Bromocriptine, administration

Cerebrospinal fluid rhinorrhea has been described as an interesting but highly unusual sequel of bromocriptine administration (SEDA-8, 143). The reverse effect, air aspiration through a sellar-pharyngeal leak, has also been encountered (SEDA-9,126). 

Carranza-Lira S, Gonzalez-Sanchez JL, Martinez-Chequer JC. Vaginal bromocriptine administration in patients with hyperprolactinemia. Int J Gynaecol Obstet 1999 65 77-78. 

The disposition of bromocriptine has been studied in several animal species and man following single oral and intravenous administration of the drug labelled with either tritium or carbon-14. 

Peak plasma levels are reached about 1.5 h after oral ingestion, the maximum concentrations being in the order of 2 - 3 ng equivalents/ml (parent drug + metabolites) for an oral 1 mg dose. The elimination from the plasma is biphasic and proceeds with mean half-lives of 6 h (a-phase) and 50 h ((3-phase). Similar elimination half-lives are obtained from the urinary excretion. The cumulative renal excretion is practically the same after oral and intravenous administration and amounts to 6 - 7 % of the radioactivity dosed. The main portion of the dose, either oral or intravenous, is eliminated by the biliary route into the faeces. The kinetics of bromocriptine has been demonstrated to be linear in the oral dose range from 2.5 to 7.5 mg. 

Six patients with Parkinson s disease were withdrawn from their antiparkinsonian medications (L-DOPA/carbidopa, bromocriptine, or lisuride) (Rabey et al. 1992, 1993). After 12 hours off medication, the subjects ate 250 g of cooked fava beans. Significant improvements in motor symptoms were noted, comparable to those seen with 125 mg of L-DOPA and 12.5 mg of carbidopa. In fact, three subjects developed severe dyskinesias after fava ingestion, akin to those seen after larger doses of pharmaceutical L-DOPA. Plasma levels of L-DOPA increased after fava ingestion in a manner comparable to that seen with administration of oral L-DOPA. These results suggest that the L-DOPA contained in fava beans was transported into the CNS and converted to dopamine. In five nonparkinsonian, healthy volunteers, a similar increase in plasma L-DOPA was observed after fava ingestion, although much lower. The difference in plasma L-DOPA between normal volunteers and parkinsonian patients is apparently due to a residual effect of carbidopa in the subjects with Parkinson s disease. Without carbidopa, the L-DOPA from fava is rapidly converted to dopamine in the blood stream and never crosses the blood-brain barrier. 

Neuroleptic malignant syndrome is an acute iatrogenic condition caused by neuroleptics, characterized by tremor, catatonia, fluctuating consciousness, hyperthermia, and cardiovascular instability. It is relatively uncommon, occuring in 1-1.5% of patients but is fatal in 11-38%, most often due to cardiovascular collapse (Jahan et al. 1992). The pathogenesis of neuroleptic malignant syndrome is poorly understood, but it is believed to result from altered dopamine and serotonin transmission in the hypothalamus, spinal cord, and striatum. Treatment includes discontinuation of neuroleptics and administration of drugs that increase dopamine transmission bromocriptine or L-dopa (Jahan etal. 1992 Baldessarini 1996). 

Administration of bromocriptine necessitates monitoring pituitary gland function, especially during pregnancy, whereas in psychotic disorders, including schizophrenia, bromocriptine must be administered with caution. There is no need to reduce the dose or administer bromocriptine with caution in patients with renal impairment. 

Consistent with earlier studies, Muscat et al. ( 58) reported on chronic exposure to mild unpredictable stress in rats as a model to study the antidepressant-reversible decreases in the consumption of palatable sweets. Using this model, they found that certain dopamine agonists (i.e., quinpirole, bromocriptine) administered intermittently had the same positive effects as TCAs. They further postulated that the infrequent, intermittent administration of dopamine agonists (e.g., psychostimulants) may avoid problems with tolerance and abuse while providing a clinically relevant antidepressant strategy. A report by Kapur and Mann ( 59) comprehensively reviews the role of dopamine in depressive disorders. They discuss several lines of evidence, including the following ... 

The ergot alkaloids are variably absorbed from the gastrointestinal tract. The oral dose of ergotamine is about 10 times larger than the intramuscular dose, but the speed of absorption and peak blood levels after oral administration can be improved by administration with caffeine (see below). The amine alkaloids are also absorbed from the rectum and the buccal cavity and after administration by aerosol inhaler. Absorption after intramuscular injection is slow but usually reliable. Bromocriptine and cabergoline are well absorbed from the gastrointestinal tract. 

All available dopamine agonists are active as oral preparations, and all are eliminated by metabolism. They can also be absorbed systemically after vaginal insertion of tablets. Cabergoline, with a half-life of approximately 65 hours, has the longest duration of action. Quinagolide has a half-life of about 20 hours, whereas the half-life of bromocriptine is about 7 hours. After vaginal administration, serum levels peak more slowly. 

A dopamine agonist alone or in combination with pituitary surgery, radiation therapy, or octreotide administration can be used to treat acromegaly. The doses required are higher than those used to treat hyperprolactinemia. For example, patients with acromegaly require 20-30 mg/d of bromocriptine and seldom respond adequately to bromocriptine alone unless the pituitary tumor secretes prolactin as well as GH. 

The effects of DA receptor agonists on cocaine self-administration have been examined, with some success—bromocriptine, lisuride, and SDZ 208911 have been reported to lower intravenous self-administration of cocaine (Pulvirenti and Koob 1994). 

Wise, Roy A., Aileen Murray, and Michael A. Bozarth. 1990. "Bromocriptine Self-Administration and Bromocriptine Reinstatement of Cocaine-Trained and Heroin-Trained Lever Pressing in Rats." Psychopharmacology 100 355-60. 

Other drugs of the depressant, antianxiety, antipyschotic, and anticonvulsive types are being investigated as treatments for cocaine abuse. Those which have been or will be covered in this course include the heterocyclic antidepressants desipramine and imipramine, which diminish cocaine use and craving as well as improve the outcome in the first few months of treatment. Buprenorphine (depressant) may augment the reward system (it has been found to suppress self-administration of cocaine in monkeys). Lithium sometimes works for those who are clinically depressives. Carbamazapine, bromocriptine and mazindol are also used as well as fluphenthixol and buspirone. 

All dopamine agonists may be administered orally. Additionally, bromocriptine and cabergoline are absorbed systemically after intravaginal insertion of tablets. Following intravaginal administration, serum levels peak more gradually. 

Incompatibilities of metoclopramide depend on drug concentration, pH, and temperature. It is incompatible with cephalosporins, chloramphenicol, sodium bicarbonate, doxorubicin, cisplatin, and cyclophosphamide. Caution should be exercised with simultaneous administration of metoclopramide with lithium, sym-pathomimetics, antidepressants, bromocriptine, and carbamazepine. Omperazole interacts with tolbutamide, clarithromycin, and phenytoin. Coadministration of rantidine and cisapride increases the plasma concentration of rantidine. Abuse of senna laxative has been reported and may cause hepatitis.176-178... 

Degim, I., Acrturk, F., Erdogan, D., and Lortlar, N. 2003. Transdermal administration of bromocriptine. Biol. Pharm. Bull., 26,501. 

Wise RA, Murray A, Bozarth MA (1990) Bromocriptine self-administration and bromocriptine-reinstatement of cocaine-trained and heroin-trained lever pressing in rats. Psychopharmacology 700(3) 355-360. 

The rapid (i.e. less than 4 h) activation of TH in the median eminence by prolactin that constitutes the tonic component of prolactin stimulation does not require protein synthesis, but is probably associated with effects on the catalytic properties of this enzyme. Pasqualini and coworkers (1994) demonstrated in vitro that prolactin acts directly on TH in the mediobasal hypothalamus to trigger the phosphorylation of this enzyme. This effect, possibly mediated by protein kinase C, makes the enzyme less susceptible to inhibition by newly synthesized DA. That is, prolactin-induced short-term activation of TH results from the removal of end-product inhibition of the enzyme. Conversely, the acute reduction in TH activity measured in vitro in median eminence removed from rats 4 h after administration of bromocriptine is prevented by the coadministration of prolactin (Arbogast and Voogt, 1995). This can also be prevented by an inhibitor of phosphoprotein phosphatases, suggesting that rapid suppression of TH activity secondary to the bromocriptine-induced hypoprolactinemia may also result from dephosphorylation of the enzyme. 

Bromocriptine Therapy of hyperprolactinemia Oral tablet and vaginal suppository Proved to be effective and safe, without the adverse effects of oral administration vaginal suppository obtained higher reduction in serum prolactin 330... 

Three women aged 22, 24, and 40 years took bromocriptine 2.5 mg bd for 2-5 days postpartum and complained of headache two lost consciousness (8). One subsequently died and another had a residual neurological deficit. In all three cases intracerebral hemorrhage, confirmed by CT or MRI scans, occurred on the sixth day of administration. Maximal recorded blood pressures were 200/100, 173/120, and 180/ 118 mmHg. 

In one series, three of 18 patients developed blurred vision during high-dose treatment of Parkinson s disease (SEDA-3, 124). Diplopia has been incidentally reported. In three patients with chronic hepatic encephalopathy, reversible ototoxicity developed after the administration of bromocriptine (11). 

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