For how long time can ergotamine-induced disturbances in circulation be lasting after the drug has

Fråga: For how long time can ergotamine-induced disturbances in circulation be lasting after the drug has been withdrawn? The patient concerned has used ergotamine for twenty years. The dosage she used is unknown. The patient shows disturbances in the circulation of the limbs although she has been off ergotamine for more than two weeks.

Sammanfattning: Generally, remission of vascular ergotism seems to occur within a few days after withdrawal of the drug, but there is a large interindividual variation. One report mentioned a total recovery period of more than two months after ergotamine had been withdrawn. No reports could be found specifically concerning the time needed for vascular disturbances to improve. The discrepancy between the short plasma half-life of the drug and the long duration of vasoconstriction could be explained by the formation of active metabolites, accumulation or binding of the drug to the arteries. Prolonged hemodynamic disturbances could be the manifestation of endothelial damage and medial and adventitial abnormalities produced during chronical use of the drug.

Svar: Ergotamine belongs to the natural amino acid alkaloids and is used in the treatment of migraine and migraine variant headaches (1,2). Ergotamine acts on several types of receptors and its dominant effect on bloodvessels is vasoconstriction (3). If the drug is chronically used, a vicious circle can arise, withdrawal headaches leading to the use of increasing doses. The vasoconstrictive effects can give rise to a syndrome called vascular ergotism, already recognized in the Middle Ages as "St Anthony´s Fire". The clinical picture is that of cold or blue limbs, paresthesia, intermittent claudication and absent peripheral arterial pulses, eventually leading to gangrene (4). Spasms of the renal mesenteric and coronary arteries have been reported as well (5). The degree of tolerance of patients to these vasoconstrictive effects varies widely (6): They can occur as a result of longstanding therapeutic use of the drug, after acute ingestions of excessive amounts or as an acute result of ingestion of a small dose, probably representing a hypersensitive type of reaction.

Pharmacokinetic data obtained by an ergotamine-specific mass spectrometry method (7) showed that the drug is quickly absorbed following oral and rectal administration of 2 mg. Peak plasma concentrations appeared after 69 and 50 minutes respectively and the mean half life was 2.5 hours. The relative bioavailability of the oral dose was low, only 5 percent compared to the rectal dose, which was ascribed to a high first-pass effect. After oral administration, about 60 percent of ergotamine is absorbed (8).

There is a pronounced discrepancy between plasma levels of ergotamine and its effect on arteries. The effect of a single dose of ergotamine tartrate (0.5 mg/70 kg) given intravenously to 17 migraine patients was measured by the decrease in peripheral systolic blood pressure. This decrease was well sustained for more than 22 hours (9). A recent study (10) used 0.5 mg of ergotamine tartrate injected intramuscularly and the effects on peripheral arteries were measured as a decrease in toe-arm systolic gradients. The authors described time aspects of the dynamic effects of ergotamine in relation to its plasma concentrations. The long standing effect of ergotamine may be a result of binding to the arteries. Also, the formation of active metabolites (7,11) have been suggested. One older study (11) used a radioimmunoassay for quantitation which could also detect metabolites. A 2 mg oral dose of ergotamine was administered to healthy volunteers at 24-hour intervals on three consecutive days. Plasma levels began to rise after three days, reaching a maximum on the sixth day, supporting the concept of accumulation of the drug or the formation of immunoreactive metabolites.

Generally, remission of the vascular symptoms seems to occur within a few days after the drug has been withdrawn but some case reports describe prolonged vasospastic conditions: a 32-year old woman developed an impending foot-gangrene after using ergotamine tartrate suppositories during three years in a dosage of 0.1-0.6 mg daily. Although she had not been taking ergotamine for the last two weeks before admission, the symptoms grew worse (6). Another case report (12) describes a 26-year old woman developing an ischemic condition of the lower limbs after ergotamine abuse. In this case, the time to recover took more than two months, after withdrawal of the drug.

Besides exerting a vasoconstrictive effect, ergotamine can also damage the capillary endothelium (2,6) or, during chronical use, give rise to medial and adventitial abnormalities (12) which could play a causal role in the development of prolonged hemodynamic disturbances, thrombosis and gangrene. 1 FASS, sid 119-120 2 Goodman and Gilman, The pharmacological basis of therapeutics. 1985; 7th ed: 931-940 3 Katzung, Basic and clinical pharmacology. 1987; 3rd ed: 196-200 4 Ergot Alkaloids and related compounds: Handbook of experimental pharmacology. B Berde, HO Schild. Vol 49. Springer-Verlag, 1978, page 817-818 5 Meyler´s. Side effects of drugs. Ed by MNG Dukes. Elsevier Amsterdam. 1988; 11th ed: 272-273 6 Brismar B, Somell A, Lockner D: Arterial insufficiency caused by ergotism. Acta Chir Scand 1977; 143: 319-321 7 Sanders SW, Haering N, Mosberg H, Jaeger H: Pharmacokinetics of ergotamine in healthy volunteers following oral and rectal dosing. Eur J Clin Pharmacol 1986; 30: 331-334 8 Aellig WH, Nuesch E: Comparative pharmacokinetic investigations with tritium-labeled ergot alkaloids after oral and intravenous administration in man. Int J Clin Pharmacol 1977; 15: 106-112 9 Tfelt-Hansen P, Eickhoff JH, Olesen J: The effect of single dose ergotamine tartrate on peripheral arteries in migraine patients: methodological aspects and time effect curve. Acta Pharmacol Toxicol 1980; 47: 151-156 10 Tfelt-Hansen P, Paalzow L: Intramuscular ergotamine: plasma levels and dynamic activity. Clin Pharmacol Ther 1985; 37: 29-35 11 Ala-Hurula V, Myllylä VV, Arvela P, Kärki NT, Hokkanen E: Systemic availability of egotamine tartrate after three successive doses and during continuous medication. Eur J Clin Pharmacol 1979; 16: 355-360 12 Zicot M, Grandfils F, Honore D: Prolonged arterial hemodynamic disturbances in the lower limbs after oral use of ergotamine. Angiology 1978; 29: 495-496