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β-Adrenoceptor antagonists and antianginal drugs
A.P. Maggioni, M.G. Franzosi and R. Latini
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/3-Adrenoceptor antagonists and antianginal drugs
/3-ADRENOCEPTOR ANTAGONISTS (SED-13, 491;
SEDA-17, 234; SEDA-18, 213; SEDA-19, 201) ORGANS AND SYSTEMS Cardiovascular Like other antidysrhythmic drugs, sotalol has a negative inotropic effect. Among 37 patients with atrial fibrillation, after electrical cardioversion (when atrial stunning is prominent) sotalol (n = 17) had a more negative inotropic effect than placebo (n = 20) (lC). However, this effect was temporary, since echocardiograms showed that there was no difference between sotalol and placebo in terms of myocardial contractility 1 month later. This effect can prejudice longterm maintenance of sinus rhythm after cardioversion. Sotalol had prodysrhythmic effects in seven (10%) of 71 children (mean age 7.3 years) with various supraventricular and ventricular dysrhythmias, detected by surface ECG and serial Hoiter monitoring (2c). Prodysrhythmia required withdrawal of sotalol in four children: one with sino-atrial block, two with complex ventricular dysrhythmias, and one with recurrent syncope due to torsade de pointes. No other factors (such as electrolyte imbalance or concomitant medications) predisposing to these dysrhythmias were found. These prodysrhythmic effects of sotalol are consistent with similar reports in adults (SED13,493; SEDA-13, 149; SEDA-16, 191). Respiratory Topical/3-blockers given for the treatment of glaucoma may be absorbed systemically and cause bronchospasm especially 9 1997 Elsevier Science B.V. All rights reserved.
Side Effects of Drugs, Annual 20 J.K. Aronson, ed.
among elderly people, even if they have no history of reversible airways disease. A randomized comparison of topical betaxolol, a cardioselective /3-adrenoceptor antagonist, and dipifevrine, a sympathomimetic, has been carried out in 80 patients aged over 60 years who had no history of reversible airways disease and who were already using timolol. There was significant improvement in exercise tolerance, forced expiratory volume, and mean peak flow rate in both groups. The use of topical/3-blockers for life is not a low-risk strategy. Ophthalmologists should consider alternatives, and if none is suitable, should preferably use cardioselective drugs (3c). Skin and appendages Two reports have suggested that /3-adrenoceptors have a role in pigmentation. Of 548 patients with vitiligo, seven developed rapid worsening of depigmentation within 3 months of starting/3-blocking therapy for hypertension. The drugs used were atenoloi and metoprolol, neither of which has any partial agonist (intrinsic sympathomimetic) activity (4c). Three cases of periocular cutaneous pigmentary changes have been described in patients using topical betaxolol for glaucoma: two patients developed periocular cutaneous hypopigmentation and one hyperpigmentation (5c). The first two cases may have been examples of Koebner-induced vitiligo, caused by selective toxic effect on melanocytes of betaxolol (or of an excipient in the formulation). The authors suggested that the case of hyperpigmentation might have stemmed from the same toxic effect. The skin changes resolved on withdrawal; all three patients refused to undertake rechallenge. Museuloskeletal The occurrence of muscle cramps has been evaluated in 78 patients with 183
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essential hypertension treated with fl-blockers with and without partial agonist activity (6c). The patients were randomized to receive pindolol or carteolol (drugs with partial agonist activity) or propranolol, metoprolol, or aretinolol (drugs without partial agonist activity) for 3 months each in a crossover design. Cramps occurred in 27 patients taking pindo1ol and in 32 taking carteolol. No muscle cramps occurred during treatment with propranolol or aretinolol, while two patients suffered cramps while taking metoprolol. Serum CK and CK-MB activities increased significantly during treatment with pindolol and carteolol, but did not change during treatment with the drugs without partial agonist activity. There was no correlation between the severity of muscle cramps and CK activity. The association of/3-blockers with partial agonist activity and increased CK-MB activity suggests that B-blockers with partial agonist activity can cause myocardial cell injury. Leg cramps have been attributed to dileva1ol in a study of 114 patients aged over 65 who were randomized to receive bendrofluazide or dilevalol for essential hypertension (7c). Both drugs caused equivalent reductions in blood pressure, but pre-existing leg cramps worsened by 27% in patients treated with dilevalol, and by 6% in those treated with bendrofluazide. Use in pregnancy The effects of/3-adrenoceptor antagonists in pregnancy-induced hypertension have been evaluated in two studies. In the first study 51 women with pregnancy-induced hypertension were randomly allocated to hydralazine, hydralazine plus propranolol, or hydralazine plus pindolol (8c). All three regimens significantly reduced blood pressure. None of the women developed eclampsia during pregnancy or delivery. However, there were more adverse effects (palpitation, dizziness, and headache) in the women treated with hydralazine alone than in those treated with the combination of hydralazine plus a /3-blocker. Mean birth weight and blood glucose at birth were significantly lower in the babies whose mothers had taken hydralazine plus propranolol compared with the other two groups. These findings suggest that /3-adrenoceptor antagonists without partial agonist activity reduce uteroplacental blood
A.P. Maggioni, M.G. Franzosi and R. Latini
flow in pregnancy-induced hypertension, resuiting in worse fetal development. In the second study 104 women with pregnancy-induced hypertension were randomized to labetalol or methyldopa (9c). Labetalol was quicker and more effective in controlling blood pressure and caused fewer adverse effects. Furthermore, the rate of cesarean section for uncontrolled pregnancy-induced hypertension was significantly lower with labetalol. However, a case of neonatal lowoutput congestive heart failure has been reported after a large prenatal dose of labetalol (300 mg) for pre-eclampsia (10c). The baby improved steadily after infusion of glucagon, which is the agent of first choice for the treatment of B-blocker toxicity, since it stimulates /3-adrenoceptors and is less likely than direct /3-adrenoceptor agonists (such as isoproterenol) to cause dysrhythmias. INDIVIDUAL fl-ADRENOCEPTOR
ANTAGONISTS Carvedilol (SED-13, 504; SEDA-19, 202)
A reversible case of renal failure has been reported in a randomized clinical trial of carvedilol versus placebo in 56 patients with severe chronic congestive heart failure (llC).
Celiprolol (S E D-13 , 505) In 171 hyperlipidemic hypertensive patients celiprolol had significantly more favorable effects on serum lipids than metoprolol (12c). There were no changes in plasma fibrinogen concentrations with celiprolol or metoprolol. NITRATE DERIVATIVES (S E D-13, 506; SEDA-17, 237; SEDA-18, 214; SEDA-19, 203) Isosorbide-5-mononitrate
Nadolol has been compared with isosorbide-5 mononitrate plus nadolol in a multicenter randomized clinical trial in the prophylaxis of variceal bleeding in 96 patients with cirrhosis and esophageal varices (13c). The combination did not increase the risk of renal failure or the development of ascites.
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CALCIUM ANTAGONISTS (SED-13, 509;
Overall, among 8350 patients with a history of myocardial infarction, angina, or unstable angina, the use of short-acting nifedipine was associated with a significant increase in total mortality (risk ratio 1.16; 95% CI 1.01--1.33). The increase was dose related: for daily nifedipine doses of 30--50, 60, and 80mg the risk ratios for total mortality were 1.06, 1.18, and 2.83, respectively. The reflex increase in sympathetic activity that short-acting calcium antagonists induce has been suggested to be the underlying mechanism of the proischemic, negative inotropic, and dysrhythmogenic effects of these compounds. The authors stressed the lack of adequate documentation of long-term safety of calcium antagonists, and the need for well-designed, large-scale clinical trials. The prospective cohort study (16 cr) followed 906 hypertensive elderly patients for 4 years to determine whether elderly patients with hypertension treated with calcium antagonists and A C E inhibitors had a higher risk of mortality than those treated with [j-blockers. With respect to [j-blockers, the relative risks (95% CI) for mortality were short-acting nifedipine 1.7 (1.1--2.7), diltiazem 1.3 (0.8--2.1), verapamil 0.8 (0.4--1.4), and ACE-inhibitors 0.9 (0.6--1.4). The authors concluded that even if selective factors influencing the use of specific drugs in high-risk patients could not be completely discounted, the results showed a significantly reduced survival of elderly hypertensive patients treated with nifedipine compared with [j-blockers. These papers have been extensively discussed (17r)--(20~). Major arguments against the first study (14 cr) were: (a) that selection bias could have resulted from the fact that calcium antagonists were used for hypertensive patients whose concomitant disorders also required a calcium antagonist; (b) the possible existence of a confounding bias, for which the study was not controlled (20c~). The meta-analysis (15 cR) has also been widely criticized. One of the accompanying editorials (19 Cr) stated that there are grave defects in the dossier and that the allegations focus on short-acting nifedipine, so that even if correct, they cannot be applied to other calcium antagonists; the accusation of a dose-related increase in mortality rests on a biased selection of data chosen for the meta-analysis; and several of the me-
SEDA-17, 237; SEDA-18, 215; SEDA-19, 203)
The cardiovascular safety of calcium antagonists The issue of the cardiovascular safety of calcium antagonists has been widely debated following the publication of three articles: (a) a case-control study on the occurrence of myocardial infarction in hypertensive patients treated with a short-acting calcium antagonist (14cr); (b) a meta-analysis of 16 randomized secondary prevention trials of nifedipine in patients with coronary heart disease (15CR); (C) a prospective cohort study in hypertensive elderly patients of the comparative risks of mortality with calcium antagonists, ACE-inhibitors, or [j-blockers (16cr). In the first study, 623 hypertensive patients in the Group Health Co-operative of Puget Sound who had sustained a first myocardial infarction were matched with 2032 randomly selected hypertensive controls from the same care organization (14c~). Among individuals without cardiovascular disease (335 cases and 1395 controls) the risk ratio for myocardial infarction was increased by about 60% among users of calcium antagonists with or without diuretics. In a second analysis, among patients taking a calcium antagonist or a fl-blocker (384 cases and 1108 controls), the use of calcium antagonists compared with fl-blockers was associated with about a 60% increase in the adjusted risk of myocardial infarction. While high dosages of [J-blockers were associated with a reduced risk of myocardial infarction, high dosages of calcium antagonists were associated with an increased risk. The accompanying editorial commented that these results, although not conclusive and possibly confounded by indication, raised the possibility that calcium antagonists might be harmful (17cr). Further evidence against nifedipine has been produced by a meta-analysis of secondary prevention trials (15CR). The purpose of this study was to assess the effect of the dosage of nifedipine on the mortality risk of patients with coronary heart disease and to review the mechanisms by which this adverse effect might occur.
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chanisms suggested for the proposed adverse effects are unlikely. The controversy is not over, and more data and publications are expected. At present, the widespread use of calcium antagonists (in particular the short-acting dihydropyridines, such as nifedipine) should await the results of further randomized trials. Overdosage The widespread use of calcium antagonists increases the possibility of accidental or deliberate self-poisoning in adults and children. Although only a few cases have been described (SED-13, 514; SEDA:16, 198), these drugs account for a high proportion of deaths in cases of overdosage associated with cardiovascular drugs. Factors that increase the risk of death include the dosage, the use of modified-release formulations, the presence of concomitant diseases, and the time elapsed from ingestion to intervention. In a review of the reported cases of calcium antagonist poisoning the presenting symptoms have been described and their management discussed (21R). It has recently been reported that the halflife of verapamil was prolonged after overdose in a 59-year-old man (22c). The authors suggested that this was due to rate-limiting prolongation of the rate of absorption and, therefore, that repeated administration of activated charcoal should be routine in such cases, even if an ordinary-release formulation has been taken. INDIVIDUAL CALCIUM ANTAGONISTS
Amiodipine (SED-13, 515; SEDA-17, 239; SEDA-18, 215) The safety profile of amlodipine, in dosages of 2.5--10 mg daily, is similar to that of other dihydropyridines, headache and peripheral edema being the most frequent adverse events (23c), (24c). In an open, cross-over comparison of amlodipine 5 mg daily and modifiedrelease nifedipine 20 mg daily in 426 hypertensive patients, amlodipine was better tolerated: the withdrawal rate because of adverse effects was 4.5% for amlodipine and 11.7% for nifedipine (25c). In a comparison of the effects of amlodipine, atenolol, and their combination on is-
A.P. Maggioni, M.G. Franzosi and R. Latini
chemia during treadmill testing and 48-h ambulatory monitoring, adverse events requiring withdrawal were 14.6% in the patients randomized to atenoiol and 2% in the amlodipine group, among whom one patient withdrew because of a feeling of pressure at the base of the throat (26c). In a study of the effects of amlodipine in 35 hypertensive patients with renal impairment, serum creatinine concentration was increased slightly in four of the patients (27c). Diitiazem (SED-13, 515; SEDA-18, 215;
SEDA-19, 203) Liver In a multicenter, double-blind, crossover comparison of two formulations of diltiazem, modified-release and plain, 41 patients with stable angina pectoris were randomized. The frequency and seriousness of the adverse events did not differ between the two groups. However, during 18 days of treatment with modified-release diltiazem a 55year-old man without known liver disease developed fatigue, dyspepsia, increasing nausea, abdominal pain, and increased activities of hepatic enzymes. The symptoms resolved by 2 weeks after withdrawal and ultrasonography of the liver and gallbladder showed nothing abnormal (28c). Skin and appendages Adverse cutaneous effects are uncommon with diltiazem (SED-13, 516; SEDA-14, 164; SEDA-16, 197, SEDA18, 215). A 60-year-old man developed erythema multiforme within 4 days of diltiazem therapy, followed by an increase in hepatic enzymes. The hepatic enzymes returned to normal after withdrawal and the erythema progressively disappeared (29c). Felodipine (SED-13, 516; SEDA-17, 239) Felodipine has been compared with enalapril in a double-blind randomized trial for 16 weeks in 46 patients with heart failure of N Y H A class II or III (30cr). There were similar improvements in quality of life and tolerability in the two groups, the only statistically significant difference being an increase in peripheral edema with felodipine. Two once-a-day modified-release formulations, felodipine E R and nifedipine CR, have
[3-Adrenoceptor antagonists and antianginal drugs
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been compared in a double-blind, cross-over study in 41 hypertensive patients (31cr). The treatments had similar effects. Felodipine (2.5--10 mg bd) has been given to 132 patients with N Y H A class II or III heart failure for 12 weeks in a multicenter, double-blind, placebo-controlled randomized trial (32cr). The effects of felodipine on exercise tolerance and ejection fraction were similar to those of placebo; however, felodipine significantly reduced blood pressure. The two adverse events that were more common with felodipine than placebo were peripheral edema without weight gain (23%) and worsening symptoms of heart failure requiring withdrawal (8%).
Nifedipine (SED-13, 516; SEDA-18, 216;
Isradipine (SEDA-17, 239; SEDA-18, 215;
SEDA-19, 203) The efficacy and tolerability of isradipine have been reviewed (33R). Its adverse reaction profile is qualitatively similar to that of other calcium antagonists; isradipine seems to be better tolerated as monotherapy than in combination with A C E inhibitors, /3-blockers, or diuretics. The incidence of adverse reactions is independent of age. Isradipine (5 mg bd) has been given orally for 3 weeks to 54 hypertensive pregnant women in a placebo-controlled, double-blind, randomized trial (34CR). Overall, treatment did not reduce blood pressure, but it did so in the subgroup without proteinuria. Isradipine was as safe as placebo in mothers and fetuses, there was no tocolytic effect, and the outcome of pregnancy was unaffected. Nicardipine (SEDA-17, 239; SEDA-18, 215;
SEDA-19, 204) Nicardipine can be administered intravenously, with several indications, including control of blood pressure intraoperatively in response to tracheal intubation and in the postoperative phase (35R). Nicardipine should have limited negative inotropic effects, and excessive hypotension seems to be rare after intravenous infusion or bolus administration. However, clinical experience is insufficient to define the benefit/risk profile of intravenous nicardipine.
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SEDA-19, 204) Liver Potentially, calcium antagonists should reduce the hepatic venous pressure gradient in patients with cirrhosis. However, verapamil and nicardipine have not had beneficial effects on portal pressure in clinical studies, and the results with nifedipine are controversial. The effects of nifedipine on splanchnic hemodynarnics have been studied in 10 control subjects and 13 patients with cirrhosis and portal hypertension using hepatic venous catheterization and pulsed Doppler ultrasound (36c). Nifedipine significantly increased the hepatic venous pressure gradient and portal vein blood flow. The increase in portal vein blood flow was related to splanchnic arterial vasodilatation. The authors concluded that nifedipine should be used with caution in patients with chronic liver disease, since it may increase the risk of variceal hemorrhage in patients with less advanced varices. Endocrine, metabolic The results of studies of the metabolic effects of nifedipine have been divergent, with both improvement and impairment of glucose metabolism. The metabolic effects of nifedipine have been compared with those of furosemide in a doubleblind crossover study in 23 patients with hypertension; both drugs caused abnormalities in glucose metabolism (37c). Nifedipine caused a significant increase in glycosylated hemoglobin and in steady-state insulin concentration during hyperinsulinemic clamp, probably representing a fall in insulin clearance. The effects on glucose metabolism were related to the occurrence of tachycardia, suggesting that sympathetic nervous activation could be involved. Use in pregnancy A non-randomized comparison of the hemodynamic effects of oral nifedipine and intravenous dihydralazine in 20 pregnant women with severe pre-eclampsia has shown similar reductions in arterial blood pressure and systemic vascular resistance, and similar rises in heart rate and cardiac output (38c). Pulmonary capillary wedge pressure fell significantly less with nifedipine than with dihydralazine. In patients treated with nifedi-
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pine there were no signs of fetal distress, whereas with dihydralazine the fetal cardiotoeogram showed reduced variability and late deceleration in five cases. Two patients treated with nifedipine complained of mild headache and eight treated with dihydralazine complained of severe headache, accompanied in seven of them by nausea and vomiting. The authors concluded that from the hemodynamic point of view nifedipine seems to be useful in the treatment of hypertensive emergencies in pregnancy. The results of several studies have suggested that nifedipine is at least as effective for tocolysis as ritodrine, terbutaline, or magnesium sulfate, with fewer maternal adverse effects (SEDA-18, 216; (39R)). A retrospective study on the treatment of preterm labor in 61 women with oral nifedipine compared with intravenous ritodrine has confirmed a lower incidence of maternal adverse effects in nifedipine-treated patients and has suggested that nifedipine is more successful in postponing delivery than ritodrine, with a better perinatal outcome (40c). Nimodipine (SEDA-17, 240) High intravenous doses of nimodipine (2-4 mg/h) reduced vasospasm in 11 patients with subarachnoid hemorrhage and signs of vasospasm before starting treatment (41cr). Drug infusion under strict control of arterial pressure and cerebral flow with transcranial Doppler only caused minor reductions in blood pressure. In 87 consecutive similar patients, intravenous nimodipine in a maximum dose of 2 mg/h caused hypotension (mean arterial pressure below 75 mmHg for longer than 30 min) in 26 patients (42cr). However, hypotension occurred in only five cases during maintenance oral dosing. The authors considered the risk of hypotension with intravenous nimodipine unacceptable, and they therefore suggested that nimodipine be given orally from the start; intubated patients can receive nimodipine through a nasogastric tube. High-dose nimodipine (180--270 mg/day) has been given to 10 patients with depressive episodes and without cardiovascular disorders (43cr). There were no serious adverse effects; mild orthostatic hypotension occurred in three patients and gastrointestinal symptoms in two.
A.P. Maggioni, M.G. Franzosi and R. Latini
A randomized, placebo-controlled, doubleblind trial of nimodipine (30 mg qds) was prematurely stopped after 149 patients had been enrolled because of excess mortality on the active treatment (8/75 vs. 1/74 deaths on nimodipine and placebo, respectively) (44Cr). Excess mortality was due to an increased incidence of major surgical bleeding (10 vs. 2 on nimodipine and placebo, respectively): this is the first report of this adverse event with a calcium antagonist.
Nisoldipine (S E D A-17, 240) The effects of age and liver failure have been studied in 17 hypertensive patients and seven patients with cirrhosis or chronic active hepatitis who took nisoldipine (5 mg/day) for 1--4 weeks (45cr). One of the patients with liver disease developed fluid retention, worsening of ascites, and weight gain. The duration of treatment in the elderly was too short (1 week) to obtain a reliable estimate of the incidence of adverse reactions, which were in any case insignificant. A new modified-release formulation of nisoldipine (Coat Core) has been tested in a randomized, double-blind, placebo-controlled trial of efficacy and safety in 312 out-patients with chronic stable angina for 2 weeks in daily doses of 20, 40, and 60 mg (46cr). Adverse reactions consisted mainly of headache and fluid retention and were deafly dose-related. Cardiac ischemic events (changes in anginal pattern or myocardial infarction) that were considered serious by the investigator occurred in two patients taking placebo (2.6%), none taking nisoldipine 20 mg, six (8%) taking 40mg, and two (2.4%) taking 60mg. Treatment was withdrawn because of adverse reactions in 21 patients in all. Verapamil (SEDA-15, 194) Endocrine, metabolic Verapamil has been reported to increase serum prolactin concentrations. A patient with verapamil-induced hyperprolactinemia, whose management was complicated by the presence of a pituitary microadenoma, as seen on magnetic resonance imaging, has been described, highDighting the importance of obtaining a drug
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history in patients with hyperprolactinemia (47c).
cells is controlled primarily by tonic inhibition by prolactin inhibitory factor (dopamine) and by stimulatory factors, including thyrotropinreleasing h o r m o n e and vasoactive intestinal peptide, each of which requires calcium for its release. H o w e v e r , the mechanism by which calcium antagonism with verapamil alters the release of prolactin is unknown. M o r e o v e r , hyperprolactinemia is not associated with the use of other calcium antagonists, such as nifedipine or diltiazem. Verapamil may increase dopaminergic activity by blocking calcium channels in the cell m e m b r a n e s of neurones in the tuberoinfundibular tract, rather than in the lactotrophic cell m e m b r a n e itself, where dopamine receptor antagonists are thought to act.
A 74-year-old man with impotence had increased prolactin and low testosterone concentrations. He underwent extensive testing to rule out a pituitary tumor. Magnetic resonance imaging showed a 6mm lesion consistent with a pituitary microadenoma that had remained unchanged for 6 months. Verapamil was withdrawn and within 1 month the prolactin concentration fell to within the reference range. The pituitary lesion was not responsible for the increase in prolactin, but rather complicated the identification of a drug-induced disorder. The initial failure to identify the hyperprolactinemic effect of verapamil may have resulted in unnecessary radiological procedures in this patient. Prolactin secretion by pituitary lactotrophic
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18. Yusuf S. Calcium antagonists in coronary artery disease and hypertension. Time for reevaluation? Circulation 1995;92:1079--82. 19. Opie LH, Messerli FH. Nifedipine and mortality. Grave defects in the dossier. Circulation 1995 ;92:1068-- 72. 20. Messerli FH. Case-control study, metaanalysis, and bouillabaisse: putting the calcium antagonist scare into context. Ann Int Med 1995;123:888--9. 21. Lip GYH, Femer RE. Poisoning with antihypertensive drugs: calcium antagonists. J Hum Hypertens 1995;9:155--61. 22. Buckley CD, Aronson JK. Prolonged half-life of verapamil in a case of overdose: implications for therapy. Br J Clin Pharmacol 1995;39:680-3. 23. Ezekowitz MD, Hossack K, Mehta JL, Thadani U, Weidler DJ, Kostuk W, Awan N, Grossman W, Bommer W. Amlodipine in chronic stable angina: results of a multicenter double-blind crossover trial. Am Heart J 1995;129:527--35. 24. Omvik P, Herland OB, Thaulow E, Eide I, Midha R, Turner RR. Evaluation and qualityof-life assessment of amlodipine and enalapril in patients with hypertension. J Hum Hypertens 1995;9 Suppl I:$17--$24. 25. Detry L-MR, Block P, De Backer G, Degaute JP, Six R. Patient compliance and therapeutic coverage: comparison of amlodipine and slow release nifedipine in the treatment of hypertension. Eur J Clin Pharmacol 1995;47:477--81. 26. Davies RF, Habibi H, Klinke WP, Dessain P, Nadeau C, Phaneuf DC, Lepage S, Raman S, Herbert M, Foris K, O'Linden W, Buttars JA. Effect of amlodipine, atenolol and their combination on myocardial ischemia during treadmill exercise and ambulatory monitoring. J Am Coil Cardiol 1995;25:619--25. 27. Saruta T, Kanno Y, Hayashi K, Suzuki H. Renal effects of amlodipine. J Hum Hypertens 1995;9 Suppl. I:$11--$16. 28. Boman K, Saetre H, Karlsson LG, Ritter B, Marsell R, Wingman H, Lrvheim, Michaeli EW, Lrfdahl P, Olsson SOR. Antianginal effect of conventional and controlled release diltiazem in stable angina pectoris. Eur J Clin Pharmacol 1995;49:27--30. 29. Avila JR. Elevation of hepatic enzymes after cutaneous reaction caused by diltiazem. Ann Pharmacother 1995;29:317--8. 30. de Vries RJM, Quer6 M, Lok DJA, Sijbring P, Bucx J J J, van Veldhuisen D J, Dunselman PHJM. Comparison of effects on peak oxygen consumption, quality of life and neurohormones of felodipine and enalapril in patients with congestive heart failure. Am J Cardiol 1995; 76:1253--8. 31. Carrol J, Shamiss A, Zevis D, Levi J, Rosenthal T. Twenty-four-hour blood pressure monitoring during treatment with extended-release felodipine versus slow-release nifedipine: cross-over study. J Cardiovasc Pharmacol 1995;26:974--7. 32. Littler WA, Sheridan DJ. Placebo controlled
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trial of felodipine in patients with mild to moderate heart failure. Br Heart J 1995;73:428--33. 33. Brogden RN, Sorkin EM. Isradipine. An update of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the treatment of mild to moderate hypertension. Drugs 1995;49:618--49. 34. Wide-Svensson DH, Ingemarsson I, Lunell NO, Forman A, Skajaa K, Lindberg B, Lindeberg S, Mars~tl K, Andersson KE. Calcium channel blockade (isradipine) in treatment of hypertension in pregnancy: a randomized placebo-controlled study. Am J Obstet Gynecol 1995; 173:872--8 35. Tobias JD. Nicardipine: applications in anesthesia practice. J Clin Anesth 1995;7:525--33. 36. Ota K, Shijo H, Kokawa H, Kubara K, Kim T, Akiyoshi N, Yokoyama M, Okumura M. Effects of nifedipine on hepatic venous pressure gradient and portal vein blood flow in patients with cirrhosis. J Gastroenterol Hepatol 1995;10:198--204. 37. Lind L, Berne C, Pollare T, Lithell H. Metabolic effects of anti-hypertensive treatment with nifedipine or furosemide: a double-blind, crossover study. J Hum Hypertens 1995;9:137--41. 38. Visser W, Wallenburg HCS. A comparison between the haemodynamic effects of oral nifedipine and intravenous dihydralazine in patients with severe pre-eclampsia. J Hypertens 1995; 13:791 --5. 39. Ray D, Dyson D. Calcium channel blockers. Clin Obstet Gynecol 1995;38:713--21. 40. van Dijk KGJ, Dekker GA, van Gaijn HP. Ritodrine and nifedipine as tocolytic agents: a preliminary comparison. J Perinat Med 1995; 23:409--15. 41. Zygmunt SC, Delgado-Zygmunt TJ. The haemodynamic effect of transcranial Doppler-guided high-dose nimodipine treatment in established vasospasm after subarachnoid haemorrhage. Acta Neurochir 1995;135:179--85. 42. Porchet F, Chiolrro R, de Tribolet N. Hypotensive effect of nimodipine during treatment for aneurysmal subarachnoid haemorrhage. Acta Neurochir 1995;137:62--9. 43. Walden J, Fritze J, Van Calker D, Berger M, Grunze H. A calcium antagonist for the treatment of depressive episodes: single case reports. J Psychiatr Res 1995;29:71--6. 44. Wagenknecht LE, Furberg CD, Hammon JW, Legault C, Troost BT. Surgical bleeding: unexpected effect of a calcium antagonist. Br Med J 1995;310:776--7. 45. Davidsson GK, Edwards JS, Davidson C. The effect of age and liver disease on the pharmacokinetics of the calcium antagonist, nisoldipine. Curr Med Res Opin 1995;13:285--97. 46. Glasser SP, Ripa S, Garland T, Weiss R, Nademanee K, Singh S, Bittar N. Antianginal and antiischemic efficacy of monotherapy extendedrelease nisoldipine (Coat Core) in chronic stable angina. J Clin Pharmacol 1995;35:780--4. 47. Dombrowski RC, Romeo JH, Aron DC. Verapamil-induced hyperprolactinemia complicated by a pituitary incidentaloma. Ann Pharmacother 1995;29:999--1001.
18
/3-Adrenoceptor antagonists and antianginal drugs
/3-ADRENOCEPTOR ANTAGONISTS (SED-13, 491;
SEDA-17, 234; SEDA-18, 213; SEDA-19, 201) ORGANS AND SYSTEMS Cardiovascular Like other antidysrhythmic drugs, sotalol has a negative inotropic effect. Among 37 patients with atrial fibrillation, after electrical cardioversion (when atrial stunning is prominent) sotalol (n = 17) had a more negative inotropic effect than placebo (n = 20) (lC). However, this effect was temporary, since echocardiograms showed that there was no difference between sotalol and placebo in terms of myocardial contractility 1 month later. This effect can prejudice longterm maintenance of sinus rhythm after cardioversion. Sotalol had prodysrhythmic effects in seven (10%) of 71 children (mean age 7.3 years) with various supraventricular and ventricular dysrhythmias, detected by surface ECG and serial Hoiter monitoring (2c). Prodysrhythmia required withdrawal of sotalol in four children: one with sino-atrial block, two with complex ventricular dysrhythmias, and one with recurrent syncope due to torsade de pointes. No other factors (such as electrolyte imbalance or concomitant medications) predisposing to these dysrhythmias were found. These prodysrhythmic effects of sotalol are consistent with similar reports in adults (SED13,493; SEDA-13, 149; SEDA-16, 191). Respiratory Topical/3-blockers given for the treatment of glaucoma may be absorbed systemically and cause bronchospasm especially 9 1997 Elsevier Science B.V. All rights reserved.
Side Effects of Drugs, Annual 20 J.K. Aronson, ed.
among elderly people, even if they have no history of reversible airways disease. A randomized comparison of topical betaxolol, a cardioselective /3-adrenoceptor antagonist, and dipifevrine, a sympathomimetic, has been carried out in 80 patients aged over 60 years who had no history of reversible airways disease and who were already using timolol. There was significant improvement in exercise tolerance, forced expiratory volume, and mean peak flow rate in both groups. The use of topical/3-blockers for life is not a low-risk strategy. Ophthalmologists should consider alternatives, and if none is suitable, should preferably use cardioselective drugs (3c). Skin and appendages Two reports have suggested that /3-adrenoceptors have a role in pigmentation. Of 548 patients with vitiligo, seven developed rapid worsening of depigmentation within 3 months of starting/3-blocking therapy for hypertension. The drugs used were atenoloi and metoprolol, neither of which has any partial agonist (intrinsic sympathomimetic) activity (4c). Three cases of periocular cutaneous pigmentary changes have been described in patients using topical betaxolol for glaucoma: two patients developed periocular cutaneous hypopigmentation and one hyperpigmentation (5c). The first two cases may have been examples of Koebner-induced vitiligo, caused by selective toxic effect on melanocytes of betaxolol (or of an excipient in the formulation). The authors suggested that the case of hyperpigmentation might have stemmed from the same toxic effect. The skin changes resolved on withdrawal; all three patients refused to undertake rechallenge. Museuloskeletal The occurrence of muscle cramps has been evaluated in 78 patients with 183
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essential hypertension treated with fl-blockers with and without partial agonist activity (6c). The patients were randomized to receive pindolol or carteolol (drugs with partial agonist activity) or propranolol, metoprolol, or aretinolol (drugs without partial agonist activity) for 3 months each in a crossover design. Cramps occurred in 27 patients taking pindo1ol and in 32 taking carteolol. No muscle cramps occurred during treatment with propranolol or aretinolol, while two patients suffered cramps while taking metoprolol. Serum CK and CK-MB activities increased significantly during treatment with pindolol and carteolol, but did not change during treatment with the drugs without partial agonist activity. There was no correlation between the severity of muscle cramps and CK activity. The association of/3-blockers with partial agonist activity and increased CK-MB activity suggests that B-blockers with partial agonist activity can cause myocardial cell injury. Leg cramps have been attributed to dileva1ol in a study of 114 patients aged over 65 who were randomized to receive bendrofluazide or dilevalol for essential hypertension (7c). Both drugs caused equivalent reductions in blood pressure, but pre-existing leg cramps worsened by 27% in patients treated with dilevalol, and by 6% in those treated with bendrofluazide. Use in pregnancy The effects of/3-adrenoceptor antagonists in pregnancy-induced hypertension have been evaluated in two studies. In the first study 51 women with pregnancy-induced hypertension were randomly allocated to hydralazine, hydralazine plus propranolol, or hydralazine plus pindolol (8c). All three regimens significantly reduced blood pressure. None of the women developed eclampsia during pregnancy or delivery. However, there were more adverse effects (palpitation, dizziness, and headache) in the women treated with hydralazine alone than in those treated with the combination of hydralazine plus a /3-blocker. Mean birth weight and blood glucose at birth were significantly lower in the babies whose mothers had taken hydralazine plus propranolol compared with the other two groups. These findings suggest that /3-adrenoceptor antagonists without partial agonist activity reduce uteroplacental blood
A.P. Maggioni, M.G. Franzosi and R. Latini
flow in pregnancy-induced hypertension, resuiting in worse fetal development. In the second study 104 women with pregnancy-induced hypertension were randomized to labetalol or methyldopa (9c). Labetalol was quicker and more effective in controlling blood pressure and caused fewer adverse effects. Furthermore, the rate of cesarean section for uncontrolled pregnancy-induced hypertension was significantly lower with labetalol. However, a case of neonatal lowoutput congestive heart failure has been reported after a large prenatal dose of labetalol (300 mg) for pre-eclampsia (10c). The baby improved steadily after infusion of glucagon, which is the agent of first choice for the treatment of B-blocker toxicity, since it stimulates /3-adrenoceptors and is less likely than direct /3-adrenoceptor agonists (such as isoproterenol) to cause dysrhythmias. INDIVIDUAL fl-ADRENOCEPTOR
ANTAGONISTS Carvedilol (SED-13, 504; SEDA-19, 202)
A reversible case of renal failure has been reported in a randomized clinical trial of carvedilol versus placebo in 56 patients with severe chronic congestive heart failure (llC).
Celiprolol (S E D-13 , 505) In 171 hyperlipidemic hypertensive patients celiprolol had significantly more favorable effects on serum lipids than metoprolol (12c). There were no changes in plasma fibrinogen concentrations with celiprolol or metoprolol. NITRATE DERIVATIVES (S E D-13, 506; SEDA-17, 237; SEDA-18, 214; SEDA-19, 203) Isosorbide-5-mononitrate
Nadolol has been compared with isosorbide-5 mononitrate plus nadolol in a multicenter randomized clinical trial in the prophylaxis of variceal bleeding in 96 patients with cirrhosis and esophageal varices (13c). The combination did not increase the risk of renal failure or the development of ascites.
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CALCIUM ANTAGONISTS (SED-13, 509;
Overall, among 8350 patients with a history of myocardial infarction, angina, or unstable angina, the use of short-acting nifedipine was associated with a significant increase in total mortality (risk ratio 1.16; 95% CI 1.01--1.33). The increase was dose related: for daily nifedipine doses of 30--50, 60, and 80mg the risk ratios for total mortality were 1.06, 1.18, and 2.83, respectively. The reflex increase in sympathetic activity that short-acting calcium antagonists induce has been suggested to be the underlying mechanism of the proischemic, negative inotropic, and dysrhythmogenic effects of these compounds. The authors stressed the lack of adequate documentation of long-term safety of calcium antagonists, and the need for well-designed, large-scale clinical trials. The prospective cohort study (16 cr) followed 906 hypertensive elderly patients for 4 years to determine whether elderly patients with hypertension treated with calcium antagonists and A C E inhibitors had a higher risk of mortality than those treated with [j-blockers. With respect to [j-blockers, the relative risks (95% CI) for mortality were short-acting nifedipine 1.7 (1.1--2.7), diltiazem 1.3 (0.8--2.1), verapamil 0.8 (0.4--1.4), and ACE-inhibitors 0.9 (0.6--1.4). The authors concluded that even if selective factors influencing the use of specific drugs in high-risk patients could not be completely discounted, the results showed a significantly reduced survival of elderly hypertensive patients treated with nifedipine compared with [j-blockers. These papers have been extensively discussed (17r)--(20~). Major arguments against the first study (14 cr) were: (a) that selection bias could have resulted from the fact that calcium antagonists were used for hypertensive patients whose concomitant disorders also required a calcium antagonist; (b) the possible existence of a confounding bias, for which the study was not controlled (20c~). The meta-analysis (15 cR) has also been widely criticized. One of the accompanying editorials (19 Cr) stated that there are grave defects in the dossier and that the allegations focus on short-acting nifedipine, so that even if correct, they cannot be applied to other calcium antagonists; the accusation of a dose-related increase in mortality rests on a biased selection of data chosen for the meta-analysis; and several of the me-
SEDA-17, 237; SEDA-18, 215; SEDA-19, 203)
The cardiovascular safety of calcium antagonists The issue of the cardiovascular safety of calcium antagonists has been widely debated following the publication of three articles: (a) a case-control study on the occurrence of myocardial infarction in hypertensive patients treated with a short-acting calcium antagonist (14cr); (b) a meta-analysis of 16 randomized secondary prevention trials of nifedipine in patients with coronary heart disease (15CR); (C) a prospective cohort study in hypertensive elderly patients of the comparative risks of mortality with calcium antagonists, ACE-inhibitors, or [j-blockers (16cr). In the first study, 623 hypertensive patients in the Group Health Co-operative of Puget Sound who had sustained a first myocardial infarction were matched with 2032 randomly selected hypertensive controls from the same care organization (14c~). Among individuals without cardiovascular disease (335 cases and 1395 controls) the risk ratio for myocardial infarction was increased by about 60% among users of calcium antagonists with or without diuretics. In a second analysis, among patients taking a calcium antagonist or a fl-blocker (384 cases and 1108 controls), the use of calcium antagonists compared with fl-blockers was associated with about a 60% increase in the adjusted risk of myocardial infarction. While high dosages of [J-blockers were associated with a reduced risk of myocardial infarction, high dosages of calcium antagonists were associated with an increased risk. The accompanying editorial commented that these results, although not conclusive and possibly confounded by indication, raised the possibility that calcium antagonists might be harmful (17cr). Further evidence against nifedipine has been produced by a meta-analysis of secondary prevention trials (15CR). The purpose of this study was to assess the effect of the dosage of nifedipine on the mortality risk of patients with coronary heart disease and to review the mechanisms by which this adverse effect might occur.
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chanisms suggested for the proposed adverse effects are unlikely. The controversy is not over, and more data and publications are expected. At present, the widespread use of calcium antagonists (in particular the short-acting dihydropyridines, such as nifedipine) should await the results of further randomized trials. Overdosage The widespread use of calcium antagonists increases the possibility of accidental or deliberate self-poisoning in adults and children. Although only a few cases have been described (SED-13, 514; SEDA:16, 198), these drugs account for a high proportion of deaths in cases of overdosage associated with cardiovascular drugs. Factors that increase the risk of death include the dosage, the use of modified-release formulations, the presence of concomitant diseases, and the time elapsed from ingestion to intervention. In a review of the reported cases of calcium antagonist poisoning the presenting symptoms have been described and their management discussed (21R). It has recently been reported that the halflife of verapamil was prolonged after overdose in a 59-year-old man (22c). The authors suggested that this was due to rate-limiting prolongation of the rate of absorption and, therefore, that repeated administration of activated charcoal should be routine in such cases, even if an ordinary-release formulation has been taken. INDIVIDUAL CALCIUM ANTAGONISTS
Amiodipine (SED-13, 515; SEDA-17, 239; SEDA-18, 215) The safety profile of amlodipine, in dosages of 2.5--10 mg daily, is similar to that of other dihydropyridines, headache and peripheral edema being the most frequent adverse events (23c), (24c). In an open, cross-over comparison of amlodipine 5 mg daily and modifiedrelease nifedipine 20 mg daily in 426 hypertensive patients, amlodipine was better tolerated: the withdrawal rate because of adverse effects was 4.5% for amlodipine and 11.7% for nifedipine (25c). In a comparison of the effects of amlodipine, atenolol, and their combination on is-
A.P. Maggioni, M.G. Franzosi and R. Latini
chemia during treadmill testing and 48-h ambulatory monitoring, adverse events requiring withdrawal were 14.6% in the patients randomized to atenoiol and 2% in the amlodipine group, among whom one patient withdrew because of a feeling of pressure at the base of the throat (26c). In a study of the effects of amlodipine in 35 hypertensive patients with renal impairment, serum creatinine concentration was increased slightly in four of the patients (27c). Diitiazem (SED-13, 515; SEDA-18, 215;
SEDA-19, 203) Liver In a multicenter, double-blind, crossover comparison of two formulations of diltiazem, modified-release and plain, 41 patients with stable angina pectoris were randomized. The frequency and seriousness of the adverse events did not differ between the two groups. However, during 18 days of treatment with modified-release diltiazem a 55year-old man without known liver disease developed fatigue, dyspepsia, increasing nausea, abdominal pain, and increased activities of hepatic enzymes. The symptoms resolved by 2 weeks after withdrawal and ultrasonography of the liver and gallbladder showed nothing abnormal (28c). Skin and appendages Adverse cutaneous effects are uncommon with diltiazem (SED-13, 516; SEDA-14, 164; SEDA-16, 197, SEDA18, 215). A 60-year-old man developed erythema multiforme within 4 days of diltiazem therapy, followed by an increase in hepatic enzymes. The hepatic enzymes returned to normal after withdrawal and the erythema progressively disappeared (29c). Felodipine (SED-13, 516; SEDA-17, 239) Felodipine has been compared with enalapril in a double-blind randomized trial for 16 weeks in 46 patients with heart failure of N Y H A class II or III (30cr). There were similar improvements in quality of life and tolerability in the two groups, the only statistically significant difference being an increase in peripheral edema with felodipine. Two once-a-day modified-release formulations, felodipine E R and nifedipine CR, have
[3-Adrenoceptor antagonists and antianginal drugs
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been compared in a double-blind, cross-over study in 41 hypertensive patients (31cr). The treatments had similar effects. Felodipine (2.5--10 mg bd) has been given to 132 patients with N Y H A class II or III heart failure for 12 weeks in a multicenter, double-blind, placebo-controlled randomized trial (32cr). The effects of felodipine on exercise tolerance and ejection fraction were similar to those of placebo; however, felodipine significantly reduced blood pressure. The two adverse events that were more common with felodipine than placebo were peripheral edema without weight gain (23%) and worsening symptoms of heart failure requiring withdrawal (8%).
Nifedipine (SED-13, 516; SEDA-18, 216;
Isradipine (SEDA-17, 239; SEDA-18, 215;
SEDA-19, 203) The efficacy and tolerability of isradipine have been reviewed (33R). Its adverse reaction profile is qualitatively similar to that of other calcium antagonists; isradipine seems to be better tolerated as monotherapy than in combination with A C E inhibitors, /3-blockers, or diuretics. The incidence of adverse reactions is independent of age. Isradipine (5 mg bd) has been given orally for 3 weeks to 54 hypertensive pregnant women in a placebo-controlled, double-blind, randomized trial (34CR). Overall, treatment did not reduce blood pressure, but it did so in the subgroup without proteinuria. Isradipine was as safe as placebo in mothers and fetuses, there was no tocolytic effect, and the outcome of pregnancy was unaffected. Nicardipine (SEDA-17, 239; SEDA-18, 215;
SEDA-19, 204) Nicardipine can be administered intravenously, with several indications, including control of blood pressure intraoperatively in response to tracheal intubation and in the postoperative phase (35R). Nicardipine should have limited negative inotropic effects, and excessive hypotension seems to be rare after intravenous infusion or bolus administration. However, clinical experience is insufficient to define the benefit/risk profile of intravenous nicardipine.
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SEDA-19, 204) Liver Potentially, calcium antagonists should reduce the hepatic venous pressure gradient in patients with cirrhosis. However, verapamil and nicardipine have not had beneficial effects on portal pressure in clinical studies, and the results with nifedipine are controversial. The effects of nifedipine on splanchnic hemodynarnics have been studied in 10 control subjects and 13 patients with cirrhosis and portal hypertension using hepatic venous catheterization and pulsed Doppler ultrasound (36c). Nifedipine significantly increased the hepatic venous pressure gradient and portal vein blood flow. The increase in portal vein blood flow was related to splanchnic arterial vasodilatation. The authors concluded that nifedipine should be used with caution in patients with chronic liver disease, since it may increase the risk of variceal hemorrhage in patients with less advanced varices. Endocrine, metabolic The results of studies of the metabolic effects of nifedipine have been divergent, with both improvement and impairment of glucose metabolism. The metabolic effects of nifedipine have been compared with those of furosemide in a doubleblind crossover study in 23 patients with hypertension; both drugs caused abnormalities in glucose metabolism (37c). Nifedipine caused a significant increase in glycosylated hemoglobin and in steady-state insulin concentration during hyperinsulinemic clamp, probably representing a fall in insulin clearance. The effects on glucose metabolism were related to the occurrence of tachycardia, suggesting that sympathetic nervous activation could be involved. Use in pregnancy A non-randomized comparison of the hemodynamic effects of oral nifedipine and intravenous dihydralazine in 20 pregnant women with severe pre-eclampsia has shown similar reductions in arterial blood pressure and systemic vascular resistance, and similar rises in heart rate and cardiac output (38c). Pulmonary capillary wedge pressure fell significantly less with nifedipine than with dihydralazine. In patients treated with nifedi-
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pine there were no signs of fetal distress, whereas with dihydralazine the fetal cardiotoeogram showed reduced variability and late deceleration in five cases. Two patients treated with nifedipine complained of mild headache and eight treated with dihydralazine complained of severe headache, accompanied in seven of them by nausea and vomiting. The authors concluded that from the hemodynamic point of view nifedipine seems to be useful in the treatment of hypertensive emergencies in pregnancy. The results of several studies have suggested that nifedipine is at least as effective for tocolysis as ritodrine, terbutaline, or magnesium sulfate, with fewer maternal adverse effects (SEDA-18, 216; (39R)). A retrospective study on the treatment of preterm labor in 61 women with oral nifedipine compared with intravenous ritodrine has confirmed a lower incidence of maternal adverse effects in nifedipine-treated patients and has suggested that nifedipine is more successful in postponing delivery than ritodrine, with a better perinatal outcome (40c). Nimodipine (SEDA-17, 240) High intravenous doses of nimodipine (2-4 mg/h) reduced vasospasm in 11 patients with subarachnoid hemorrhage and signs of vasospasm before starting treatment (41cr). Drug infusion under strict control of arterial pressure and cerebral flow with transcranial Doppler only caused minor reductions in blood pressure. In 87 consecutive similar patients, intravenous nimodipine in a maximum dose of 2 mg/h caused hypotension (mean arterial pressure below 75 mmHg for longer than 30 min) in 26 patients (42cr). However, hypotension occurred in only five cases during maintenance oral dosing. The authors considered the risk of hypotension with intravenous nimodipine unacceptable, and they therefore suggested that nimodipine be given orally from the start; intubated patients can receive nimodipine through a nasogastric tube. High-dose nimodipine (180--270 mg/day) has been given to 10 patients with depressive episodes and without cardiovascular disorders (43cr). There were no serious adverse effects; mild orthostatic hypotension occurred in three patients and gastrointestinal symptoms in two.
A.P. Maggioni, M.G. Franzosi and R. Latini
A randomized, placebo-controlled, doubleblind trial of nimodipine (30 mg qds) was prematurely stopped after 149 patients had been enrolled because of excess mortality on the active treatment (8/75 vs. 1/74 deaths on nimodipine and placebo, respectively) (44Cr). Excess mortality was due to an increased incidence of major surgical bleeding (10 vs. 2 on nimodipine and placebo, respectively): this is the first report of this adverse event with a calcium antagonist.
Nisoldipine (S E D A-17, 240) The effects of age and liver failure have been studied in 17 hypertensive patients and seven patients with cirrhosis or chronic active hepatitis who took nisoldipine (5 mg/day) for 1--4 weeks (45cr). One of the patients with liver disease developed fluid retention, worsening of ascites, and weight gain. The duration of treatment in the elderly was too short (1 week) to obtain a reliable estimate of the incidence of adverse reactions, which were in any case insignificant. A new modified-release formulation of nisoldipine (Coat Core) has been tested in a randomized, double-blind, placebo-controlled trial of efficacy and safety in 312 out-patients with chronic stable angina for 2 weeks in daily doses of 20, 40, and 60 mg (46cr). Adverse reactions consisted mainly of headache and fluid retention and were deafly dose-related. Cardiac ischemic events (changes in anginal pattern or myocardial infarction) that were considered serious by the investigator occurred in two patients taking placebo (2.6%), none taking nisoldipine 20 mg, six (8%) taking 40mg, and two (2.4%) taking 60mg. Treatment was withdrawn because of adverse reactions in 21 patients in all. Verapamil (SEDA-15, 194) Endocrine, metabolic Verapamil has been reported to increase serum prolactin concentrations. A patient with verapamil-induced hyperprolactinemia, whose management was complicated by the presence of a pituitary microadenoma, as seen on magnetic resonance imaging, has been described, highDighting the importance of obtaining a drug
~-Adrenoceptor antagonists and antianginal drugs
Chapter18
history in patients with hyperprolactinemia (47c).
cells is controlled primarily by tonic inhibition by prolactin inhibitory factor (dopamine) and by stimulatory factors, including thyrotropinreleasing h o r m o n e and vasoactive intestinal peptide, each of which requires calcium for its release. H o w e v e r , the mechanism by which calcium antagonism with verapamil alters the release of prolactin is unknown. M o r e o v e r , hyperprolactinemia is not associated with the use of other calcium antagonists, such as nifedipine or diltiazem. Verapamil may increase dopaminergic activity by blocking calcium channels in the cell m e m b r a n e s of neurones in the tuberoinfundibular tract, rather than in the lactotrophic cell m e m b r a n e itself, where dopamine receptor antagonists are thought to act.
A 74-year-old man with impotence had increased prolactin and low testosterone concentrations. He underwent extensive testing to rule out a pituitary tumor. Magnetic resonance imaging showed a 6mm lesion consistent with a pituitary microadenoma that had remained unchanged for 6 months. Verapamil was withdrawn and within 1 month the prolactin concentration fell to within the reference range. The pituitary lesion was not responsible for the increase in prolactin, but rather complicated the identification of a drug-induced disorder. The initial failure to identify the hyperprolactinemic effect of verapamil may have resulted in unnecessary radiological procedures in this patient. Prolactin secretion by pituitary lactotrophic
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