Prolactin Inhibitors

PROLACTIN INHIBITORS

Bromocriptine

This synthetic ergot derivative 2bromoαergocryptine is a potent dopamine agonist; most of its actions are based on this property. It has greater action on D2 receptors, while at certain dopamine sites in the brain it acts as a partial agonist or antagonist of D1 receptor. It is also a weak α adrenergic blocker but not an oxytocic.

Actions

1.     Decreases prolactin release from pituitary by activating dopaminergic receptors on lactotrope cells—a strong antigalactopoietic.

2.     Increases GH release in normal individuals, but decreases the same from pituitary tumours that cause acromegaly.

3.     Has levodopa like actions in CNS—antiparkinsonian and behavioral effects.

4.     Produces nausea and vomiting by stimulating dopaminergic receptors in the CTZ.

5.     Hypotension—due to central suppression of postural reflexes and weak peripheral α adrenergic blockade.

6.     Decreases gastrointestinal motility.

Pharmacokinetics

Only 1/3 of an oral dose of bromocriptine is absorbed; bioavailability is further lowered by high first pass metabolism in liver. Even then, it has higher oral: parenteral activity ratio than ergotamine. Metabolites are excreted mainly in bile. Its plasma t½ is 3–6 hours.

PROCTINAL, PARLODEL, SICRIPTIN, BROMOGEN 1.25 mg, 2.5 mg tabs.

Uses

Bromocriptine should always be started at a low dose, 1.25 mg BD and then gradually increased till response occurs otherwise side effects become limiting.

1)    Hyperprolactinemia due to microprolactinomas causing galactorrhoea, amenorrhoea and infertility in women; gynaecomastia, impotence and sterility in men. Bromocriptine and cabergoline are the first line drug for most cases. Relatively lower doses (bromocriptine 2.5–10 mg/ day or cabergoline 0.25–1.0 mg twice weekly) are effective. Response occurs in a few weeks and serum prolactin levels fall to the normal range; many women conceive. Bromocriptine should be stopped when pregnancy occurs, though no teratogenic effect is reported. Most (60–75%) tumours show regression during therapy. However, response is maintained only till the drug is given—recurrences occur on stopping; lifelong maintenance therapy is needed.

2)    Acromegaly due to small pituitary tumours and inoperable cases. Relatively higher doses are required (5–20 mg/day) and it is less effective than somatostatin/octreotide. Oral administration and lower cost are the advantages..

3)    Parkinsonism Bromocriptine, if used alone, is effective only at high doses (20–80 mg/day) which produce marked side effects. However, response is similar to that of levodopa. It is now recommended in low dose only, as an adjunct to levodopa in patients not adequately benefited and in those showing marked ‘onoff’ effect.

4)    Hepatic coma: Bromocriptine may cause arousal.

5)    Bromocriptine suppresses lactation and breast engorgement in case of neonatal death, but not recommended due to unfavourable risk: benefit ratio.

Side Effects: Side effects are frequent and dose related.

Early: Nausea, vomiting, constipation, nasal blockage. Postural hypotension may be marked at initiation of therapy—syncope may occur if starting dose is high. Hypotension is more likely in patients taking antihypertensives.

Late: Behavioral alterations, mental confusion, hallucinations, psychosis—are more prominent than with levodopa.

Abnormal movements, livedo reticularis.

Cabergoline

It is a newer D2 agonist; more potent; more D2 selective and longer acting (t½ > 60 days) than bromocriptine; needs to be given only twice weekly. Incidence of nausea and vomiting is also lower; some patients not tolerating or not responding to bromocriptine have been successfully treated with cabergoline. It is being preferred for treatment of hyperprolactinemia and acromegali.

Dose: Start with 0.25 mg twice weekly; if needed increase after every 4–8 weeks to max. of 1 mg twice weekly.

CABERLIN 0.5 mg tab, CAMFORTE 0.5, 1 mg tabs.

Pergolide and Quinagolide are other D2 agonists effective in hyperprolactinemia.