Continuing Education Activity

Bromocriptine is a medication currently used in the management and treatment of type 2 diabetes mellitus. It is an ergot alkaloid derivative in the dopamine D2 agonist class of drugs. This activity will review the indications, contraindications, and mechanism of action for bromocriptine as a valuable agent in managing type 2 diabetes mellitus, as well as its more traditional uses in Parkinson disease acromegaly pituitary prolactinomas. Further, throughout this activity, we will highlight the mechanism of action, adverse event profile, and other key factors pertinent to all inter-professional healthcare teams in managing patients with Type 2 diabetes mellitus, Parkinson disease, acromegaly, and pituitary prolactinomas using bromocriptine.

Objectives:

• Identify the mechanism of action of bromocriptine.
• Describe the potential adverse effects of bromocriptine.
• Review the appropriate monitoring for patients receiving therapy with bromocriptine.
• Summarize interprofessional team strategies for improving care coordination and communication to advance bromocriptine and improve outcomes.

Indications

Bromocriptine is a medication currently used in the management and treatment of Type 2 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 of type 2 diabetes mellitus, as well as its more traditional uses in Parkinson disease, acromegaly, and pituitary prolactinomas. 

Diabetes Mellitus Type 2

The most recently FDA-approved indication for bromocriptine mesylate is a supplemental medication for adults with type 2 diabetes mellitus (type 2 DM) to help with glycemic control.[1] Type 2 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 – prolactinoma.[3][4] Prolactinomas affect both men and women and often 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] 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 blood concentrations of growth hormone (GH). GH is affected by the sympathetic nervous system, where the binding of catecholamines to alpha receptors increases blood concentrations of GH, and the binding of beta receptors decreases blood concentrations of GH. In an average adult, catecholamines, including norepinephrine, epinephrine, and L-DOPA, would increase blood concentrations of GH.[6] Paradoxically, this sympathetic stimulation decreases GH in patients with acromegaly, 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 (PD) 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, there is a decline in efficacy and motor complications with chronic use.[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. 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]

Mechanism of Action

Bromocriptine is a dopamine receptor agonist with selective 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 blood concentrations of GH.[14][6] In type 2 DM, bromocriptine alters monoamine neurotransmitter concentrations 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 2 diabetes mellitus.[15][16] The 2.5 to 5 mg is the standard release formulation that reaches peak blood concentrations 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 blood concentrations 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 blood concentrations are reached, with maintenance doses ranging from 7.50 to 30.0 mg/day.[7][6]
• Parkinson 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 a low dose considered less than 30.0 mg/day and a high dose considered 31.0 to 100 mg/day.[16][9][12]
• Type 2 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 [18][19][15]

• Nausea
• Vomiting
• Dizziness
• Hypotension
• Headache
• Fatigue

More Serious Side Effects [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. Patients with syncopal migraines should also avoid bromocriptine due to its ability to spark hypotensive episodes, and breastfeeding 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. 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) to check for elevated liver enzymes and 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 many dopaminergic effects, most notably hypotension. Treatment of overdose includes using activated charcoal to prevent systemic absorption 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 2 diabetes mellitus, acromegaly, hyperprolactinemia, and Parkinson disease require not only an astute patient-centered approach from physicians but an interprofessional team of healthcare workers who can guide patients from their first clinic visit until achieving symptomatic control. When clinicians, nurses, pharmacists, 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, better outcomes in chronic disease, and improvements in patient safety.[24][25] [Level 3] Lapses in interprofessional 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 clinician’s diagnosis is dependent on the combination of clinical findings with laboratory tests. To prescribe the appropriate medication dosage and administration, the clinician 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 department, 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 healthcare team members.[26] [Level 5]

Even with patients regularly taking their medication as prescribed, health management continues. Patients with type 2 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.