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Clinical data | |
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Trade names | Dostinex, others |
AHFS/Drugs.com | Monograph |
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Routes of administration | By mouth |
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Pharmacokinetic data | |
Bioavailability | First-pass effect seen; absolute bioavailability unknown |
Protein binding | Moderately bound (40–42%); concentration-independent |
Metabolism | Liver, predominately via hydrolysis of the acylurea bond or the urea moiety |
Elimination half-life | 63–69 hours (estimated) |
Excretion | Urine (22%), feces (60%) |
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CompTox Dashboard (EPA) | |
ECHA InfoCard | 100.155.380 |
Chemical and physical data | |
Formula | C26H37N5O2 |
Molar mass | 451.615 g·mol−1 |
3D model (JSmol) | |
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Cabergoline, sold under the brand name Dostinex among others, is a dopaminergic medication used in the treatment of high prolactin levels, prolactinomas, Parkinson's disease, and for other indications. [2] It is taken by mouth.
Cabergoline is an ergot derivative and a potent dopamine D2 receptor agonist. [3]
Cabergoline was patented in 1980 and approved for medical use in 1993. [4] It is on the World Health Organization's List of Essential Medicines. [5]
Cabergoline is frequently used as a first-line agent in the management of prolactinomas due to its higher affinity for D2 receptor sites, less severe side effects, and more convenient dosing schedule than the older bromocriptine, though in pregnancy bromocriptine is often still chosen since there is less data on safety in pregnancy for cabergoline.
Cabergoline has at times been used as an adjunct to SSRI antidepressants as there is some evidence that it counteracts certain side effects of those drugs, such as reduced libido and anorgasmia. It also has been suggested that it has a possible recreational use in reducing or eliminating the male refractory period, thereby allowing men to experience multiple ejaculatory orgasms in rapid succession, and at least two scientific studies support those speculations. [9] [10] : e28–e33 Additionally, a systematic review and meta-analysis concluded that prophylactic treatment with cabergoline reduces the incidence, but not the severity, of ovarian hyperstimulation syndrome (OHSS), without compromising pregnancy outcomes, in females undergoing stimulated cycles of in vitro fertilization (IVF). [11] Also, a study on rats found that cabergoline reduces voluntary alcohol consumption, possibly by increasing GDNF expression in the ventral tegmental area. [12] It may be used in the treatment of restless legs syndrome.[ citation needed ]
Relatively little is known about the effects of this medication during pregnancy and lactation. In some cases the related bromocriptine may be an alternative when pregnancy is expected.[ citation needed ]
Side effects are mostly dose dependent. Much more severe side effects are reported for treatment of Parkinson's disease and (off-label treatment) for restless leg syndrome which both typically require very high doses. The side effects are considered mild when used for treatment of hyperprolactinemia and other endocrine disorders or gynecologic indications where the typical dose is one hundredth to one tenth that for Parkinson's disease.[ citation needed ]
Cabergoline requires slow dose titration (2–4 weeks for hyperprolactinemia, often much longer for other conditions) to minimize side effects. The extremely long bioavailability of the medication may complicate dosing regimens during titration and require particular precautions.
Cabergoline is considered the best tolerable option for hyperprolactinemia treatment although the newer and less tested quinagolide may offer similarly favourable side effect profile with quicker titration times.
Approximately 200 patients with newly diagnosed Parkinson's disease participated in a clinical study of cabergoline monotherapy. [14] Seventy-six (76) percent reported at least one side effect. These side effects were chiefly mild or moderate:
In a combination study with 2,000 patients also treated with levodopa, the incidence and severity of side effects was comparable to monotherapy. Encountered side effects required a termination of cabergoline treatment in 15% of patients. Additional side effects were infrequent cases of hematological side effects, and an occasional increase in liver enzymes or serum creatinine without signs or symptoms.
As with other ergot derivatives, pleuritis, exudative pleura disease, pleura fibrosis, lung fibrosis, and pericarditis are seen. These side effects are noted in less than 2% of patients. They require immediate termination of treatment. Clinical improvement and normalization of X-ray findings are normally seen soon after cabergoline withdrawal. It appears that the dose typically used for treatment of hyperprolactinemia is too low to cause this type of side effects.
In two studies published in the New England Journal of Medicine on January 4, 2007, cabergoline was implicated along with pergolide in causing valvular heart disease. [15] [16] As a result of this, the FDA removed pergolide from the U.S. market on March 29, 2007. [17] Since cabergoline is not approved in the U.S. for Parkinson's Disease, but for hyperprolactinemia, the drug remains on the market. The lower doses required for treatment of hyperprolactinemia have been found to be not associated with clinically significant valvular heart disease or cardiac valve regurgitation. [18] [19]
No interactions were noted with levodopa or selegiline. The drug should not be combined with other ergot derivatives. Dopamine antagonists such as antipsychotics and metoclopramide counteract some effects of cabergoline. The use of antihypertensive drugs should be intensively monitored because excessive hypotension may result from the combination.
Site | Affinity (Ki [nM]) | Efficacy (Emax [%]) | Action |
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D1 | 214–32,000 | ? | ? |
D2S | 0.5–0.62 | 102 | Full agonist |
D2L | 0.95 | 75 | Partial agonist |
D3 | 0.80–1.0 | 86 | Partial agonist |
D4 | 56 | 49 | Partial agonist |
D5 | 22 | ? | ? |
5-HT1A | 1.9–20 | 93 | Partial agonist |
5-HT1B | 479 | 102 | Full agonist |
5-HT1D | 8.7 | 68 | Partial agonist |
5-HT2A | 4.6–6.2 | 94 | Partial agonist |
5-HT2B | 1.2–9.4 | 123 | Full agonist |
5-HT2C | 5.8–692 | 96 | Partial agonist |
5-HT3 | >10,000 | – | – |
5-HT4 | 3,000 | ? | ? |
5-HT6 | 1,300 | ? | ? |
5-HT7 | 2.5 | ? | Antagonist |
α1A | 288–>10,000 | 0 | Silent antagonist |
α1B | 60–1,000 | ? | ? |
α1D | 166 | ? | ? |
α2A | 12–132 | 0 | Silent antagonist |
α2B | 17–72 | 0 | Silent antagonist |
α2C | 22–364 | 0 | Silent antagonist |
α2D | 3.6 | ? | ? |
H1 | 1,380 | ? | ? |
M1 | >10,000 | – | – |
SERT | >10,000 | – | – |
Notes: All sites are human except α2D-adrenergic, which is rat (no human counterpart). [20] Negligible affinity (>10,000 nM) for various other receptors (β1- and β2-adrenergic, adenosine, GABA, glutamate, glycine, nicotinic acetylcholine, opioid, prostanoid). [21] Sources: [20] [22] [23] [21] [24] |
Cabergoline is a long-acting dopamine D2 receptor agonist. In-vitro rat studies show a direct inhibitory effect of cabergoline on the prolactin secretion in the lactotroph cells of the pituitary gland and cabergoline decreases serum prolactin levels in reserpinized rats.[ citation needed ] Although cabergoline is commonly described principally as a D2 receptor agonist, it also possesses significant affinity for the dopamine D3, and D4, serotonin 5-HT1A, 5-HT2A, 5-HT2B, and 5-HT2C, and α2-adrenergic receptors, as well as moderate/low affinity for the dopamine D1, serotonin 5-HT7, and α1-adrenergic receptors. [20] [21] [25] Cabergoline functions as an partial or full agonist at all of these receptors except for the 5-HT7, α1-adrenergic, and α2-adrenergic receptors, where it acts as an antagonist. [22] [23] [21] Cabergoline has been associated with cardiac valvulopathy due to activation of 5-HT2B receptors. [26]
Ergot derivatives like cabergoline have been described as non-hallucinogenic in spite of acting as serotonin 5-HT2A receptor agonists. [27]
Following a single oral dose, resorption of cabergoline from the gastrointestinal (GI) tract is highly variable, typically occurring within 0.5 to 4 hours. Ingestion with food does not alter its absorption rate. Human bioavailability has not been determined since the drug is intended for oral use only. In mice and rats the absolute bioavailability has been determined to be 30 and 63 percent, respectively. Cabergoline is rapidly and extensively metabolized in the liver and excreted in bile and to a lesser extent in urine. All metabolites are less active than the parental drug or inactive altogether. The human elimination half-life is estimated to be 63 to 68 hours in patients with Parkinson's disease and 79 to 115 hours in patients with pituitary tumors. Average elimination half-life is 80 hours.
Cabergoline was first synthesized by scientists working for the Italian drug company Farmitalia-Carlo Erba in Milan who were experimenting with semisynthetic derivatives of the ergot alkaloids, and a patent application was filed in 1980. [28] [29] [30] The first publication was a scientific abstract at the Society for Neuroscience meeting in 1991. [31] [32]
Farmitalia-Carlo Erba was acquired by Pharmacia in 1993, [33] which in turn was acquired by Pfizer in 2003. [34]
Cabergoline was first marketed in The Netherlands as Dostinex in 1992. [28] The drug was approved by the FDA on December 23, 1996. [35] It went generic in late 2005 following US patent expiration. [36]
Brand names of cabergoline include Cabaser, Dostinex, Galastop (veterinary), and Kelactin (veterinary), among others. [37]
Cabergoline was studied in one person with Cushing's disease, to lower adrenocorticotropic hormone (ACTH) levels and cause regression of ACTH-producing pituitary adenomas. [38]
Hyperprolactinaemia is a condition characterized by abnormally high levels of prolactin in the blood. In women, normal prolactin levels average to about 13 ng/mL, while in men, they average 5 ng/mL. The upper normal limit of serum prolactin is typically between 15 to 25 ng/mL for both genders. Levels exceeding this range indicate hyperprolactinemia.
Bromocriptine, originally marketed as Parlodel and subsequently under many brand names, is an ergoline derivative and dopamine agonist that is used in the treatment of pituitary tumors, Parkinson's disease, hyperprolactinaemia, neuroleptic malignant syndrome, and, as an adjunct, type 2 diabetes.
Pergolide, sold under the brand name Permax and Prascend (veterinary) among others, is an ergoline-based dopamine receptor agonist used in some countries for the treatment of Parkinson's disease. Parkinson's disease is associated with reduced dopamine synthesis in the substantia nigra of the brain. Pergolide acts on many of the same receptors as dopamine to increase receptor activity.
Ergoloid mesylates (USAN), co-dergocrine mesilate (BAN) or dihydroergotoxine mesylate, trade name Hydergine, is a mixture of the methanesulfonate salts of three dihydrogenated ergot alkaloids.
Amoxapine, sold under the brand name Asendin among others, is a tricyclic antidepressant (TCA). It is the N-demethylated metabolite of loxapine. Amoxapine first received marketing approval in the United States in 1980, approximately 10 to 20 years after most of the other TCAs were introduced in the United States.
Domperidone, sold under the brand name Motilium among others, is a dopamine antagonist medication which is used to treat nausea and vomiting and certain gastrointestinal problems like gastroparesis. It raises the level of prolactin in the human body and is used off label to induce and promote breast milk production. It may be taken by mouth or rectally.
A prolactinoma is a tumor (adenoma) of the pituitary gland that produces the hormone prolactin. It is the most common type of functioning pituitary tumor. Symptoms of prolactinoma are due to abnormally high levels of prolactin in the blood (hyperprolactinemia), or due to pressure of the tumor on surrounding brain tissue and/or the optic nerves. Based on its size, a prolactinoma may be classified as a microprolactinoma or a macroprolactinoma.
Dopaminergic means "related to dopamine", a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.
A dopamine agonist is a compound that activates dopamine receptors. There are two families of dopamine receptors, D1-like and D2-like. They are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the D2-like family includes D2, D3 and D4 receptors. 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. Impulse control disorders are associated with the use of dopamine agonists for whatever condition.
Lisuride, sold under the brand name Dopergin among others, is a monoaminergic medication of the ergoline class which is used in the treatment of Parkinson's disease, migraine, and high prolactin levels. It is taken by mouth.
Rotigotine, sold under the brand name Neupro among others, is a dopamine agonist of the non-ergoline class of medications indicated for the treatment of Parkinson's disease and restless legs syndrome. It is formulated as a once-daily transdermal patch which provides a slow and constant supply of the drug over the course of 24 hours.
Dihydroergocryptine (DHEC), sold under the brand names Almirid and Cripar among others, is a dopamine agonist of the ergoline group that is used as an antiparkinson agent in the treatment of Parkinson's disease. It is taken by mouth.
Metergoline, also known as methergoline and sold under the brand names Contralac (veterinary) and Liserdol (clinical), is a monoaminergic medication of the ergoline group which is used as a prolactin inhibitor in the treatment of hyperprolactinemia and to suppress lactation.
Levodopa, also known as L-DOPA and sold under many brand names, is a dopaminergic medication which is used in the treatment of Parkinson's disease and certain other conditions like dopamine-responsive dystonia and restless legs syndrome. The drug is usually used and formulated in combination with a peripherally selective aromatic L-amino acid decarboxylase (AAAD) inhibitor like carbidopa or benserazide. Levodopa is taken by mouth, by inhalation, through an intestinal tube, or by administration into fat.
Pimavanserin, sold under the brand name Nuplazid, is an atypical antipsychotic which is approved for the treatment of Parkinson's disease psychosis. Unlike other antipsychotics, pimavanserin is not a dopamine receptor antagonist, but rather is a selective inverse agonist of the serotonin 5-HT2A receptor.
Befiradol is an experimental drug being studied for the treatment of levodopa-induced dyskinesia. It is a potent and selective 5-HT1A receptor full agonist.
Peripherally selective drugs have their primary mechanism of action outside of the central nervous system (CNS), usually because they are excluded from the CNS by the blood–brain barrier. By being excluded from the CNS, drugs may act on the rest of the body without producing side-effects related to their effects on the brain or spinal cord. For example, most opioids cause sedation when given at a sufficiently high dose, but peripherally selective opioids can act on the rest of the body without entering the brain and are less likely to cause sedation. These peripherally selective opioids can be used as antidiarrheals, for instance loperamide (Imodium).
A prolactin modulator is a drug which affects the hypothalamic–pituitary–prolactin axis by modulating the secretion of the pituitary hormone prolactin from the anterior pituitary gland. Prolactin inhibitors suppress and prolactin releasers induce the secretion of prolactin, respectively.
Female fertility agents are medications that improve female’s ability to conceive pregnancy. These agents are prescribed for infertile female who fails to conceive pregnancy after 1-year of regular and unprotected sexual intercourse. The following will cover the advancements of female fertility agents, major causes of female infertility. Next, it emphasizes on common female fertility agents in terms of their mechanism of action, side effects, fetal consideration and clinical application and ended up by the introduction of supplements and herbal medicines for female infertility.
Mesdopetam (INNTooltip International Nonproprietary Name; developmental code names IRL-790, IPN60170) is a dopamine D2 and D3 receptor antagonist with preference for the D3 receptor which is under development for the treatment of Parkinson's disease, drug-induced dyskinesia, and psychotic disorders. It has been described by its developers as having "psychomotor stabilizing" properties.