecular weight of about 426. It is the larger, more polar molecule of the pair, and it does not enter the brain in useful amounts. Same D2 antagonism, same antiemetic effect at the trigger zone, and essentially no extrapyramidal effects: the difference between these two pictures is the difference between the two side-effect profiles.
Amisulpride is a benzamide again, with an ethylsulfonyl group where metoclopramide has a chlorine. Note the carbon on the pyrrolidine ring bearing the ethyl group: it is a genuine stereocentre, and PubChem’s record leaves it undefined — the drug is manufactured and given as the racemate, not as a resolved single enantiomer. Do not assume a modern, single-target drug has been resolved; check the structure.
Aside from their antidopaminergic effect, the benzamides stimulate the gastrointestinal tract by a cholinergic mechanism: contraction of the lower oesophageal sphincter and gastric fundus, increased gastric and small-intestinal motility, and decreased muscle activity in the pylorus and duodenum as the stomach contracts. Metoclopramide and domperidone are the two in current use.
At a glance
Metoclopramide
- Class and structure
- Substituted benzamide — small, lipophilic, molecular weight about 300, and it crosses the blood-brain barrier freely
- Receptor and mechanism
- Three actions, and an answer should name all three with the direction of each: D2 antagonism at the trigger zone, which is the antiemetic action; 5-HT3 antagonism, which may account for some of the antiemetic effect; and 5-HT4 agonism, peripherally and at higher doses, which belongs with the prokinetic action. The prokinetic effect on the stomach is a separate cholinergic mechanism.
- Dose
- 10 mg is the standard clinical dose; it appears most effective when 20 mg is given at the end of anaesthesia rather than at induction. Higher doses of 20 to 25 mg are more effective but produce more akathisia.
- Kinetics
- Well absorbed from the gut, but first-pass metabolism varies widely, giving an oral bioavailability range of 30 to 90%. May be given intravenously. Conjugated in the liver and excreted, with some unchanged drug, in the urine.
- Adverse effects
- Extrapyramidal effects up to 72 hours after administration, more common in young females at about 1 in 5000; dystonic reactions in under 1% of those treated chronically, usually on large oral doses of 40 to 80 mg daily, though neurological dysfunction has been reported after a single preoperative dose. Akathisia after intravenous administration. Sedation, more common with long-term use; agitation occasionally after intramuscular premedication with 10 to 20 mg. Rarely, neuroleptic malignant syndrome. Hypotension, tachycardia and bradycardia after rapid intravenous administration.
- Cautions and contraindications
- Use with caution, if at all, in Parkinson’s disease, restless legs syndrome and other movement disorders related to dopamine inhibition or depletion.
- What separates it from its neighbours
- It is the only drug in this lesson that is a prokinetic as well as an antiemetic, and the only one whose antiemetic evidence is genuinely equivocal. It crosses the blood-brain barrier, which is both why it works centrally and why it causes almost everything on its adverse list.
At a glance
Domperidone
- Class and structure
- Benzimidazolone — grouped with the benzamides by use rather than by structure; molecular weight about 426, and much the more polar of the pair
- Receptor and mechanism
- Dopamine D2 antagonism at the trigger zone, which lies outside the blood-brain barrier and is therefore reachable by a drug that cannot enter the brain
- Kinetics
- Available only as tablets or suppositories. The intravenous preparation was withdrawn after serious arrhythmias during administration of large doses.
- Adverse effects
- Raises prolactin, and may cause galactorrhoea and gynaecomastia — the pituitary is outside the barrier too, so this effect is not avoided. Extrapyramidal effects are much less likely, which is the whole point of the drug: it was identified in 1974 as a D2 antagonist unable to cross the barrier, allowing safer use as an antiemetic.
- Cautions and contraindications
- Its use in children is limited to sickness following chemotherapy or radiotherapy. It is not available in the United States, following regulatory concern about its use by lactating women to increase milk production — although its own risk of QTc prolongation was found to be low.
- What separates it from its neighbours
- It is the experiment that proves the point of this whole lesson. Same mechanism as metoclopramide, same site of useful action, and almost none of the central adverse effects — because it cannot get to the receptors that produce them.
At a glance
Amisulpride
- Class and structure
- Substituted benzamide, manufactured and given as the racemate despite carrying a stereocentre
- Receptor and mechanism
- Selective dopamine D2 and D3 antagonist, developed as a second-generation antipsychotic and investigated as an antiemetic because of that activity and its safety profile
- Dose
- 5 mg intravenously over 1 to 2 minutes at induction for prevention; 10 mg intravenously over 1 to 2 minutes for treatment
- Kinetics
- Not well characterised; it is the newest agent in the class and the perioperative kinetic data are thin
- Adverse effects
- QTc prolongation, raised prolactin, hypokalaemia, hypotension, abdominal distension, and pain at the infusion site
- What separates it from its neighbours
- The newest addition to the class. A double-blind randomised controlled trial found it superior to placebo with no increased risk of QTc prolongation or extrapyramidal effects, and a meta-analysis of five studies found low-dose amisulpride safe and effective for both prevention and treatment. It was approved by the US regulator in 2020 for this indication.
H1 blockade, with an anticholinergic assist
Antihistamines
One shared fragment, and a salt that is two drugs in one bottle
Three of these four are built on the same fragment: a benzhydryl group, two phenyl rings on a single carbon. In cyclizine and meclizine it sits directly on a piperazine; in diphenhydramine it sits on an ether oxygen with a short dimethylaminoethyl tail. That bulky diphenyl group is what makes these molecules fit the H1 receptor, and it is also what makes them fit the muscarinic receptor — which is why the antiemetic H1 antagonists are all more or less anticholinergic, and why dry mouth and drowsiness are the class side effects.
Dimenhydrinate is the one worth looking at twice. Its PubChem record shows two separate molecules, because that is what the drug is: it is diphenhydramine — the upper fragment, identical to the diphenhydramine structure beside it — paired as a salt with 8-chlorotheophylline, the xanthine below. Dimenhydrinate is not a distinct H1 antagonist. It is diphenhydramine delivered with a mild stimulant attached, which is the standard explanation for its being the travel-sickness preparation.
Many of the H1 antagonists used as antiemetics — diphenhydramine, dimenhydrinate, cyclizine and promethazine — also have significant anticholinergic activity, concomitantly blocking muscarinic receptors in the vestibular system. Part of the antiemetic effect is attributable to that second mechanism rather than to H1 blockade alone. The class has a particular efficacy against nausea and vomiting precipitated by vestibular pathways, with documented benefit in travel sickness and in surgery for strabismus or involving the middle ear. Some H2 antagonists have been tried for antiemetic effect, with mixed results.
At a glance
Cyclizine
- Class and structure
- Piperazine derivative — a benzhydryl group on a methylpiperazine
- Receptor and mechanism
- H1 antagonist, with anticholinergic properties that may contribute significantly to the antiemetic action
- Kinetics
- Well absorbed orally, with an oral bioavailability of about 75%. Surprisingly little else about its kinetics is well characterised.
- Adverse effects
- Pain on injection: the parenteral preparation is formulated with lactic acid at pH 3.2, so intramuscular and intravenous injection can be particularly painful. Mild anticholinergic effects, occasionally increasing heart rate after intravenous injection. Extrapyramidal effects and sedation are rare complications.
- What separates it from its neighbours
- It increases lower oesophageal sphincter tone, where the antimuscarinics in the next section decrease it. Used for motion sickness, radiotherapy-induced emesis, postoperative sickness and opioid-induced emesis, and to control the symptoms of Ménière’s disease.
Dimenhydrinate and diphenhydramine
Dimenhydrinate is diphenhydramine combined with 8-chlorotheophylline, the xanthine having been added to reduce drowsiness — a fact that is visible in its structure above, which shows two separate molecules. It treats both postoperative sickness and motion sickness, and its efficacy in each may reflect inhibition of the integrative function of the vestibular nuclei, reducing vestibular and visual input. 1 mg/kg intravenously in adults decreases vomiting after outpatient surgery, and its antiemetic effectiveness has been deemed similar to that of both droperidol and the 5-HT3 antagonists.
Manipulation of the extraocular muscles in strabismus surgery may trigger an oculo-emetic reflex, analogous to the oculocardiac reflex. If the afferent limb of that reflex also depends on the vestibular apparatus, dimenhydrinate may attenuate it. In children, antihistamines significantly decrease vomiting after ophthalmic surgery but not after adenotonsillectomy.
Diphenhydramine, 25 to 50 mg orally or intravenously, is the other commonly used member. Most antihistamines are extensively metabolised by the hepatic cytochrome system, and patients with increased CYP3A4 or CYP2D6 activity may show altered effect. The class adverse effects follow directly from the anticholinergic activity: marked sedation, dry mouth, urinary retention and blurred vision.
Promethazine and meclizine
An antihistamine that is chemically a phenothiazine
Promethazine is taught with the H1 antagonists because that is the receptor its antiemetic use is credited to, but the picture shows a phenothiazine nucleus — the same tricyclic plate as chlorpromazine, shown again here for the comparison. Two differences: promethazine carries no chlorine on the ring, and its side chain is a branched two-carbon chain rather than a straight three-carbon one. That is the structural basis of a drug that is antihistaminic first and antidopaminergic second, and it is why promethazine is answered as an H1 antagonist while sharing the phenothiazine adverse-effect list.
Promethazine is answered as an H1 antagonist and is chemically a phenothiazine, as the structures above show. It is given at 12.5 to 25 mg intramuscularly, and a small dose of 6.25 mg appears among the second-line options for a patient still vomiting after first-line rescue.
Meclizine is a long-acting, minimally sedating H1 antagonist and anti-motion-sickness agent, effective both for postoperative sickness and for preventing symptoms after discharge. In the United States it is inexpensive and available without prescription, which makes it a practical take-home option — an indication that has more to do with availability than with pharmacology, and worth naming as such.
Blocking the vestibular pathway
Anticholinergics
Muscarinic acetylcholine receptors are found in the vestibular system near the trigger zone; their activation contributes to activation of the zone and hence to nausea, and the antimuscarinics block that pathway. The naturally occurring tertiary amines — atropine and hyoscine — are esters of tropic acid combined with an organic base, tropine or scopine, and being uncharged both cross the blood-brain barrier: their central effects include sedation, amnesia, antiemesis and, in excess, the central anticholinergic syndrome. Glycopyrrolate is a synthetic quaternary amine, permanently charged, and so has no central effects at all.
Two esters that cross, and one charged molecule that cannot
Hyoscine and atropine are the two naturally occurring tertiary amines, and they are near-identical: the same tropic acid esterified to the same bicyclic amine. The one difference is an oxygen bridging two adjacent carbons of hyoscine’s ring — the epoxide that makes scopine out of tropine. That single oxygen is the whole chemical difference between the more antiemetic, more sedative, more amnesic drug and the more chronotropic, more bronchodilating one. Both are uncharged at body pH, both cross into the brain, and both can therefore produce the central anticholinergic syndrome.
Glycopyrrolate settles the contrast. Its nitrogen carries four bonds and a positive charge, balanced by a bromide ion drawn beside it — a permanently charged quaternary amine. It cannot cross a lipid membrane in useful quantity, which is why its oral bioavailability is under 5%, why 80% is excreted unchanged, why it has no central effects at all, and why it has no antiemetic action worth the name. One picture explains all four facts.
One more thing is visible here. Both drugs are conventionally described as racemic mixtures of which only the l-form is active. The depictions bear that out for atropine, whose tropate carbon carries no stereodescriptor at all; the hyoscine structure shown is the l-enantiomer specifically, with every stereocentre defined. Worth knowing before repeating “hyoscine is racemic” as though the two drugs were identical in that respect.
At a glance
Hyoscine
- Class and structure
- Tertiary amine; the tropic acid ester of scopine, differing from atropine by a single epoxide bridge. Described as a racemic mixture of which only the l-form is active.
- Receptor and mechanism
- Muscarinic antagonism, blocking transmission to the medulla of impulses arising from the vestibular apparatus
- Dose
- Given transdermally as a postauricular patch. Three figures are quoted for it, and they describe three different things: the patch is labelled 1.5 mg, it is designed to deliver about 1 mg at a constant rate over three days, and the absorbed dose is under 0.5 mg, at roughly 5 µg per hour for 72 hours. Traditionally also given intramuscularly with an opioid as premedication, in which setting it reduces postoperative sickness.
- Kinetics
- Oral absorption is variable, with an oral bioavailability of 10 to 50%; transdermal administration is effective despite very low plasma concentrations. Extensively metabolised by liver esterases, with only a small unchanged fraction in the urine. Its duration of action is shorter than atropine’s; once the patch is removed the half-life is 9 hours.
- Adverse effects
- Dry mouth is the commonest, with somnolence, dizziness and blurred vision; generally described as mild. A higher rate of visual disturbance at 24 to 48 hours, usually a unilateral dilated pupil from digital contamination of the eye after handling the patch — more than 90% occur on the same side as the patch, confirmed by the mydriasis failing to respond to topical pilocarpine. In excess, the central anticholinergic syndrome.
- What separates it from its neighbours
- It is the anticholinergic used most for antiemetic purposes perioperatively, and the one whose onset is the problem: it becomes effective only 2 to 4 hours after the patch goes on, which is why protection against motion-induced nausea is greatest when it is applied at least 4 hours before the stimulus, and why applying it the night before surgery works better than applying it in the anaesthetic room.
Atropine — and why it is not an antiemetic
Atropine is used to treat bradycardia, as an anti-sialagogue, and to antagonise the muscarinic side effects of anticholinesterases. It is not used to treat postoperative sickness, specifically because of its cardiovascular effects. Like hyoscine it is described as a racemic mixture in which only the l-form is active, and its structural record is genuinely the racemate.
| System | Effect |
|---|---|
| Central nervous system | Less likely to cause a central cholinergic crisis than hyoscine, and less sedative |
| Cardiovascular | May cause an initial bradycardia after a small intravenous dose — either a central effect on the vagal nucleus or a partial-agonist action at cardiac muscarinic receptors |
| Respiratory | More marked bronchodilation than hyoscine, increasing dead space; bronchial secretions reduced |
| Gut | A less effective anti-sialagogue than hyoscine; decreases lower oesophageal sphincter tone; a small decrease in gastric acid secretion |
| Miscellaneous | Inhibits sweating, which may provoke a pyrexia in children; given topically it may raise intraocular pressure, which matters in glaucoma |
Kinetics. Intestinal absorption is rapid but unpredictable; it is 50% protein bound, extensively metabolised by liver esterases, and only a tiny fraction is excreted unchanged.
Glycopyrrolate
Indicated for anti-sialagogue premedication, treating bradycardia, and protecting against the unwanted muscarinic effects of anticholinesterases. Its charged quaternary structure gives it entirely different kinetics from the tertiary amines: intestinal absorption is negligible and oral bioavailability under 5%; it does not cross the blood-brain barrier and is therefore devoid of central effects; and it is minimally metabolised, with 80% excreted unchanged in the urine. It has no useful antiemetic action, for exactly that reason.
| Effect | Hyoscine | Atropine | Glycopyrrolate |
|---|---|---|---|
| Antiemetic potency | ++ | + | 0 |
| Sedation and amnesia | +++ | + | 0 |
| Anti-sialagogue | +++ | + | ++ |
| Mydriasis | +++ | + | 0 |
| Placental transfer | ++ | ++ | 0 |
| Bronchodilation | + | ++ | ++ |
| Heart rate | + | +++ | ++ |
Read the first two rows against the last: the drug that is most antiemetic is the one that is most sedative and most amnesic, and the drug with no central access has neither property. That is one molecule’s worth of blood-brain barrier, twice over.
When the barrier works against you
The central anticholinergic syndrome, overdose, and barrier pressure
Physostigmine, a lipid-soluble tertiary amine anticholinesterase, is the specific treatment at 15 to 60 µg/kg intravenously, repeated every 1 to 2 hours because it is metabolised rapidly. Edrophonium, neostigmine and pyridostigmine are ineffective, because their quaternary ammonium structure prevents them entering the central nervous system. That is the same structural argument as glycopyrrolate against hyoscine, running in the opposite direction — and it is a favourite because it can only be answered by someone who understands the chemistry rather than the drug list.
Overdose
Deliberate or accidental anticholinergic overdose produces the classic picture: dry mouth, difficulty swallowing and talking, blurred vision, photophobia, tachycardia, dry flushed skin — sometimes with a rash over the face, neck and upper chest, the “blush area” — and a raised body temperature from inhibited sweating, since the sweat glands are innervated by sympathetic fibres releasing acetylcholine. Small children are particularly vulnerable to this, and “atropine fever” is described in that age group after even a therapeutic dose. Minute ventilation may rise slightly, from central stimulation and increased physiological dead space. Fatal overdose causes seizures, coma and paralysis of the medullary ventilatory centre. Physostigmine is again the specific treatment.
Barrier pressure
Note the direction, because it is the opposite of cyclizine’s and of metoclopramide’s: the antimuscarinics reduce the barrier to reflux, while cyclizine raises lower oesophageal sphincter tone and metoclopramide contracts the sphincter as part of its prokinetic action. Three drugs in one lesson moving the same variable in two directions is exactly the sort of thing a question is built on.
Bringing it together
The receptor antagonists side by side
| Class | Receptor and direction | Principal site | Members taught here |
|---|---|---|---|
| 5-HT3 antagonists | 5-HT3 antagonism | Peripheral — gut and vagal afferents — and central at the trigger zone | Ondansetron, tropisetron, granisetron, dolasetron, palonosetron |
| Phenothiazines | D2 antagonism, plus muscarinic, α1, α2, H1 and 5-HT antagonism | Trigger zone, with broad central and peripheral effects | Chlorpromazine, prochlorperazine, perphenazine |
| Butyrophenones | D2 antagonism, with antinoradrenergic, anticholinergic and antihistaminergic activity | Trigger zone | Droperidol, haloperidol |
| Benzamides | D2 antagonism, 5-HT3 antagonism and 5-HT4 agonism | Trigger zone centrally; the gut peripherally | Metoclopramide, domperidone, amisulpride |
| Antihistamines | H1 antagonism, with significant muscarinic antagonism | Area postrema, vomiting centre, vestibular nucleus, nucleus tractus solitarius | Cyclizine, dimenhydrinate, diphenhydramine, promethazine, meclizine |
| Anticholinergics | Muscarinic antagonism | Vestibular system near the trigger zone; central effects only for the tertiary amines | Hyoscine, atropine, glycopyrrolate |