European Journal of Clinical Pharmacology © by Springer-Verlag 1979
Eur. J. Clin. Phannacol. 16, 425-426 (1979)
Ergotism in a Patient with a Portosystemic Shunt V. Hansteen l, C. Eika 2, and S. Birkeland 3 1Medical Department VIII, 2Medical Department IX, and 3Surgical Department IlI, UllevfilHospital, Oslo, Norway
Summary. A case of ergotism is described in a patient with Banti's syndrome in whom a porto-systemic shunt had been made three times. She was admitted to hospital with severe ischaemia of the extremities after having taken a single oral dose of 1 mg ergotamine tartrate. Her condition improved rapidly after 2 to 3 days and the circulation was normal after one week. The possible mechanism of ergotism in this patient is discussed. Although the plasma concentration of ergotamine was not measured, the likeliest explanation was that the serious side effects were related to the altered pharmacokinetics and loss of first-pass metabolism of the drug due to the venous bypass of the liver. Key words: ergotamine tartrate, ergotism; Banti's syndrome; portosystemic shunt, first pass metabolism
This report discribes a young woman with ergotism, probably due to altered pharmacokinetics of ergotamine. In the patient suffering from Banti's syndrome with portal hypertension and recurrent haemorrhage from varicose oesophageal veins a porto-systemic shunt had been made three times. She had experienced attacks of migraine for several years, and during the last year she had taken a few tablets containing ergotamine tartrate 0.5 mg. One month prior to the present illness she took four tablets of ergotamine, followed after a few hours by coldness, burning pains and paraesthesiae in the feet, which lasted for several days. The day before admission she had another attack of migraine and took two tablets of ergotamine. A few hours later she experienced excruciating pains in the feet, which were cold and showed blueishly discolouration. She was admitted to hospital for threatened gangrene of the feet.
On admission, the patient, who was 29 years old, had tremor of both hands. She was mentally confused, the body temperature was slightly elevated, the BP could not be measured in the arms, and no wrist or ankle pulses were palpable. A stenotic murmur could be heard over both brachial and iliac arteries. The skin of both feet was slightly swollen, with a marmorated blue and waxy pale discolouration. All blood tests were normal, including liver function tests. E C G showed ischaemic changes, oscillography of the extremities demonstrated almost total loss of oscillographic deflections in the ankle and wrist regions; there was a pressure gradient of 20 to 35 mm Hg from the upper arms to wrists and ankles (Doppler technique). A few days later both E C G and oscillography had returned to normal, and the pressure gradient had disappeared. Arteriography on admission showed spastic, segmental narrowing of the iliac, femoral and popliteal arteries (Fig. 1), and complete normalization a week later (Fig. 2). The patient was treated with Macrodex-40 infusion, repeated intravenous injections of chlorpromazine and fi-Pyridylcarbinol (Ronicol) tablets. The relationship between treatment and the improvement in her condition after 2-3 days is uncertain.
Comment Although ergot alkaloids have been extensively used in the treatment of migraine and gynaecological disorders, very few studies have been performed to elucidate their pharmacokinetic properties. Recently, however, a radioimmunoassay for ergotamine has been reported [1], so it should soon be possible to gain better understanding of the metabolism and disposition, and pharmacological rationale, for the use of ergotamine. 0031 - 6970/79/0016/0425/$01.00
426
V. Hansteen et al.: Ergotism and Portosystemic Shunt
Fig. 1. Arteriography on admission Fig. 2. Arteriography after recovery
According to Ala-Hurula et al. [1] high plasma concentrations can be demonstrated after parenteral administration of ergotamine. After oral administration, considerably lower plasma concentrations are found, presumably because of incomplete absorption and/or extensive first-pass metabolism in tile liver. Our patient presented the typical clinical picture of ergotism with a favourable outcome. This serious side effect of ergotamine treatment is most commonly caused by rectal or parenteral overdosage of the drug [2]. Serious ergotism has also been reported in patients with acute liver disease and reduced liver function [3]. In a few reports of ergotism after small oral doses of ergotamine, the explanation may be individual hypersensitivity to ergotamine, or altered pharmacokinetic disposition of the drug for some as yet obscure reason [4, 5]. Unfortunately, plasma or tissue concentrations of ergotamine were not measured in any of these cases. In our patient ergotism appeared after a small "therapeutic" dose of ergotamine. The possibility of individual hypersensitivity to ergotamine cannot be completely ruled out, but the most plausible explanation seems to be loss of first-pass metabolism of the drug because of the portosystemic shunt. The patient demonstrates an important problem of drug treatment in patients with portosystemic
shunts. Ergotamine-containing drugs should probably, not be administered to such patients, and all drugs subject to first-pass metabolism in the liver (e. g. certain beta-blockers, antidepressants and opiate analgesics) should be used with great caution and in considerably reduced dosage.
References 1. Ala-Hurula, V., Myllylh, V. V., Arvela, P., K~irki,N. & Hokkahen, E.: Systemic availability of ergotamine tartrate after oral, rectal and intramuscular administration. Eur. J. Clin. Pharmacol. 15, 51-55 (1979) 2. Young, J. R., Humphries, A. W.: Severe arteriospasm after use of ergotamine tartrate suppositories. J. Am. Med. Assoc. 1'75, 114I-i145 (t961) 3. Whelton, M.J., Allaway, A., Stewart, A., Kreel, L.: Ergot poisoning in acute hepatic necrosis, Gut 9, 287-289 (1968) 4. Enge, I., Sivertssen, E.: Ergotism due to therapeutic doses of ergotamine tartrate. Am. Heart J. 70, 665-670 (1965) 5. Cameron, E. A., French, E. B.: St. Anthony's fire rekindled due to t h e r ~ u t i c doses of ergot. Br. Med. J. 1960/1I, 28-30 Received: August 13, 1979 accepted: September 7, 1979 Dr. V. Hansteen Medical Department VIII Ullev~t Hospital Oslo, Norway
Eur. J. Clin. Phannacol. 16, 425-426 (1979)
Ergotism in a Patient with a Portosystemic Shunt V. Hansteen l, C. Eika 2, and S. Birkeland 3 1Medical Department VIII, 2Medical Department IX, and 3Surgical Department IlI, UllevfilHospital, Oslo, Norway
Summary. A case of ergotism is described in a patient with Banti's syndrome in whom a porto-systemic shunt had been made three times. She was admitted to hospital with severe ischaemia of the extremities after having taken a single oral dose of 1 mg ergotamine tartrate. Her condition improved rapidly after 2 to 3 days and the circulation was normal after one week. The possible mechanism of ergotism in this patient is discussed. Although the plasma concentration of ergotamine was not measured, the likeliest explanation was that the serious side effects were related to the altered pharmacokinetics and loss of first-pass metabolism of the drug due to the venous bypass of the liver. Key words: ergotamine tartrate, ergotism; Banti's syndrome; portosystemic shunt, first pass metabolism
This report discribes a young woman with ergotism, probably due to altered pharmacokinetics of ergotamine. In the patient suffering from Banti's syndrome with portal hypertension and recurrent haemorrhage from varicose oesophageal veins a porto-systemic shunt had been made three times. She had experienced attacks of migraine for several years, and during the last year she had taken a few tablets containing ergotamine tartrate 0.5 mg. One month prior to the present illness she took four tablets of ergotamine, followed after a few hours by coldness, burning pains and paraesthesiae in the feet, which lasted for several days. The day before admission she had another attack of migraine and took two tablets of ergotamine. A few hours later she experienced excruciating pains in the feet, which were cold and showed blueishly discolouration. She was admitted to hospital for threatened gangrene of the feet.
On admission, the patient, who was 29 years old, had tremor of both hands. She was mentally confused, the body temperature was slightly elevated, the BP could not be measured in the arms, and no wrist or ankle pulses were palpable. A stenotic murmur could be heard over both brachial and iliac arteries. The skin of both feet was slightly swollen, with a marmorated blue and waxy pale discolouration. All blood tests were normal, including liver function tests. E C G showed ischaemic changes, oscillography of the extremities demonstrated almost total loss of oscillographic deflections in the ankle and wrist regions; there was a pressure gradient of 20 to 35 mm Hg from the upper arms to wrists and ankles (Doppler technique). A few days later both E C G and oscillography had returned to normal, and the pressure gradient had disappeared. Arteriography on admission showed spastic, segmental narrowing of the iliac, femoral and popliteal arteries (Fig. 1), and complete normalization a week later (Fig. 2). The patient was treated with Macrodex-40 infusion, repeated intravenous injections of chlorpromazine and fi-Pyridylcarbinol (Ronicol) tablets. The relationship between treatment and the improvement in her condition after 2-3 days is uncertain.
Comment Although ergot alkaloids have been extensively used in the treatment of migraine and gynaecological disorders, very few studies have been performed to elucidate their pharmacokinetic properties. Recently, however, a radioimmunoassay for ergotamine has been reported [1], so it should soon be possible to gain better understanding of the metabolism and disposition, and pharmacological rationale, for the use of ergotamine. 0031 - 6970/79/0016/0425/$01.00
426
V. Hansteen et al.: Ergotism and Portosystemic Shunt
Fig. 1. Arteriography on admission Fig. 2. Arteriography after recovery
According to Ala-Hurula et al. [1] high plasma concentrations can be demonstrated after parenteral administration of ergotamine. After oral administration, considerably lower plasma concentrations are found, presumably because of incomplete absorption and/or extensive first-pass metabolism in tile liver. Our patient presented the typical clinical picture of ergotism with a favourable outcome. This serious side effect of ergotamine treatment is most commonly caused by rectal or parenteral overdosage of the drug [2]. Serious ergotism has also been reported in patients with acute liver disease and reduced liver function [3]. In a few reports of ergotism after small oral doses of ergotamine, the explanation may be individual hypersensitivity to ergotamine, or altered pharmacokinetic disposition of the drug for some as yet obscure reason [4, 5]. Unfortunately, plasma or tissue concentrations of ergotamine were not measured in any of these cases. In our patient ergotism appeared after a small "therapeutic" dose of ergotamine. The possibility of individual hypersensitivity to ergotamine cannot be completely ruled out, but the most plausible explanation seems to be loss of first-pass metabolism of the drug because of the portosystemic shunt. The patient demonstrates an important problem of drug treatment in patients with portosystemic
shunts. Ergotamine-containing drugs should probably, not be administered to such patients, and all drugs subject to first-pass metabolism in the liver (e. g. certain beta-blockers, antidepressants and opiate analgesics) should be used with great caution and in considerably reduced dosage.
References 1. Ala-Hurula, V., Myllylh, V. V., Arvela, P., K~irki,N. & Hokkahen, E.: Systemic availability of ergotamine tartrate after oral, rectal and intramuscular administration. Eur. J. Clin. Pharmacol. 15, 51-55 (1979) 2. Young, J. R., Humphries, A. W.: Severe arteriospasm after use of ergotamine tartrate suppositories. J. Am. Med. Assoc. 1'75, 114I-i145 (t961) 3. Whelton, M.J., Allaway, A., Stewart, A., Kreel, L.: Ergot poisoning in acute hepatic necrosis, Gut 9, 287-289 (1968) 4. Enge, I., Sivertssen, E.: Ergotism due to therapeutic doses of ergotamine tartrate. Am. Heart J. 70, 665-670 (1965) 5. Cameron, E. A., French, E. B.: St. Anthony's fire rekindled due to t h e r ~ u t i c doses of ergot. Br. Med. J. 1960/1I, 28-30 Received: August 13, 1979 accepted: September 7, 1979 Dr. V. Hansteen Medical Department VIII Ullev~t Hospital Oslo, Norway
