Dopamine Agonists: Common Uses, Negative Consequences, and More
Parkinson’s disease sufferers take dopamine agonists. For restless legs syndrome, dopamine agonists such as ropinirole are the first line of therapy, while bromocriptine is used to treat the neuroleptic malignant syndrome. Additionally, dopamine agonists are given to treat hyperprolactinemia brought on by dopamine antagonists.
Central Nervous System and Peripheral Tissue Dopaminergic Signaling
Dopamine plays a key role in controlling voluntary movement, reward- and addiction-related behavior, emotions including mania and sadness, cognition, memory, learning, sleep, and food intake.
Additionally, prolactin production and release from the pituitary gland are inhibited by dopamine. Dopamine is crucial for the cardiovascular system, kidney, pancreas, and gastrointestinal system to operate in peripheral tissue. As a result, dopamine agonists and antagonists are crucial pharmacotherapeutic drugs. (Read also Dysentery from Cryptosporidiosis: Causes, Symptoms, and Treatment).
Parkinson’s disease treated with dopamine replacement therapy
Levodopa has been the main pharmacological treatment for Parkinson’s disease since it was discovered that giving the dopamine precursor levodopa improved symptoms of the condition significantly.
Extrapyramidal adverse effects from levodopa medication, unfortunately, develop after many years of treatment. Initially, dopamine agonists were created as a supplement to levodopa therapy because of their higher therapeutic potency. (Read Cholecystitis – Symptoms, and causes).
Dopamine agonist monotherapy is currently advised for young patients to delay levodopa medication and the following onset of extrapyramidal side effects due to the adverse consequences of long-term levodopa treatment. Ergot alkaloids and non-ergot alkaloids are dopamine agonists.
Bromocriptine, cabergoline, lisuride, and pergolide are some of the most traditional ergot derivatives. Due to the possibility of valvular and pulmonary fibrosis, they are now seldom used to treat Parkinson’s disease. Due to an elevated risk of heart fibrosis, pergolide has been taken off the US market.
The more recent non-ergot dopamine agonists include apomorphine, rotigotine, pramipexole, ropinirole, and piribedil. Pramipexole and ropinirole are the two dopamine agonists that are most often administered in the US. For another movement problem, restless legs syndrome, these dopamine agonists are the first line of therapy.
Patients who have trouble adhering to their medication regimens might benefit from transdermal rotigotine. Apomorphine is only administered parenterally to individuals who have failed to respond to previous therapies and are having an abrupt “off” phase episode while receiving levodopa medication.
Dopamine Agonists to Treat Antipsychotic Drug Side Effects
Antipsychotic drugs can have a deadly adverse effect known as a neuroleptic malignant syndrome. Rarely, discontinuing dopamine agonists may have lethal adverse effects in Parkinson’s disease patients.
Over the course of 1 to 3 days (and 1 to 2 weeks following the start of antipsychotic medication), fever, mental state changes, and muscular stiffness (and subsequent respiratory distress) take place. Amantadine, a dopamine agonist, and muscle relaxants like lorazepam and dantrolene are alternatives to bromocriptine.
Treatment of Hyperprolactinemia with Dopamine Antagonists
Dopamine agonists are the first-line treatment for hyperprolactinemia as well as accompanying endocrine disorders including hypogonadism and infertility that are brought on by a pituitary tumor.
Patients who cannot tolerate their medications should only undergo surgery or radiation treatment. Bromocriptine and cabergoline, which are dopamine D2 receptor agonists, are suggested.
Particularly in individuals using first-generation antipsychotics, hyperprolactinemia is a very common adverse effect of antipsychotic therapy. Dopamine agonists are not advised due to the possibility of recurrence and aggravation of psychotic symptoms.
Type 2 Diabetes Treatment with Dopamine Antagonists
Bromocriptine has been shown to enhance glycemic control in type 2 diabetes, despite the fact that research has not clarified the cellular and molecular mechanisms of action.
Emergency Hypertension Treatment using Dopamine Antagonists
A selective D1 receptor agonist, fenoldopam dilates blood vessels in the skeletal muscles, the renal, splanchnic, and coronary arteries. The beginning of pharmacological effect after intravenous injection is quick (10 minutes), and the dose-response relationship is linear.
Additionally, its half-life of elimination is brief. As a result, in cases of acute kidney damage or cerebrovascular accident, fenoldopam is advised for parenteral treatment of hypertensive situations.
The Intracellular Signaling Mechanisms and Dopamine Receptors
Chemical substances known as dopamine agonists attach to dopamine receptors and stimulate cellular signaling pathways. Based on their pharmacological, physiological, and genetic characteristics, dopamine receptors may be divided into two families: the D1-like dopamine receptor family, which contains D1 and D5 receptors, and the D2-like dopamine receptor family, which includes D2, D3, and D4 receptors. Every dopamine receptor forms a bond with G proteins.
Adenylyl cyclase is activated when an agonist binds to the D1 and D5 receptors because they are linked to the Gs family of G proteins, which in turn induces the creation of cAMP.
Agonists block adenylyl cyclase, preventing the generation of cAMP, at the D2, D3, and D4 receptors, which are coupled to the Gi/o family of G proteins.
Protein kinase A is activated by an increase in intracellular cAMP, which in turn phosphorylates a variety of downstream protein targets, including the 32-kDa dopamine and cAMP-regulated phosphoprotein (DARPP-32), the ionotropic glutamate receptor, and GABA receptors.
DARPP-32 controls the phosphorylation status and consequently the activity of several protein kinases A target proteins as well as neuronal activity by inhibiting protein phosphatase 1.
According to research, the D1 and D2 dopamine receptors play a major role in regulating voluntary movement, rewarding and addictive behavior, as well as learning and memory.
D2 dopamine receptors have a key role in the psychotic behavior seen in bipolar illness and schizophrenia. Dopamine receptors D3, D4, and D5’s function in the brain is presently being studied.
In addition to acting as monomers, dopamine receptors may also function as homodimers (such as D1-D1), heterodimers (such as D1-D2, D1-D3, or D2-D3), or heteromers (e.g., D2-D3-adenosine A2 receptor or D2-somatostatin receptor 5). (Read Are Kiwi Skins Edible?).
It’s interesting to note that D1-D2 receptor dimers and D5 receptors are connected to the Gq family of G proteins, which activate phospholipase C and raise intracellular calcium levels.
Additionally, dopamine receptors may decrease the activity of glycogen synthase kinase 3 via G protein-independent methods such as direct interactions with ion channels and cAMP-independent control of protein kinase B (Akt). (Read Why Health Insurance Is Important: The Top 4 Reasons).
The emergence of schizophrenia, bipolar disorders, and other behavioral alterations associated with dopamine receptor activation has been linked to the latter signaling route as an intracellular signaling mechanism. (Read Why Vitamin B is important for your health).
The Brain’s Dopaminergic Pathways
The brain has four main dopaminergic pathways: nigrostriatal, mesolimbic, mesocortical, and tuberoinfundibular. The coordination of voluntary movement is mediated by dopaminergic neurons that arise from the substantia nigra and send their axons to the dorsal striatum (nigrostriatal pathway).
The nigrostriatal pathway’s diminished dopaminergic activity is thought to contribute to Parkinson’s disease. Dopaminergic neurons that emerge from the hypothalamus and extend toward the pituitary gland control prolactin synthesis and secretion (tuberoinfundibular pathway).
The mesocortical pathway is formed of neurons that originate in the ventral tegmental region of the brainstem and project to the prefrontal cortex and nucleus accumbens, respectively.
The mesolimbic pathway is triggered by addictive substances. In contrast, disruption of the mesocortical pathway may be the cause of the negative symptoms of schizophrenia. It may also play a role in the positive symptoms of schizophrenia. (Read Will cholecystitis go away? The truth revealed).
Parkinson’s disease Symptom Relief with Dopamine Antagonists
Parkinson’s disease has been linked to damage to the dopaminergic neurons in the substantia nigra. Following the impressive clinical improvement seen with levodopa therapy, the goal of pharmacological treatments for Parkinson’s disease has been to restore dopaminergic function by giving patients dopamine precursors, dopamine receptor agonists, and dopamine metabolism inhibitors.
Levodopa, a dopamine precursor, is given since dopamine itself cannot cross the blood-brain barrier. Levodopa is provided together with carbidopa, which inhibits levodopa from being converted into the peripheral tissue and lessens the negative effects of peripheral tissue’s high dopamine levels.
Dopamine activity in the brain may be raised by a variety of dopamine agonists. D2 dopamine receptor agonists make up the bulk of dopamine agonists used to treat Parkinson’s disease.
Older ergot compounds, which are dopamine agonists, also interact with serotonin and adrenergic receptors in addition to dopamine D1 and D2 receptors. Modern non-ergot dopamine agonists have a high affinity for dopamine D2 and D3 receptors. A dopamine agonist is not amantadine.
It could boost dopamine synthesis and release while decreasing dopamine reuptake. N-methyl-D-aspartate (NMDA)-type glutamate receptors and D2 dopamine receptors may both be inhibited by amantadine. (Read The Importance of Knowing Your Body Mass Index Average).
Dopamine Agonists to Treat Antipsychotic Drug Side Effects
Patients using an antipsychotic medication, particularly first-generation medications, often have extrapyramidal symptoms like those of Parkinson’s disease. The extrapyramidal side effects are thought to be caused by the blockage of D2 dopamine receptors in the nigrostriatal pathway.
Administration of levodopa or dopamine agonists to treat Parkinson’s syndrome brought on by antipsychotics may conflict with antipsychotic therapy and increase psychotic symptoms.
It is believed that atypical, second-generation antipsychotic drugs have a decreased affinity for D2 dopamine receptors and serotonin receptor activity, which lessens extrapyramidal adverse effects.
Treatment of Hyperprolactinemia with Dopamine Antagonists
The hypothalamus releases dopamine into the body. It binds to dopamine D2 receptors and prevents the anterior pituitary gland from producing and secreting prolactin. Dopamine antagonistic antipsychotic drugs prevent dopamine from attaching to its receptors.
Hyperprolactinemia is a relatively frequent side effect of several antipsychotics because it removes the inhibitory effects of dopamine on prolactin production. Up to 70% of individuals are thought to have antipsychotic-induced hyperprolactinemia. The usual, second-generation antipsychotics are more likely to cause hyperprolactinemia than the atypical antipsychotics.
Increased prolactin inhibits the hypothalamic production of gonadotropin-releasing hormone, which lowers estrogen levels in females and testosterone levels in men.
Sexual dysfunction, infertility, galactorrhea, amenorrhea, and gynecomastia in females, as well as oligospermia and gynecomastia in males, are all clinical signs of hyperprolactinemia.
Type 2 Diabetes Treatment with Dopamine Antagonists
The use of bromocriptine in the management of type 2 diabetes has received FDA approval. The D2 receptor is agonized by bromocriptine, whereas the D1 receptor is antagonized.
The molecular/cellular mechanism of action of bromocriptine in insulin release and better glycemic control in type 2 diabetes is still unknown since insulin release is reduced by activation of the D2 receptor and inhibition of the D1 receptor.
Bromocriptine, however, may enhance glycemic management by restoring normal hypothalamus circadian activity, according to some research. Therefore, to simulate hypothalamic circadian activity, bromocriptine should be used to treat type 2 diabetes within two hours after awakening.
Emergency Hypertension Treatment using Dopamine Antagonists
The smooth muscle of the renal, mesenteric, and coronary arteries as well as the peripheral blood vessels in the skeletal muscle have D1 receptors. Blood pressure is lowered by dopamine’s action on these receptors because vasodilation lowers peripheral vascular resistance. D2 receptors are not favored by dopamine agonists used to treat hypertensive crises.
Oral administration of pramipexole is the preferred method. There are two types of tablets: instant release and prolonged release. The immediate-release tablet’s starting dosage is 0.125 mg three times per day. To reach the typical maintenance dosage of 0.5 to 1.5 mg/three times/day every 5 to 7 days, the following doses should be progressively increased by 0.125 mg every dose.
Until the daily dosage is 0.75 mg, the decreased dose for cessation should be 0.75 mg. Reduce the dosage by 0.375 mg every day after that. Extended-release pills should be consumed whole rather than chewed, crushed, or split. The starting dosage for the tablets with an extended release is 0.375 mg once a day.
The dosage may be raised by 0.75 mg once a day for 5–7 days, and then by 0.75 mg each time up to 4.5 mg once daily. Treatment should be stopped gradually; first, lower the dosage by 0.75 mg per day until it reaches 0.75 mg once per day, and then lower it by 0.375 mg per day.
The medication ropinirole is also taken by mouth. The beginning dosage for the immediate-release pill is 0.25 mg three times per day. For four weeks, the dosage may be raised by 0.75 mg/day.
The dosage may be raised by 1.5 mg/day, weekly, up to 9 mg/day after four weeks. Following then, the dosage may be raised once a week by up to 3 mg/day, up to a maximum of 24 mg/day.
For weeks 1 and 2 of extended-release tablets, the beginning dosage is 2 mg once a day. Up to a maximum dosage of 24 mg/day, the dose may be increased by 2 mg/day once a week or at more frequent intervals. (Read When Take Omega 3 Supplements: Tips for Getting the Most Out of Them).
An adhesive transdermal patch is used to administer the routine. The first use of a 2 mg/24 hours patch once per day is advised for Parkinson’s disease in its early stages.
The lowest effective dose is 4 mg every 24 hours, while the highest amount that is advised is 6 mg every 24 hours. It is advised to apply a 4 mg/24-hour patch once a day for the first treatment of advanced-stage Parkinson’s disease.
The greatest dosage employed in the clinical studies was 16 mg/24 hours, whereas the suggested dose is 8 mg/24 hours. The dosage should be gradually reduced, preferably by no more than 2 mg/24 hours every other day. (Read The Best Dark Chocolate Brands).
A subcutaneous injection is used to give apomorphine. Avoid intravenous injection since crystallization might result in thrombus or embolism. Levodopa “off” episodes benefit from supplementary apomorphine medication.
To avoid negative outcomes, antiemetic medication is advised three days before to beginning but for no more than two months. 0.2 mL is the initial test dose (2 mg).
If necessary, a beginning dosage of 0.2 mL (2 mg) is advised if a patient tolerates and reacts to the test dose. Up to a maximum dosage of 0.6 mL, the dose may be raised by 0.1 mL (1 mg) every few days (6 mg). (Read If you or a loved one has been diagnosed with mesothelioma).
Irritable Bowel Syndrome
Patients may begin taking pramipexole in the immediate-release version at a dosage of 0.125 mg once a day. Every four to seven days, the amount may be raised up to 0.5 to 0.75 mg/day. Every 4 to 7 days, the dosage should be progressively decreased in order to stop the medication.
The initial dosage for ropinirole immediate-release tablets may be 0.25 mg once a day. The dosage may be raised to 0.5 mg/day and 1 mg/day, respectively, after 2 and 7 days. The dosage may be raised by 0.5 mg/week in the next weeks until it reaches 3 mg/day, at which point it may be increased to a maximum of 4 mg/day the following week.
It is recommended to take ropinirole and pramipexole two to three hours before going to bed. The patient may split the dosage into many daily doses, including one early in the day, if augmentation develops. (Read about Alzheimer’s Disease).
One mg of rotigotine transdermal patch may be used initially, once daily for 24 hours. A weekly dosage increase of 1 mg/24 hours is possible. The minimum and highest efficacious doses are 1 mg/24 hours and 3 mg/24 hours, respectively. Reduce the dosage by 1 mg/24 hours every other day to stop the therapy.
Malignant Neuroleptic Syndrome
Oral or gastric tube administration of bromocriptine is also an option. If necessary, a dosage of 2.5 mg may be administered every 8 to 12 hours up to a daily maximum of 45 mg. Levodopa and dopamine agonists should not be suddenly terminated, but rather tapered down gradually to prevent the development of neuroleptic malignant syndrome.
The recommended starting oral dose of bromocriptine is 1.25 to 2.5 mg/day to treat hyperprolactinemia. Up to the typical maintenance dosage range of 2.5 to 15 mg/day, the dose may be progressively increased by 2.5 mg/day/every 2 to 7 days.
Orally given cabergoline is started at 0.25 mg twice weekly. The dosage may be changed at least once every four weeks and raised very gradually by 0.25 mg/twice/weekly. In senior people, cabergoline has a half-life of 63 to 69 hours. One milligram given twice weekly is the maximum dosage. There may be less gastrointestinal upset and greater tolerability when taken with or after meals.
Diabetes Mellitus Type 2
Orally is how bromocriptine is delivered. Starting dosage of 0.8 mg once a day, ideally within three hours of waking, is advised for the treatment of type 2 diabetes mellitus. The dose can be increased if tolerated up to 1.6 to 4.8 mg once daily at 0.8 mg increments once a week.
Using a calibrated infusion pump, fenoldopam is continuously infused intravenously. Adults should start with 0.1 to 0.3 microgram/kg/min. It is advised to start with this low dosage to avoid reflex tachycardia. Every 15 to 20 minutes, the dose is raised by 0.05 to 0.1 microgram/kg/min. There is a 1.6 microgram/kg/min maximum dosage. It should only be used for a maximum of 48 hours.
Dopamine agonists most often cause nausea, vomiting, orthostatic hypotension, headaches, dizziness, and cardiac arrhythmias. Most of these negative effects are dose-dependent. To lower the risk of orthostatic hypotension, it is strongly advised to begin these drugs at a low dose. Dopamine agonists may have a greater hypotensive impact when used with serotonin receptor antagonist antiemetics.
Dopamine agonist usage over an extended period of time might result in psychological disorders, choreiform, and dystonic movements.
Some of the most frequent side effects associated with the prolonged use of these drugs include hallucinations, delusions, disorientation, depression, and many Patients on pramipexole and ropinirole have reported experiencing impulse control problems such as hypersexuality, excessive gambling or shopping, hyperphagia, and compulsive hobbying. In addition to the D2 dopamine receptors, these dopamine agonists also exhibit a strong affinity for the mesolimbic D3 dopamine receptors.
Patients using ropinirole and pramipexole may have uncontrollable sleep episodes. Dopamine agonist usage has been linked to symptoms such as increased sedation, yawning, somnolence, and daytime sleepiness. (Read about Monkeypox).
Patients having a history of hypertension, cardiovascular, renal, or hepatic problems should utilize dopamine agonists with care. There are links between the usage of ergot dopamine agonists and a higher incidence of fibrotic diseases. In patients on long-term bromocriptine and cabergoline treatment, pleural thickening, pleural effusion, and pulmonary fibrosis may develop.
Heart valve regurgitation was more common when cabergoline and pergolide were used. Pergolide has therefore been taken from the US market.
Bromocriptine and cabergoline are not advised for the treatment of Parkinson’s disease since they need to be taken for a longer period of time and at a greater dosage than they would for hyperprolactinemia.
Dopamine agonists are contraindicated during pregnancy and in nursing women because they interfere with breastfeeding.
Any ingredient in the formulation, including bromocriptine, cabergoline, and derivatives of ergot, may cause hypersensitivity responses. Ropinirole, rotigotine, and apomorphine dopamine agonists that are not ergot-based—can also result in hypersensitivity responses to these medications or any formulation component.
Ergot dopamine agonists have a significant risk of peritoneal, pulmonary, or cardiac valvular fibrosis. Ergot dopamine agonists shouldn’t be prescribed to those who have had fibrosis in the past.
Bromocriptine is contraindicated in individuals with uncontrolled hypertension who are also pregnant while receiving therapy for prolactinoma, acromegaly, or Parkinson’s disease due to the possibility of elevated blood pressure. Additionally, postpartum women with significant cardiovascular disease or a history of coronary artery disease should avoid using it.
Strong vasodilator and emetic, apomorphine. The anti-Parkinson effects of apomorphine are countered by antiemetics that inhibit central dopamine receptors. Antiemetics called serotonin receptor antagonists to cause significant hypotension and unconsciousness.
Serotonin antagonists, antihypertensives, or vasodilators should not be used concurrently with apomorphine. Patients with severe renal or hepatic impairment should not use it.
Dopamine agonists shouldn’t be prescribed by doctors together with monoamine oxidase inhibitors (MAOI). It must be stopped for at least two weeks before taking a dopamine agonist.
Monitoring of vital signs, electrocardiograms, and central nervous system depression is necessary for symptomatic individuals. Patients who have continued vomiting need to have their fluid and electrolyte levels checked as well.
Patients on bromocriptine should have pregnancies checked every four weeks if they are experiencing amenorrhea or if their period is more than three days late. The following tests should be performed: complete blood counts with differential, liver function tests, BUN/Cr, and cardiovascular examination.
Pramipexole users should have their baseline creatinine levels, orthostatic hypotension, and skin responses checked regularly.
The patient should keep an eye on any skin responses and orthostatic hypotension when taking ropinirole, particularly during dosage titration.
Dopamine agonist overdose is uncommon. When there is only minor toxicity, supportive treatment should be given to the patient (such as hydration, electrolyte replacement, and rest). Symptoms include dyskinesia, dystonia, hypotension, and dysrhythmias that may manifest in extreme poisoning instances.
The physician in these situations should reduce the medicine dose and provide supportive treatment. To treat dystonia, doctors may also prescribe benzodiazepines and antispasmodic drugs. Dysrhythmias should be treated with antiarrhythmic medications, and hypotension should be addressed with intravenous fluids.
Improving Healthcare Team Results
Providers should keep an eye out for any indications of CNS depression, orthostatic hypotension, or an electrolyte imbalance in patients on dopamine agonists. Clinicians and the entire interprofessional healthcare team should work together to closely monitor patients, especially during the titration phase.
Before beginning the medicine, a baseline complete blood count with differential, liver function test, BUN/Cr, and cardiovascular examinations are required. It is possible that patients using dopamine agonists are unaware of the signs and symptoms of orthostatic hypotension.
The pharmacist should examine potential drug interactions on the patient’s prescription profile and communicate with the doctor about the appropriateness of the agent chosen and the recommended dose.
The healthcare staff must educate patients about falls since they may result in accidents, significant consequences, and even death in older people.
The nursing staff may be a valuable resource for providing information on drug administration and dose, warning patients of potential side effects, and acting as a conduit to the physician.
Patients who did not previously display abnormal compulsive behaviors like gambling or hypersexuality may now develop them after starting dopamine agonist medication.
Patients can be embarrassed to mention these behavioral changes. The healthcare team’s advice for individuals receiving dopamine agonist treatment is a psychological assessment. These illustrations show how prescription dopamine agonist medicines require interprofessional coordination.