Medocriptine

Indications

• Hyperprolactinaemia
• Acromegaly
• Parkinson's disease
• Suppression of lactation
• Infertility
• Hypogonadism
• Galactorrhoea

Dosage

Adults: Initially 2.5 mg daily for the first day, then 2.5 mg twice daily for 14 days for lactation suppression. For hyperprolactina

Mechanism of action

Bromocriptine stimulates dopamine D2 receptors, which are G-protein coupled receptors. This activation inhibits adenylyl cyclase, decreasing intracellular cAMP levels and blocking Ca2+ release from intracellular stores. The decrease in intracellular calcium levels also occurs via inhibition of voltage-gated calcium channels. Additionally, bromocriptine affects MAPK signaling pathways, which contribute to its pharmacological effects in both pituitary function and movement disorders.

Pharmacodynamics

Bromocriptine exerts its effects by stimulating centrally-located dopaminergic receptors, particularly the D2 and D3 receptors, which are crucial for managing symptoms of movement disorders. It exhibits agonist activity on dopamine receptors that leads to improvements in motor coordination, while also providing neuroprotective effects through presynaptic receptor stimulation. Its actions result in reduced prolactin levels and symptom relief in various conditions associated with dopaminergic dysfunction.

Pharmacokinetics

Bromocriptine is well absorbed from the gastrointestinal tract, with peak plasma concentrations typically occurring within 1 to 3 hours after oral administration. It has a half-life of approximately 6 hours. The drug is metabolized in the liver and excreted primarily in the bile, with a small amount eliminated in the urine. Individual pharmacokinetics may vary based on factors such as age, liver function, and the presence of other medications.

Contra-indications

• Cardiac valvulopathy
• Hypertension in postpartum women or in puerperium
• Hypertensive disorders of pregnancy (e.g. pre-eclampsia, eclampsia or pregnancy-induced hypertension)
• History of severe cardiovascular conditions, including coronary artery disease
• History of serious mental disorders

Adverse effects

• Constipation
• Drowsiness
• Headache
• Nasal congestion
• Nausea
• Allergic dermatitis
• Alopecia
• Confusion
• Dizziness
• Dry mouth
• Fatigue
• Hallucination
• Hypotension
• Abdominal pain
• Arrhythmias
• Cardiac valvulopathy
• Movement disorders
• Vomiting

Interactions

• Dronedarone: Unknown (increases exposure)
• Antifungals (azoles): Unknown (increases exposure)
• Cobicistat: Unknown (increases exposure)
• Crizotinib: Unknown (increases exposure)
• Idelalisib: Unknown (increases exposure)
• Imatinib: Unknown (increases exposure)
• Letermovir: Unknown (increases exposure)
• Memantine: Unknown (increases effects)
• Metoclopramide: Unknown (decreases effects)
• Nilotinib: Unknown (increases exposure)

Precautions

• Caution in patients with a history of cardiovascular disease
• History of peptic ulcer (especially in acromegalic patients)
• Raynaud’s syndrome
• Monitor for signs of CNS toxicity and discontinue if severe headache or visual disturbances occur

Pregnancy

Bromocriptine is contraindicated in hypertensive disorders of pregnancy and should be used with caution in other indications.

Breast-feeding

Bromocriptine is not recommended during breastfeeding due to its effects on lactation suppression.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Tablets: 2.5 mg, 5 mg

Indications

• Hypertension
• Heart failure
• Chronic kidney disease

Dosage

Children: Refer to established guidelines for specific dosing recommendations.

Adults: Refer to established guidelines for specific dosing recommendations.

Mechanism of action

Mesilate acts as a selective inhibitor of certain pathways involved in the renin-angiotensin-aldosterone system (RAAS). By inhibiting angiotensin-converting enzyme (ACE), it reduces the formation of angiotensin II, a potent vasoconstrictor, leading to vasodilation and a decrease in blood pressure. This mechanism also promotes natriuresis, aiding in the reduction of blood volume and further contributing to its antihypertensive effects.

Pharmacodynamics

The pharmacodynamics of mesilate involve its influence on vascular smooth muscle tone and the modulation of renal function. By decreasing systemic vascular resistance, mesilate lowers both systolic and diastolic blood pressure without significantly affecting heart rate. Its effects can be observed within hours of administration, with peak antihypertensive effects typically seen within 24 hours.

Pharmacokinetics

Mesilate is absorbed well from the gastrointestinal tract, with peak plasma concentrations reached within 1 to 2 hours post-administration. It is metabolized in the liver through various pathways, and its metabolites are primarily excreted via the kidneys. The elimination half-life of mesilate generally ranges from 6 to 12 hours, allowing for once or twice daily dosing in clinical practice.

Contra-indications

• Hypersensitivity to mesilate or any component of the formulation
• Severe hepatic impairment
• Active gastrointestinal bleeding

Adverse effects

• Nausea
• Vomiting
• Diarrhea
• Abdominal pain
• Headache
• Dizziness
• Fatigue
• Skin rash

Interactions

• Anticoagulants may have their effects potentiated
• Caution with concomitant use of other medications that affect liver function

Precautions

• Use with caution in patients with liver disease
• Monitor for signs of gastrointestinal bleeding
• Assess renal function prior to use

Pregnancy

There is limited data on the safety of mesilate in pregnancy. It should be used only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether mesilate is excreted in human milk. Caution should be exercised when administering to a nursing mother.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Tablets
• Injectable solution

Mechanism of action

The dopamine D₂ receptor is a 7-transmembrane G-protein coupled receptor associated with G_i proteins. In lactotrophs, stimulation of dopamine D₂ receptor causes inhibition of adenylyl cyclase, which decreases intracellular cAMP concentrations and blocks IP3-dependent release of Ca²⁺ from intracellular stores. Decreases in intracellular calcium levels may also be brought about via inhibition of calcium influx through voltage-gated calcium channels, rather than via inhibition of adenylyl cyclase. Additionally, receptor activation blocks phosphorylation of p42/p44 MAPK and decreases MAPK/ERK kinase phosphorylation. Inhibition of MAPK appears to be mediated by c-Raf and B-Raf-dependent inhibition of MAPK/ERK kinase. Dopamine-stimulated growth hormone release from the pituitary gland is mediated by a decrease in intracellular calcium influx through voltage-gated calcium channels rather than via adenylyl cyclase inhibition. Stimulation of dopamine D₂ receptors in the nigrostriatal pathway leads to improvements in coordinated muscle activity in those with movement disorders.

Pharmacodynamics

Bromocriptine stimulates centrally-located dopaminergic receptors resulting in a number of pharmacologic effects. Five dopamine receptor types from two dopaminergic subfamilies have been identified. The dopaminergic D1 receptor subfamily consists of D₁ and D₅ subreceptors, which are associated with dyskinesias. The dopaminergic D2 receptor subfamily consists of D₂, D₃ and D₄ subreceptors, which are associated with improvement of symptoms of movement disorders. Thus, agonist activity specific for D2 subfamily receptors, primarily D₂ and D₃ receptor subtypes, are the primary targets of dopaminergic antiparkinsonian agents. It is thought that postsynaptic D₂ stimulation is primarily responsible for the antiparkinsonian effect of dopamine agonists, while presynaptic D₂ stimulation confers neuroprotective effects. This semisynthetic ergot derivative exhibits potent agonist activity on dopamine D₂-receptors. It also exhibits agonist activity (in order of decreasing binding affinity) on 5-hydroxytryptamine (5-HT)_1D, dopamine D₃, 5-HT_1A, 5-HT_2A, 5-HT_1B, and 5-HT_2C receptors, antagonist activity on α_2A-adrenergic, α_2C, α_2B, and dopamine D₁ receptors, partial agonist activity at receptor 5-HT_2B, and inactivates dopamine D₄ and 5-HT₇ receptors. Parkinsonian Syndrome manifests when approximately 80% of dopaminergic activity in the nigrostriatal pathway of the brain is lost. As this striatum is involved in modulating the intensity of coordinated muscle activity (e.g. movement, balance, walking), loss of activity may result in dystonia (acute muscle contraction), Parkinsonism (including symptoms of bradykinesia, tremor, rigidity, and flattened affect), akathesia (inner restlessness), tardive dyskinesia (involuntary muscle movements usually associated with long-term loss of dopaminergic activity), and neuroleptic malignant syndrome, which manifests when complete blockage of nigrostriatal dopamine occurs. High dopaminergic activity in the mesolimbic pathway of the brain causes hallucinations and delusions; these side effects of dopamine agonists are manifestations seen in patients with schizophrenia who have overractivity in this area of the brain. The hallucinogenic side effects of dopamine agonists may also be due to 5-HT_2A agonism. The tuberoinfundibular pathway of the brain originates in the hypothalamus and terminates in the pituitary gland. In this pathway, dopamine inhibits lactotrophs in anterior pituitary from secreting prolactin. Increased dopaminergic activity in the tuberoinfundibular pathway inhibits prolactin secretion making bromocriptine an effective agent for treating disorders associated with hypersecretion of prolactin. Pulmonary fibrosis may be associated bromocriptine’s agonist activity at 5-HT_1B and 5-HT_2B receptors.