| Indication |
For the treatment of hyperprolactinemic disorders, either
idiopathic or due to prolactinoma (prolactin-secreting adenomas). May
also be used to manage symptoms of Parkinsonian Syndrome as monotherapy
during initial symptomatic management or as an adjunct to levodopa
therapy during advanced stages of disease. |
| Pharmacodynamics |
Cabergoline stimulates centrally-located dopaminergic receptors
resulting in a number of pharmacologic effects. Five dopamine receptor
types from two dopaminergic subfamilies have been identified. The
dopaminergic D1 receptor subfamily consists of D1 and D5 subreceptors, which are associated with dyskinesias. The dopaminergic D2 receptor subfamily consists of D2, D3 and D4
subreceptors, which are associated with improvement of symptoms of
movement disorders. Thus, agonist activity specific for D2 subfamily
receptors, primarily D2 and D3 receptor subtypes,
are the primary targets of dopaminergic antiparkinsonian agents. It is
thought that postsynaptic D2 stimulation is primarily responsible for
the antiparkinsonian effect of dopamine agonists, while presynaptic D2
stimulation confers neuroprotective effects. This semisynthetic ergot
derivative exhibits potent agonist activity on dopamine D2- and D3-receptors. It also exhibits: agonist activity (in order of decreasing binding affinities) on 5-hydroxytryptamine (5-HT)2B, 5-HT2A, 5-HT1D, dopamine D4, 5-HT1A, dopamine D1, 5-HT1B and 5-HT2C receptors and antagonist activity on α2B, α2A, and α2C
receptors. Parkinsonian Syndrome manifests when approximately 80% of
dopaminergic activity in the nigrostriatal pathway of the brain is lost.
As this striatum is involved in modulating the intensity of coordinated
muscle activity (e.g. movement, balance, walking), loss of activity may
result in dystonia (acute muscle contraction), Parkinsonism (including
symptoms of bradykinesia, tremor, rigidity, and flattened affect),
akathesia (inner restlessness), tardive dyskinesia (involuntary muscle
movements usually associated with long-term loss of dopaminergic
activity), and neuroleptic malignant syndrome, which manifests when
complete blockage of nigrostriatal dopamine occurs. High dopaminergic
activity in the mesolimbic pathway of the brain causes hallucinations
and delusions; these side effects of dopamine agonists are
manifestations seen in patients with schizophrenia who have
overractivity in this area of the brain. The hallucinogenic side effects
of dopamine agonists may also be due to 5-HT2A agonism. The
tuberoinfundibular pathway of the brain originates in the hypothalamus
and terminates in the pituitary gland. In this pathway, dopamine
inhibits lactotrophs in anterior pituitary from secreting prolactin.
Increased dopaminergic activity in the tuberoinfundibular pathway
inhibits prolactin secretion. |
| Mechanism of action |
The dopamine D2 receptor is a 7-transmembrane G-protein coupled receptor associated with Gi proteins. In lactotrophs, stimulation of dopamine D2 causes inhibition of adenylyl cyclase, which decreases intracellular cAMP concentrations and blocks IP3-dependent release of Ca2+
from intracellular stores. Decreases in intracellular calcium levels
may also be brought about via inhibition of calcium influx through
voltage-gated calcium channels, rather than via inhibition of adenylyl
cyclase. Additionally, receptor activation blocks phosphorylation of
p42/p44 MAPK and decreases MAPK/ERK kinase phosphorylation. Inhibition
of MAPK appears to be mediated by c-Raf and B-Raf-dependent inhibition
of MAPK/ERK kinase. Dopamine-stimulated growth hormone release from the
pituitary gland is mediated by a decrease in intracellular calcium
influx through voltage-gated calcium channels rather than via adenylyl
cyclase inhibition. Stimulation of dopamine D2 receptors in
the nigrostriatal pathway leads to improvements in coordinated muscle
activity in those with movement disorders. Cabergoline is a long-acting
dopamine receptor agonist with a high affinity for D2 receptors.
Receptor-binding studies indicate that cabergoline has low affinity for
dopamine D1, α1,- and α2- adrenergic, and 5-HT1- and 5-HT2-serotonin receptors. |
| Absorption |
First-pass effect is seen, however the absolute bioavailability is unknown. |
| Volume of distribution |
Not Available |
| Protein binding |
Moderately bound (40% to 42%) to human plasma proteins in a concentration-independent manner. |
| Metabolism |
Hepatic. Cabergoline is extensively metabolized, predominately
via hydrolysis of the acylurea bond of the urea moiety. Cytochrome P-450
mediated metabolism appears to be minimal. The main metabolite
identified in urine is 6-allyl-8b-carboxy-ergoline (4-6% of dose). Three
other metabolites were identified urine (less than 3% of dose). |
| Route of elimination |
After oral dosing of radioactive cabergoline to five healthy
volunteers, approximately 22% and 60% of the dose was excreted within 20
days in the urine and feces, respectively. Less than 4% of the dose was
excreted unchanged in the urine. |
| Half life |
The elimination half-life is estimated from urinary data of 12 healthy subjects to range between 63 to 69 hours. |
| Clearance |
- renal cl=0,008 L/min
- nonrenal cl=3.2 L/min
|
| Toxicity |
Overdosage might be expected to produce nasal congestion, syncope, or hallucinations. |
