Clinical Pharmacology and Therapeutics

254 ALIMENTARY SYSTEM AND LIVER
• Cyclizine given 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.
• Promethazine is also an effective anti-emetic. It is more
sedative than cyclizine.
• Betahistine is used in vertigo, tinnitus and hearing loss
associated with Ménière’s disease.
• Cinnarizine is 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
Metoclopramide is 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. Extrapyramidal
effects (which occur in about 1% of patients) consist
of dystonic effects including akathisia, oculogyric crises, trismus,
torticollis and opisthotonos, but parkinsonian features
are absent. These effects are more common in females and in
the young. They are treated by stopping metoclopramide and
giving benztropine or diazepam acutely 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 metoclopramide block 5HT 3 receptors.
Pharmacokinetics
Metoclopramide is 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 t 1/2 is four hours.
Drug interactions
Metoclopramide potentiates 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
as aspirin, tetracycline and paracetamol.
DOMPERIDONE
Domperidone is a dopamine-receptor antagonist similar to
metoclopramide. It does not penetrate the blood–brain barrier,
however, and therefore seldom causes sedation or
extrapyramidal effects. However, the CTZ lies functionally
outside the barrier and thus domperidone is an effective antiemetic
which can logically be given with centrally acting
dopamine agonists or levodopa or apomorphine to 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, trifluoperazine,
perphenazine and chlorpromazine.
These are effective against opioid- and radiation-induced
vomiting and are sometimes helpful in vestibular disturbances.
They are least effective in the treatment of motion sickness.
All of them carry a risk of extrapyramidal disturbances,
dyskinesia and restlessness. Perphenazine is 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 cytotoxic
chemotheraphy, although they offer little advantage for
delayed emesis, occurring secondary to cytotoxic chemotherapy
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, dolasetron and
tropisetron.
CANNABINOIDS
Cannabis and its major constituent, D-9-tetrahydrocannabinol
(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 nabilone is not known, but an action on