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Home , Bromocriptine, Ergocristine

LONDON, SATURDAY 20 DECEMBER 1975 Br Med J: first published as 10.1136/bmj.4.5998.667 on 20 December 1975. Downloaded from MEDICAL JOURNAL

Bromocriptine -a changing scene

Ergot, known to man since ancient times, is a product of the Levodopa has been used to lower levels, but its fungus that grows on rye and grain. A action does not last long enough; has a much symposium' at the Royal College of Physicians last May longer action and is therefore more effective. reviewed the pharmacology and clinical uses of the older as Since bromocriptine has been shown not to be teratogenic it well as the more recently introduced compounds. All the has been used recently in restoring fertility. Its place has still ergot are derivatives of : the best known finally to be defined, but it appears to be effective not only in are the oxytocic and the mixed ao-adrenergic patients with but also in some with agonist and antagonist ergometrine compounds. Nevertheless, normal prolactin levels, as described by M 0 Thorner et al,14 the first group of ergot compounds isolated by Barger, Carr, at p 694 of this issue. There is, however, some danger in and Dale in 1906, and called ergotoxine,2 is a mixture of ergot restoring fertility in women with small pituitary tumours, alkaloids: , , and ergokryptine. since such lesions may rapidly enlarge, with visual impairment, The inhibition oflactation by ergot was described by Dodart3 during pregnancy. Arguably the tumour should be irradiated in 1676. When in 1954 Shelesnyak found that ergotoxine before pregnancy to reduce these risks,14 but there is no general affected endometrial function in the rat4 he began the un- agreement on the best management. ravelling of a subtle endocrine relationship in reproduction. Bromocriptine is also used for suppression of puerperal

He suggested that ergotoxine inhibited release of prolactin lactation,' 15 16 and will probably become the treatment of http://www.bmj.com/ from the pituitary,5 and this was later confirmed.6 In the rat choice: it is effective, has few side effects, and does not affect prolactin stimulates the corpus luteum to secrete progesterone, the blood clotting system.1 which in turn prepares the endometrium for implantation ofthe In both disease and health bromocriptine's clinical efficiency fertilised ovum. Ergotoxine prevents implantation by sup- in lowering prolactin levels is unsurpassed. Not only has it pressing prolactin sectetion; this effect may be reversed by the fulfilled the purpose for which it was developed but it has also administration of either prolactin or progesterone.4 Having helped in our understanding of how prolactin secretion is confirmed Shelesnyak's findings, Fluckiger embarked on a controlled. Only three years ago bromocriptine was showntobe specific search for an ergot that would inhibit prolactin a specific receptor-agonist with a prolonged action." on 28 September 2021 by guest. Protected copyright. release without the oxytocic and cardiovascular effects At that time secretion of the hypothalamic prolactin-release- associated with the parent ergotoxine compounds, since he inhibiting factor (PIF) was thought to be under believed that such a drug would have great therapeutic im- control. Subsequently Schally and colleagues found that one portance. Bromocriptine (2-brom-oc-ergokryptine, CB154), of their hypothalamic extracts with the most potent PIF the compound that was developed,' 7suppresses prolactin activity was devoid of the expected polypeptide content but secretion by a direct action on the pituitary.8 instead contained only dopamine and noradrenaline,'8 and In man prolactin suppression does not block implantation of further that dopamine itself could act at the receptors in the the ovum, and bromocriptine is therefore not contraceptive as pituitary cell. This discovery prompted the suggestion that it is in the rat: on the contrary it is frequently effective in dopamine might be one of the physiologically important restoring normal gonadal function in both hypogonodal men PIFs.'9 The mode of action of bromocriptine in lowering and women with hyperprolactinaemia.9 -1 Irrespective of the prolactin levels both in patients with hyperprolactinaemia and cause of the raised prolactin levels, the only patients in this post partum then became clear: it acts predominantly on the group who do not respond seem to be the minority who are pituitary cells by activating dopamine receptors, as a functional shown to be truly deficient in gonadotrophins. There is now analogue of PIF. increasing evidence that in hyperprolactinaemia the hypo- Bromocriptine also stimulates other dopaminergic receptors gonadism is at least in part due to a prolactin-induced blockade apart from those ofthe prolactin-secreting cells. Its long action, of the action of the gonadotrophins on the gonads."1-13 When its direct action on the dopamine receptors, and its lack of prolactin levels are lowered with bromocriptine the gonado- agonist activity on the other receptors make it a specific trophins can exert their normal effects and thus gonadal research tool as well as a very useful drug. Acromegalicpatients function returns to normal. Some of the patients with hyper- have a paradoxical response to the administration of dopa- prolactinaemia also have galactorrhoea, and it too ceases with minergic agonists. In normal people (GH) this treatment, usually using doses of 7-5 to 15 mg daily. levels rise after administration of a , while in C) BRITISH MEDICAL JOURNAL 1975. All reproduction rights reserved. NO 5998 PAGE 667 668 BRITISH MEDICAL JOURNAL 20 DECEMBER 1975 most patients with GH levels fall.20 21 Again, 21 Camanni, F, et al, Journal of Clinical Endocrinology and Metabolism, 1975, 40, 363. levodopa was shown to have too short an action, and 22 Liuzzi, A, et al, Journal of Clinical Endocrinology and Metabolism, 1974, Br Med J: first published as 10.1136/bmj.4.5998.667 on 20 December 1975. Downloaded from single doses of bromocriptine in acromegalic patients were 38, 910. found to lower GH levels.22 Patients have been treated 23 Thorner, M 0, et al, British Medical_Journal, 1975, 1, 299. 24 Chiodini, P G, et al,Journal ofClinical Endocrinology and Metabolism, 1975, successfually for up to nine months in the reports published so 40, 705. far.23-25 Higher doses are required than have been used for 25 Thorner, M 0, et al, Abstract 125, Proceedings of 75th Annual Meeting of the Endocrine Society, 1975. hyperprolactinaemia, usually between 20 and 60 mg per day. 26 Calne, D B, et al, British Medical Journal, 1974, 4, 442. The results of this medical treatment are encouraging: many 27 Calne, D B, et al, Lancet, 1974, 2, 1355. patients have clinical, biochemical, and metabolic improve- 28 Teychenne, P S, et al, Lancet, 1975, 2, 473. ment. Since surgery and radiotherapy are often ineffective in 29 Thorner, M 0, Lancet, 1975, 1, 662. reversing these manifestations bromocriptine will be a major therapeutic advance if its current promise is upheld. Another obvious indication for bromocriptine is in treating . There are theoretical advantages in the use of a dopamine agonist which, unlike levodopa, does not Acute appendicitis in require to be metabolised to the active compound by dopa- pregnancy minergic neurones. All the reports indicate that bromocriptine may be superior to levodopa, though the results are not as dramatic as might have been expected on theoretical "The mortality of appendicitis complicating pregnancy and grounds.2 26-28 the puerperium is the mortality of delay," wrote Bablerl The side effects of bromocriptine are important. They may in 1908, when he found a 49% mortality among 103 pregnant be divided into those which occur at the start of treatment and women with perforated appendicitis. We now have the means those found when patients are established on high doses. Any to salvage many more patients-in 1967-9 in England and patient given a sufficiently large initial dose may develop Wales2 only two women died from acute appendicitis during nausea, vomiting, and postural hypotension. Micturition pregnancy-but we still make too many late diagnoses and syncope has also been described. Normal people are the most see some gravely ill patients. From 1950 to 1973 the incidence sensitive to these initiating side effects; patients with hyperpro- of gangrene and perforation of the appendix in pregnant lactinaemia and acromegaly less so; and finally the most women in Oxford3 was twice that among the non-pregnant, resistant are women immediately post partum, in whom side while in the same series two out of four fetal deaths occurred effects are virtually unknown. Side effects may, however, in mothers who had been treated conservatively in hospital for usually be avoided if a really small dose is given at the start of two and a halfand for three days. Similar figures were reported treatment and then increased very slowly. Preferably treatment from Melbourne4 in 1972, where the incidence of perforation should be started in the evening, the dose being taken with food in the last trimester was five times that in the first. when going to bed. The clinical picture of acute appendicitis is in fact little The other side effects, found during continuous therapy, are changed in the first three or four months of pregnancy. It rare when the daily dose is less than 20 mg: they include mild is especially in the last trimester and the puerperium that constipation, muzziness, nasal congestion, cramps in the legs difficulties arise and delay in diagnosis may occur. What can be http://www.bmj.com/ at night, and dystonic reactions in the Parkinsonian patients. done to improve the situation ? Cardiac dysrhythmias have also occurred occasionally when There may be an understandable tendency for obstetricians high doses were given. to look for obstetric causes when acute abdominal pain occurs Probably in the future new ergot derivatives with even more in their patients, but they must not overlook the fairly specific effects will be found. Bromocriptine is likely to be the uncommon but dangerous surgical complications of pregnancy first of a new class of therapeutic agents-the dopamine and the puerperium. A report from Aberdeen on some cases .at 691 of this issue. The receptor agonists-for which further indications will be found difficult appear page symptoms on 28 September 2021 by guest. Protected copyright. as the role of dopamine in the peripheral autonomic nervous and signs of acute appendicitis (and other surgical system is delineated.29 emergencies) are considerably modified during late pregnancy and the puerperium. Parker,5 in a paper which 1 should be read by all obstetricians and general surgeons, Symposium Ergot Compounds-The Changing Scene, Proceedings to be these differences. There be a classical shift published in Postgraduate Medical_Journal. identified may of 2 Barger, G, Carr, F H, and Dale, H, British Medical_Journal, 1906, 2, 1792. pain, but often pain is only vaguely localised. Tenderness will 3 Dodart, M,J_ournal des Savants, 1676, p 76. be found over the appendix, but it is likely to be higher than 4 Shelesnyak, M C, Recent Progress in Hormone Research, 1957, 13, 269. 5 Shelesnyak, M C, Acta Endocrinologica, 1958, 27, 99. usual and may be situated under the right costal margin 6 Zeilmaker, G H, and Carlsen, R A, Acta Endocrinologica, 1962, 41, 321. or out in the right flank. In particular, muscle guarding 7 Fluckiger, E, and Wagner, H R, Experientia, 1968, 24, 1130. tends to be or and this mislead the 8 Pasteels, J L, et al, Annales d'Endocrinologie (Paris), 1971, 32, 188. slight wholly absent, may 9 Besser, G M, et al, British Medical_Journal, 1972, 3, 669. examiner into underestimating the significance of local 10 Del Pozo, E, et al, Journal of Clinical Endocrinology and Metabolism, 1974, tenderness. The umeful sign of altered tenderness described 39, 18. 1 Thorner, M 0, et al, British Medical Journal, 1974, 2, 419. by Alders6 will help to differentiate uterine from extrauterine 12 McNatty, K P, Sawers, R S, and McNeilly, A S, Nature, 1974, 250, 653. lesions, and the "heel-stamping" sign7 may alert the examiner 13 Zarate, A, et al, American Journal of Obstetrics and Gynecology, 1972, 112, to the presence of peritoneal irritation. Acute pyelitis may be a 1130. 14 Thorner, M 0, et al, British Medical3Journal, 1975, 4, 694. problem in differential diagnosis, but it is unwise to accept 16 Varga, L, et al, British Medical_Journal, 1972, 2, 743. (as too often happens) that a few pus cells in the urine confirm 16 Rolland, R, and Schellekens, L A, Journal of Obstetrics and Gynaecology a of The Aberdeen stresses that of the British Commonwealth, 1973, 80, 945. diagnosis pyelitis. paper 17 Hokfelt, T, and Fuxe, K, Neuroendocrinology, 1972, 9, 100. anything more than intermittent mild colicky lower abdominal 18 Schally, A V, et al, Federation Proceedings, 1974, 33, 237. pain is abnormal in the puerperium. 1 Takahara, J, Arimura, A, and Schally, A V, Endocrinology, 1974, 95, 462. 20 Liuzzi, A, et al, J7ournal of Clinical Endocrinology and Metabolism, 1972, In these diagnostic difficulties there is a natural unwilling- 35, 941. nass to risk disturbing thepregnancy or theinvoluting uterus by