PROBLEM-BASED LEARNING; PARKINSONS DISEASE

DOMPERIDONE

By: Faisal Zahidi 1008-1835

Mechanism of Action
Domperidone is a dopamine type 2-receptor antagonist. Structurally related to the butyrophenones (Haloperidol, Droperidol; antipsychotics). Does not normally cross the BBB. Peristaltic stimulant. Dual anti-emetic effect.

Mechanism of Action

1
blocks dopamine receptor in the CTZ

2
blocks D2 receptors at the gastrooesophageal and gastroduodenal junction

Anti-Emetic effect

counteracts "dopamine brake"

Anti-Emetic effect

Indications
Treatment of nausea and vomiting of various origins including functional, organic, infectious, dietetic origin, or induced by radiotherapy or medicine therapy. Epigastric sense of fullness, feeling of abdominal distension, upper abdominal pain, eructation, flatulence, heartburn.

Dosing & Available DF

Available in tablets, suppositories, suspensions. By mouth: ADULT and CHILD body weight over 35kg, 10-20mg, 3-4 times daily, max 80mg daily. CHILD body weight up to 35kg, 250500mcg/kg, 3-4 times daily, max 2.4mg/kg daily. By rectum: ADULT and CHILD body weight over 35kg, 60mg twice daily. CHILD 15-35kg, 30mg twice daily. CHILD body weight under 15kg, not recommended.

Pharmacokinetic Profile
Absorption: rapidly absorbed, peaks at 30-60 minutes. Undergoes extensive 1st pass metabolism, but enhanced F if taken after a meal Distribution: 91-93% protein bound. Metabolism: metabolised by CYP450, undergoes N-Dealkylation, hydroxylation. Elimination: 31% urinary, 66% fecal, T1/2 is 79 hrs but prolonged in renal insufficiency.

Special Precautions
Hepatic Impairment:
the AUC and Cmax of domperidone is 2.9- and 1.5-fold higher, respectively. The unbound fraction is increased by 25% terminal elimination half-life is prolonged from 15 to 23 hours.

Renal impairment:
severe renal insufficiency (serum creatinine > 6 mg/100 mL, i.e., > 0.6 mmol/L) the half-life of domperidone is increased from 7.4 to 20.8 hours.

Special Precautions
Use in Pregnancy
Domperidone should only be used during pregnancy when justified by the anticipated therapeutic benefit.

Use in Lactation
Therefore breast-feeding is not recommended for mothers who are taking Domperidone.

Use in Infants
Domperidone tablets are unsuitable for use in children weighing less than 35 kg.

Contraindications
Known hypersensitivity to domperidone or any of the excipients. Prolactin-releasing pituitary tumour (prolactinoma) Co-administration with CYP3A4 inhibitors whichh prolongs the QTc interval (erythromycin, fluconazole, voriconazole, clarithromycin, amiodarone, and telithromycin)

Contraindications
Should not be used whenever stimulation of gastrointestinal motility might be dangerous such as in the presence of gastrointestinal haemorrhage, mechanical obstruction, or perforation. In patients with moderate or severe hepatic impairment.

Side Effects
Very common (>10%): gynaecomastia, galactorrhoea, amenorrhoea (secondary to increased prolactin secretion), reduced libido, transient colic. Common (<10%, >1%): pruritus, rash, cramp, headache. Very rare (<0.01%): extrapyramidal effects (acute dystonias), which resolve rapidly and completely once domperidone is stopped.14 In two women with polycystic ovaries, hyperoestrogenism may have been a predisposing factor.

Adverse Effects
Very rare case reports of QTc prolongation, ventricular arrhythmia, and sudden death (usually via IV route). Extrapyramidal disorder in neonates. CNSrelated effects of convulsion and agitation in infants and children.

Warning
Cardiovascular effects Domperidone should be used with caution in older patients, or those with current or history of cardiac disease. (increase in the risk of serious ventricular arrhythmias and sudden cardiac death) Use of Domperidone and other drugs in patients with significant electrolyte disturbances or CHF and existing prolongation of cardiac conduction intervals, particularly QTc, (prolonged QTc)

Warning
Lactose Intolerance Tablet contains lactose, may be unsuitable for patients with lactose intolerance, galactosemia or glucose/galactose malabsorption. Antacids or antisecretory agents Should not be taken simultaneously with Domperidone, as they lower the oral bioavailability. Prolactin levels Domperidone produces an increase in plasma prolactin.

Drug Interactions
Anticholinergic drugs (concomitant use): may antagonise the anti-dyspeptic effect of Domperidone. Atropine: Domperidone reduces the relaxant effect of atropine upon the lower oesophageal sphincter, but has no reversing effect if atropine is administered first. Antacids or antisecretory agents: lower the oral bioavailability of Domperidone. CYP450 inhibitors: increased plasma levels of domperidone.

Other Uses
Concomitant use with Neuroleptics, without potentiation of their activity. Concomitant use with Dopaminergic agonists (bromocriptine, L-dopa) for suppression of unwanted peripheral effects such as digestive disorders, nausea and vomiting, without affecting their central activity. Promotes milk production in breast feeding mothers.

Overdose/Toxicity
Symptoms
Overdose has been reported primarily in infants and children. Agitation, altered consciousness, convulsion, disorientation, somnolence and extrapyramidal reactions.

Overdose/Toxicity
Treatment of Overdose
There is no specific antidote Gastric lavage within one hour of ingestion as well as the administration of activated charcoal may be useful. Anticholinergics, anti-Parkinsonian agents may be helpful in controlling the extrapyramidal reactions. Close observation and supportive therapy is recommended.

Related Article
Domperidone and levodopa in Parkinson's disease. Shindler JS, Finnerty GT, Towlson K, Dolan AL, Davies CL, Parkes JD.

Domperidone slightly increases the immediate bioavailability (over 4 h) and antiparkinsonian response to a given dose of Levodopa.