Dopamine agonist

A dopamine agonist is a compound that activates dopamine D₂ receptors and belong to one of two different subclasses: ergoline and non-ergoline. Examples of ergoline agonists are cabergoline and bromocriptine and examples of non-ergoline agonists are pramipexole, ropinirole and rotigotine. Ergoline agonists have been linked to cartilage formation in heart valves.
Dopamine agonists are primarily used in the treatment of the motor symptoms of Parkinson's disease, and to a lesser extent, in hyperprolactinemia and restless legs syndrome. They are also used off-label in the treatment of clinical depression. One notable risk in the use of dopamine agonist is an increased risk of developing impulse control disorders.

Medical uses

Parkinson's disease

s are mainly used in the treatment of Parkinson's disease. In Parkinson's disease dopaminergic neurons in the brain slowly break down and can eventually die. With decreasing levels of dopamine, the brain cannot function properly. This causes abnormal brain activity, which ultimately leads to the symptoms of Parkinson's disease. In their function as a treatment for Parkinson's disease, dopamine agonists act directly on the dopamine receptors and mimic dopamine's effect.

Treatment of depression in Parkinson's patients

and disorders are common in patients with Parkinson's disease and can affect their quality of life. Increased anxiety can accentuate the symptoms of Parkinson's and is therefore essential to treat. Instead of conventional antidepressant medication in treating depression, treatment with dopamine agonists has been suggested. Although preliminary evidence of clinical trials has shown interesting results, further research odds crucial to establish the anti-depressive effects of dopamine agonists in treating depressive symptoms and disorders in those with Parkinson's.

Hyperprolactinemia

inhibits the production of prolactin in the human body. Therefore, anything that disrupts the production of dopamine would cause an increase in the production of prolactin. The ergoline-derived dopamine agonists bromocriptine and cabegoline are used in the treatment of hyperprolactinaemia. These agents are associated with the reduction in the size of prolactinomas. It is believed that they do so by suppressing the hypersecretion of prolactin, resulting in normal gonadal function.

Restless leg syndrome

Numerous clinical trials have been performed to assess the use of dopamine agonists for the treatment of restless legs syndrome. RLS is identified by the strong urge to move and is a dopamine-dependent disorder. RLS symptoms decrease with the use of drugs that stimulate dopamine receptors and increase dopamine levels, such as dopamine agonists.

Adverse effects

Side effects

Between the two classes of dopamine agonists, ergolines tend to cause the most side effects due to their lack of specificity, targeting D₁, 5-HT and adrenergic receptors in addition to their intended D₂ receptor target. In addition, the risk of side effects is much higher in the elderly than the general population.
The most common adverse effects are constipation, nausea and headaches. Other serious side effects are hallucinations, peripheral edema, gastrointestinal ulcers, pulmonary fibrosis and psychosis.
Dopamine agonists have been linked to cardiac problems, with side effects such as hypotension, myocardial infarction, congestive heart failure, cardiac fibrosis, pericardial effusion and tachycardia. A high risk for valvular heart disease has been established in association with ergot-derived agonists especially in elderly patients with hypertension.
In some studies, almost 30% of patients are reported to have suffered from somnolence and sleep attacks when using dopamine agonists. Daytime sleepiness, insomnia and other sleep disturbances are also frequently associated with the use of these drugs.
Impulse control disorder, which manifests in behaviors such as gambling, hypersexuality, compulsive shopping or binge eating, can be another serious adverse effect of dopamine agonists.
After long-term use of dopamine agonists a withdrawal syndrome may occur when discontinuing the drug or reducing the dose. The following side effects are possible: anxiety, panic attacks, dysphoria, depression, agitation, irritability, suicidal ideation, fatigue, orthostatic hypotension, nausea, vomiting, diaphoresis, generalised pain and drug cravings. For some individuals, these withdrawal symptoms are short-lived, and they make a full recovery. For others, a protracted withdrawal syndrome may occur with symptoms persisting for months or years.

Interactions

Dopamine agonists interact with a number of drugs but there is little evidence that they interact with other Parkinson's drugs. In most cases there is no reason not to co-administer Parkinson's drugs, but there have been indications that the concurrent use of dopamine agonists with L-DOPA can cause psychosis, and therefore in these cases it is recommended that either the dopamine agonist be discontinued or the dose of L-DOPA reduced. Since ergot-dopamine agonist have antihypertensive qualities it is wise to monitor blood pressure when using dopamine agonists with antihypertensive drugs to ensure that the patient does not get hypotension. That includes the drug sildenafil which is commonly used to treat erectile dysfunction but also used for pulmonary hypertension.
There is evidence that suggests that since ergot dopamine agonists are metabolized by CYP3A4 enzyme concentration rises with the use of CYP3A4 inhibitors. For example, in one study bromocriptine was given with a CYP3A4 inhibitor and the AUC increased 268%. Ropinirole is a non-ergot derived dopamine agonist and concomitant use with a CYP1A2 inhibitor can result in a higher concentration of ropinirole. When discontinuing the CYP1A2 inhibitor, if using both drugs, there is a chance that a dose adjustment for ropinirole is needed. There is also evidence the dopamine agonists inhibit various CYP enzymes and therefore they may inhibit the metabolism of certain drugs.

Ergoline Agonists

Ergoline agonists share the same base ergoline structure, which is derived from the ergot fungus. Ergot alkaloids are divided into two groups: amino acid ergot alkaloids and amine ergot alkaloids.
In terms of efficacy, there does not seem to be much difference between ergoline agonists and their non-ergoline counterparts. However, ergolines are known to have a more concerning side effect profile, chiefly the added risk of valvular heart disease and cartilage formation within the heart valves. In addition, ergoline agonists are less specific than non-ergoline agonists, targeting both 5-HT receptors and adrenergic receptors in addition to the primary D₂ receptor targets. It is for this reason that non-ergoline agonists are currently more preferred for treatment.

Pharmacokinetics

Ergolines

Bromocriptine

of bromocriptine oral dose is approximately 28%; however, only 6% reaches the systemic circulation unchanged, due to a substantial first-pass effect. Bromocriptine reaches mean peak plasma levels after about 1–1.5 hours after a single oral dose. The drug has high protein binding, ranging from 90-96% bound to serum albumin. Bromocriptine is metabolized by CYP3A4 and excreted primarily in the feces via biliary secretion. Metabolites and parent drugs are mostly excreted via the liver, but also 6% via the kidney. It has a half-life of 2–8 hours.

Pergolide

has a long half-life of about 27 hours and reaches a mean peak plasma level in about 2–3 hours after a single oral dose. The protein binding is 90% and the drug is mainly metabolized in the liver by CYP3A4 and CYP2D6. The major route of excretion is through the kidneys.

Drug	Maintenance	Half-life	Protein binding	Peak plasma	Metabolism	Excretion
Bromocriptine	Oral, 2.5–40 mg/day	2–8 hours	90-96%	1-1,5 hours	Hepatic, via CYP3A4, 93% first-pass metabolism	Bile, 94-98% Renal, 2-6%
Pergolide	Oral, 0.05 mg/day Usual response up to 0.1 mg per day	27 hours	90%	2–3 hours	Extensively hepatic	Renal, 50% Fecal 50%

Non-ergolines

Pramipexole

, in its instant release formulation, reaches maximum plasma concentration 1–3 hours post-dose. It is about 15% bound to plasma proteins and the metabolism is minimal. The elimination half-life of pramipexole is varies with age, being approximately 8 hours in younger subjects and 12 hours in the elderly. The drug is mostly excreted in the urine, around 90%, but also in feces.

Ropinirole

is rapidly absorbed after a single oral dose, reaching plasma concentration in approximately 1–2 hours. The half-life is around 5–6 hours. Ropinirole is heavily metabolized by the liver and in vitro studies show that the enzyme involved in the metabolism of ropinirole is CYP1A2.

Rotigotine

Since rotigotine is a transdermal patch it provides continuous drug delivery over 24 hours. It has a half-life of 3 hours and the protein binding is around 92% in vitro and 89.5% in vivo. Rotigotine is extensively and rapidly metabolized in the liver and by the CYP enzymes. The drug is mostly excreted in urine, but also in feces.

Drug	Maintenance	Half-life	Protein binding	Peak plasma	Metabolism	Excretion
Pramipexole	Oral, 0.125 mg 3x/day Oral, 0.375 mg/day	8–12 hours	15%	1–3 hours	Minimal < 10%	Urine 90% Fecal 2%
Ropinirole	Oral, 0.25 mg 3x/day Oral, 2 mg/day	5–6 hours	10-40%	1–2 hours	Hepatic, via P450 CYP1A2 — can increase ↑ INR	Renal > 88%
Rotigotine	Transdermal, 2 – 4 mg/day	3 hours	92%	24 hours	Hepatic.	Urine 71% Fecal 23%