4. Drugs Used in the Treatment of Nausea and Vomiting

there are various scoring systems, such as the Apfel score, which estimate the likelihood of PONV according to the number of predisposing factors. (Apfel uses previous history, non-smoking, female gender and administration of opioids). The incidence of PONV in relation to the number of factors is quoted as 0–10%, 1–20%, 2–40%, 3–60% and 4–80% This suggests that a non-smoking female undergoing, say, routine day-case orthopaedic surgery, would have a 40% likelihood of PONV. Clinical experience suggests that this would seem unduly, if not improbably high, but validations of the various models suggest that they can be useful.

Nausea and vomiting are mediated by a number of sites with different receptors. This means that these symptoms can be treated by ‘balanced anti-emesis’ using drugs of differing actions. Although some drugs act at more than one receptor, their anti-emetic actions usually predominate at one.

These contain histamine (H1) muscarinic ACh (M3) receptors. Drugs acting at this site include cyclizine, promethazine (H1-antagonists), hyoscine, atropine and glycopyrrolate (anticholinergic M3-antagonists).

: these are mediated by serotonin (5-HT3) receptors in the gut wall and myenteric plexus. Drugs acting at this site include ondansetron, granisetron

Vomiting centre (VC): this contains primarily muscarinic ACh (M3) and some histamine (H1) receptors. It may also contain μ-opioid receptors. Drugs acting at this site are the same as those which affect the vestibular apparatus.

mpulses from the CTZ to the VC appear to be mediated mainly via dopamine (D2) serotonin (5-HT3) receptors. It may also contain δ-opioid receptors. In addition, substance P, which is a slow excitatory neurotransmitter, may have a role by acting at neurokinin-1 (NK1) receptors. NK1-receptors are abundant in the brain stem where emetic afferents converge. Drugs acting at the CTZ include metoclopramide, domperidone, prochlorperazine, , haloperidol droperidol, which has recently again become available in the UK (D2-antagonists). The newest agents are NK1-antagonists of which aprepitant is the example now available in the UK. Its cost, if nothing else (each dose is approximately £15) makes it a second-line treatment.

• Cannabinoids: synthetic derivatives such as nabilone appear to antagonize the emetic effects of drugs which stimulate the CTZ. Because the cannabinoid effects can themselves be antagonized by naloxone, it is postulated that opioid receptors are involved in their actions. There are at least two endogenous cannabinoid receptors, CB1 and CB2, which modulate neurotransmitter release. • Corticosteroids: high-dose steroids such as dexamethasone or methyl prednisolone act as anti-emetics by mechanisms that are unclear. • Propofol: its antiemetic property is disputed, but its effective use in patients with chemotherapy-induced emesis suggests otherwise. It would appear therefore to act at the CTZ.

Antimuscarinic drugs (atropine, hyoscine, glycopyrrolate): all are potent antisialogogues, and so a dry mouth is almost invariable. Hyoscine is sedative. All three agents can cause the central anticholinergic syndrome, although it is very much less common with glycopyrrolate (as a quaternary ammonium compound, its ability to cross the blood–brain barrier is very limited).

metoclopramide, prochlorperazine, haloperidol, droperidol): • acute extrapyramidal and dystonic effects which are caused by a preponderance of the antidopaminergic stimulatory actions over anticholinergic inhibitory actions in other parts of the CNS. This imbalance can be restored almost instantly with an intravenous anticholinergic agent such as procyclidine 5–10 mg. • The phenothiazines may also cause sedation • Droperidol is associated with prolongation of the QT interval (with the potential development of torsade de pointes) so should be avoided in any patient with a prolonged QTc (corrected QT interval)

is, however, dose-dependent, and in the lower doses given for anti-emesis it does not present significant risk in patients taking one of the many other drugs that have the same effect. (These include Class Ia and Class III antiarrhythmic drugs, antihistamines such as terfenadine, some 5-HT3 antagonists which might be prescribed as part of multimodal antiemetic therapy, and some antibiotics, quinolones and macrolides, including erythromycin)

(ondansetron, granisetron, palonosetron): ondansetron and granisetron are associated with QT interval prolongation, whereas palonosetron is not; otherwise their side effect profile is favourable, with headache being reported as the main side effect, complicating treatment in 3–5% of patients.

(nabilone, dronabinol): sedation is common, and the drugs may sometimes exert psychotomimetic effects similar to those induced by the parent compounds. Dry mouth and postural hypotension may also occur.

(methyl prednisolone, dexamethasone): the list of acute side effects includes steroid psychosis, which is related to a sudden increase in plasma levels of corticoids, metabolic disturbance, including hyperglycaemia, fluid retention hypokalaemia. Short courses of high-dose steroids may cause peptic ulceration