Causes of NV and sites of drug action
The major classes of drug used to combat NV possess receptor antagonism at D2, M3, H1 and 5-HT3 receptors. The more common agents and their receptor specificity are shown in Figure 34.3.
| D2 | M3 | H1 | 5-HT3 | |
|---|---|---|---|---|
| Hyoscine | 0 | ++++ | + | 0 |
| Promethazine | + | ++ | +++ | 0 |
| Chlorpromazine | ++ | + | ++ | + |
| Metoclopramide | + | 0 | + | ++ |
| Droperidol | +++ | 0 | + | + |
| Ondansetron | 0 | 0 | 0 | ++++ |
| Prochlorperazine | ++++ | + | + | 0 |
Antiemetic activity is ascribed to the following categories of drug:
Anticholinergic drugs
Phenothiazines
Butyrophenones
Antihistamines
5-HT3 receptor antagonists
Cannabinoids
Neurokinin receptor antagonists
Steroids
Additionally, metoclopramide and domperidone are two peripherally acting antiemetic drugs of importance.
Anticholinergic drugs
Examples – atropine, hyoscine
Atropine and hyoscine cross the blood–brain barrier (unlike glycopyrrolate) and act on muscarinic cholinergic receptors in the vomiting centre and in the gastrointestinal tract. Anticholinergic drugs are antispasmodic, reducing intestinal tone and inhibiting sphincter relaxation. They also reduce salivary and gastric secretions and so reduce gastric distension. These are the drugs of choice for the treatment of motion sickness and opioid-induced nausea. Hyoscine has been popular for premedication in conjunction with opioids for this reason, and because it possesses a sedative effect. The side effects of anticholinergic drugs are predictable from the known effects of muscarinic cholinergic receptors. In particular, dry mouth and blurred vision can be a problem, and drowsiness is not uncommon. Bronchial secretions become more viscid, but a degree of bronchodilatation is seen (increasing anatomical dead space). Pupillary constriction may be abolished, which removes a useful indicator of depth of anaesthesia. Anticholinergic agents that cross the blood–brain barrier are implicated in the development of the central anticholinergic syndrome, which is detailed in Figure 34.4.
Causes
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Risk factors
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Features
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Treatment of the central anticholinergic syndrome is accomplished by the use of an anticholinesterase that can cross the blood–brain barrier. In practice, this requires a tertiary amine structure, and thus physostigmine would be the drug of choice, but it is no longer available.
Phenothiazines
Examples – perphenazine, prochlorperazine, promethazine
Phenothiazines have a variety of effects, including antiemesis. Trifluoperazine is a potent antiemetic, but its antipsychotic effects preclude its routine use for this purpose. Phenothiazines act on the D2 receptors in the chemoreceptor trigger zone in the area postrema, and on M3 receptors in the same way as anticholinergic agents. The major effect of promethazine is antihistaminic, although it has antidopaminergic and antimuscarinic activity that contribute to the antiemetic effect. Sedation may limit the usefulness of promethazine as an antiemetic drug. 6 mg of buccal prochlorperazine may be a useful alternative to IM injection.
Butyrophenones
Examples – benperidol, droperidol, haloperidol
Droperidol is an antagonist of D2 receptors in the chemoreceptor trigger zone. It has potent antiemetic activity but can cause a dissociative phenomenon even in relatively small doses, when the patient appears outwardly content but experiences an unpleasant feeling of helplessness and vulnerability. It can prolong the QT interval of the ECG and is contraindicated in hypokalaemia and hypomagnesaemia.
Haloperidol and benperidol are primarily used as antipsychotic agents, but haloperidol possesses substantial anticonvulsant activity. It causes α1-adrenoceptor blockade, which may result in postural hypotension.
Butyrophenones are metabolised in the liver. Side effects include extrapyramidal phenomena, neuroleptic malignant syndrome and hyperprolactinaemia with gynaecomastia.
Antihistamines
Examples – buclizine, cinnarizine, cyclizine, diphenhydramine
Several categories of drug may show antihistaminic activity. Figure 34.5 lists the main categories.
| Ethanolamines | Diphenhydramine Dimenhydrinate |
| Piperazines | Cyclizine Buclizine Cinnarizine |
| Phenothiazines | Promethazine |
There are a number of chemically different agents that are antagonists at histaminergic receptors. The general term antihistamine tends to be used to describe anti-H1 drugs alone. These are particularly effective in the treatment and prevention of motion sickness. The antiemetic action is centrally mediated, but H1 antagonism may not be the sole mechanism of antiemesis. The sedative effects of antihistamines contribute to the treatment of nausea.
Ethanolamines (such as diphenhydramine) are potent antihistamines with some anticholinergic activity, which are thought to work at the labyrinth and the neural interface between the labyrinth and the vomiting centre.
Cyclizine is used for motion sickness and for PONV. It has anticholinergic activity, resulting in dry mouth, and can cause tachycardia if given intravenously. Cinnarizine is almost insoluble in water and only available in the tablet form. Buclizine has a long duration of action but is only available in combined formulation with other drugs.
5-Hydroxytryptamine (5-HT3) receptor antagonists
Examples – granisetron, ondansetron, tropisetron
There are four basic types of serotonergic (5-HT) receptors (5-HT1–4). 5-HT1 receptors are subdivided further (5-HT1A, etc.). An especially high density of 5-HT3 receptors is found in the area postrema and nucleus tractus solitarius, where they are probably on the vagus nerve terminals. Receptors have also been identified on peripheral sections of the vagus nerve in the gastrointestinal tract, and the emetogenic effect of 5-HT release can also be blocked here.
Cannabinoids
Example – nabilone
Cannabis is derived from the plant Cannabis sativa. The active constituents of cannabis are called cannabinoids. Delta-9-tetrahydrocannabinol (∆9-THC) is the major active cannabinoid. A specific cannabinoid receptor has been identified in the CNS, and it is thought that cannabinoids act at the chemoreceptor trigger zone. Naloxone may be used to overcome their effects. Nabilone is a synthetic derivative of the naturally occurring tetrahydrocannabinol. It is effective against NV induced by opioids, cytotoxic therapy and radiotherapy. Taken orally, it is well absorbed and has a half-life of 120 minutes. Indications for cannabinoid therapy are limited by the side effects of hallucinations, psychosis, dizziness and dry mouth.
Neurokinin receptor antagonists
Example – aprepitant
Selective neurokinin (NK1) receptor antagonists have been shown to have antiemetic activity via the nucleus of the tractus solitarius and dorsal motor nucleus of the vagus nerve. Aprepitant has a broader spectrum of antiemetic activity than 5-HT3 antagonists. It has a half-life of 11 hours. Aprepitant is only available as oral capsules. Fosaprepitant is a prodrug of aprepitant and provides an intravenous alternative with rapid conversion in hepatic microsomes (97% conversion within 15 minutes) by dephosphorylation. Although fosaprepitant has some affinity for NK1 receptors, the rapid conversion means that its clinical effect is produced by the resultant prepitant.
Steroids
Example – dexamethasone
Dexamethasone is a synthetic steroid that has found many diverse clinical uses. It appears to be effective in the prevention of PONV. Postulated mechanisms of action include prostaglandin inhibition (reducing the effect of surgically mediated tissue damage), inhibition of gut 5-HT release, inhibition of neuronal 5-HT and reduced release of endorphins. There may be a small risk of increased postoperative infection and of postoperative bleeding in high-risk patients on concomitant NSAIDs.
Dexamethasone is supplied in ampoules containing 3.3 mg of dexamethasone per mL of solution. It also contains sodium and phosphate such that it combines two forms of dexamethasone. The molar masses are as follows: dexamethasone 392, phosphate 94, sodium 23. So the solutions contain 3.3 mg dexamethasone, which is equivalent to 4 mg dexamethasone phosphate or 4.3 mg dexamethasone sodium phosphate.
Peripherally acting antiemetic drugs
Examples – domperidone, metoclopramide
Metoclopramide and domperidone are chemically unrelated yet functionally similar. Metoclopramide hydrochloride is a white crystalline salt that is chemically related to procaine. It is readily soluble and stable in water. It has antidopaminergic (D2) activity in the chemoreceptor trigger zone and also inhibits the emetic effects of gastric irritants. It also antagonises H1 and 5-HT3 receptors and promotes gastric emptying through the pylorus. Extrapyramidal effects (such as oculogyric crisis) are the major potential side effects. Metoclopramide is indicated for PONV, opioid-induced nausea and NV related to cytotoxic drug treatment and radiotherapy.
Domperidone is a benzimidazole derivative that has both centrally and peripherally mediated effects. Peripherally, domperidone promotes gastric emptying and increases lower oesophageal sphincter tone. It crosses the blood–brain barrier (but only slowly) and then acts on dopamine receptors in the chemoreceptor trigger zone. This impaired transit across the blood–brain barrier reduces the incidence of extrapyramidal side effects. Domperidone is indicated for the treatment of PONV and opioid-induced NV but it is limited in its application as it cannot be given parenterally. The major application of the drug is in the treatment of cytotoxic and radiotherapy-induced NV. These agents may also be useful in promoting gastric transit when this is impaired by diabetic autonomic neuropathy.
Domperidone can also cause QT-interval prolongation and ventricular tachydysrhythmias, and sudden death has been reported.
Miscellaneous antiemetics
Specific pharmacology of antiemetic drugs
Units (unless stated otherwise) are:
Volume of distribution at steady state (Vd): L kg–1
Clearance (Cl): mL kg–1 min–1
Terminal half-life (t½): hours
Cyclizine hydrochloride and lactate
Structure – piperazine
Presentation
Oral – tablets 50 mg
IV/IM – 50 mg in 1 mL
Pharmacokinetics
| Bioavailability | 80% |
| t½ | 10 |
Blood–brain barrier – crossed
CNS – antiemetic, with some sedation
CVS – slight tachycardia
RS – minimal effect
Other – increase in lower oesophageal sphincter pressure
Elimination – N-demethylation to norcyclizine (half-life 20 h, minimal activity), and also some to the oxide
Side effects – anticholinergic; dry mouth, blurred vision, drowsiness
Dexamethasone
Structure – glucocorticoid steroid
Presentation – IV, clear colourless solution; 8 mg dexamethasone in 2 mL; 3.3 mg dexamethasone in 1 mL (see box above)
CNS – may cause convulsions and increase ICP (but indicated for treatment of cerebral oedema)
CVS – minimal effect
RS – may be used for asthma and aspiration pneumonitis
Elimination – liver metabolised
Droperidol
Structure – butyrophenone
Presentation – clear colourless solution, 2.5 mg mL–1 in 1 mL for IV administration
Pharmacokinetics
| Protein binding | 90% |
| Vd | 2 |
| t½ | 12 |
Blood–brain barrier – crossed
CNS – anxiolysis, placid state, indifference to environment, may be unpleasant feelings of helplessness not outwardly expressed; antiemesis via central D2 antagonism in the chemoreceptor trigger zone
CVS – vasodilatation and decreased arterial pressure due to α-adrenergic blockade may occur when given intravenously
RS – minute volume, functional residual capacity and airway resistance all slightly decreased
Elimination – oxidative N-dealkylation in the liver
Side effects – extrapyramidal effects, gastrointestinal dysfunction, QT-interval prolongation
Metoclopramide hydrochloride
Structure – chlorinated procainamide derivative
