Bromocriptine

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BROMOCRIPTINE:

BROMOCRIPTINE BY SHASHIDHAR PATIL

Bromocriptine:

Bromocriptine Bromocriptine is a D2 agonist This drug has been widely used to treat Parkinson's disease and has also been used to treat certain endocrinologic disorders,especially hyperprolactinemia but in lower doses than for parkinsonism . Bromocriptine is absorbed to a variable extent from the gastrointestinal tract; peak plasma levels are reached within 1–2 hours after an oral dose. It is excreted in the bile and feces.

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Dopamine agonists may cause nausea, headache, lightheadedness, orthostatic hypotension, and fatigue . Psychiatric manifestations occasionally occur even at lower doses and may take months to resolve . Erythromelalgia occurs rarely. High dosages of ergot-derived preparations may cause coldinduced peripheral digital vasospasm. Pulmonary infiltrates may occur with chronic high-dosage therapy

BROMOCRIPTINE:

BROMOCRIPTINE It is synthetic ergot dervative , 2 bromo -alpha- ergocryptine It is a potent dopamine agnoist It has greater action on D2 receptors,while at certain dopamine sites it acts as partial agnoist or antagonist of D1 receptor. It is also a weak alpha adrnergic blockerbut not on oxytocic

The Ergot Alkaloids :

The Ergot Alkaloids Ergot alkaloids are produced by Claviceps purpurea , a fungus that infects grain—especially rye— under damp growing or storage conditions. This fungus synthesizes histamine, acetylcholine, tyramine , and other biologically active products in addition to a score or more of unique ergot alkaloids . These alkaloids affect adrenoceptors , dopamine receptors, 5-HT receptors, and perhaps other receptor types. Similar alkaloids are produced by fungi parasitic to a number of other grasslike plants .

Major Ergoline Derivatives (Ergot Alkaloids).:

Major Ergoline Derivatives (Ergot Alkaloids).

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The ergot alkaloids are variably absorbed from the gastrointestinal tract . The oral dose of ergotamine is about ten times larger than the intramuscular dose, but the speed of absorption and peak blood levels after oral administration can be improved by administration with caffeine The amine alkaloids are also absorbed from the rectum and the buccal cavity and after administration by aerosol inhaler. Absorption after intramuscular injection is slow but usually reliable . Bromocriptine and the amine derivative cabergoline are well absorbed from the gastrointestinal tract.

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The ergot alkaloids are extensively metabolized in the body. The primary metabolites are hydroxylated in the A ring, and peptide alkaloids are also modified in the peptide moiety.

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The endogenous catecholamine dopamine produces a variety of biologic effects that are mediated by interactions with specific dopamine receptors There is extensive polymorphic variation in the D4 human receptor gene.

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The terminology of the various subtypes is D1, D2, D3, D4, and D5. They comprise two D1-like receptors (D1 and D5) and three D2-like (D2, D3, and D4). These subtypes may have importance for understanding the efficacy and adverse effects of novel antipsychotic drugs

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Dopamine, the immediate metabolic precursor of norepinephrine, activates D1 receptors in several vascular beds, which leads to vasodilation . The activation of presynaptic D2 receptors, which suppress norepinephrine release, contributes to these effects to an unknown extent. Dopamine activates 1 receptors in the heart. At low doses, peripheral resistance may decrease. At higher rates of infusion, dopamine activates vascular receptors, leading to vasoconstriction, including in the renal vascular bed. Consequently, high rates of infusion of dopamine may mimic the actions of epinephrine.

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Receptor Agnoist Antagonist Effect Gene on chromosome

MECHANISM OF ACTION:

MECHANISM OF ACTION As suggested above, the ergot alkaloids act on several types of receptors. Their effects include agonist , partial agonist, and antagonist actions at adrenoceptors and serotonin receptors ( especially 5-HT1A and 5-HT1D; less for 5-HT1C, 5-HT2, and 5-HT3); and agonist or partial agonist actions at central nervous system dopamine receptors

Actions of bromocriptine:

Actions of bromocriptine Decerases prolactin release from pituitary by activating dopaminergic receptors on lactotrope cells-a strong antigalactopoietic Increases growth hormone release in normal individuals but decerases the same from pituitary tumors causing acromegaly Has levodopa like action in CNS- antiparkinsonian and behavourial effects Produces nausea and vomitting by stimulating dopaminergic receptors in CTZ

Actions cont’d:

Actions cont’d Hypotension – due to central suppression of postural reflexes and weak peripheral alpha blockade Decerases gasrtointestinal motility

pharmacokinetics:

pharmacokinetics Only 1/3 of bromocriptine is absorbed orally Bioavailability is further lowered by high first pass metebolism in liver Its plasma half life is 3 hours It is mainly excereted in bile

uses:

uses Hyperprolactinemia Parkinsons disease Acromegaly Hepatic coma Supression of lactation and Breast engorgement

hyperprolactinemia:

hyperprolactinemia Oral dopamine agonists are the mainstay of treatment for patients with micro or macro prolactinomas Dopamine agonists suppress PRL secretion and synthesis as well as lactotrope cell proliferation. About 20 % of patients are resistant to dopaminergic treatment; these adenomas may exhibit decreased D2 dopamine receptor numbers or a postreceptor defect. D2 receptor gene mutations in the pituitary have not been reported

Medical Therapy:

Medical Therapy Bromocriptine Pergolide Quinagolide Cabergoline

Bromocriptine:

Bromocriptine Serum levels peak after 3 hour, action is observed at 7 hour Continued biologic effect even with undetectable serum levels Considerable interindividual variability, implying differences in sensitivity to the drug Not only decreases prolactin synthesis but also prolactin mRNA and DNA synthesis, cell multiplication and tumor growth When bromocriptine stop, rapid regrowth of tumor cell but not always occur if longer periods of treatment

Treatment to reduce Hyperprolactinemia:

Treatment to reduce Hyperprolactinemia Normal prolactin levels were achieved only in 70-80% Substantial reductions in prolactin levels to still slightly elevated levels often enough to restore ovulation and menses 80-90%

Bromocriptine Resistance:

Bromocriptine Resistance 5-10% do not respond to bromocriptine or only minimal responses Decreased numbers of dopamine receptors Also defects in posttranscriptional splicing

uses:

uses Bromocriptine is used to treat galactorrhoea and cyclical benign breast disease. It was widely used for many years to suppress lactation after childbirth, but its use for this purpose is now discouraged

Effect on lactation :

Effect on lactation Milk formation during late pregnancy occurs under the combined stimulus of oestrogens , prolactin (placental lactogen ) and progesterone. Insulin and cortisol may also have a role. Oestrogens antagonise the effects of prolactin on milk secretion and lactation is stimulated when oestrogen levels fall after delivery. Oestrogens were once used widely to suppress lactation in the puerperium , but they were found to be relatively ineffective, and to increase the risk of potentially life threatening thromboembolism.

cabergoline:

cabergoline An ergoline derivative, cabergoline is a long-acting dopamine agonist with high D2 receptor affinity. The drug effectively suppresses PRL for >14 days after a single oral dose and induces prolactinoma shrinkage in most patients. Cabergoline ( 0.5 to 1.0 mg twice weekly) achieves normoprolactinemia and resumption of normal gonadal function in ~80% of patients with microadenomas ; galactorrhea improves or resolves in 90% of patients. Cabergoline normalizes PRL and shrinks ~70% of macroprolactinomas . Mass effect symptoms, including headaches and visual disorders, usually improve dramatically within days after cabergoline initiation

Bromocriptine:

Bromocriptine Because it is short-acting , the drug is preferred when pregnancy is desired. In microadenomas bromocriptine rapidly lowers serum prolactin levels to normal in up to 70% of patients, decreases tumor size, and restores gonadal function. In patients with macroadenomas , prolactin levels are also normalized in 70% of patients and tumor mass shrinkage ( 50%) is achieved in up to 40% of patients. Therapy is initiated by administering a low bromocriptine dose (0.625–1.25 mg) at bedtime with a snack, followed by gradually increasing the dose. Most patients are successfully controlled with a daily dose of 7.5 mg (2.5 mg tid ).

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More recently, reports have appeared of mothers having seizures, strokes, heart attacks and sudden severe hypertension while taking bromocriptine to suppress lactation Cabergoline (q.v.) is a more recently introduced analogue with a longer half life. It seems to be relatively free from the problems associated with the use of bromocriptine to suppress lactation

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Bromocriptine 2.5 mg twice a day for 2 weeks speeds the suppression of lactation, although milk production almost always increases again for a time after treatment is stopped.

acromegaly:

acromegaly Bromocriptine and cabergoline may suppress GH secretion in some patients, particularly those with cosecretion of PRL. High bromocriptine doses ( 20 mg/d) are usually required to achieve modest GH therapeutic efficacy. Cabergoline also modestly suppresses GH when given at a relatively high dose of 0.5 mg/d. Combined treatment with octreotide and cabergoline may induce additive biochemical control compared to either drug alone.

Parkinsons disease:

Parkinsons disease Bromocriptine,if used alone is effective only at high dose (20-80mg/day) which produces marked side effects However response is similar to that of levodopa It is now recomonded in low doses only ,as an adjuvnt to levodopa in patients not adequately benefited and in those showing marked on and off effects

Pharmacotherapy :

Pharmacotherapy Levodopa Dopamine agonists COMT inhibitors Amantadine Anticholinergics Selegiline

Dopamine Agonists “Synthetic Dopamine”:

Dopamine Agonists “Synthetic Dopamine” Bromocriptine Mesylate (Parlodel) Pergolide Mesylate (Permax) Pramipexol (Mirapex) Ropinirole HCL (Requip)

Dopamine Agonists:

Dopamine Agonists Monotherapy or combination Are particulary usefull for: Prolonging the effective treatment period in patients with deteriorating response. Delaying the onset of L-dopa therapy. Particularly in younger patients. Treating patients who cannot tolerate high doses of L-dopa. Associated with more side effects than L-dopa Potential adverse effects include somnolence, dyskinesias, nausea, vomiting, orthostatic hypotension, nightmares, hallucinations, confusion, dizziness

Ergot Agonist Dosing:

Ergot Agonist Dosing Bromocriptine (Parlodel) Initial 1.25mg QD-BID Titrate 1.25mg to 2.5mg/d every week Average dose <30mg/day. Some patients may require up to 120mg/day Pergolide (Permax) 13 times more potent than bromocriptine Initial 0.05mg/d for 2 days, increasing by 0.1 to 0.15mg/d every 3 days over a 12 day period May increase by 0.25mg every 3 days until symptoms are eliminated or adverse effects occur Mean dose 3mg/d

Adverse effects:

Adverse effects abdominal pain constipation depression diarrhea dizziness or lightheadedness, especially when rising from a lying or sitting position (more common during the first few days of treatment )- postural hypotension drowsiness or tiredness dry mouth leg cramps at night loss of appetite nausea or vomiting stuffy nose tingling or pain in fingers and toes when exposed to cold

Bromocriptine should not be taken by anyone who:

Bromocriptine should not be taken by anyone who is allergic to bromocriptine , other ergot alkaloids, or any of the ingredients of this medication has coronary artery disease and other severe heart conditions has high blood pressure after giving birth has high blood pressure disorders of pregnancy has symptoms or history of serious psychiatric disorders has uncontrolled high blood pressure

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