Anti-dopaminergics

Dopamine plays an important role in the chemoreceptor trigger zone and the area postrema, hence almost all drugs that antagonize D2 receptors have anti-emetic properties. Dopamine antagonists used clinically as anti-emetics include:

- Phenothiazines
- Butyrophenones
- Benzamides

A] Phenothiazines

[i] Chlorpromazine

Structure



Uses: In the prevention and treatment of nausea and vomiting associated with terminal illness, schizophrenia and intractable hiccup.

Chemical: Phenothiazine (aliphatic side chain).

Presentation: Tablets (10/25/50/100 mg), syrup (5 mg/ml) and straw coloured solution for injection (25 mg/ml).

Mode of action: Antiemetic effects are due to central dopaminergic blockade. Results in an increased threshold for vomiting at the chemoreceptor trigger zone.

Dose: Adult oral dose is 10-50 mg 8 hourly. IM/IV dose is 25-50 mg 8 hourly.

Effects

CVS: Negative inotropy. Postural hypotension with reflex tachycardia. May cause prolongation of the P-R and Q-T intervals, flattening of T waves and S-T depression.

Respiratory: Respiratory depression, reduced bronchial secretions.

CNS: Potent sedative and anxiolytic effect. Lowers seizure threshold.

Gastrointestinal: Increases appetite. Decreases salivation, gastric secretion and GI motility.

Toxicity: May produce extrapyramidal syndromes and anticholinergic effects. Jaundice and blood dyscrasias may occur with usage.

Absorption: Good oral absorption but prone to extensive first-pass metabolism (bioavailability 30%).

Distribution: 95% protein bound. Volume of distribution 10-30 L/kg.

Metabolism: Hepatic metabolism. Undergoes oxidation, dealkylation, demethylation and hydroxylation. Many active metabolites.

Excretion: 1% excreted unchanged in the urine. Clearance is 5-11 ml/min/kg. Elimination half life is 30 hours. Not removed by haemodialysis.

[i] Ondansetron versus chlorpromazine for preventing emesis in bone marrow transplant recipients: a double-blind randomized study.
Bosi A et al.
J Chemother 1993; 5(3): 191-6.


ii] Prochlorperazine

Uses: Symptomatic treatment of nausea and vomiting, vertigo, mania and schizophrenia.

Chemical: Phenothiazine of the piperazine sub-class.

Presentation: Tablets (3/5/25 mg), syrup 1 mg/ml, suppositories (5/25 mg) and a clear colourless solution for injection (12.5 mg).

Mode of action: Antagonism of central dopaminergic D2 receptors. Higher doses have an inhibitory effect at the vomiting centre.

Dose: Adult dose is 5-20 mg 8-12 hourly, IM dose is 12.5 mg (6 hourly).

Effects

CVS: Orthostatic hypotension (due to alpha-adrenergic blockade). ECG changes associated with its use include an increased Q-T interval, ST depression and T and U wave changes.

Respiratory: Mild respiratory depression.

CNS: Some neuroleptic effects.

Gastrointestinal: Increases lower oesophageal sphincter tone.

Toxicity: May produce extrapyramidal reactions. The drug causes an increase in prolactin. Jaundice, leucopenia and neuroleptic malignant syndrome may occur with its use.

Absorption: Poor oral absorption (bioavailability 0-15%).

Distribution: Volume of distribution 20 L/kg.

Metabolism: Hepatic first-pass metabolism.

[i] Comparison of ondansetron and prochlorperazine for the prevention of nausea and vomiting after adenotonsillectomy.
van den Berg AA.
Br J Anaesth 1996; 76(3): 449-51.

B] Butyrophenones

i] Droperidol

Structure:



Uses: Premedication, neuroleptanalgesia, treatment of nausea and vomiting, treatment of psychosis, treatment of hiccups.

Chemical: Butyrophenone derivative.

Presentation: 10 mg tablets, a syrup containing 1 mg/ml and as a clear solution for injection.

Mode of action: Antagonism of central dopaminergic D2 receptors. Also post-synaptic GABA antagonism.

Dose: Adult dose is 5-10 mg 8-12 hourly. Anti-emetic effects occur with low doses, 0.5 mg.

Effects

CVS: Hypotension may occur (due to alpha-adrenergic blockade).

Respiratory: Mild decrease in minute volume, functional residual capacity and airways resistance.

CNS: Some neuroleptic effects.

Toxicity: May produce extrapyramidal reactions. The drug causes abnormalities of liver function tests and allergy.

Absorption: Good IM absorption.

Distribution: 90% protein bound. Volume of distribution 2.5 L/kg.

Metabolism: Hepatic metabolism.

Droperidol has been discontinued since 31 March 2001. The manufacturer chose voluntarily to discontinue the drug following an extensive risk-benefit assessment. The manufacturer concluded that the oral formulations should be discontinued to prevent use in chronic conditions and that the injectable form would no longer be commercially viable. This arose from The Medicines Control Agency (MCA) raising concerns about the potential effect of droperidol on the cardiac QT interval.

ii] Domperidone

Structure

Uses: Symptomatic treatment of nausea and vomiting.

Chemical: Butyrophenone derivative.

Presentation: Tablets (10 mg), suspension 1 mg/ml, suppositories also available. Intravenous preparation no longer available due to reports of cardiac arrest post rapid IV bolus.

Mode of action: Antagonism of peripheral dopaminergic D2 receptors. Results in increased gastrointestinal motility and tone. Also has a central antiemetic effect.

Dose: Adult oral dose is 10-20 mg, suppository 60 mg (4-8 hourly).

Effects

CVS: Nil

Respiratory: Nil

CNS: Does not readily cross the blood-brain barrier, hence nil.

Gastrointestinal: Increases lower oesophageal sphincter tone and the rate of gastric emptying.

Toxicity: May produce extrapyramidal reactions. Galactorrhoea and gynaecomastia may occur with usage. The drug causes an increase in prolactin.

Absorption: Poor oral absorption due to extensive first-pass metabolism (bioavailability 10-15%).

Distribution: 92% protein bound. Volume of distribution 6 L/kg.

Metabolism: Hepatic metabolism. 90% undergoes oxidative N-dealkylation and hydroxylation.

Excretion: 30% excreted in the urine, 60% in the faeces. Elimination half life is 7 hours.

References

[i] Domperidone: a peripherally acting dopamine2-receptor antagonist.
Barone JA.
Ann Pharmacother 1999; 33(4): 429-40. Review.

[ii] Comparison of the use of domperidone, droperidol and metoclopramide in the prevention of nausea and vomiting following gynaecological surgery in day cases.
Madej TH, Simpson KH.
Br J Anaesth 1986; 58(8): 879-83.

[iii] Nausea and vomiting during spinal anaesthesia. Effect of metoclopramide and domperidone: a double-blind trial.
Spelina KR
Anaesthesia 1984; 39(2): 132-7.

C] Benzamides

i] Metoclopramide

Structure:



Uses: Symptomatic treatment of nausea and vomiting, digestive disorders (hiatus hernia, reflux), migraine and postoperative gastric hypotonia.

Chemical: Chlorinated procainamide derivative.

Presentation: Tablets (10 mg), slow-release capsules (15/30 mg), syrup 1 mg/ml and a clear, colourless solution for injection (5 mg/ml).

Mode of action: Antagonism of peripheral dopaminergic D2 receptors. Results in increased gastrointestinal motility and tone. Antiemetic effects possibly mediated by central dopaminergic (D2) blockade and a decrease in sensitivity of visceral nerves supplying afferents to the vomiting centre.

Dose: Adult oral dose/iv/im is 10 mg (8 hourly). Cisplatin induced nausea and vomiting, dose of 1-2 mg/kg is recommended.

Effects

CVS: Hypotension has been noted.

Respiratory: Nil

CNS: Neuroleptic effects due to central anti-dopaminergic effects.

Gastrointestinal: Increases lower oesophageal sphincter tone and the rate of gastric emptying.

Toxicity: May produce extra-pyramidal reactions e.g. oculogyric crisis.The drug causes an increase in prolactin.

Absorption: Rapid oral absorption (bioavailability 30-95%).

Distribution: 10-20% protein bound. Volume of distribution 2-3.5 L/kg.
Metabolism: Hepatic metabolism. Major metabolite is sulphate derivative.

Excretion: 80% excreted in the urine, 20% of which is unchanged. Remainder is non-metabolised drug conjugated to a sulphate or glucoronide. Elimination half life is 2.5-5 hours. Not removed by haemodialysis.

[i] Metoclopramide in the prevention of postoperative nausea and vomiting: a quantitative systematic review of randomized, placebo-controlled studies.
Henzi I et al.
Br J Anaesth 1999; 83(5): 761-71.

[ii] Ondansetron is more effective than metoclopramide for the treatment of opioid-induced emesis in post-surgical adult patients. Ondansetron OIE Post-Surgical Study Group.
Chung F et al.
Eur J Anaesthesiol 1999; 16(10): 669-77.

[iii] Antiemetic efficacy of prophylactic ondansetron in laparoscopic surgery: randomized, double-blind comparison with metoclopramide.
Raphael JH, Norton AC.
Br J Anaesth 1993; 71(6): 845-8. 

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