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β-adrenoceptor antagonists and antianginal drugs
L. Offerhaus
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/5-Adrenoceptor antagonists and antianginal drugs
/3-ADRENOCEPTOR ANTAGONISTS (SED-11, 360; SEDA-13, 149; SEDA-14, 159) Nervous system A troublesome limitation to the use of beta-blocking drugs is the occurrence of CNS effects, such as sleep disturbances, tiredness, forgetfulness, and even depression (SEDA- 13, 151). The results of a number of recent investigations are contradictory. In a large open out-patient study involving 205 Norwegian patients the incidence of such side effects elicited on interview seemed to correlate with the lipid solubility of the drug and ~l-adrenoceptor selectivity played only a minor role (1 c). In 5 different double-blind studies in which atenolol, metoprolol, and propranolol were compared with placebo the same question was tackled using standardized psychological tests. In one study there was clear evidence that at equipotent 3-adrenoceptor blocking doses propranolol caused more psychological disturbances and tiredness than atenolol, but all the patients had been on beta-blockers before the trial (2c). Another similar study could not confirm this difference (3c). Despite minor differences in the tests affected, atenolol and metoprolol scored approximately equally; both were associated with subjective symptoms, but the incidence was low (4c, 5c). Dimsdale and colleagues have performed a meta-analysis of 55 studies of the cognitive side effects of beta-blockade. They did not find any firm evidence that lipophilic drugs caused more side effects than hydrophilic ones. Betablockers may have had a sedative effect, but in some studies that was compensated by a better performance in complicated tasks. However, many of these studies were small and poorly
9 1991 Elsevier Science Publishers B.V.
Side Effects of Drugs Annual 15 M.N.G. Dukes and J.K. Aronson, editors
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controlled and one wonders whether the usual psychological tests are appropriate in this situation (6R). However, recent data confirming a correlation between lipophilicity and serum concentrations on the one hand and CNS side effects on the other have reopened the discussion (7R).
Sexual function and beta-blockade Increasingly, attention is being drawn to the high incidence o f sexual symptoms in men treated with beta-blockers. Loss o f libido and difficulty in sustaining an erection are the main problems, and can even be reproduced in young healthy volunteers (8c). These effects are especially likely to occur during treatment with lipophilic drugs, such as propranolol (9c) and pindolol (lOC), although Japanese men are similarly affected by atenolol (lle); in two o f these studies (10 e, 11c) ,there was also a significant fall in plasma testosterone concentrations. A personalized approach seems necessary to detect such symptoms, because they were not observed in a large multicenter study o f 1285 men and 1080 women sponsored by the British Health Ministry, the DHSS (12c).
Risk situations The drug information service of the University of California has reviewed the literature data on the dangers of anaphylactoid reactions in patients on beta-blockers (13r). Such patients are difficult to treat adequately and the resultant complications, such as shock and bradycardia, may be serious, because the signs of anaphylaxis may be masked by the beta-blocker. Immediate hospitalization may be necessary, because patients do not respond to adrenaline and may need resuscitation. Thirty such cases have been described. A particularly dangerous situation may arise if patients on
13-Adrenoceptor antagonists and antianginal drugs Chapter 19 long-term beta-blockade experience anaphylactoid reactions to drugs, such as chymopapaine and iodine-containing X-ray contrast media (14c). For the same reason the French authorities have warned doctors not to use the analgesic glafenine, known to cause anaphylactic shock (SEDA-13, 82), in patients on beta-blockers (15r). Similarly, patients with spontaneous attacks of angio-edema or urticaria may be at risk when given beta-blockers, a d r u g - disease interaction which may be fatal (16R). A physician who was being treated with atenolol and aspirin after a myocardial infarction has described how after being stung by a wasp he was brought to hospital in shock and did not regain consciousness until the following day (17c). He was unaware of the danger because he had received wasp stings in the past. Interactions The combined use of calcium antagonists and beta-blockers, both for the treatment of hypertension and angina pectoris, is increasingly being recommended. However, there are risks. The combination of verapamil with beta-blockers may cause severe bradycardia, heart block, hypotension, or congestive cardiac failure in 1 0 - 15o70 of patients (18R). This interaction has both pharmacodynamic (19c, 20C) and pharmacokinetic (20c, 21c) characteristics. Although a minority of patients with hypertension taking nifedipine with betablockers may show further improvement, most are not better off than on monotherapy, and many may experience more side effects. The combination may be useful in stable angina pectoffs (22 c) but it should be discouraged in unstable angina (23c). There seems to be a limited indication for the addition of diltiazem to beta-blockade, though even the usefulness of this combination has been questioned; if insufficient benefit is obtained with a single calcium antagonist, increasing the dose is often a better and safer alternative than adding a beta-blocker (24R). The possible clinical relevance of pharmacokinetic interactions of propranolol with H 2 antagonists (cimetidine and ranitidine) has been reviewed (25R). Although both drugs increase the systemic availability and decrease the clearance of most/3-adrenoceptor antagonists, there is no firm evidence that this has ever led to increased effects of these drugs. Two cases
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which are described in detail are confounded by a number of factors. Nevertheless, Sax advises that dosages of beta-blockers should be carefully adjusted in individual patients taking H 2 antagonists (25R). Excessive bradycardia has been noted in 2 elderly patients taking the MAO inhibitor phenelzine after the addition of a beta-blocker. The mechanism of this interaction has to be further investigated (26c). Life-threatening bradycardia with dizziness and visual disturbances was also observed when amiodarone was given to patients taking metoprolol (27c). Prolonged bradycardia and hypotension have been reported after neostigmine and atropine administration in a patient taking atenolol (101c). The patient was a 78-year-old woman who was admitted for an elective hip operation. She was maintained on atenolol for control of her hypertensive ischemic heart disease and had stable angina pectoris treated with nitrates and atenolol. After routine anesthesia with pancuronium bromide, isoflurane, and nitrous oxide she was given neostigmine and atropine for reversal of muscle relaxation. Prolonged bradycardia and hypotension then developed, necessitating the use of adrenaline and isoprenaline. INDIVIDUAL/3-ADRENOCEPTOR ANTAGONISTS The number of beta blockers available is steadily increasing; despite similar efficacy and closely related chemical structures, unexpected adverse reactions which are specific for individual drugs are being reported with some regularity. One should therefore always be on the alert for unexpected events, as the following data show. A c e b u t o l o l (SED-11, 160," SEDA-12, 161)
A patient with bronchiolitis obliterans, reversible after withdrawal of the drug, has been reported. The histology was characterized by connective tissue growth in small air passages, as in similar cases attributed to other drugs. Although an immunological mechanism was suspected, immunological investigations were negative (28c).
Chapter 19 L. Offerhaus
190 Six cases of hepatitis, reversible after withdrawal, have been reported to the U.S. Food and Drug Administration; in 2 of them rechallenge was positive (29c). Atenoiol (Sed-11, 362) Although atenolol is generally held to be one of the safest beta-blockers, severe and unusual side effects are occasionally reported, such as profound hypotension after a single oral dose (30c), organic brain syndrome with acute delirium (31c), cutaneous vasculitis with purpuric skin lesions (32c) and cholestatic hepatitis (33c). Despite its low lipid solubility enough atenolol can diffuse into human milk to cause bradycardia and hypotension in a breastfeeding infant (34c). Bevantolol (SEDA-12, 162) Although this new cardioselective betablocker seems to have a favorable side effects profile the incidence of headache, dizziness, and fatigue in 2 comparative trials was slightly higher than with atenolol or propranolol (35c, 36c). Carvediioi Carvedilol is a new non-selective j3adrenoceptor antagonist with a high degree of partial agonist activity. Early trials have shown a rather high incidence of skin reactions, but it seems to be too early to know whether or not these are drug-induced (37c).
Dilevalol Dilevalol, one of the 4 enantiomers of labetalol (the R,R'-isomer), has no c~adrenoceptor blocking properties, and it can be classified as one of the newer non-selective agents with partial agonist activity. It has been reported to cause few side effects, with the exception of diarrhea in about 7% (40c). However, at the beginningof 1991 the drug was withdrawn by the manufacturer from those markets into which it had been introduced, and all trials were discontinued because of an unacceptably high incidence of liver damage (102r). Labetalol (SED-11, 371) A case of fatal non-A, non-B hepatitis in which no other drug could be implicated has been reported by Douglas et al (41 C) and a further 10 cases have been reported by the U.S. Food and Drug Administration, in 2 of whom the outcome was also fatal (42c). Metoprolol (SEDA-13, 154) Larrey et al have further investigated the case of metoprolol-induced hepatitis which they described before. They concluded that the patient was a poor metabolizer of metoprolol and that he therefore must have taken a relative overdose of the drug. Whether or not there is an association between plasma metoprolol concentrations and the risk of liver injury is as yet unclear (43c). Propranolol (SED-11, 360; SEDA-12, 159;
SEDA-14, 160) Celiprolol (SED-12, 162; SEDA-13, 154;
SEDA-14, 161) Although celiprolol, a cardioselective t3adrenoceptor antagonist with high partial agonist activity, shares with pindolol the theoretical advantage of the absence of negative effects on serum lipids, it caused 'particularly unpleasant' subjective side effects in the majority of patients in one trial, including feeling cold and generally unwell, headache and sleepiness (38c), although the absence of an adverse effect on lung function, even in patients with asthma, was confirmed (39c).
Nervous system The use of propranolol as an anti-anxiety drug may be inappropriate in individual neurotic patients with panic attacks, palpitation, and mitral valve prolapse, as a report of 2 such cases, in which even low dosages resulted in an increase in the number and severity of such attacks, has shown (44c). Strong, though indirect, support for the hypothesis that propranolol might be the cause of depression was recently brought forward in a study in which increased use of antidepressants was found in patients on propranolol therapy (45c), if depression is generally under-
[3-Adrenoceptor antagonists and antianginal drugs Chapter 19 treated the problem could be much worse than suggested (46r).
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INDIVIDUAL NITRATES Isosorbide-5-mononitrate
Endocrine, metabolic It has been recognized for many years that the use of propranolol to prevent hemorrhage from esophageal varices may worsen symptoms of hepatic encephalopathy. Snady and Lieber measured arterial blood ammonia concentrations and performed a number of psychometric tests in 12 patients with severe liver cirrhosis(47c). They found a rise of arterial ammonia concentrations of about 30~ with a corresponding deterioration in psychological performance. The maintenance dose of propranolol in such patients should therefore be kept as low as possible. Sotalol (SED-11, 371)
Hypokalemia and the use of high dosages of sotalol are known risk factors in the induction of ventricular tachydysrhythmias, particularly torsade de pointes. However, despite the use of low dosages and a normal serum potassium concentration, ventricular tachycardia may occur (48c). Prodysrhythmic effects formed a frequent ( 2 0 - 2 5 % ) reason for discontinuing sotalol in a study of patients suffering from resistant ventricular dysrhythmias (49c).
NITRATE DERIVATIVES (SED-11, 371;
SEDA-12; SEDA-13, 154; SEDA-14, 162) General Acute gouty flare-ups with very high serum uric acid concentrations were noted in 4 patients with unstable angina receiving intravenous infusions of glyceryl trinitrate. After exclusion of all other possible causes it was thought that the solvent, ethanol, had caused the attacks (50c). Buenger and Mauro in a comprehensive literature review have again drawn attention to the possible danger of causing methemoglobinemia by infusing nitrates, particularly glyceryl trinitrate, at too high a rate and/or too high a dose (51r). Increases in methemoglobin of over 2% are very common, although clinical symptoms seem to be rare and recovery is rapid once the condition is recognized and methylene blue injected.
Deep transient hypotension with oliguria was observed in 1 of 4 patients who were treated with an intravenous infusion of isosorbide-5mononitrate for pulmonary edema due to leftsided cardiac failure; there were no permanent sequelae (52c). The recently introduced high-dose once-aday slow-release formulations of oral isosorbide-5-mononitrate not unexpectedly cause frequent side effects, such as headache, dizziness, and nausea; in 2 multicenter trials such side effects accounted for premature withdrawal in about 1% of cases (53c, 54c), although in individual controlled trials the incidence of such adverse reactions seems to be much higher (55c). Transdermal glyeeryl trinitrate Since it was recognized that leaving glyceryl trinitrate patches in place would lead to rapid tolerance and loss of efficacy, intermittent use has been advocated. In other words, patches should be removed late in the afternoon and replaced on the following morning. Although this dosing regimen does not reduce the rather high incidence of headache it does lead, more so than continuous application, to increased painful skin irritation at the application site in about 30o70 of patients (56c, 57c).
CALCIUM ANTAGONISTS (SED-11, 373; SEDA-12, 163; SEDA-13, 155; SEDA-14, 162) Although the calcium antagonists have many pharmacodynamic properties in common, both their efficacy and their adverse reactions profile favor a division into 3 groups, the dihydropyridine congeners (nifedipine and its derivatives), the verapamil group (verapamil, tiapamil, and gallopamil), and diltiazem (58R). Differences in the patterns of side effects of these 3 groups of drugs are substantial (59r). A large number of new dihydropyridines with divergent pharmacodynamic and pharmacokinetic properties
192 have now been developed, and they have differences and similarities in this respect as well (60R).
Gastrointestinal
All calcium antagonists inhibit esophageal contraction, and some have been found useful for the treatment of esophageal spasm. However, this might facilitate esophageal reflux and thereby cause atypical chestpain. Caution in the use of these drugs in the treatment of esophagitis has therefore been advised (61r).
Skin and appendages
Collected data from the U.S. Food and Drug Administration and the adverse reaction register of the American Academy of Dermatology have shown that skin reactions to calcium antagonists are rare, but that some of them are serious. Nifedipine, verapamil, and diltiazem have all been implicated as possible causes of toxic epidermal necrolysis (Lyell's syndrome) and/or exfoliative dermatitis, as well as Stevens-Johnson syndrome. Although the incidence of minor skin reactions is higher with nifedipine and verapamil use, serious reactions tend to be more frequent with diltiazem (62c). INDIVIDUAL CALCIUM ANTAGONISTS
Amlodipine Amlodipine has a side effect profile which is very similar to that of related dihydropyridine derivatives, including ankle edema, headache, and flushing. However, the incidence of side effects is low, and only 1aT0of patients withdrew from clinical trials for this reason (63c).
Bepridil (SED-11, 377; SEDA-12, 166," SEDA-13, 160) Although in a small trial of 19 patients with stable angina pectoris it was again confirmed that long-term treatment with bepridil can cause a significant prolongation of the corrected QTinterval, no ventricular dysrhythmias were observed (64c).
Diltiazem (SEDA-12, 166; SEDA-13, 160; SEDA-14, 164) Cardiovascular After the publication of a
Chapter 19 L. Offerhaus brief report by Waller and Inman (SEDA-14, 64) additional cases of serious dysrhythmias (junctional bradycardia, sino-atrial block) at therapeutic dosages have been reported (65c, 66c).
Skin and appendages Severe cutaneous reactions to diltiazem continue to be reported. In 1 patient the peripheral vasodilatation associated with a rash caused an aggravation of her angina (67r Widespread cutaneous vasculitis was observed in 2 similar cases (68r Two cases of hypertrophic gingivitis have been reported during treatment with diltiazem (69c). This has also been reported with nifedipine (SEDA-14, 163; see below).
Interactions The accidental addition of nifedip&e to maintenance treatment with diltiazem caused an acute ileus in a 41-year-old man; positive rechallenge twice with nifedipine after a negative laporotomy made the connection likely (70c).
Felodipine (SED-11, 378; SEDA-12, 166; SEDA-13, 161) Wider experience with this long-acting dihydropyridine derivative has shown that its side-effect profile is similar to those of nifedipine and nitrendipine and includes headache, peripheral edema, and flushing; the incidence of these vasodilatory effects is dosedependent (71c). A study in healthy volunteers has clearly shown that the ankle edema caused by felodipine can be explained by a combination of increased capillary pressure and interference with microvascular smooth muscle control (72c). The edema does not result from retention of salt and water (73c).
Gallopamil (SEDA-11, 171) Gallopamil, a forerunner of verapamil, has not gained wide acceptance as a therapeutic option. Its adverse effects are similar to those of verapamil, although gallopamil seems to cause more abdominal cramps (74r).
Isradipine (SEDA-13, 161) Isradipine, another dihydropyridine derivative, has an adverse reaction profile which is
3-Adrenoceptor antagonists and antianginal drugs Chapter 19 similar to nifedipine, and includes palpitation, headache, fatigue, dizziness, and ankle edema. In one multicenter study side effects were observed in about 10~ of patients; reactions were dose-dependent and rarely necessitated withdrawal (75c). Joint (knee and ankle) pains were reported by 4 patients in another trial, but there were no objective symptoms of joint inflammation (76c),
Nicardipine (SED-11, 378; SEDA-13, 161; SEDA-14, 165) Although the side effects of nicardipine are similar to those of other dihydropyridines, it is slightly more prone to cause headache, ankle edema, and flushing, although this difference might be explained by the relatively high recommended dosage (77c). A novel formulation (50~ slow-release) in a twice daily dose of 60 mg caused troublesome side effects in 9 out of 14 patients, 2 of whom were unable to finish a 4-week trial (78c). Almost identical patterns of side effects have been observed during treatment with nisoldipine (SEDA-13, 161) and nitrendipine (SED-11, 378; SEDA-12, 166; 79 c, 80c).
Nifedipine (SED-11, 373; SEDA-13, 149; SEDA-14, 155) Episodes of silent ischemia have been reported in 2 of 34 patients with angina pectoris consecutively treated with nifedipine. This constitutes a rare but wellrecognized risk, particularly in unstable angina (81c). Nifedipine may sensitize the carotid sinus and so facilitate cardiac arrest during induction of anesthesia (82r
Cardiovascular
drugs) may cause a fall in body temperature and even clinical hypothermia (85c).
Gastrointestinal Acute abdominal pain caused by mesenteric ischemia, mimicking an abdominal emergency, has been reported (86c).
Liver Another case of hepatic steatosis with Mallory inclusion bodies has been reported, bringing the number of nifedipine-induced cases of liver injury to 10 (87r most of the cases previously described have presented as cholestatic jaundice; in one of these cases Mallory bodies were also noted; the histochemical nature of the inclusion bodies in this case was unclear. Reversible acute renal failure followed oral nifedipine treatment of severe hypertension in a 82-year-old man with congestive cardiac failure who had been treated simultaneously with furosemide and isosorbide dinitrate. His pulmonary congestion improved only after discontinuation of nifedipine (88c). This was seen as a hemodynamic reaction of the kidney to altered perfusion.
Urinary system
Skin and appendages
Dermatological reactions to nifedipine seem to be rare, and a case of exfoliative dermatitis brings the total number of severe skin reactions reported to 3. The reappearance of the syndrome after re-exposure of nifedipine because of poor blood pressure control confirmed the causative role of the drug (89c). Cases of nifedipine-induced gingivitis continue to be reported; it seems therefore that this side effect may not be as rare as has been previously thought (SEDA-14, 163; 90c).
Interactions Nervous system In one not optimally documented case severe parkinsonism developed during nifedipine treatment for hypertension. This has also been reported with cinnarizine and flunarizine (SEDA-14, 167), but it is not clear what the relationship is to calcium antagonism (83r). Depression has also been associated with nifedipine treatment in 4 patients (84c).
Endocrine, metabolic On rare occasions the vasodilator effects of nifedipine (and similar
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Previous suspicions that nifedipine would interact with lithium ions have now been confirmed. During long-term treatment with nifedipine, lithium clearance fell by 30~ the mechanism was not clear, but seems to have involved sodium - lithium exchange in the renal tubules (91c). Nifedipine metabolism is significantly inhibited by ciclosporin; in 1 patient high concentrations of unchanged nifedipine were associated with a deep flush (92c). A substantial increase of the systemic availability of nifedipine occurs when either
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alcohol or citrus f r u i t juice (grapefruit or orange) is c o n s u m e d a t the same time; absorption m a y increase by as m u c h as 5007o a n d side effects such as t a c h y c a r d i a have been observed as a result o f these unexpected interactions (93 C, 94c).
Tiapamii (SEDA-12, 167) The available data o n tiapamil are still r a t h e r limited. During a n o p e n dose-titration study its a n t i h y p e r t e n s i v e effect, even at high dosages, was d i s a p p o i n t i n g , while debilitating side effects, particularly dizziness, occurred in over 50~ o f the patients. In 9 o f the 31 patients tiapamil h a d t h e r e f o r e to be w i t h d r a w n p r e m a t u r e l y (95c).
Verapamil (SED-11, 374; SEDA-14, 165) Cardiovascular A n u m b e r o f case-reports have warned against the use o f v e r a p a m i l in atrial fibrillation with a rapid ventricular rate
Chapter 19 L. Offerhaus c o m p l i c a t i n g the W o l f f - P a r k i n s o n - W h i t e synd r o m e , which c a n easily cause ventricular fibrillation (96 C, 97c). V e r a p a m i l was given to 10 o f 18 patients w h o presented to an emergency d e p a r t m e n t . All survived, b u t 3 required cardioversion. The diagnosis m a y be particularly difficult, because a rapid irregular r h y t h m with wide pre-excitation complexes m a y easily be m i s t a k e n for a b r o a d - c o m p e x t a c h y c a r d i a (98c). T h e negative inotropic effect of verapamil m a y be particularly d a n g e r o u s in the elderly, as was the case in 2 w o m e n with h y p e r t e n s i o n , w h o only a few days after b e g i n n i n g to take slowrelease verapamil, 240 m g / d a y , developed acute heart failure (99c).
Interactions The potent enzyme-inducing a g e n t rifampicin may reduce the systemic availability o f verapamil to extremely low levels a n d so completely u n d o any p h a r m a c o d y n a m i c effect o f the drug. This c o m b i n a t i o n should be avoided (100c).
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13-Adrenoceptor antagonists and antianginal drugs 16. Howard PJ, Lee MR (1988) Beware betaadrenergic blockers in patients with severe urticaria! Scott. Med. J. 33, 344. 17. Pedersen DL (1989) Hymenoptera stings and beta-blockers (Letter). Lancet, 334, 619. 18. Strauss WE, Parisi AF (1988) Combined use of calcium-channel and beta-adrenergic blockers for the treatment of chronic stable angina. Rationale, efficacy, and adverse effects. Ann. Intern. Med., 109, 570. 19. Carruthers SG, Freeman DJ, Bailey DG (1989) Synergistic adverse hemodynamic interaction between oral verapamil and propranolol. Clin. PharmacoL Ther., 46, 469. 20. McCourty JC, Silas JH, Tucker GT, Lennard MS (1988) The effect of combined therapy on the pharmacokinetics and pharmacodynamics of verapamil and propranolol in patients with angina pectoris. Br. J. Clin. Pharmacol., 25, 349. 21. Keech AC, Harper RW, Harrison PM et al (1988) Extent and pharmacokinetic mechanisms of oral atenolol - verapamil interaction in man. Fur. J. Clin. Pharmacol., 35, 363. 22. Nesto RW, White HD, Wynne J e t al (1987) Comparison of nifedipine and isosorbide dinitrate when added to maximal propranolol therapy in stable angina pectoris. Am. J. Cardiol., 60, 256. 23. Tijssen JGP, Lubsen J (1988) Early treatment of unstable angina with nifedipine and metroprolol - the HINT trial. J. Cardiovasc. PharmacoL, 12 (Suppl. 1), $71. 24. Packer M (1989) Combined beta-adrenergic and calcium-entry blockade in anigina pectoris. N. EngL J. Mecl., 320, 709. 25. Sax MJ (1988) Analysis of possible drug interactions between cimetidine (and ranitidine) and betablockers. Adv. Ther., 5, 210. 26. Reggev A, Vollhardt BR (1989) Bradycardia induced by an interaction between phenelzine and beta-blockers. Psychosomatics, 30, 106. 27. Leor J, Levartowsky, D, Sharon C, Farfel Z (1988) Amiodarone and beta-adrenergic blockers: an interaction with metoprolol but not with atenolol (Letter). Am. Heart J., 116, 206. 28. Camus P, Lombard JN, Perrichon M e t al (1989) Bronchiolitis obliterans organising pneumonia in patients taking acebutolol or amiodarone. Thorax, 44, 711. 29. Tanner LA, Bosco LA, Zimmermann HJ (1989) Hepatic toxicity after acebutolol therapy. Ann. Intern. Med., 111, 533. 30. Kholeif M, Isles C (1989) Profound hypotension after atenolol in severe hypertension. Br. Med. J., 298, 161. 31. Arber N (1988) Delirium induced by atenolol. Br. Med. J., 297, 1048. 32. Wolf R, Ophir, J, Elman M, Krakowski (1989) Atenolol-induced cutaneous vasculitis. Cutis, 43, 231.
Chapter 19
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33. Schwartz MS, Frank MS, YanoffA, Morecki R (1989) Atenolol-induced cholestasis. Am. J. Gastroenterol., 84, 1084. 34. Schimmel MS, Eidelman A J, Wilschanski MA et al (1989) Toxic effects of atenolol consumed during breast feeding. J. Pediatr., 114, 476. 35. Maclean D (1988) Bevantolol vs propranolol: a double-blind controlled trial in essential hypertension. Angiology, 39, 487. 36. Rodrigues EA, Lawrence JD, Dasgupta P e t al (1988) Comparison of bevantolol and atenolol in chronic stable angina. Am. J. Cardiol., 61, 1204. 37. Kohno M, Takeda T, lshii M e t al (1988) Therapeutic benefits and safety of carvedilol in the treatment of renal hypertension. An open, short term study. Drugs, 36 (Suppl. 6), 129. 38. Busst CM, Bush A (1989) Comparison of the cardiovascular and pulmonary effects of oral celiprolol, propranolol and placebo in normal volunteers. Br. J. Clin. Pharmacol., 27, 405. 39. van Zyl AI, Jennings AA, Bateman ED, Opie LH (1989) Comparison of respiratory effects of two cardioselective beta-blockers, celiprolol and atenolol, in asthmatics with mild to moderate hypertension. Chest, 95, 209. 40. Schoenberger JA, Wallin JD, Gorwit JI et al (1989) A multicenter double-blind study of the efficacy and safety of once and twice daily dilevalol compared to propranolol. Am. J. Hypertens., 2, 840. 41. Douglas DD, Yang RD, Jensen P, Thiele DL (1989) Fatal labetalol-induced hepatic injury. Am. J. Med., 87, 235. 42. Clark JA, Zimmerman HJ, Tanner LA (1990) Labetalol hepatotoxicity. Ann. Intern. Med., 113, 210. 43. Larrey D, Henrion J, Heller F et al (1989) Metroprolol-induced hepatitis: ls the rate of oxidation related to drug-induced hepatotoxicity? Hepatology, 9, 163. 44. Levinson DF, Acquaviva J (1988) Exacerbation of panic disorder during propranolol therapy. J. Clin. PsychopharmacoL, 8, 193. 45. Thiessen BQ, Wallace SM, Blackburn JL et al (1990) Increased prescribing of antidepressants subsequent to beta-blocker therapy. Arch. Intern. Med., 150, 2286. 46. Gelenberg AJ (1990) Depression, depressants, and antidepressants (Editorial). Arch. Intern. Med., 150, 2245. 47. Snady H, Liever CS (1988) Venous, arterial, and arterialized-venous blood ammonia levels and their relationship to hepatic encephalopathy after propranolol. Am. J. Gastroenterol., 83, 249. 48. Ophoff N, Toker Y (1988) Ventrikul/ire Tachyarrhythmie unter niedriger Sotalol-Dosierung: Torsade de pointes oder polymorphe ventrikul~ire Tachykardie? Z. KardioL, 77, 393. 49. Ruder MA, Ellis T, Lebsack C et al (1989)
196 Clinical experience with sotalol in patients with drug-refractory ventricular arrhythmias. J. Am. Coll. Cardiol., 13, 145. 50. Shergy W J, Gilkeson GS, German DC (1988) Acute gouty arthritis and intravenous nitroglycerin. Arch. Intern. Med., 148, 2505. 51. Bt,enger JW, Mauro VF (1989) Organic nitrateinduced methemoglobinemia. Drug. Intell. Clin. Pharm., 23, 283. 52. Harf C, Welter R (1988) Emergency treatment of severe cardiogenic pulmonary edema with intravenous isosorbide-5-mononitrate. Am. J. Cardiol., 61 (Suppl. E), 22E. 53. Herrmann H, Kuhl A, Maier-Lenz H (1988) Der Einfluss des Dosierungszeitpunktes von Isosorbidmononitrat auf objektive und selective Parameter der Angina pectoris. Arzneim.-Forseh., 38 694. 54. Ankier S, Fay L, Warrington SJ, Woodings DF (1989) A multicentre open comparison of isosorbide-5-mononitrate and nifedipine given prophylactically to general practice patients with chronic stable angina pectoris. J. lnt. Med. Res., 17, 172. 55. Lagioia R, Scrutinio D, Mangini SG et al (1989) Efficacia e durata d'azione di una formulazione a lento rilascio di isosorbide-5-mononitrato nell'angina da sforzo stabile. Cardiologia, 34, 155. 56. Greco R, d'Alterio D, Schiattarella M e t al (1988) Efficacy of a new transdermal nitroglycerin patch (Deponit 10) for stable angina pectoris. Am. J. Cardiol., 61 (Suppl. E), 44E. 57. Waters DD, Juneau M, Gossard D et al (1989) Limited usefulness of intermittent nitroglycerin patches in stable angina. J. A m. Coll. Cardiol. , 13, 421. 58. Dustan HP (1989) Calcium channel blockers. Potential medical benefits and side effects. Hypertension, 13 (Suppl./), 1 - 137. 59. Lavarenne J (1989) Effets ind6sirables des inhibiteurs calciques. Th~rapie, 44, 197. 60. Wood AJJ (1989) Calcium antagonists. Pharmacologic differences and similarities. Circulation, 80 (Suppl. IV), 184. 61. Gaginella TS, Maxfield DL (1988) Calciumchannel blocking agents and chest pain. Drug lntell. Clin. Pharm., 22, 623. 62. Stern R, Khalsa JH (1989) Cutaneous adverse reactions associated with calcium channel blockers. Arch. Intern. Med., 149, 829. 63. Osterloh I (1989) The safety of amlodipine. Am. Heart J., 118, 1114. 64. Sharma MK, Voyles W, Prasad R et al (1988) Long-term bepridil monotherapy for angina pectoris. Am. J. Cardiol., 61, 1210. 65. Nagle RE, Low-Beer T, Horton R (1989) Diltiazem and heart block (Letter). Lancet, 1, 907. 66. Spadaro M, Farrugio M, Mililli A et al (1988) Blocco seno-atriale da diltiazem orale. Cardiotogia, 33, 1 0 9 5 - 6. 67. Jones SK, Reynolds NJ, Crossley J, Kennedy
Chapter 19
L. Offerhaus
CTC (1989) Cutaneous reaction to diltiazem resulting in an exacerbation of angina. Clin. Exp. DermatoL, 14, 457. 68. Sheehan-Dare RA, Goodfield MJD (1988) Widespread cutaneous vasculitis associated with diltiazem. Postgrad. Med. J., 64, 467. 69. Cucchi G, Guigni (1988) Gengivite ipertrofica da diltiazem. Minerva Cardioangiol., 36, 509. 70. Lamaison D, Abrieu V, Fialip J e t al (1989) Occlusion intestinale aigu6 et antagonistes calciques. Thdrapie, 44, 201. 71. Andrejak M, Witchitz S, Morand P e t al (1989) La f61odipine dans l'hypertension art6rielle. Comparaison en double aveugle avec l'at6nolol. Thdrapie, 44, 167. 72. Gustafsson D, L~mneT, Bjerkhoel P et al (1989) Microvascular effects and oedema formation of felodipine in man. J. H ypert ens., 7(Suppl. 4), S161. 73. Toftdahl DB, Andersen GS (1989) Effect of long-term nifedipine treatment on body fluid composition in essential hypertension. J. Hum. Hypertens., 3, 203. 74. Mildenberger D, Klepzig H, Hopf R, Kaltenbach M (1989) Nebenwirkungsspektrum von Gallopamil im Vergleich zu anderen Kalziumantagonisten. Z. KardioL, 78 (Suppl. 5), 25. 75. Shepherd AMM, Carr AA, Davidov M e t al (1989) Efficacy and safety of isradipine in hypertension. J. Cardiovasc. Pharmacol., 13, 580. 76. Parker JO, Enjalbert M, Bernstein V (1988) efficacy of the calcium antagonist isradipine in angina pectoris. Cardiovasc. Drugs Ther., 1, 661. 77. Castle CH, Wolbach RA (1989) Long-term systemic arterial blood pressure control with nicardipine. Am. J. Cardiol., 64 (Suppl. H), 35H. 78. Webster J, Witte I~, Rawles J e t al (1989) Evaluation of a long acting formulation of nicardipine in hypertension by clinic and home recorded blood pressures and Doppler aortovelography. Br. J. Clin. PharmacoL, 27, 563. 79. Nechwatal W, Berger J, Blumrich Wet al (1988) A double-blind comparative study of doxazosin and nitrendipine in patients with mild-to-moderate hypertension. Am. Heart J., 116, 1806. 80. Jansen RWM M, van Lier H J J, Hoefnagels WIlL (1989) Nitrendipine versus hydrochlorothiazide in hypertensive patients over 70 years of age. Clin. Pharmacol. Ther., 45, 291. 81. Casolo GC, Balli E, Poggesi L, Gensini GF (1989) Increase in number of myocardial ischemic episodes following nifedipine administration in two patients. Detection of silent episodes by Holter monitoring and role of heart rate. Chest, 95, 541. 82. Plotkin CN, Eckenbrecht PD, Waldo DA (1989) Consecutive cardiac arrests on induction of anesthesia associated with nifedipine-induced carotid sinus hypersensitivity. Anesth. Analg., 68, 402.
13-Adrenoceptor antagonists and antianginal drugs 83. Hefner R, Fischer PA (1988) Zunahme der Parkinson-Symptomatik under Kalzium-Antagonisten. Nervenarzt, 60, 187. 84. Hullett F J, Potkin SG, Levy AB, Ciasca R (1988) Depression associated with nifedipineinduced calcium channel blockade. Am. J. Psychiatry, 145, 1277. 85. Wollersheim H, Berden J, Thien T (1989) Decreased rectal body temperature induced by different vasodilatory drugs. Neth. J. Med., 34, 189. 86. Goglin WK, Elliott BM, Deppe SA (1989) Nifedipine-induced hypotension and mesenteric ischemia. South. Med J., 82, 274. 87. Babany G, Uzzan F, Larrey D et al (1989) Alcoholic-like liver lesions induced by nifedipine. J. Hepatol., 9, 252. 88. Eicher JC, Morelon P, Chalopin JM et al (1988) Acute renal failure during nifedipine therapy in a patient with congestive heart failure. Crit. Care Med., 16, 1163. 89. Reynolds NJ, Jones SK, Crossley J, Harman RRM (1989) Exfoliative dermatitis due to nifedipine. Br. J. Dermatol., 121, 401. 90. Barak S, Kaplan I (1988) The CO 2 laser in the excision of gingival hyperplasia caused by nifedipine. J. Clin. PeriodontoL, 15, 633. 91. Bruun NE, Ibsen H, Skott Pet al (1988) Lithium clearance and renal tubular sodium handling during acute and long-term nifedipine treatment in essential hypertension. Clin. Sci., 75, 609. 92. McFadden JP, Pontin JE, Powles AV et al Cyclosporin decreases nifedipine metabolism. Br. Med. J., 299 1224. 93. Qureshi S, Langani~re S, McGilveray IJ et al
Chapter 19
197
(1990) Nifedipine-alcohol interaction. J. Am. Med. Assoc., 264, 1660. 94. Bailey DG, Spence JD, Mufioz C, Arnold JMO (1991) Interaction of citrus juices with felodipine and nifedipine. Lancet, 337, 268. 95. Lacourci~re Y, Carrier M, Toal CB (1989) Efficacy and tolerability of tiapamil in patients with mild to moderate essential hypertension. J. Cardiovasc. Pharmacol., 14, 166. 96. Strasberg B, Sagie A, Rechavia E et al (1989) Deleterious effects of intravenous verapamil in Wolff-Parkinson-White patients and atrial fibrillation. Cardiovasc. Drugs Ther., 2, 801. 97. Michel B, Goy J J, Kappenberger L (1989) Syndrome de Wolff-Parkinson-White et vrrapamil: propos d'un cas de fibrillation ventriculaire. Schweiz. Med. Wochenschr., 119, 630. 98. Garratt C, Ward D, Antoniou A, Camm AJ (1989) Misuse of verapamil in pre-excited atrial fibrillation. Lancet, 1, 367. 99. Mohindra SK, Udeani GO (1989) Long-acting verapamil and heart failure (Letter). J. Am. Med. Assoc., 261, 994. 100. Barbarash RA, Bauman JL, Fischer JH et al (1989) Near-total reduction in verapamil bioavailability by rifampin. Electrocardiographic correlates. Chest, 94, 954. 101. Eldor J, Hoffman B, Davidson T (1987) Prolonged bradycardia and hypotension after neostigmine administration in a patient receiving atenolol. Anaesthesia, 42, 1294. 102. Harvengt C (1991) Labetalol hepatotoxicity (Letter). Ann. Intern. Med., 114, 341.
19
/5-Adrenoceptor antagonists and antianginal drugs
/3-ADRENOCEPTOR ANTAGONISTS (SED-11, 360; SEDA-13, 149; SEDA-14, 159) Nervous system A troublesome limitation to the use of beta-blocking drugs is the occurrence of CNS effects, such as sleep disturbances, tiredness, forgetfulness, and even depression (SEDA- 13, 151). The results of a number of recent investigations are contradictory. In a large open out-patient study involving 205 Norwegian patients the incidence of such side effects elicited on interview seemed to correlate with the lipid solubility of the drug and ~l-adrenoceptor selectivity played only a minor role (1 c). In 5 different double-blind studies in which atenolol, metoprolol, and propranolol were compared with placebo the same question was tackled using standardized psychological tests. In one study there was clear evidence that at equipotent 3-adrenoceptor blocking doses propranolol caused more psychological disturbances and tiredness than atenolol, but all the patients had been on beta-blockers before the trial (2c). Another similar study could not confirm this difference (3c). Despite minor differences in the tests affected, atenolol and metoprolol scored approximately equally; both were associated with subjective symptoms, but the incidence was low (4c, 5c). Dimsdale and colleagues have performed a meta-analysis of 55 studies of the cognitive side effects of beta-blockade. They did not find any firm evidence that lipophilic drugs caused more side effects than hydrophilic ones. Betablockers may have had a sedative effect, but in some studies that was compensated by a better performance in complicated tasks. However, many of these studies were small and poorly
9 1991 Elsevier Science Publishers B.V.
Side Effects of Drugs Annual 15 M.N.G. Dukes and J.K. Aronson, editors
188
controlled and one wonders whether the usual psychological tests are appropriate in this situation (6R). However, recent data confirming a correlation between lipophilicity and serum concentrations on the one hand and CNS side effects on the other have reopened the discussion (7R).
Sexual function and beta-blockade Increasingly, attention is being drawn to the high incidence o f sexual symptoms in men treated with beta-blockers. Loss o f libido and difficulty in sustaining an erection are the main problems, and can even be reproduced in young healthy volunteers (8c). These effects are especially likely to occur during treatment with lipophilic drugs, such as propranolol (9c) and pindolol (lOC), although Japanese men are similarly affected by atenolol (lle); in two o f these studies (10 e, 11c) ,there was also a significant fall in plasma testosterone concentrations. A personalized approach seems necessary to detect such symptoms, because they were not observed in a large multicenter study o f 1285 men and 1080 women sponsored by the British Health Ministry, the DHSS (12c).
Risk situations The drug information service of the University of California has reviewed the literature data on the dangers of anaphylactoid reactions in patients on beta-blockers (13r). Such patients are difficult to treat adequately and the resultant complications, such as shock and bradycardia, may be serious, because the signs of anaphylaxis may be masked by the beta-blocker. Immediate hospitalization may be necessary, because patients do not respond to adrenaline and may need resuscitation. Thirty such cases have been described. A particularly dangerous situation may arise if patients on
13-Adrenoceptor antagonists and antianginal drugs Chapter 19 long-term beta-blockade experience anaphylactoid reactions to drugs, such as chymopapaine and iodine-containing X-ray contrast media (14c). For the same reason the French authorities have warned doctors not to use the analgesic glafenine, known to cause anaphylactic shock (SEDA-13, 82), in patients on beta-blockers (15r). Similarly, patients with spontaneous attacks of angio-edema or urticaria may be at risk when given beta-blockers, a d r u g - disease interaction which may be fatal (16R). A physician who was being treated with atenolol and aspirin after a myocardial infarction has described how after being stung by a wasp he was brought to hospital in shock and did not regain consciousness until the following day (17c). He was unaware of the danger because he had received wasp stings in the past. Interactions The combined use of calcium antagonists and beta-blockers, both for the treatment of hypertension and angina pectoris, is increasingly being recommended. However, there are risks. The combination of verapamil with beta-blockers may cause severe bradycardia, heart block, hypotension, or congestive cardiac failure in 1 0 - 15o70 of patients (18R). This interaction has both pharmacodynamic (19c, 20C) and pharmacokinetic (20c, 21c) characteristics. Although a minority of patients with hypertension taking nifedipine with betablockers may show further improvement, most are not better off than on monotherapy, and many may experience more side effects. The combination may be useful in stable angina pectoffs (22 c) but it should be discouraged in unstable angina (23c). There seems to be a limited indication for the addition of diltiazem to beta-blockade, though even the usefulness of this combination has been questioned; if insufficient benefit is obtained with a single calcium antagonist, increasing the dose is often a better and safer alternative than adding a beta-blocker (24R). The possible clinical relevance of pharmacokinetic interactions of propranolol with H 2 antagonists (cimetidine and ranitidine) has been reviewed (25R). Although both drugs increase the systemic availability and decrease the clearance of most/3-adrenoceptor antagonists, there is no firm evidence that this has ever led to increased effects of these drugs. Two cases
189
which are described in detail are confounded by a number of factors. Nevertheless, Sax advises that dosages of beta-blockers should be carefully adjusted in individual patients taking H 2 antagonists (25R). Excessive bradycardia has been noted in 2 elderly patients taking the MAO inhibitor phenelzine after the addition of a beta-blocker. The mechanism of this interaction has to be further investigated (26c). Life-threatening bradycardia with dizziness and visual disturbances was also observed when amiodarone was given to patients taking metoprolol (27c). Prolonged bradycardia and hypotension have been reported after neostigmine and atropine administration in a patient taking atenolol (101c). The patient was a 78-year-old woman who was admitted for an elective hip operation. She was maintained on atenolol for control of her hypertensive ischemic heart disease and had stable angina pectoris treated with nitrates and atenolol. After routine anesthesia with pancuronium bromide, isoflurane, and nitrous oxide she was given neostigmine and atropine for reversal of muscle relaxation. Prolonged bradycardia and hypotension then developed, necessitating the use of adrenaline and isoprenaline. INDIVIDUAL/3-ADRENOCEPTOR ANTAGONISTS The number of beta blockers available is steadily increasing; despite similar efficacy and closely related chemical structures, unexpected adverse reactions which are specific for individual drugs are being reported with some regularity. One should therefore always be on the alert for unexpected events, as the following data show. A c e b u t o l o l (SED-11, 160," SEDA-12, 161)
A patient with bronchiolitis obliterans, reversible after withdrawal of the drug, has been reported. The histology was characterized by connective tissue growth in small air passages, as in similar cases attributed to other drugs. Although an immunological mechanism was suspected, immunological investigations were negative (28c).
Chapter 19 L. Offerhaus
190 Six cases of hepatitis, reversible after withdrawal, have been reported to the U.S. Food and Drug Administration; in 2 of them rechallenge was positive (29c). Atenoiol (Sed-11, 362) Although atenolol is generally held to be one of the safest beta-blockers, severe and unusual side effects are occasionally reported, such as profound hypotension after a single oral dose (30c), organic brain syndrome with acute delirium (31c), cutaneous vasculitis with purpuric skin lesions (32c) and cholestatic hepatitis (33c). Despite its low lipid solubility enough atenolol can diffuse into human milk to cause bradycardia and hypotension in a breastfeeding infant (34c). Bevantolol (SEDA-12, 162) Although this new cardioselective betablocker seems to have a favorable side effects profile the incidence of headache, dizziness, and fatigue in 2 comparative trials was slightly higher than with atenolol or propranolol (35c, 36c). Carvediioi Carvedilol is a new non-selective j3adrenoceptor antagonist with a high degree of partial agonist activity. Early trials have shown a rather high incidence of skin reactions, but it seems to be too early to know whether or not these are drug-induced (37c).
Dilevalol Dilevalol, one of the 4 enantiomers of labetalol (the R,R'-isomer), has no c~adrenoceptor blocking properties, and it can be classified as one of the newer non-selective agents with partial agonist activity. It has been reported to cause few side effects, with the exception of diarrhea in about 7% (40c). However, at the beginningof 1991 the drug was withdrawn by the manufacturer from those markets into which it had been introduced, and all trials were discontinued because of an unacceptably high incidence of liver damage (102r). Labetalol (SED-11, 371) A case of fatal non-A, non-B hepatitis in which no other drug could be implicated has been reported by Douglas et al (41 C) and a further 10 cases have been reported by the U.S. Food and Drug Administration, in 2 of whom the outcome was also fatal (42c). Metoprolol (SEDA-13, 154) Larrey et al have further investigated the case of metoprolol-induced hepatitis which they described before. They concluded that the patient was a poor metabolizer of metoprolol and that he therefore must have taken a relative overdose of the drug. Whether or not there is an association between plasma metoprolol concentrations and the risk of liver injury is as yet unclear (43c). Propranolol (SED-11, 360; SEDA-12, 159;
SEDA-14, 160) Celiprolol (SED-12, 162; SEDA-13, 154;
SEDA-14, 161) Although celiprolol, a cardioselective t3adrenoceptor antagonist with high partial agonist activity, shares with pindolol the theoretical advantage of the absence of negative effects on serum lipids, it caused 'particularly unpleasant' subjective side effects in the majority of patients in one trial, including feeling cold and generally unwell, headache and sleepiness (38c), although the absence of an adverse effect on lung function, even in patients with asthma, was confirmed (39c).
Nervous system The use of propranolol as an anti-anxiety drug may be inappropriate in individual neurotic patients with panic attacks, palpitation, and mitral valve prolapse, as a report of 2 such cases, in which even low dosages resulted in an increase in the number and severity of such attacks, has shown (44c). Strong, though indirect, support for the hypothesis that propranolol might be the cause of depression was recently brought forward in a study in which increased use of antidepressants was found in patients on propranolol therapy (45c), if depression is generally under-
[3-Adrenoceptor antagonists and antianginal drugs Chapter 19 treated the problem could be much worse than suggested (46r).
191
INDIVIDUAL NITRATES Isosorbide-5-mononitrate
Endocrine, metabolic It has been recognized for many years that the use of propranolol to prevent hemorrhage from esophageal varices may worsen symptoms of hepatic encephalopathy. Snady and Lieber measured arterial blood ammonia concentrations and performed a number of psychometric tests in 12 patients with severe liver cirrhosis(47c). They found a rise of arterial ammonia concentrations of about 30~ with a corresponding deterioration in psychological performance. The maintenance dose of propranolol in such patients should therefore be kept as low as possible. Sotalol (SED-11, 371)
Hypokalemia and the use of high dosages of sotalol are known risk factors in the induction of ventricular tachydysrhythmias, particularly torsade de pointes. However, despite the use of low dosages and a normal serum potassium concentration, ventricular tachycardia may occur (48c). Prodysrhythmic effects formed a frequent ( 2 0 - 2 5 % ) reason for discontinuing sotalol in a study of patients suffering from resistant ventricular dysrhythmias (49c).
NITRATE DERIVATIVES (SED-11, 371;
SEDA-12; SEDA-13, 154; SEDA-14, 162) General Acute gouty flare-ups with very high serum uric acid concentrations were noted in 4 patients with unstable angina receiving intravenous infusions of glyceryl trinitrate. After exclusion of all other possible causes it was thought that the solvent, ethanol, had caused the attacks (50c). Buenger and Mauro in a comprehensive literature review have again drawn attention to the possible danger of causing methemoglobinemia by infusing nitrates, particularly glyceryl trinitrate, at too high a rate and/or too high a dose (51r). Increases in methemoglobin of over 2% are very common, although clinical symptoms seem to be rare and recovery is rapid once the condition is recognized and methylene blue injected.
Deep transient hypotension with oliguria was observed in 1 of 4 patients who were treated with an intravenous infusion of isosorbide-5mononitrate for pulmonary edema due to leftsided cardiac failure; there were no permanent sequelae (52c). The recently introduced high-dose once-aday slow-release formulations of oral isosorbide-5-mononitrate not unexpectedly cause frequent side effects, such as headache, dizziness, and nausea; in 2 multicenter trials such side effects accounted for premature withdrawal in about 1% of cases (53c, 54c), although in individual controlled trials the incidence of such adverse reactions seems to be much higher (55c). Transdermal glyeeryl trinitrate Since it was recognized that leaving glyceryl trinitrate patches in place would lead to rapid tolerance and loss of efficacy, intermittent use has been advocated. In other words, patches should be removed late in the afternoon and replaced on the following morning. Although this dosing regimen does not reduce the rather high incidence of headache it does lead, more so than continuous application, to increased painful skin irritation at the application site in about 30o70 of patients (56c, 57c).
CALCIUM ANTAGONISTS (SED-11, 373; SEDA-12, 163; SEDA-13, 155; SEDA-14, 162) Although the calcium antagonists have many pharmacodynamic properties in common, both their efficacy and their adverse reactions profile favor a division into 3 groups, the dihydropyridine congeners (nifedipine and its derivatives), the verapamil group (verapamil, tiapamil, and gallopamil), and diltiazem (58R). Differences in the patterns of side effects of these 3 groups of drugs are substantial (59r). A large number of new dihydropyridines with divergent pharmacodynamic and pharmacokinetic properties
192 have now been developed, and they have differences and similarities in this respect as well (60R).
Gastrointestinal
All calcium antagonists inhibit esophageal contraction, and some have been found useful for the treatment of esophageal spasm. However, this might facilitate esophageal reflux and thereby cause atypical chestpain. Caution in the use of these drugs in the treatment of esophagitis has therefore been advised (61r).
Skin and appendages
Collected data from the U.S. Food and Drug Administration and the adverse reaction register of the American Academy of Dermatology have shown that skin reactions to calcium antagonists are rare, but that some of them are serious. Nifedipine, verapamil, and diltiazem have all been implicated as possible causes of toxic epidermal necrolysis (Lyell's syndrome) and/or exfoliative dermatitis, as well as Stevens-Johnson syndrome. Although the incidence of minor skin reactions is higher with nifedipine and verapamil use, serious reactions tend to be more frequent with diltiazem (62c). INDIVIDUAL CALCIUM ANTAGONISTS
Amlodipine Amlodipine has a side effect profile which is very similar to that of related dihydropyridine derivatives, including ankle edema, headache, and flushing. However, the incidence of side effects is low, and only 1aT0of patients withdrew from clinical trials for this reason (63c).
Bepridil (SED-11, 377; SEDA-12, 166," SEDA-13, 160) Although in a small trial of 19 patients with stable angina pectoris it was again confirmed that long-term treatment with bepridil can cause a significant prolongation of the corrected QTinterval, no ventricular dysrhythmias were observed (64c).
Diltiazem (SEDA-12, 166; SEDA-13, 160; SEDA-14, 164) Cardiovascular After the publication of a
Chapter 19 L. Offerhaus brief report by Waller and Inman (SEDA-14, 64) additional cases of serious dysrhythmias (junctional bradycardia, sino-atrial block) at therapeutic dosages have been reported (65c, 66c).
Skin and appendages Severe cutaneous reactions to diltiazem continue to be reported. In 1 patient the peripheral vasodilatation associated with a rash caused an aggravation of her angina (67r Widespread cutaneous vasculitis was observed in 2 similar cases (68r Two cases of hypertrophic gingivitis have been reported during treatment with diltiazem (69c). This has also been reported with nifedipine (SEDA-14, 163; see below).
Interactions The accidental addition of nifedip&e to maintenance treatment with diltiazem caused an acute ileus in a 41-year-old man; positive rechallenge twice with nifedipine after a negative laporotomy made the connection likely (70c).
Felodipine (SED-11, 378; SEDA-12, 166; SEDA-13, 161) Wider experience with this long-acting dihydropyridine derivative has shown that its side-effect profile is similar to those of nifedipine and nitrendipine and includes headache, peripheral edema, and flushing; the incidence of these vasodilatory effects is dosedependent (71c). A study in healthy volunteers has clearly shown that the ankle edema caused by felodipine can be explained by a combination of increased capillary pressure and interference with microvascular smooth muscle control (72c). The edema does not result from retention of salt and water (73c).
Gallopamil (SEDA-11, 171) Gallopamil, a forerunner of verapamil, has not gained wide acceptance as a therapeutic option. Its adverse effects are similar to those of verapamil, although gallopamil seems to cause more abdominal cramps (74r).
Isradipine (SEDA-13, 161) Isradipine, another dihydropyridine derivative, has an adverse reaction profile which is
3-Adrenoceptor antagonists and antianginal drugs Chapter 19 similar to nifedipine, and includes palpitation, headache, fatigue, dizziness, and ankle edema. In one multicenter study side effects were observed in about 10~ of patients; reactions were dose-dependent and rarely necessitated withdrawal (75c). Joint (knee and ankle) pains were reported by 4 patients in another trial, but there were no objective symptoms of joint inflammation (76c),
Nicardipine (SED-11, 378; SEDA-13, 161; SEDA-14, 165) Although the side effects of nicardipine are similar to those of other dihydropyridines, it is slightly more prone to cause headache, ankle edema, and flushing, although this difference might be explained by the relatively high recommended dosage (77c). A novel formulation (50~ slow-release) in a twice daily dose of 60 mg caused troublesome side effects in 9 out of 14 patients, 2 of whom were unable to finish a 4-week trial (78c). Almost identical patterns of side effects have been observed during treatment with nisoldipine (SEDA-13, 161) and nitrendipine (SED-11, 378; SEDA-12, 166; 79 c, 80c).
Nifedipine (SED-11, 373; SEDA-13, 149; SEDA-14, 155) Episodes of silent ischemia have been reported in 2 of 34 patients with angina pectoris consecutively treated with nifedipine. This constitutes a rare but wellrecognized risk, particularly in unstable angina (81c). Nifedipine may sensitize the carotid sinus and so facilitate cardiac arrest during induction of anesthesia (82r
Cardiovascular
drugs) may cause a fall in body temperature and even clinical hypothermia (85c).
Gastrointestinal Acute abdominal pain caused by mesenteric ischemia, mimicking an abdominal emergency, has been reported (86c).
Liver Another case of hepatic steatosis with Mallory inclusion bodies has been reported, bringing the number of nifedipine-induced cases of liver injury to 10 (87r most of the cases previously described have presented as cholestatic jaundice; in one of these cases Mallory bodies were also noted; the histochemical nature of the inclusion bodies in this case was unclear. Reversible acute renal failure followed oral nifedipine treatment of severe hypertension in a 82-year-old man with congestive cardiac failure who had been treated simultaneously with furosemide and isosorbide dinitrate. His pulmonary congestion improved only after discontinuation of nifedipine (88c). This was seen as a hemodynamic reaction of the kidney to altered perfusion.
Urinary system
Skin and appendages
Dermatological reactions to nifedipine seem to be rare, and a case of exfoliative dermatitis brings the total number of severe skin reactions reported to 3. The reappearance of the syndrome after re-exposure of nifedipine because of poor blood pressure control confirmed the causative role of the drug (89c). Cases of nifedipine-induced gingivitis continue to be reported; it seems therefore that this side effect may not be as rare as has been previously thought (SEDA-14, 163; 90c).
Interactions Nervous system In one not optimally documented case severe parkinsonism developed during nifedipine treatment for hypertension. This has also been reported with cinnarizine and flunarizine (SEDA-14, 167), but it is not clear what the relationship is to calcium antagonism (83r). Depression has also been associated with nifedipine treatment in 4 patients (84c).
Endocrine, metabolic On rare occasions the vasodilator effects of nifedipine (and similar
193
Previous suspicions that nifedipine would interact with lithium ions have now been confirmed. During long-term treatment with nifedipine, lithium clearance fell by 30~ the mechanism was not clear, but seems to have involved sodium - lithium exchange in the renal tubules (91c). Nifedipine metabolism is significantly inhibited by ciclosporin; in 1 patient high concentrations of unchanged nifedipine were associated with a deep flush (92c). A substantial increase of the systemic availability of nifedipine occurs when either
194
alcohol or citrus f r u i t juice (grapefruit or orange) is c o n s u m e d a t the same time; absorption m a y increase by as m u c h as 5007o a n d side effects such as t a c h y c a r d i a have been observed as a result o f these unexpected interactions (93 C, 94c).
Tiapamii (SEDA-12, 167) The available data o n tiapamil are still r a t h e r limited. During a n o p e n dose-titration study its a n t i h y p e r t e n s i v e effect, even at high dosages, was d i s a p p o i n t i n g , while debilitating side effects, particularly dizziness, occurred in over 50~ o f the patients. In 9 o f the 31 patients tiapamil h a d t h e r e f o r e to be w i t h d r a w n p r e m a t u r e l y (95c).
Verapamil (SED-11, 374; SEDA-14, 165) Cardiovascular A n u m b e r o f case-reports have warned against the use o f v e r a p a m i l in atrial fibrillation with a rapid ventricular rate
Chapter 19 L. Offerhaus c o m p l i c a t i n g the W o l f f - P a r k i n s o n - W h i t e synd r o m e , which c a n easily cause ventricular fibrillation (96 C, 97c). V e r a p a m i l was given to 10 o f 18 patients w h o presented to an emergency d e p a r t m e n t . All survived, b u t 3 required cardioversion. The diagnosis m a y be particularly difficult, because a rapid irregular r h y t h m with wide pre-excitation complexes m a y easily be m i s t a k e n for a b r o a d - c o m p e x t a c h y c a r d i a (98c). T h e negative inotropic effect of verapamil m a y be particularly d a n g e r o u s in the elderly, as was the case in 2 w o m e n with h y p e r t e n s i o n , w h o only a few days after b e g i n n i n g to take slowrelease verapamil, 240 m g / d a y , developed acute heart failure (99c).
Interactions The potent enzyme-inducing a g e n t rifampicin may reduce the systemic availability o f verapamil to extremely low levels a n d so completely u n d o any p h a r m a c o d y n a m i c effect o f the drug. This c o m b i n a t i o n should be avoided (100c).
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Chapter 19
L. Offerhaus
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Chapter 19
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