Dopamine Agonists

Mechanism of Action

Dopamine Receptors and Intracellular Signaling Mechanisms

Dopamine agonists are chemical agents that bind to the dopamine receptors and activate cellular singling pathways. Dopamine receptors classify into two families based on their pharmacological, biochemical, and genetic properties: the D1-like dopamine receptor family includes D1 and D5 receptors, whereas the D2-like dopamine receptor family includes D2, D3, and D4 receptors. All dopamine receptors couple to G proteins. The D1 and D5 receptors couple to the Gs family of G proteins, and therefore an agonist binding to these receptors activate adenylyl cyclase and thus stimulates cAMP synthesis. The D2, D3, and D4 receptors couple to the Gi/o family of G proteins, and agonists inhibit adenylyl cyclase and thus cAMP synthesis. Increased intracellular cAMP activates protein kinase A, which phosphorylates many downstream protein targets, including 32-kDa dopamine and cAMP-regulated phosphoprotein (DARPP-32), ionotropic glutamate receptor, and GABA receptors. Because the DARPP-32 inhibits protein phosphatase 1, this phosphoprotein regulates the phosphorylation state and thus activity of various protein kinase A target proteins and neuronal activity.[12]

Research has shown that D1 and D2 dopamine receptors are primarily involved in the control of voluntary movement, reward and addictive behavior, and learning and memory. D2 dopamine receptors are important in the psychotic behavior manifested in schizophrenia and bipolar disorder. The role of D3, D4, and D5 dopamine receptors in the brain is currently under investigation.

Dopamine receptors act not only as monomers but also as homodimers (e.g., D1-D1), heterodimers (e.g., D1-D2, D1-D3, or D2-D3), or heteromers (e.g., D2-D3-adenosine A2 receptor or D2-somatostatin receptor 5). Interestingly, D1-D2 receptor dimers, as well as D5 receptors, are coupled to the Gq family of G proteins that activate phospholipase C and increase intracellular calcium concentrations. Also, dopamine receptors may act via G protein-independent mechanisms, such as direct interactions of dopamine receptors with ion channels and cAMP-independent regulation of protein kinase B (Akt), inhibiting glycogen synthase kinase 3 activity. The latter signaling pathway has been suggested as an intracellular signaling mechanism for the development of schizophrenia, bipolar disorders, and other behavioral changes involved in dopamine receptor activity.

Dopaminergic Pathways in the Brain

Four major dopaminergic pathways exist in the brain: the nigrostriatal, mesolimbic, mesocortical, and tuberoinfundibular pathways. Dopaminergic neurons that originate from substantia nigra and project their axons to the dorsal striatum (nigrostriatal pathway) are involved in the coordination of voluntary movement. Parkinson disease is attributed to the decreased dopaminergic activity in the nigrostriatal pathway. Prolactin synthesis and secretion are regulated by dopaminergic neurons, originating from the hypothalamus and project towards the pituitary gland (tuberoinfundibular pathway). Neurons originating from the ventral tegmental area in the brainstem project to the nucleus accumbens to form the mesolimbic pathway, and the prefrontal cortex, to form the mesocortical pathway. The mesolimbic pathway becomes activated by addictive drugs. It may also be involved in the positive symptoms of schizophrenia, while dysfunction of the mesocortical pathway may underlie the negative symptoms of schizophrenia. 

Dopamine Agonists to Relieve Symptoms of Parkinson’s disease

Damage to the dopaminergic neurons found in the substantia nigra has been the suggested cause of Parkinson disease. After the results of remarkable symptomatic relief by levodopa treatment, restoring dopaminergic activity has been the basis of the pharmacological treatment of Parkinson disease by administering dopamine precursors, dopamine receptor agonists, and inhibitors of dopamine metabolism. Because dopamine can’t pass the blood-brain barrier, the precursor of dopamine, levodopa, is administered. Levodopa is co-administered with carbidopa, which prevents the conversion of levodopa in the peripheral tissue and reduces side effects from high dopamine levels in the peripheral tissue. Various dopamine agonists can increase dopamine activity in the brain. The majority of dopamine agonists used in Parkinson disease are D2 dopamine receptor agonists.[3] Ergot derivatives, older dopamine agonists, interact not only with dopamine D1 and D2 receptors but many other neurotransmitter receptors such as serotonin and adrenergic receptors. Newer dopamine agonists, which are non-ergot agents, have a high affinity to dopamine D2 and D3 receptors. Amantadine is not a dopamine agonist. It may inhibit the reuptake of dopamine and increase the synthesis and release of dopamine. Amantadine may inhibit D2 dopamine receptors and N-methyl-D-aspartate (NMDA)-type glutamate receptors. 

Dopamine Agonists to Treat Side Effects of Antipsychotic Agents

Extrapyramidal symptoms similar to those in Parkinson disease are common in the patients treated with antipsychotic agents, especially first-generation drugs. The blockade of the D2 dopamine receptors in the nigrostriatal pathway is the suggested mechanism responsible for the extrapyramidal side effects. Administration of dopamine agonists or levodopa to treat antipsychotic-induced Parkinson syndrome may antagonize antipsychotic treatment and exacerbate psychotic symptoms. Atypical, second-generation antipsychotic agents exhibit lower affinity for D2 dopamine receptors and have activity at serotonin receptors, which is thought to reduce extrapyramidal side effects.

Dopamine Agonists to Treat Hyperprolactinemia

Dopamine gets released from the hypothalamus. It binds to dopamine D2 receptors and inhibits the synthesis and secretion of prolactin from the anterior pituitary gland. Antipsychotic agents, which have dopamine antagonist properties that block dopamine binding to its receptors. By eliminating the inhibitory effects of dopamine on prolactin secretion, hyperprolactinemia is a very common adverse effect of many antipsychotics. Estimates are that antipsychotic-induced hyperprolactinemia occurs in up to 70% of patients. Hyperprolactinemia is more common with the typical antipsychotics than atypical, second-generation antipsychotics. Elevated prolactin has a negative feedback effect on the release of gonadotropin-releasing hormone from the hypothalamus, resulting in decreased estrogen levels in females and testosterone in the male. Clinical symptoms of hyperprolactinemia include sexual dysfunction, infertility, galactorrhea, amenorrhea in females, and gynecomastia and oligospermia in males.

Dopamine Agonists to Treat Type 2 Diabetes

The FDA has approved bromocriptine for the treatment of type 2 diabetes. Bromocriptine is an agonist to the D2 receptor and an antagonist to the D1 receptor. Because insulin release gets inhibited by stimulation of the D2 receptor and inhibition of the D1 receptor, the molecular/cellular mechanism of action of bromocriptine in insulin release and improved glycemic control in type 2 diabetes is still unclear. It is, however, suggested that bromocriptine may improve glycemic control by normalizing hypothalamic circadian activities.[9] Therefore, the recommended administration of bromocriptine to treat type 2 diabetes is within two hours of waking up in the morning to mimic hypothalamic circadian activity.

Dopamine Agonists to Treat Hypertensive Emergency

The D1 receptors are present on the smooth muscle of the renal, mesenteric, and coronary arteries and peripheral blood vessels in the skeletal muscle. Dopamine action on these receptors produces decreased blood pressure by reducing peripheral vascular resistance due to vasodilation. Dopamine agonists used to treat hypertensive emergencies do not show an affinity for D2 receptors.  

Administration

Parkinson Disease

Pramipexole administration is via the oral route. There are two tablet forms: immediate or extended-release tablets. The initial dose for the immediate-release tablet is 0.125 mg/three times/day. The subsequent doses should increase gradually by 0.125 mg per dose to the usual maintenance dose of 0.5 to 1.5 mg/three times/day every 5 to 7 days. For discontinuation, the reduction dose should be 0.75 mg per day until the total daily dose is 0.75 mg. After then, reduce the dose by 0.375 mg/day. Extended-release tablets should not be chewed, crushed, or divided but should be swallowed whole. The initial dose for the extended-release tablets is 0.375 mg/once/day. The dose can be increased every 5 to 7 days to 0.75 mg/once/day and then increased by 0.75 mg per dose up to 4.5 mg/once/day. Discontinuation of therapy should be gradual: reduce dose by 0.75 mg/day until reaching 0.75 mg/once/day, and then reduce by 0.375 mg/day.

Ropinirole is also an orally administered drug. For the immediate-release tablet, the starting dose is 0.25 mg/three times/day. The dose may be increased by 0.75 mg/day every week for four weeks. After four weeks, the dose may be increased weekly by 1.5 mg/day until 9 mg/day. After then, the dose may be increased weekly by up to 3 mg/day until a total of 24 mg/day. For extended-release tablets, the initial dose of 2 mg/once/day for weeks 1 and 2. The dose may increase by 2 mg/day weekly or longer intervals up to a maximum dose of 24 mg/day.

Rotigotine administration is via a transdermal patch. For early-stage Parkinson’s disease, the initial application of 2 mg/24 hours patch/once/day is the recommended dose. The lowest effective dosage is 4 mg/24 hours, and the maximum recommended dose is 6 mg/24 hours. For advanced-stage Parkinson’s disease, the initial application of 4 mg/24 hours patch/once/day is recommended. The recommended dose is 8 mg/24 hours, and the maximum dose used in the clinical trials is 16 mg/24 hours. Discontinuation should be gradual and preferable decreased by equal to or less than 2 mg/24 hours every other day.

Apomorphine is administered by subcutaneous injection. Avoid intravenous administration as it may cause thrombus or embolism due to crystallization. Apomorphine is useful as adjunctive therapy for “off” episodes with levodopa. Antiemetic therapy is recommended three days before initiation but for less than two months to prevent adverse events. The initial test dose is 0.2 mL (2 mg). If a patient tolerates and responds to the test dose, a starting dose of 0.2 mL (2 mg) is the recommendation if needed. The dose may be increased by 0.1 mL (1 mg) every few days up to the maximum dose of 0.6 mL (6 mg).

Restless Legs Syndrome

Patients may start the immediate-release form of pramipexole at an initial dose of 0.125 mg/once/day. The dose can be doubled every 4 to 7 days up to 0.5 to 0.75 mg/day. The therapy should be discontinued by gradually reducing the dose every 4 to 7 days.

Ropinirole immediate-release tablets may start with the initial dose of 0.25 mg/once/day. After 2 and 7 days, the dose may be increased to 0.5 mg/day and 1 mg/day, respectively. In the following weeks, the dose may be increased by 0.5 mg/week until 3 mg/day and then to a maximum dose of 4 mg/day in the following week.

Pramipexole and ropinirole should be administered 2 to 3 hours before bedtime. If augmentation occurs, the patient may divide the dose into multiple daily doses, including a dose earlier in the day.

Rotigotine transdermal patch may be applied initially at 1 mg/24 hours patch/once/day. The dose may be increased weekly by 1 mg/24 hours. The lowest effective dosage is 1 mg/24 hours, and the maximum dose is 3 mg/24 hours. For discontinuation of treatment, decrease by 1 mg/24 hours every other day.

Neuroleptic Malignant Syndrome

Bromocriptine can be administered orally or via a gastric tube. The dose of 2.5 mg can be given every 8 to 12 hours to the maximum dose of 45 mg/day if needed. Bromocriptine should not be discontinued abruptly and should be tapered slowly, as the sudden withdrawal of levodopa and dopamine agonists may precipitate the neuroleptic malignant syndrome. 

Hyperprolactinemia

To treat hyperprolactinemia, the starting oral dose of bromocriptine 1.25 to 2.5 mg/day is recommended. The dose can be gradually titrated upward by 2.5 mg/day/every 2 to 7 days up to the usual maintenance dose range of 2.5 to 15 mg/day.

Cabergoline is administered orally and initiated at 0.25 mg/twice/weekly. The dose can be increased very slowly by 0.25 mg/twice/weekly and adjusted at a minimum of every four weeks. The half-life of cabergoline in the elderly is 63 to 69 hours. The maximum dose is 1 mg/twice/weekly. When taken with or after meals, there may be a decreased gastrointestinal distress and increased tolerability.

Type 2 Diabetes Mellitus

Bromocriptine is administered orally. To treat type 2 diabetes mellitus, starting a dose of 0.8 mg/once/day, preferably in the morning within 3 hours of awakening, is recommended. If tolerable, the dose can be titrated up to 1.6 to 4.8 mg/once/day at 0.8 mg increments weekly.

Hypertensive Emergency

Fenoldopam is administered by continuous intravenous infusion using a calibrated infusion pump. The starting dose in adults is 0.1 to 0.3 microgram/kg/min. This low initial dose is recommended to prevent reflex tachycardia. Dose is increased by 0.05 to 0.1 microgram/kg/min every 15 to 20 minutes. The maximum dose is 1.6 microgram/kg/min. Its use should be limited to not more than 48 hours.

Adverse Effects

Nausea, vomiting, orthostatic hypotension, headache, dizziness, and cardiac arrhythmia are the most common side effect of dopamine agonists.[13] These adverse effects are mostly dosage-dependent. It is highly recommended to start these medications at a low dosage to reduce the risk of orthostatic hypotension. Serotonin receptor antagonist antiemetics should not be taken together as they may enhance the hypotensive effect of dopamine agonists.

Long-term use of dopamine agonists may cause choreiform and dystonic movements and psychiatric disturbances. Hallucinations, delusions, confusion, depression, and mania are some of the most common adverse effects related to the long-term use of these medications. Impulse control disorders such as hypersexuality, excessive gambling or shopping, hyperphagia, obsessive hobbying have been reported in patients treated with pramipexole and ropinirole.[14] These dopamine agonists have a high affinity to D3 dopamine receptors in the mesolimbic area in addition to the D2 dopamine receptors.

Irresistible sleep attacks may occur in patients who are taking pramipexole and ropinirole. Symptoms such as increased sedation, yawning, drowsiness, somnolence, and daytime sleepiness have been observed with dopamine agonist use.

Dopamine agonist use requires caution in patients with a medical history of hypertension, cardiovascular, renal, and hepatic disease. The use of ergot dopamine agonists has correlations with an increased risk of fibrotic disorders. Pulmonary fibrosis, pleural effusion, and pleural thickening can occur in long-term bromocriptine and cabergoline therapy. Cabergoline and pergolide were associated with an increased incidence of cardiac valve regurgitation. Therefore, pergolide has been removed from the US market. Bromocriptine and cabergoline are not recommended for treating Parkinson’s disease as it requires long-term use at a relatively higher dose in Parkinson’s disease than hyperprolactinemia.

Contraindications

Contraindications to dopamine agonists include pregnancy and for nursing mothers, as these medications inhibit lactation.

Hypersensitivity reactions to ergot derivatives, bromocriptine, and cabergoline, or any component of the formulation may occur. Non-ergot dopamine agonists, ropinirole, rotigotine, and apomorphine, may also cause hypersensitivity reactions to these drugs or any component of the formulation.

Ergot dopamine agonists have a high risk for cardiac valvular, pulmonary, or peritoneal fibrotic disorders. Prescription of ergot dopamine agonists is contraindicated in patients with a history of fibrosis.

In patients with uncontrolled hypertension and who are also pregnant during treatment for prolactinoma, acromegaly, or Parkinson disease, bromocriptine is contraindicated because of the risk of increased hypertension. It is also contraindicated in postpartum women with severe cardiovascular disease or a history of coronary artery disease.

Apomorphine is a potent emetic and vasodilator. Antiemetics that block central dopamine receptors antagonize the anti-Parkinson action of apomorphine. Serotonin receptor antagonists are antiemetics that produce profound hypotension and loss of consciousness. Therefore, concomitant use of serotonin antagonists, antihypertensives, or vasodilators is contraindicated with apomorphine. It is also contraindicated in patients with severe renal or hepatic impairment.

Clinicians should not prescribe dopamine agonists with monoamine oxidase inhibitors (MAOI). It requires discontinuation at least two weeks prior to starting the dopamine agonist.

Monitoring

Central nervous system depression, vital signs, and electrocardiograms require monitoring in symptomatic patients. Fluids and electrolytes should be monitored in patients with prolonged vomiting as well.

Patients on bromocriptine should be tested for pregnancy every four weeks during amenorrhea or if the menstrual period is late by more than three days. Complete blood counts with differential, liver function test, BUN/Cr, and cardiovascular evaluation should take place.

Patients on pramipexole should receive monitoring for baseline creatinine levels, orthostatic hypotension, and skin reactions. 

When taking ropinirole, the patient should monitor skin reactions and orthostatic hypotension, especially during dose titration. 

Toxicity

Overdose on dopamine agonists is rare. In cases of mild toxicity, symptomatic, and the patient should receive supportive care (such as hydration, electrolyte replacement, and rest). In severe cases of toxicity, symptoms such as dyskinesia, dystonia, hypotension, and dysrhythmias may occur. In these cases, the clinician should decrease the drug dosage should and supportive care provided. Other medications, such as benzodiazepines and antispasmodic agents, can be given to treat dystonia. Hypotension should have treatment with IV fluids and dysrhythmias treated with antiarrhythmic agents.

Enhancing Healthcare Team Outcomes

Providers should monitor patients on dopamine agonists for any signs and symptoms of CNS depression, orthostatic hypotension, or electrolyte imbalance. Patients should be closely monitored by clinicians and the collaboration of all interprofessional healthcare team members, especially during the titration period. Baseline complete blood count with differential, liver function test, BUN/Cr should be obtained before starting the medication, and cardiovascular evaluations are necessary. Patients treated with dopamine agonists might not be aware of the symptoms of orthostatic hypotension. The clinician should consult with a pharmacist on the appropriateness of the agent selected correct dosing and have the pharmacist check for drug interactions on the patient's medication profile.

Because falls in the elderly can cause injuries, serious complications, and even death, patient education is necessary for the healthcare team. Nursing staff can be a crucial resource for answering medication dosing and administration questions, alerting patients to possible adverse effects, and serving as an access point to the prescriber. Abnormal obsessive behaviors such as gambling and hypersexuality may occur in patients who did not exhibit these behavioral problems before initiating dopamine agonist therapy. Patients may not report these changes in behaviors due to embarrassment. A psychological evaluation by the healthcare team is the recommendation for patients under dopamine agonist therapy. These examples demonstrate the necessity for interprofessional teamwork when prescribing dopamine agonist medications. [Level 5]