Dopaminergic Signaling in the Central Nervous System and Peripheral Tissues
Dopamine is an important neurotransmitter that regulates voluntary movement, reward and addictive behavior, moods such as mania and depression, cognition, memory, learning, sleep, and food intake. Dopamine also inhibits the synthesis and secretion of prolactin from the pituitary gland. In the peripheral tissue, dopamine plays an important role in the function of the cardiovascular system, kidney, pancreas, and gastrointestinal system. Dopamine agonists and antagonists, therefore, are important pharmacotherapeutic agents.
Dopamine Replacement Therapy in Parkinson Disease
After the discovery that the administration of levodopa, the precursor of dopamine, produced marked symptomatic improvement in Parkinson disease, levodopa has been the primary pharmacological therapeutic for Parkinson disease. Unfortunately, levodopa therapy causes unavoidable extrapyramidal side effects, which occur after several years of treatment. Dopamine agonists originally underwent development as adjunctive therapy to more potent levodopa treatment. Due to the side effects of long-term treatment with levodopa, initiation of treatment with dopamine agonist monotherapy is now recommended in young patients to postpone therapy with levodopa and the subsequent development of extrapyramidal side effects. Dopamine agonists include ergot alkaloids and non-ergot alkaloids. The older ergot derivatives are bromocriptine, cabergoline, lisuride, and pergolide. They are rarely used in Parkinson’s disease these days due to the risk of valvular and lung fibrosis. Pergolide has been withdrawn from the US market due to an increased risk of cardiac fibrosis. The newer non-ergot dopamine agonists are pramipexole, ropinirole, rotigotine, apomorphine, and piribedil. The most frequently prescribed dopamine agonists in the US are pramipexole and ropinirole. These dopamine agonists are the first-line treatment for another movement disorder, restless legs syndrome. Transdermal rotigotine is useful for non-compliant patients on drug adherence. Parenteral administration of apomorphine is reserved for those patients who are experiencing a sudden “off” period episode during levodopa therapy and are resistant to other treatments.
Dopamine Agonists to Treat Side Effects of Antipsychotic Agents
The neuroleptic malignant syndrome is rare but can be a fatal side effect of antipsychotic agents. Rarely, in patients with Parkinson's disease, withdrawal of dopamine agonists may also cause deadly side effects. Fever, mental status changes, and muscle rigidity (and ensuing respiratory distress) occur over 1 to 3 days (and 1 to 2 weeks after the initiation of antipsychotic therapy). Bromocriptine, a dopamine agonist, and amantadine are options as well as muscle relaxants such as lorazepam and dantrolene.
Dopamine Agonists to Treat Hyperprolactinemia
These agents are also first-line of therapy for hyperprolactinemia, and associated endocrine abnormalities such as hypogonadism and infertility, secondary to a pituitary tumor, are dopamine agonists. Radiation therapy and surgery are reserved for medication-intolerant patients. The dopamine D2 receptor agonists, bromocriptine, and cabergoline are recommended.
Hyperprolactinemia is a highly prevalent side effect of antipsychotic treatment, particularly in patients treated with first-generation antipsychotics. Due to the risk of relapse and exacerbation of psychotic symptoms, the use of dopamine agonists is not recommended.
Dopamine Agonists to Treat Type 2 Diabetes
Although research has not elucidated the cellular and molecular mechanisms of action, bromocriptine has been shown to improve glycemic control in type 2 diabetes.
Dopamine Agonists to Treat Hypertensive Emergency
Fenoldopam is a selective D1 receptor agonist that causes vasodilation of renal, splanchnic, and coronary arteries as well as blood vessels in the skeletal muscles. After intravenous injection, the onset of drug action is rapid (10 minutes), and the dose-response relationship is linear. It also has a short elimination half-life. Therefore, fenoldopam is recommended for the parenteral treatment of hypertensive emergencies in a setting of acute kidney injury or cerebrovascular accident.
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 Gs family of G proteins, and therefore an agonist binding to these receptors activates adenylyl cyclase and thus stimulates cAMP synthesis. The D2, D3, and D4 receptors couple to 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.
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), which inhibits 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 pathway. 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, which originate from the hypothalamus and project towards the pituitary gland (tuberoinfundibular pathway). Neurons that originate 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. 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 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 also have activity at serotonin receptors, which is thought to reduce the occurrence of 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 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 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, which results in decreased levels of estrogens 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 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. Therefore, the recommended administration of bromocriptine for the treatment of 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 the reduction of peripheral vascular resistance due to vasodilation. Dopamine agonists used to treat hypertensive emergencies do not show an affinity for D2 receptors.
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 a 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 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 hour. The lowest effective dosage is 1 mg/24 hour, and the maximum dose is 3 mg/24 hours. For discontinuation of treatment, decrease by 1 mg/24 hour every other day.
Neuroleptic Malignant Syndrome
Bromocriptine can be administered by oral 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.
For the treatment of 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. The dose can be titrated up to 1.6 to 4.8 mg/once/day at 0.8 mg increments weekly, if tolerable.
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.
Nausea, vomiting, orthostatic hypotension, headache, dizziness, and cardiac arrhythmia are the most common side effect of dopamine agonists. 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 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. 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 the treatment of Parkinson’s disease as it requires long-term use at a relatively higher dose in Parkinson’s disease than hyperprolactinemia.
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.
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 have monitoring for skin reactions and orthostatic hypotension, especially during dose titration.
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.
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 members of the interprofessional healthcare team, 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 should take place. 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 to 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 the initiation of 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]
|||Stathis P,Konitsiotis S,Antonini A, Dopamine agonists early monotherapy for the delay of development of levodopa-induced dyskinesias. Expert review of neurotherapeutics. 2015 Feb; [PubMed PMID: 25578445]|
|||Blandini F,Armentero MT, Dopamine receptor agonists for Parkinson's disease. Expert opinion on investigational drugs. 2014 Mar; [PubMed PMID: 24313341]|
|||Cacabelos R, Parkinson's Disease: From Pathogenesis to Pharmacogenomics. International journal of molecular sciences. 2017 Mar 4; [PubMed PMID: 28273839]|
|||Giorgi L,Asgharian A,Hunter B, Ropinirole in patients with restless legs syndrome and baseline IRLS total scores ≥ 24: efficacy and tolerability in a 26-week, double-blind, parallel-group, placebo-controlled study followed by a 40-week open-label extension. Clinical therapeutics. 2013 Sep; [PubMed PMID: 23938061]|
|||Boyle A,Ondo W, Role of apomorphine in the treatment of Parkinson's disease. CNS drugs. 2015 Feb; [PubMed PMID: 25676564]|
|||Ware MR,Feller DB,Hall KL, Neuroleptic Malignant Syndrome: Diagnosis and Management. The primary care companion for CNS disorders. 2018 Jan 4; [PubMed PMID: 29325237]|
|||Auriemma RS,Pirchio R,De Alcubierre D,Pivonello R,Colao A, Dopamine Agonists: From the 1970s to Today. Neuroendocrinology. 2019; [PubMed PMID: 30852578]|
|||Grigg J,Worsley R,Thew C,Gurvich C,Thomas N,Kulkarni J, Antipsychotic-induced hyperprolactinemia: synthesis of world-wide guidelines and integrated recommendations for assessment, management and future research. Psychopharmacology. 2017 Nov; [PubMed PMID: 28889207]|
|||Lopez Vicchi F,Luque GM,Brie B,Nogueira JP,Garcia Tornadu I,Becu-Villalobos D, Dopaminergic drugs in type 2 diabetes and glucose homeostasis. Pharmacological research. 2016 Jul; [PubMed PMID: 26748034]|
|||Weber RR,McCoy CE,Ziemniak JA,Frederickson ED,Goldberg LI,Murphy MB, Pharmacokinetic and pharmacodynamic properties of intravenous fenoldopam, a dopamine1-receptor agonist, in hypertensive patients. British journal of clinical pharmacology. 1988 Jan; [PubMed PMID: 2897206]|
|||Brathwaite L,Reif M, Hypertensive Emergencies: A Review of Common Presentations and Treatment Options. Cardiology clinics. 2019 Aug; [PubMed PMID: 31279421]|
|||Beaulieu JM,Gainetdinov RR, The physiology, signaling, and pharmacology of dopamine receptors. Pharmacological reviews. 2011 Mar; [PubMed PMID: 21303898]|
|||Borovac JA, Side effects of a dopamine agonist therapy for Parkinson's disease: a mini-review of clinical pharmacology. The Yale journal of biology and medicine. 2016 Mar; [PubMed PMID: 27505015]|
|||Ahlskog JE, Pathological behaviors provoked by dopamine agonist therapy of Parkinson's disease. Physiology [PubMed PMID: 21557955]|