Parlodel Mechanism of Action

Pharmacotherapeutic Group/ATC Code: Dopamine agonists (ATC code N04B C01), prolactin inhibitors (ATC code G02C B01).
Pharmacology: Pharmacodynamics: Mechanism of Action: Parlodel inhibits the secretion of the anterior pituitary hormone prolactin without affecting normal levels of other pituitary hormones. It can, however, reduce elevated levels of growth hormone (GH) in patients with acromegaly. These effects are due to stimulation of dopamine receptors.
In the puerperium prolactin is necessary for the initiation and maintenance of puerperal lactation. At other times increased prolactin secretion gives rise to pathological lactation (galactorrhea) and/or disorders of ovulation and menstruation.
As a specific inhibitor of prolactin secretion, Parlodel can be used to prevent or suppress physiological lactation as well as to treat prolactin-induced pathological states. In amenorrhea and/or anovulation (with or without galactorrhea), Parlodel can be used to restore menstrual cycles and ovulation.
Customary measures taken during lactation suppression, such as the restriction of fluid intake, are not necessary with Parlodel. In addition, Parlodel does not impair the puerperal involution of the uterus and does not increase the risk of thromboembolism.
Parlodel has been shown to arrest the growth or to reduce the size of prolactin-secreting pituitary adenomas (prolactinomas).
In acromegalic patients in addition to lowering the plasma levels of growth hormone and prolactin, Parlodel has a beneficial effect on clinical symptoms and on glucose tolerance.
Parlodel improves the clinical symptoms of the polycystic ovary syndrome by restoring a normal pattern of LH secretion.
Because of its dopaminergic activity, Parlodel, at doses usually higher than those for endocrinological indications, is effective in the treatment of Parkinson's disease, which is characterised by a specific nigrostriatal dopamine deficiency. In this condition, the stimulation of dopamine receptors by Parlodel can restore the neurochemical balance within the striatum.
Clinically, Parlodel improves tremor, rigidity, bradykinesia and other parkinsonian symptoms at all stages of the disease. Usually the therapeutic effectiveness lasts over years (so far, good results have been reported in patients treated for up to 8 years). Parlodel can be given either alone or at both early and advanced stages combined with other antiparkinsonian drugs. Combination with levodopa treatment results in enhanced antiparkinsonian effects, often making possible a reduction of the levodopa dosage. Parlodel offers particular benefit to patients on levodopa treatment exhibiting a deteriorating therapeutic response or complications such as abnormal involuntary movements (choreo-athetoid dyskinesia and/or painful dystonia), end-of-dose failure, and 'on-off' phenomenon.
Parlodel improves the depressive symptomatology often observed in parkinsonians. This is due to its inherent antidepressant properties as substantiated by controlled studies in non-parkinsonian patients with endogenous or psychogenic depression.
Clinical Studies: Parlodel is an established product. No recent clinical studies have been conducted.
Pharmacokinetics: Absorption: Parlodel is well absorbed after oral administration. When tablets or standard capsules are administered to healthy volunteers, the absorption half-life is 0.2 to 0.5 hours, and peak plasma levels of bromocriptine are reached within 1 to 3 hours. An oral dose of 5 mg of bromocriptine results in a C_max of 0.465 ng/mL. The prolactin-lowering effect begins within 1 to 2 hours of ingestion, reaches its maximum, i.e. a reduction of prolactin in the plasma by more than 80%, within 5 to 10 hours and remains close to maximum for 8 to 12 hours.
With Parlodel SRO capsules, a form designed for once-a-day administration, peak plasma levels are reached within 7 to 10 hours, and the maximal inhibitory effect on prolactin secretion, similar in magnitude to that achieved with tablets or standard capsules, occurs within 10 to 17 hours after the ingestion. As the period of time during which plasma concentrations higher than 50% of the maximal level are maintained for about 14.5 hours (compared with 3.5 hours with standard capsules), the duration of the prolactin-lowering effect is prolonged.
With single-dose administration the bioavailability of SRO capsules relative to the standard capsules is more than 90%. Under steady-state conditions, a slight reduction in bioavailability (to about 80%) is observed, but there is no loss of therapeutic effectiveness.
Food effect: The rate of absorption (C_max) of standard bromocriptine tablets/capsules may be reduced by food to an extent of 10-40%. However, the bioavailability (AUC) of standard tablets/capsules is not significantly influenced. Food has no impact on rate and extent of absorption for modified release bromocriptine. Overall, there is no clinically significant effect of food on Parlodel and Parlodel SRO formulations.
Distribution: Plasma protein binding is 96%.
Biotransformation/Metabolism: Bromocriptine undergoes extensive first-pass biotransformation in the liver, reflected by complex metabolite profiles and by almost complete absence of parent drug in urine and feces. It shows a high affinity for CYP3A and hydroxylations at the proline ring of the cyclopeptide moiety constitute a main metabolic pathway. Inhibitors and/or potent substrates for CYP3A4 might therefore be expected to inhibit the clearance of bromocriptine and lead to increased levels. Bromocriptine is also a potent inhibitor of CYP3A4 with a calculated IC50 value of 1.69 microM. However, given the low therapeutic concentrations of free bromocriptine in patients, a significant alteration of the metabolism of a second drug whose clearance is mediated by CYP3A4 should not be expected.
Elimination: The elimination of the parent drug from plasma is biphasic, with a terminal half-life of about 15 hours (range 8 to 20 hours). Parent drug and metabolites are almost completely excreted via the liver, only 6% being eliminated via the kidney.
Special Populations: Geriatric patients (65 years of age or above): The effect of age on the pharmacokinetics of bromocriptine and its metabolites has not been evaluated.
Hepatic Impairment: In patients with impaired hepatic function, the speed of elimination may be retarded and plasma levels may increase.
Renal Impairment: The effect of renal function on the pharmacokinetics of bromocriptine has not been evaluated. The parent drug and metabolites are almost completely excreted via liver, and only approx. 6% eliminated via the kidney. Therefore, impact on patients with renal impairment is less likely.
Toxicology: Non-Clinical Safety Data: Pre-clinical data for Parlodel (bromocriptine) reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity, genotoxicity, mutagenicity, carcinogenic potential, or toxicity to reproduction.
Effects in pre-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
Uterine carcinomas were observed in pre-clinical rat studies at high dosages only. They are considered to be due to the species-specific sensitivity of the test animals to the pharmacological activity of bromocriptine.