3053 Pergolide Pergolide is a long-acting dopamine agonist approved in 1982 for the treatment of Parkinson's Disease. It is an ergot derivative that acts on the dopamine D2 and D3, alpha2- and alpha1-adrenergic, and 5-hydroxytryptamine (5-HT) receptors. It was indicated as adjunct therapy with levodopa/carbidopa in the symptomatic treatment of parkinsonian syndrome. It was later found that pergolide increased the risk of cardiac valvulopathy. The drug was withdrawn from the US market in March 2007 and from the Canadian market in August 2007. 66104-22-1 47811 C19H26N2S 314.181670 White powder. 207.5°C 5.84e-04 g/L Oral (L1929) The dopamine D₂ receptor is a 7-transmembrane G-protein coupled receptor associated with G_i proteins. In lactotrophs, stimulation of dopamine D₂ receptor 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. Ergoline alkaloids have been shown to have the significant affinity towards the 5-HT1 and 5-HT2 serotonin receptors, D1 and D2 dopamine receptors, and alpha-adrenergic receptors. This can result in a number of different effects, including vasoconstriction, convulsions, and hallucinations. Pergolide is a potent dopamine receptor agonist. It directly stimulates post-synaptic dopamine receptors at both D1 and D2 receptor sites in the nigrostriatal system. This can reduce the motor complications associated with Parkinson's. Agonism of 5-HT2B and 5-HT1B receptors is believed to be responsible for the fibrotic reactions and cardiac valvular disease associated with pergolide use. (A365, A2933, A2934, A2914, A2915, A2916) Pergolide undergoes extensive first-pass hepatic metabolism and its metabolism are excreted mainly in the urine. (A2932) Route of Elimination: The major route of excretion is the kidney. Half Life: 27 hours LD50: 15 mg/kg (Oral, Rat) (A308) No indication of carcinogenicity to humans (not listed by IARC). Indicated as adjunctive treatment to levodopa/carbidopa in the management of the signs and symptoms of Parkinson's disease. It was withdrawn from the US and Canadian markets in 2007 due to an increased risk of cardiac valvulopathy. Pergolide is an ergoline-based, long-acting dopamine agonist which is effective in the treatment of Parkinson's disease and hyperprolactinemia. It has also been observed to have antihypertensive effects. Ergoline alkaloids occurs in various species of vines of the Convolvulaceae (morning glory) family and in some species of lower fungi. (L1918, L1929) Ingestion of ergoline alkaloids is known to cause the disease ergotism. Ergotism occurs in two forms, gangrenous and convulsive, likely depending on the different kinds and amounts of ergoline alkaloids present. The use of pergolide has been shown to increase the risk of cardiac valvular disease. It also increases the risk of fibrotic complications including pulmonary, pleural, and/or retroperitoneal fibrosis, pericarditis, pleuritis, and pericardial and/or pleural effusions. (A2913, L1570) Symptoms of pergolide overdose include nausea, vomiting, convulsions, decreased blood pressure, and CNS stimulation. Convulsive ergotism can cause painful seizures and spasms, diarrhea, paresthesias, itching, headaches, nausea and vomiting. Usually the gastrointestinal effects precede the central nervous system effects. As well as seizures there can be hallucinations and mental effects including mania or psychosis. Gangrenous ergotism causes dry gangrene as a result of vasoconstriction induced in the more poorly vascularized distal structures, such as the fingers and toes. Symptoms include desquamation, weak periphery pulse, loss of peripheral sensation, edema and ultimately the death and loss of affected tissues. (L1920, L1570) Management of overdosage may require supportive measures to maintain arterial blood pressure. Cardiac function should be monitored; an antiarrhythmic agent may be necessary. If signs of CNS stimulation are present, a phenothiazine or other butvronhenone neuroleptic agent may be indicated; the efficacy of such drugs in reversing the effects of overdose has not been assessed. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Treatment for ergotism consists of vasodilators, anticoagulants and low molecular weight dextrans. If necessary, a sympathetic nerve blockade may be carried out, such as brachial plexus blockade. Temporary sedation (e.g. haloperidol) will be necessary in hallucination and diazepam is used for convulsions. There is no specific antidote. (L1921, L1930) 2009-07-21T20:28:34Z 2014-12-24T20:25:55Z Pergolide C07425 63617 Pergolide DB01186 true [H][C@]1(CSC)CN(CCC)[C@]2([H])CC3=CNC4=CC=CC(=C34)[C@@]2([H])C1 C19H26N2S InChI=1S/C19H26N2S/c1-3-7-21-11-13(12-22-2)8-16-15-5-4-6-17-19(15)14(10-20-17)9-18(16)21/h4-6,10,13,16,18,20H,3,7-9,11-12H2,1-2H3/t13-,16-,18-/m1/s1 InChIKey=YEHCICAEULNIGD-MZMPZRCHSA-N 314.488 314.181669532 Exogenous Solid 4 HMDB15317 CHEMBL531 43503 <p><a href="http://www.drugsyn.org/Pergolide.htm">DrugSyn.org</a></p>