Bromociptine is the drug that will be discussed here since it was the first drug used in treatment of hyperprolactinemia . It is formulated into Oral tablets and capsules.
2.5mg, 30mg, 60mg
5mg, 10mg, 60mg, 100mg
Trade name used currently (2010) in Fiji is Kripton and Parlodel. Mesilate is the salt or ester used in Bromocriptine tablet and capsules formulation. Hence the preparation sometimes is referred as Bromcriptine Mesilate tablet or capsule.
Bromocriptine Mesilate given through oral route and 30% of the dose is absorbed in gastrointestinal tract with peak plasma concentration reaching in 1 to 3 hours (Sweetman 2007). However its bioavailability is only 6% owing extensive first - pass effect in liver. Lysergic acid and peptides are major metabolites produced when Bromocriptine goes under metabolism in liver. Lysergic acid is responsible for its hallucinogenic and psychedelic properties(Sweetman 2007).
Bromocriptine elimination is biphasic with half lifes about 4 to 4.5hours and 15 hours for two phases (Sweetman 2007).
Fraction excreted unchanged
Bromocriptine being dopamine agonist mimics action of endogenous Dopamine. Type-2 Dopamine receptors are located on lactrotroph of anterior pituitary glands. According to Ben-Jonathan N 2001, these receptors are linked functionally to membrane channel and G-protein and binding of dopamine suppressesses the high intrinsic secretory activity of the pituitary lactotrophs. However exact mechanism of action is less understood. Author states that inhibitory action is due to decreased adenylyl cyclase activity which lowers inositol phosphate metabolism and leads to change in gene expression and subsequent decrease in lactotroph proliferation (Ben-Jonathan N 2001). Hence decrease in prolactin secretion. Detailed mechanism is shown below.
In year 1990, another mechanism was proposed by Lledo P-M, Legendre P, Israel J-M, Vincent J-D which stated that Dopamine reduced intracellular free calcium levels. This is due to coupling of D2 receptor to voltage gated calcium channels. Calcium is a substrate for phosphorylation/dephosphorylation by Protein Kinase A and Protein Kinase C (Lledo P-M 1990). However in 2001, Gregerson KA proposed that dopamine cause membrane hyperpolarization via inward rectifying current that increase potassium conductance which reduces intracellular Calcium ions (KA 2001). Since Prolactin release is coupled to Calcium, any decrease in Calcium will decrease Prolactin secretion (Ben-Jonathan N 2001)
Bromocriptine, Cabergoline and Pergolide are Ergot derivative Dopamine agonist. Neither of the above-mentioned drugs is absolutely specific for any dopamine receptor subtype, and their selectivity is based on differences in binding affinity and dissociation constants to the various receptors (Ben-Jonathan N 2001). Bromocriptine inhibits secretion of Prolactin from anterior pituitary glands. Inhibition is a result of interaction between Dopamine agonist and D 2 receptors on lactotropes of anterior pituitary. Dopamine is secreted by both hypothalamus and the posterior pituitary (Vander, Sherman and Luciano n.d.). Dopamine agonist in this section is discussed in context to its role in endocrine system. However dopamine as a neurotransmittor is also active in various dopaminergic neural pathways. Due to this reason, administration of Dopamine agonist will show Central Nervous System related side-effects such as dizziness and drowsiness.
Adverse effects of Dopamine Agonist (Bromocriptine) are as follows :
* Orthostatic hypotension (Neurodegenerative Diseases 2008)
Dosage of Bromociptine should be carefully monitored to prevent overdosing which can lead to extreme adverse effects in body.
* peripheral oedema
* retroperitoneal fibrosis (Australian Medicine Handbook 2010)
Clinical Aspects and Indications
Bromocriptine is manufactured with mesilate ester which and given by mouth. About 2.87mg of Bromocriptine mesilate is equivalent to 2.5mg of Bromocriptine (Sweetman 2007). Dopamine agonist is effective in conditions characterized by excess Prolactin. Bromocriptine is indicated for acromegaly, hyperprolactinaemia including prolactinomas (Australian Medicine Handbook 2010); hypogonadism and galactorrhoea syndromes and infertility, cyclical benign breast and menstrual disorders, prevention of puerperal lactation, suppression of established lactation (Sweetman 2007).
1.25mg 2 or 3 times daily, increase gradually up to 2.5mg 2 to 3 times daily.
Prevention of puerperal lactation
2.5mg on the day of delivery
followed by 2.5mg twice daily for 14 days
Suppression of established lactation
2.5mg daily for 2 to 3 days
Hypogonadism and galactorrhoea syndromes and infertility
7.5mg - 30mg daily
Cyclical benign breast and menstrual disorders
2.5mg twice daily
Acromegalic adjuvant with radio therapy
1.25mg once daily upto 10-30mg daily gradually. (Australian Medicine Handbook 2010)
* Sensitivity to ergot alkaloids
* Severe ischemic heart disease or peripheral vascular disease - bromocriptine has tendency to increase blood pressue (Baxter 2008). Increase blood pressure may worsen vascular disease state.
* Pituitary tumor should be evaluated before starting treatment with Bromocriptine (Bromocriptine 2003)
Major interaction of Bromocriptine with other drugs.
Anti-emetic - Dopamine Antagonist (Metaclopromide, Domperidone)
Reduce Prolactin levels
Dopamine antagonist can increase Prolactin secretion.
Macrolides - Eryhthromycin
Increase plasma Bromocriptine levels
Erythromycin inhibits metabolism of Bromocriptine
Australian Medicine Handbook. 2010. Adelaide: Australian Medicine Handbook Pty Ltd, 2010.
Baxter, Karen, ed. Stockley's Drug Interactions. Pharmaceutical Press, 2008.
Ben-Jonathan N, Hnasko R. "Dopamine as a Prolactin (PRL) Inhibitor." Endocrine Reviews 22, no. 6 (December 2001): 724-763.
"Bromocriptine." In A to Z Drug Facts, edited by David S. Tatro. Facts and Comparisons, 2003.
KA, Gregerson. "Mechanism of dopamine action on the lactotrophs." (Boston: Kluwer) 2001.
Lledo P-M, Legendre P, Israel J-M, Vincent J-D. "Dopamine inhibits two Characterized voltage-dependent calcium currents in identified rat lactotroph cells." Endocrinology (The Endocrine Society) 127 (1990): 990-1001.
"Neurodegenerative Diseases." In Lippincott's Illustrated Reviews Pharmacology, edited by Richard Finkel, Michelle A. Clark and Luigi X Cubeddu, 101. Lippincott Williams & Wilkins, 2008.
Sansom, Prof.Lloyd, ed. Australian Pharmaceutical Formulary and Handbook. 21th. Pharmaceutical Society of Australia, 2009.
Sweetman, Sean C, ed. Martindale: The Complete Drug Reference. 35th. II vols. Pharmaceutical Press, 2007.
Vander, Sherman, and Luciano. "Reproduction." In Human Physiology, 884.