What is known about high doses of belladonna-ergotamine? What can be expected when overdosing? Can

Fråga: What is known about high doses of belladonna-ergotamine? What can be expected when overdosing? Can a high dose be given and the patient monitored for side effects?

A 36-year-old woman who has been operated and then treated with antineoplastics for breast cancer is currently treated with Zoladex (goserelin) 10.8 mg implant every 12 weeks. She previously had deep venous thrombosis and therefore treatment with Tamoxifen is contraindicated. She also has vasculitis and Reynaud´s phenomenon and uses Citodon (paracetamol and codeine) and Emla-cream (lidocaine and prilocaine) when needed. Since she started treatment with Zoladex she has had marked climacteric-like side effects. She was therefore given belladonna-ergotamine which had a good effect according to the patient when on her own initiative she took 3 capsules twice daily in the morning and evening. The questioner considers treating her with this dose but the recommended dose is 1 capsule 3 to 4 times daily. The patient has a high risk of recurring cancer and will have difficulties adhering to the Zoladex treatment without something reducing the side effects.

Sammanfattning: Sparse information has been found concerning whether high doses of ergotamine can be concerned safe in continuous treatment. According to the sources above three capsules each containing 0.3 mg of ergotamine twice daily entails a dose that might be tolerated but probably could result in side effects that are potentially very serious, especially in long term treatment. If this dose is used the patient must be well informed and observant of symptoms of impaired peripheral circulation and symptoms from internal organs related to impaired circulation. She needs to be well informed of the serious side effects that could result from the treatment with ergotamine and the risks and benefits of treatment should be discussed with the patient. She also needs to be informed and observant of anticholinergic side effects related to the belladonna component. Alternative treatment with an SSRI or clonidine could possibly be considered.

Svar: Side effects related to treatment with belladonna are dry mouth, disturbance of accommodation, reduced tear production and constipation. With ergotamine treatment there is a risk of disturbance of peripheral circulation, especially in long term treatment. Belladonna extract contains several alkaloids and the pharmacological effect is predominantly related to I-hyoscyamine which has a powerful anticholinergic effect. Ergotamine stimulates alpha-adrenergic receptors and produces peripheral vasoconstriction. In therapeutic doses it has an inhibiting effect on noradrenergic reuptake which contributes to the vasoconstrictor effect. The combination of belladonna-ergotamine has a stabilizing effect on climacteric side effects such as flushing and sweating. One capsule belladonna-ergotamine APL contains 7 mg belladonna extract and 0.3 mg ergotamine (1).

The predominant signs of acute ergotamine toxicity in mammals are excitement, restlessness, excess salivation, nausea, vomiting, piloerection, mydriasis, tachypnea, tachycardia, pallor, coldness of the extremities, confusion and coma whereas chronic toxicity produces reduced peripheral circulation and ischemia of some part of the body. This is the result of unrelieved vasoconstriction which is followed by degenerative changes in the endothelium and thrombosis. Vascular occlusions can occur anywhere in the body and has been reported to produce gangrene in extremities, myocardial infarction, necrosis of the bowel and renal failure. Symptoms of an impaired peripheral circulation such as pallor, numbness, muscle pain and coldness of extremities are seen in chronic poisoning. Symptoms of circulatory disturbance such as anginal pain, tachycardia, bradychardia, and elevation or lowering of blood pressure also occurs. The most common other symptoms of chronic ergotamine poisoning are headache, nausea, diarrhea, dizziness, drowsiness, confusion, and rarely convulsions. In general vascular occlusions has occurred after daily or almost daily intake of ergotamine for weeks to months but it has also been reported with incidental use. No specific antidote exists for ergotamine. Retroperitoneal, pleuropulmonal, and endocardial fibrotic changes have also been seen with the use of ergotamine (2).

The effect of Bellergal Retard on climacteric complaints was studied in a double-blind placebo controlled study of 66 women. The patients in the treatment group (33 patients) received 1 capsule of the drug twice daily. A capsule contained 0.6 mg ergotamine tartate, 0.2 mg levorotatory alkaloids and 40 mg phenobarbital. The patients were treated for 8 weeks blinded and then for another 4 weeks during which all patients received treatment with Bellergal Retard as described above. Nineteen patients in the treatment group and 18 in the placebo group experienced side effects, 9 and 6 patients respectively dropped out because of this. The most important side effects were dry mouth, dizziness, sleepiness, headache and nausea according to the authors. Effect on climacteric complaints was seen in both groups and the difference between them was significant at the 2nd and 4th week visits, indicating better effect in the group receiving Bellergal Retard, but it did not remain at 8 weeks (3).

The commonly used dose of Belladonna-ergotamin APL in climacteric complaints is 1 capsule 3 (-4) times daily or one capsule in the morning and two in the evening (1). In the study above a dose was used which concerning ergotamine is equivalent to 2 capsules of Belladonna-ergotamin APL twice daily for 12 weeks (3). There are recommendations on a maximal dose of 6 mg ergotamine per 24 hours when treating migraine. In this recommendation it is assumed however that ergotamine is given intermittently and not more than twice a month (2). In an article from 1978 published cases of ergotism were reviewed. Average daily doses were over 4 mg, the patients were predominantly treated for migraine and in many cases intermittently (4).

Since ergotamine treatment is associated with an increased risk of thrombosis and the patient has had deep venous thrombosis and has vasculitis and Reynauds phenomenon the risk is even more increased in her case.

Alternative treatment options for vegetative climacteric complaints are SSRIs or clonidine (5). Belladonna-ergotamin. Summary of product characteristics (SPC) (APL 2004-03-24) Dollery C Sir, editor. Therapeutic drugs. 2nd ed. Edinburgh: Churchill Livingstone; 1999 Bergmans MG, Merkus JM, Corbey RS, Schellekens LA, Ubachs JM. Effect of Bellergal Retard on climacteric complaints: a double-blind, placebo-controlled study. Maturitas 1987;9(3):227-234 Harrison TE. Ergotaminism. JACEP 1978;7(4):162-169 Hammar M, Nedstrand E, Wyon Y. [Few alternatives to estrogen replacement therapy for vegetative symptoms after menopause]. Lakartidningen 2004;101(18):1612-1616