Bromocriptine

Article Author:
Matan Ozery
Article Editor:
Roopma Wadhwa
Updated:
3/14/2020 3:26:49 PM
PubMed Link:
Bromocriptine

Indications

Bromocriptine is a medication currently used in the management and treatment of Type II diabetes mellitus. It is an ergot alkaloid derivative in the dopamine D2 agonist class of drugs. This discussion reviews the indications, contraindications, and mechanism of action for bromocriptine as a valuable agent in the management for Type II diabetes mellitus, as well as its more traditional uses in Parkinson disease, acromegaly, and pituitary prolactinomas. 

Diabetes Mellitus Type II

The most recently FDA approved indication for bromocriptine mesylate is a supplemental medication for adults with Type II diabetes mellitus (Type II DM) to help with glycemic control.[1] Type II DM is a chronic metabolic disorder with multifactorial pathogenesis, characterized by insulin resistance, pancreatic beta-islet dysfunctions, and numerous additional metabolic abnormalities.[2] This complexity often requires combinations of medications that address the various aspects of the disease, making the adjunct use of bromocriptine an appealing treatment.

Hyperprolactinemia

Bromocriptine is an FDA approved medication indicated for the use of disorders causing hyperprolactinemia, which most often is due to the most common of the pituitary adenomas – the prolactinoma.[3][4] Prolactinomas affect both men and women and often will lead to sexual dysfunction, gonadal abnormalities, infertility, and headaches.[5] Before the development of dopamine agonists, surgery was the mainstay of the treatment of prolactinomas.[5] Now with the development of multiple dopamine agonists, the first being bromocriptine, the standard treatment is medical therapy. Surgery is reserved for severe cases where medical treatment has failed to reduce prolactin secretion, or the adenoma has caused visual disturbances or neurological deficits.[5] 

Acromegaly

Acromegaly characteristically demonstrates a set of complications associated with increased levels of growth hormone (GH).[6] GH is affected by the sympathetic nervous system, where the binding of catecholamines to alpha receptors increases blood levels of GH, and the binding of beta receptors decreases blood levels of GH.[6] In an average adult, catecholamines, including norepinephrine, epinephrine, and L-DOPA, would increase blood levels of GH.[6] Paradoxically, in patients with acromegaly, this sympathetic stimulation decreases GH, although its efficacy for most patients remains controversial.[6][7] As a dopamine agonist, bromocriptine is an FDA approved medication indicated for the treatment of acromegaly.

Parkinson Disease

Parkinson disease is a progressive neurological disorder characterized by resting tremor, rigidity, akinesia or bradykinesia, and postural instability due to the loss of dopaminergic neurons in the substantia nigra.[8] Although levodopa is an effective treatment of PD, with chronic use, there is a decline in efficacy and motor complications.[9][10] In these groups of patients where levodopa is no longer as effective, co-administration with dopamine agonists such as bromocriptine historically was a successful option.[9] Further, bromocriptine is also used as an early treatment for PD to delay the onset of the use of levodopa, ultimately delaying the likely dyskinesia and motor fluctuations that occur with chronic use.[11][10] Currently, PD treatment is widely variable, and with the development of newer non-ergot dopamine agonists, which possess equal to higher efficacy and a safer side effect profile, bromocriptine is not the drug of choice for many physicians despite the increase in popularity of dopamine agonists as a whole.[11][10][11]

Mechanism of Action

Bromocriptine is a dopamine agonist that has strong agonist activity on D2 dopamine receptors while simultaneously acting as a partial antagonist for D1 dopamine receptors.[12] Dopamine agonism has variable effects depending on the target tissue. In Parkinson disease, bromocriptine binds directly to striatal dopamine D2 receptors, stimulating locomotion and attenuating the bradykinetic symptoms caused by the degeneration of dopaminergic nigrostriatal neurons.[13][9] This same D2 agonistic effect on the D2 receptors of anterior pituitary lactotrophic cells blocks prolactin exocytosis and gene expression, reducing the harmful effects of hyperprolactinemia in the case of a pituitary prolactinoma. In acromegaly, bromocriptine’s dopaminergic effect can cause paradoxical blocking of GH release through tuberoinfundibular pathways, decreasing circulating levels of GH.[14][6] In Type II DM, bromocriptine alters monoamine neurotransmitter levels in the suprachiasmatic and ventromedial nuclei of the hypothalamus, causing a sympatholytic effect that decreases metabolic processes which can lead to glucose intolerance and insulin resistance.[2]

Administration

Bromocriptine is available in two forms: an oral tablet/capsule (2.5 to 5.0 mg) for the treatment of hyperprolactinemia, acromegaly, and Parkinson disease, and another oral tablet/capsule (0.8 mg) for the treatment of Type II diabetes mellitus.[15][16] The 2.5 to 5 mg is the standard release formulation that reaches peak levels after about 3 hours with a bioavailability of 28%, while the design of the 0.8 mg formulation is to have quicker release reaching peak levels after about 45 to 60 minutes with a bioavailability of 65 to 95%.[16] Treatment for any of these disorders must be individualized based on the unique characteristics of the patient; however, the following are the recommended dosages:

  • Hyperprolactinemia: Initial dose of 1.25 to 2.50 mg/day, followed by an increase over the following days with a final maintenance dose of about 5 mg/day.[17]
  • Acromegaly: Initial dose of 1.25 to 2.50 mg/day and an increase in 2.50 mg increments until desired GH levels are reached, with maintenance doses ranging from 7.50 to 30.0 mg/day.[7][6]
  • Parkinson’s Disease: Initial dose of 2.50 mg/day with an increase in increments of 2.50 mg based on tolerance and effect. Use the lowest dose possible to achieve symptomatic control with low dose considered <30.0 mg/day and high dose considered 31.0 to 100 mg/day.[16][9][12]
  • Type II Diabetes Mellitus: Initial dose of 0.8 mg/day with a weekly increase of 0.8 mg until the desired glycemic control is reached, with a maximum dose of 4.80 mg/day.[16]

Adverse Effects

Most common side effects include[18][19][15]:

- Nausea

- Vomiting

- Dizziness

- Hypotension

- Headache

- Fatigue

More serious side effects include[19][15][20]:

- Psychosis

- Fibrosis (retroperitoneal, pleural, cardiac valve)

- Cardiovascular incidents (valvular damage, stroke, myocardial infarction)

Contraindications

Bromocriptine is contraindicated as a treatment in patients with type I diabetes mellitus, syncope, and psychosis.[21] Patients with syncopal migraines should also avoid bromocriptine due to its ability to spark hypotensive episodes, and breast-feeding patients should avoid bromocriptine due to its inhibitory effect on lactation.[21] Further, bromocriptine metabolism occurs by CYP450 3A4, and should not be used concomitantly with CYP3A4 inhibitors or inducers, or in any patients with hepatic impairment.[21][16]

Monitoring

Patients using bromocriptine should take a pregnancy test if amenorrhea occurs due to the possibility of pregnancy and diminished prolactin secretion in the fetus with continued use.[22] Clinicians should discontinue bromocriptine if pregnancy is confirmed unless otherwise recommended by a physician.[22]

Patients taking bromocriptine should also receive liver function tests (LFTs) checking for elevated liver enzymes, as well as be given a cardiovascular assessment before using the drug.[16][19]

Toxicity

Bromocriptine metabolism occurs primarily in the liver via the cytochrome P450 3A4 enzymes and should be avoided in anyone with hepatic impairment.[16] Accidental overdose has been reported mainly in children, causing a list of dopaminergic effects, most notably being hypotension.[23] Treatment of overdose includes ipecac to induce vomiting to remove the oral bromocriptine from the body, as well as the use of activated charcoal and magnesium citrate by nasogastric tube, and intravenous saline to increase blood pressure.[23]

Enhancing Healthcare Team Outcomes

The diagnosis and treatment of complicated disorders such as type II diabetes mellitus, acromegaly, hyperprolactinemia, and Parkinson disease require not only an astute patient-centered approach from physicians but an inter-professional team of healthcare workers who can guide patients from their first clinic visit until achieving symptomatic control. When the nurses, physicians, laboratory technologists, medical students, and all other involved members of the healthcare team collaborate effectively, there is greater access to care, increased coordination of services, and better outcomes in chronic disease as well as improvements in patient safety.[24][25] [Level III] Lapses in inter-professional communication can cause confusion and mistakes in the treatment of patients, potentially carrying lethal consequences that may lead to unnecessary morbidity and mortality.

When a patient first enters a clinic, the initial diagnosis requires collaboration between the primary care provider and the appropriate specialist. The validity of the physician’s diagnosis is dependent on the combination of clinical findings with the laboratory tests. To prescribe the appropriate medication dosage and administration, the physician must consult with the pharmacist, and the pharmacist must communicate with the patient so that the patient understands all instructions and side effects. If the patient incorrectly takes the medication, that patient should go to the emergency room where nurses will be responsible for constant monitoring and consulting with toxicologists, radiologists, or even with pediatric specialists in the case of an accidental overdose in a child. If medical students are involved, they too must effectively communicate with the attending physician, nurses, and technologists. Medical students trained in inter-professional education demonstrate more respect and positive attitudes when working with each other and other members of the healthcare team.[26] [Level III]

Even with patients regularly taking their medication as prescribed, health management continues. Patients with type II diabetes mellitus will be assisted by Certified Diabetes Educators (CDEs) to provide diet and nutritional guidance as well as mental health professionals, podiatrists, optometrists, and other community health workers to address the various sequelae associated with the disease. Patients with Parkinson disease, acromegaly, and hyperprolactinemia must continue to be cared for by their respective neurological and endocrine teams to treat the diseases holistically. Bromocriptine is a drug with a historically safe side-effect profile and very rare severe adverse effects, but it is a necessity that communication is present between each member of the team to ensure safe and effective treatment because even one unnecessary adverse event is one too many.


References

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