A Textbook of Clinical Pharmacology and Therapeutics

• Cyclizinegiven either orally or by injection is effective
  in opiate-induced vomiting and has been given widely in
  pregnancy without any untoward effects on the fetus. The
  main side effects are drowsiness and a dry mouth.


• Promethazineis also an effective anti-emetic. It is more
  sedative than cyclizine.


• Betahistineis used in vertigo, tinnitus and hearing loss
  associated with Ménière’s disease.


• Cinnarizineis an antihistamine and calcium antagonist. It
  has an action on the labyrinth and is effective in the
  treatment of motion sickness and vertigo.

DOPAMINE ANTAGONISTS

METOCLOPRAMIDE

Use

Metoclopramideis effective for:

• post-operative vomiting;


• radiation sickness;


• drug-induced nausea;


• migraine (see Chapter 23);


• diagnostic radiology of the small intestine is facilitated by
  metoclopramide, which reduces the time required for
  barium to reach the caecum and decreases the number of
  films required;


• facilitation of duodenal intubation and endoscopy;


• emergency anaesthesia (including that required in
  pregnancy) to clear gastric contents;


• symptoms of reflux oesophagitis may be improved, as it
  prevents nausea, regurgitation and reflux.

Adverse effects

Adverse effects are usually mild but can be severe. Extra-
pyramidal effects (which occur in about 1% of patients) consist
of dystonic effects including akathisia, oculogyric crises, tris-
mus, torticollis and opisthotonos, but parkinsonian features
are absent. These effects are more common in females and in
the young. They are treated by stopping metoclopramideand
givingbenztropineordiazepamacutely if necessary (see also
Chapter 21). Overdosage in infants has produced convulsions,
hypertonia and irritability. Milder effects include dizziness,
drowsiness, lassitude and bowel disturbances.

Mechanism of action

Metoclopramide increases the amount of acetylcholine
released at post-ganglionic terminals.
It is a central dopamine antagonist and raises the threshold
of the CTZ. It also decreases the sensitivity of the visceral
nerves that carry impulses from the gut to the emetic centre. It
is relatively ineffective in motion sickness and other forms of
centrally mediated vomiting.
High doses of metoclopramideblock 5HT 3 receptors.

Pharmacokinetics

Metoclopramideis well absorbed orally and is also given by
intravenous or intramuscular injection. It undergoes metabolism

by dealkylation and amide hydrolysis, about 75% being excreted

as metabolites in the urine. The mean plasma t1/2is four hours.

Drug interactions

Metoclopramidepotentiates the extrapyramidal effects of

phenothiazines and butyrophenones. Its effects on intestinal

motility result in numerous alterations in drug absorption,

including increased rates of absorption of several drugs such

asaspirin,tetracyclineandparacetamol.

DOMPERIDONE

Domperidoneis a dopamine-receptor antagonist similar to

metoclopramide. It does not penetrate the blood–brain bar-

rier, however, and therefore seldom causes sedation or

extrapyramidal effects. However, the CTZ lies functionally

outside the barrier and thus domperidoneis an effective anti-

emetic which can logically be given with centrally acting

dopamine agonists or levodopaorapomorphineto counter

their emetogenic effect (see Chapter 21).

PHENOTHIAZINES

Use

Phenothiazines (see Chapter 20) act on the CTZ and larger

doses depress the vomiting centre as well. Phenothiazines

used as anti-emetics include prochlorperazine,trifluoper-

azine,perphenazineandchlorpromazine.

These are effective against opioid- and radiation-induced

vomiting and are sometimes helpful in vestibular disturb-

ances. They are least effective in the treatment of motion sick-

ness. All of them carry a risk of extrapyramidal disturbances,

dyskinesia and restlessness. Perphenazineis probably the

most soporific of this group.

5-HYDROXYTRYPTAMINE (5HT 3 )-RECEPTOR

ANTAGONISTS

The serotonin (5HT 3 )-receptor antagonists are highly effective

in the management of acute nausea and vomiting due to cyto-

toxic chemotheraphy, although they offer little advantage for

delayed emesis, occurring secondary to cytotoxic chemother-

apy and radiotherapy. They are also effective in the treatment

of post-operative nausea and vomiting.

Their exact site of action is uncertain. It may be peripheral

at abdominal visceral afferent neurones, or central within the

area postrema of the brain, or a combination of both.

Examples include ondansetron,granisetron, dolasetronand

tropisetron.

CANNABINOIDS

Cannabis and its major constituent, D-9-tetrahydrocanna-

binol (THC), have anti-emetic properties and have been used

to prevent vomiting caused by cytotoxic therapy. In an

attempt to reduce side effects and increase efficacy, a number

of analogues, including nabilone, have been synthesized.

The site of action of nabiloneis not known, but an action on

254 ALIMENTARY SYSTEM ANDLIVER