β-Adrenoceptor antagonists and antianginal drugs

M.N.G. Dukes

19

fl-Adrenoceptor antagonists and antianginal drugs

fl-ADRENOCEPTOR ANTAGONISTS

bradycardia or hypoglycemia or to the membrane-stabilizing properties of these substances. In the esmolol case reported by these authors, however, none o f these explanations seem to hold good (18 ~, 19~).

(SED-11, 360; SEDA-13, 149) Cardiovascular system The fact that fl-adrenergic blockers can produce symptoms o f peripheral ischemia is long known, but as a rule the effect is uncomfortable rather than serious, with complaints of Raynaud-like coldness of the extremities. Just occasionally, in patients predisposed to this effect, the impairment o f peripheral circulation may be sufficient to produce gangrene; a recent case from France is apparently the ninth on record: A man of 48 sought medical advice because of necrotic changes in all 10 toes. He had always suffered from poor peripheral circulation, most marked in cold weather, and for 2 years he had been treated for hypertension with diuretics and timolol I0 mg daily by mouth. After 7 months of treatment he had noted onset of intermittent claudication, but had not reported this to the doctor. Six months later after exposure to snow he had suffered severe pain and edema of the toes with generalized pyrexia. Despite supportive treatment distal amputation of the toes proved necessary (lCR).

Nervous system In a paper dealing primarily

Skin and appendages Alongside a general literature overview by Heng and H e n g o f the incidence o f psoriatic eruption during beta-blocker therapy which generally confirms existing impressions (2R), 1988 saw a new study of the actual frequency in a population o f 588 psoriasis patients who had in the past received ultra-violet light therapy for their condition. After examining the histories of all 588 cases, 73 were selected as being likely or potential users of beta-blockers in view of a history of cardiovascular disorders or migraine, and they received a questionnaire. Of the 47 who provided evaluable responses, 25 had indeed received one or more beta-blockers, and one current case of psoriasis flare associated with metoprolol was also noted. In the group as a whole, exacerbation of psoriasis had occurred in 9 of 13 patients on propranolol, 4 of 4 on nadolol, 6 of 8 on atenolol and 2 of 3 on metoprolol. One patient claimed that the psoriasis had improved during the beta-blockade (3cr).

with seizures induced by esmolol and discussed below, Das and Ferris provided in 1988 a short but clear review of the way in which fl-adrenoceptor antagonists may induce seizures. It is sufficient to remark here that seizures have generally followed the ingestion o f excessively high doses, though in a few cases normal doses caused seizures in susceptible individuals. The effect might in some cases be attributable to some better-known pharmacological effects of these compounds, such as the induction of

This work makes it fairly clear that about two thirds of patients on a beta-blocker are likely to experience a flare-up o f existing psoriasis, irrespective of the agent employed.

Risk situations A child with the tetralogy o f Fallot is dearly likely to be highly sensitive to the effects o f some drugs with cardiac effects. Clark et al in 1989 presented a case of a girl of 18 months with this condition who received propranolol 5 m g 3 times daily to treat attacks o f acute cyanosis. The drug appeared to be effective but during a severe episode she was admitted to hospital and the dose was raised to 8 mg

9 1990 ElsevierSciencePublishers B.V. (BiomedicalDivision)

Side Effectsof DrugsAnnual 14 M.N.G. Dukes and L. Beeley,editors 159

160 daily. Thereafter she suffered a series of episodes of near syncope which were traced to extreme bradycardia and paroxysmal sinus arrest. These new episodes disappeared when the propranolol was discontinued (4c).

Withdrawal effects See propranolol below. Interactions The fact that beta-blockers can interact violently with epinephrine (adrenaline), as one would expect from their pharmacology, is still overlooked in practice. While it has become fairly generally appreciated that a catecholamine analog will derange antihypertensive therapy with a beta-blocker, the fact that a non-selective beta-blocker can greatly increase the pressure response to epinephrine and lead to hypertension and reflex bradycardia seems to be forgotten. Gandy has described a typical case in which a man on long-term propranolol maintenance therapy was admitted with severe pharyngeal and uvular edema and was given 0.3 ml of a 1:1000 solution of epinephrine subcutaneously. Severe headache and acute hypertension occurred with sinus bradycardia, though with emergency treatment the patient recovered (5cr). Since the ability of non-steroidal anti-inflammatory drugs to counter the effects of betablockers was first discussed (SED-11,369), research groups have been anxious to find evidence that their own particular non-steroidal agent does not have this effect to any significant degree. The Boots company was able to show that 1600 mg/d ibuprofen did not significantly affect blood pressure control by propranolol (6c). In fact the effect was first demonstrated with indometacin and it seems increasingly doubtful whether it plays any real role in practice; one should simply bear in mind that if an NSAID is added to existing betablocker therapy it will be sensible to monitor the effects of the antihypertensive treatment more frequently for a while to exclude any interference. Beta-blockers can obviously potentiate or buttress one anothers" effects, and this would hardly be worth recording were it not for the fact that a systemic beta-blocker prescribed in general medicine may have at least an additive effect with one prescribed for topical use by the ophthalmologist, the possibility of the interaction having been missed by both parties. That

Chapter 19 M.N.G. Dukes ophthalmic beta-blockers can produce severe systemic effects, e.g. involving the nervous or cardiovascular systems, has been discussed repeatedly in Chapter 49 of these volumes, and documented particularly with respect to timolol and more recently as regards betaxolol (7c, 8c, 9R). A classic interaction between the 2 forms of treatment has also been reported for betaxoloi and labetalol, the joint treatment resuiting in confusion, bronchospasm and congestive heart failure in an elderly woman in intensive care (10r

INDIVIDUAL fl-ADRENOCEPTOR ANTAGONISTS

Propranolol (SED-11, 360; SEDA-12, 159) Respiratory Precipitation of asthma in susceptible individuals is a classic risk with the non-selective beta-blockers, though cases still occur where the attendant clinician overlooks the onset of wheezing as an early warning sign (1 lC). The risk is not always one which can be avoided in advance, since in much of the developing world low-cost propranolol may be the only beta-blocker available. Less typical is a report of what seems to have been hypersensitivity pneumonitis reflecting an immune lung reaction of cell-mediated type. A man of 59 with a long history of exposure both to asbestos and to pigeons and doves was treated for 30 months with propranolol (40 mg/d) and pentaethyl tetranitrate because of coronary disease. He now presented with mild fever, loss of weight, cough and dyspnea of effort. Although the clinical lung examination detected no abnormalities, there were small interstitial opacities at the lung bases on X-ray, a hypergammaglobulinemia and marked lymphocytosis. Bronchoalveolar lavage showed 3 asbestos bodies per ml, 30.3% macrophages, 18.6% neutrophils, 4.6% eosinophils, 44.9% lymphocytes and a CD4/ CD8 lymphocyte ratio of 0.58. Withdrawal of propranolol produced progressive improvement in the symptoms, X-ray and cytology, whereas rechallenge with propranolol caused recurrenee (12CR). This case points to the fact that where other risk or complicating factors are present - in this instance a suspicion of both asbestosis and psittacosis - one may need both rechallenge

fl-Adrenoceptor antagonists and antianginaldrugs Chapter19 and bronchoalveolar lavage to make the diagnosis.

Withdrawal reactions There has for a long time been some doubt as to the reality o f withdrawal reactions following beta-blocker treatment; clearly sometimes one is simply dealing with a recurrence o f the original condition which may in the meantime have become more severe. The 'overshoot' effect on the bloodpressure seems to be reasonably clear and continues to be documented with new cases (13CR); it would seem that the beta-receptors have as a result o f the drug treatment become oversensitive to circulating agonists. Sequelae can be serious, even including myocardial infarction. The withdrawal effects are not limited to the cardiovascular system; headaches, tremulousness and anxiety are common, and one sometimes also sees an acute psychic derangement when treatment is stopped, rather as one may when a short-acting benzodiazepine is withdrawn. It now seems very likely that (just as with the benzodiazepines) a minority of individuals, c o m m o n l y with a history o f normal mental function, are unable to tolerate the sudden loss of supportive treatment. A woman of 68 with no history of psychiatric problems had been treated for 10 years with 160 mg propranolol daily for essential tremor. When she ceased to take the drug, she developed over the course of a week increasing paranoid delusions, insomnia and auditory and tactile hallucinations. In the acute phase she required neuroleptic treatment, but she recovered after propranolol treatment was progressively resumed. A man of 52 with no history of mental disorder had been treated for some weeks with 80 mg propranolol daily for hypertension. He discontinued it abruptly of his own accord and began to suffer severe nightly confusion. In this case too, recovery followed reinstitution of propranolol treatment. (14c) If it is true that one is dealing with a question of particular sensitivity in a minority group this would explain why a study in 30 healthy volunteers failed to show any evidence of a C N S withdrawal syndrome after the use of practolol

(15c). Celiprolul (SEDA-12, 162; SEDA-13, 154) On present data, the adverse reaction profile of celiprolol still appears relatively favorable.

161

Since it has both fll selectively and intrinsic agonist activity it is distinct from the older and most widely-used beta-blockers; in that respect one would expect its reaction pattern to be most closely similar to those of epanolol and xamoterol. The comparisons published so far are with older drugs including atenolol and propranolol, and celiprolol has proved to be free of the headache, dizziness, fatigue and bradycardia produced by these other compounds (16R). It appears to have a more favorable effect on bronchial reactivity than metoprolol, which is cardioselective but has no agonist activity (17c). The only reservation one must make is that one is still in the early phases. W o r k examined earlier in these volumes related to a dose of 200 mg daily, whereas recent studies use some 400 mg daily. Only once one is sure o f the optimal dose range and has used the drug over the same length of time as some o f the classic products have been employed will one be able to draw firm conclusions. Esmolol (SED-11, 371; SEDA-13, 154) The most characteristic feature o f esmolol continues to be its extremely short half-life, so brief that it has little opportunity to cause adverse effects of interactions. That might be its main virtue, since when used for the treatment of conditions such as supraventricular tachyarrhythmias one needs only a brief corrective effect, after which the field should be free for the use of other agents (e.g. calcium antagonists) without the prospect of beta-blocker interactions (18c). On the other hand, this short and intensive treatment is not without its problems, one perhaps being induction of seizures, a recognized problem with excessively high doses o f beta-blockers: A very old man received esmolol i.v. for atrial tachycardia at a rate of a dose of 25 g/kg/min, doubled after 5 min and again after 10. Four minutes after the final infusion was started, the patient appeared drowsy and sleepy and he soon developed generalized tonic-clonic seizures. The infusion was terminated and the seizures abated in less than I min. After 5 min, when the patient had fully recovered, the infusion was restarted and within 3 min the patient again became drowsy and hyporesponsive; the infusion was stopped and no infusion occurred (19).

162 N I T R A T E DERIVATIVES (SED-11,371; SEDA-13, 154)

Skin and appendages Further cases of contact dermatitis with nitroglycerine patches continue to be reported, and it seems evident that both the nitroglycerine itself and one or more components of the delivery system may be involved (20 c, 21c). A clinically important finding in the former of these two reports is that as the allergic contact dermatitis developed the resorption of the active component through the inflamed area apparently declined, resulting in deterioration of the cardiovascular condition. Special senses When a man of 61 was given follow-up treatment for myocardial infarction using a nitroglycerine transdermal patch he complained that after 2 weeks he lost the sensation of bitter and salty taste, and by the sixth week his sense o f taste had disappeared completely. When the patch was withdrawn the full sense of taste returned. Rechallenge seemed to confirm the effect, bitter and salt sensations vanishing within 5 days, and returning a week after final withdrawal (22c). The patient was also being treated with sublingual nitroglycerine as required, as well as diltiazem, aspirin and metoprolol, but the time frame and rechallenge strongly suggest that the nitroglycerine patch was responsible for the loss of taste. Effects of excipients Demey et al have provided experimental evidence in a series of 28 patients that propylene glycol, used as a solvent in a commercially available intravenous nitroglycerine solution, can cause hyperosmolarity (and hence intracranial hypertension), hemolysis and lactic acidosis. The finding may in particular explain the neurological complications which sometimes occur during nitrate treatment. The risk of problems seems to be greatest where kidney function is impaired, causing the solvent to accumulate, but it is removed by hemodialysis (23).

C A L C I U M A N T A G O N I S T S (SED-11,373; SEDA-13, 155)

Cardiovascular Many of the recurrent troubles with calcium antagonists reported in the adverse reaction literature in fact reflect insufli-

Chapter 19 M.N.G. Dukes ciently close monitoring of their potent effects when they are used in high-risk patients. It is sufficiently well known that if they are used in severe congestive heart failure in old people they may produce circulatory collapse with renal failure (24 c) and that they may cause cardiogenic shock in patients with a recent myocardial infarct (25cr). These are not contraindications, but risk situations demanding great caution in the use of these drugs.

Endocrine, metabolic Calcium antagonists usually do not interfere with carbohydrate metabolism and cause no problems in most diabetic patients. One of the occasional exceptions which prove the rule may have been described by Heyman et al (26c); in their 60-year-old patient who was receiving both oral antihyperglycemic agents and insulin, nifedipine deranged the control of blood sugar. What one may note in this case, however, is that there was an earlier long history of maintenance therapy on beta-blockers (which have a known hypoglycemic effect), and from the time sequence it looks as if the increase in blood sugar levels was associated as much with the withdrawal of the beta-blockers as with the introduction of nifedipine treatment. Interaction Ever since the severe interaction between calcium antagonists and fl-adrenoceptor blockers (resulting in severe hypotension or even cardiac failure) became recognized the question has been whether one calcium antagonist is in this respect less risky than another. Intravenous verapamil has been regarded as notorious and it has been suggested (SED-13, 160) that nifedipine might be safer. Maclean's group, working with ICI, have studied the effects and tolerability of combined treatment with atenolol and nifedipine in 25 patients treated for 4 weeks with each of various dose levels; their conclusion is that tolerability was actually better than that of atenolol alone (27c). However when one looks at the vast number of relevant reports one must conclude that the risk of a serious interaction is still present, as stressed by Stockley, in discussing some recent cases in which nifedipine caused precisely the same problems when used alongside propranolol, alprenolol or atenolol (28R). The conclusion must still be that one should not lightheartedly use beta-blockers and calcium antag-

fl-Adrenoceptor antagonists and antianginal drugs Chapter 19 onists together; there must be a good reason for it.

INDIVIDUAL CALCIUM ANTAGONISTS

Nifedipine Respiratory Since pulmonary edema in the category of patients eligible for calcium antagonist therapy is most likely to be a manifestation of heart failure, the physician may look no further for an explanation. However it looks as if it might also occur as an allergic reaction to some formulations of nifedipine: A man of 76 with multiple disorders including poorly controlled hypertension was treated with 20mg tablets of controlled-release nifedipine ('Adalat L~'). Within 3 days he developed severe and symptomatic pulmonary edema. The condition normalized after withdrawal of all the drugs which he was receiving. Subsequent lymphocyte-stimulating tests using all the products which he had been taking showed positive results only with Adalat L, the highest score being noted with the substance used for coating the tablets (20c).

Hematological Nifedipine may very occasionally have caused blood dyscrasias, and a report of purpura suggests this mechanism; however in the patient described by Oren et al in 1989, a women of 63 clearly developed an acute and extensive non-thrombocytopenic purpuric reaction to nifedipine which persisted throughout the 4 weeks of treatment and then disappeared within a few days after the drug was withdrawn. One should add that she was also receiving quinidine, but this had been given for a longer period and she appeared to tolerate it well (30c). Skin and appendages A lichenoid reaction presenting clinically as an exfoliative dermatitis must be added to the list of skin reactions known with nifedipine (31); the reaction recurred twice o n subsequent rechallenges with the drug. Cases of gingival hyperplasia attributable to nifedipine continue to be reported (32 r 33CR), though the absolute incidence must be very low.

Miscellaneous A somewhat unclear report has associated the use of nifedipine with ep-

163

istaxis in a middle-aged alcoholic m a n (34c). Bearing in mind that epistaxis can be a complication of hypertension, which was the patient's principal disorder, and that epistaxis occurred on one occasion following the use of nifedipine but o n another following its withdrawal one would not be inclined to conclude that there was a link with the drug. Interactions Since calcium antagonists have been known to interfere with the effect of dantrolene it is not entirely surprising to note a recent report of what may have been a potentiating effect on the neuromuscular blockade produced by magnesium sulfate, when using both agents as tocolytic agents in premature labor. A woman of 22 experienced uterine contractions at the 32nd week of pregnancy and was given 60 mg nifedipine over a 3-hour period, followed by a maintenance dose of 20 mg every 8 h. Since after an initial response the contractions nevertheless recurred and it was considered unwise to raise the nifedipine dose any further, intravenous magnesium sulfate was given (300 mg in all). The patient developed jerky movements of the limbs and respiratory apparatus and found it difficult to swallow or raise her head because of marked muscular weakness. The effect wore off 25 min after magnesium sulfate was discontinued (35). Whether one is dealing here with true potentiation or a simple additive effect is not clear; the authors of the report recommend against using the 2 agents together for tocolysis, and at the very least cases where 1 drug alone proves insufficient should be very closely monitored if 2 are given together.

Risk situations A n interaction of calcium antagonists with volatile anesthetic agents was discussed in SEDA-13. One must now add a later case of cardiac arrest on 2 occasions apparently due to the influence of nifedipine in a woman in whom anesthesia was induced primarily with thiopental sodium; she was also receiving succinylcholine. The case was regarded as one of carotid sinus syndrome, a condition in which the induction of anesthesia can trigger cardiovascular collapse; under normal conditions the patient was asymptomatic and she had previously tolerated general anesthesia several times, but the syndrome was considered

164 to have been rendered more severe under the influence of nifedipine. Follow-up study showed that while carotid sinus massage produced a normal response so long as she was not taking nifedipine, sublingual use of the drug in a 10 mg dose was sufficient to cause sinus arrest and a fall in systolic blood pressure (36Cr). Calcium antagonists are sometimes used as vasodilators in pulmonary hypertension. A case reported by Pohar et al suggests that this may not be without risk in some cases. In their 55year-old patient with known primary pulmonary hypertension the severity of the condition increased 2 hours after a 10 mg sublingual dose of nifedipine. Since no other treatment proved effective she was ultimately stabilized under careful control on nifedipine in the form of 10 mg sustained-release tablets 4 times daily. What appears to have happened here is that the sublingual dose was initially effective, but that the rapid decline in circulating levels of nifedipine which followed its use produced some sort of withdrawal reaction. The prolonged moderate blood levels produced with the long-acting product evaded this risk (37c). This is perhaps one of the instances where slow-release preparations are entirely meaningful from the point of view of drug safety. Diltiazem (SED-11, 373; SEDA-13, 160) Hypersensitivity reactions Three recent case reports of angioneurotic edema from a single source seem incontrovertible; 2 concerned diltiazem, 1 verapamil. The cases occurred 2, 4 and 8 weeks after starting on diltiazem, and in all cases the symptoms receded completely 4872 hours after the drug was withdrawn (38c). Most calcium inhibitors have been associated with a range of allergic reactions and angioneurotic edema can probably be expected from time to time with any of them.

Cardiovascular

As noted above, the most troublesome 'adverse' effects of calcium antagonists are a consequence of their desired effect when it is exerted to excess or in high-risk situations. In a post-marketing surveillance programme, Waller and Inman in 1989 studied the incidence of heart block in a total of 10 119 patients taking the drug for at least 12 months. Atrioventricular block occurred in 22 cases, the dose of diltiazem being taken at the time ave-

Chapter 19 M.N.G.Dukes raging 180 mg. Third degree heart block occurred in 8 patients. Nine of the 22 were at the time concurrently receiving a beta-blocker, pointing to the special risk of this combination considered above and below (39c).

Nervous system In a mentally stable woman of 72 described by Bushe in 1988, treatment with 60 mg diltiazem 3 times daily apparently induced a florid organic psychosis within 2 days. The condition, characterized particularly by auditory and visual hallucinations and paranoid delusional ideas, rapidly receded over 3 days after withdrawal o f the drug, and after a week she was fully normal (40~tt). Rechallenge was not attempted, and she was treated thereafter with nifedipine which she tolerated well. Such a complication has been reported on one occasion before (by Polat in 1984, though with negative rechallenge (41c)) and it is possible that like some of the other nervous system complications discussed in this Chapter it represents an event to which a small minority of users are peculiarly susceptible.

Hematological Leukopenia

has been described earlier with diltiazem and in 1989 there was a case report of thrombopenia occurring acutely within 2 days of starting diltiazem treatment in a man of 61. The condition was marked by fever, hepatomegaly and rash, and resolved progressively over 8 days following withdrawal of the drug (42c). Skin and appendages F o r at least 5 years there has been evidence that diltiazem may cause erythema multiforme (SED-11, 376), and in 1988 the Federal German Health Authorities actually issued a warning as to this and other serious skin effects (SEDA-13, 161). What was claimed in 1989 to be the first report of the problem is thus not by any means unprecedented but it is well documented. The 67-year-old woman concerned had previously tolerated isosorbide dinitrate well for some years, but within 2 weeks of starting treatment with diltiazem she developed over much of the body a very typical erythema multiforme confirmed by biopsy. The condition normalized rapidly when diltiazem was withdrawn (43c).

Interaction The interaction between calcium antagonists and beta-blockers is discussed else-

fl-Adrenoceptor antagonists and antianginal drugs Chapter 19 where in this Chapter. A well-documented case involving diltiazem was reported by Partanen et al: A middle-aged man with a long history of angina pectoris and more recent atrial fibrillation had long been receivingatenolol and digoxin. Diitiazem 60 mg 3 times daily was added because of deterioration in his condition. Atrioventricular conduction was still normal. He tolerated the combination well for nearly 3 months but then omitted his morning medication and took all the drugs in the course of a few hours later in the day. Sinus node arrest developed and he required emergencytreatment (44c).

165

patient began to experience typical symptoms (intermittent attacks of redness, heat and pain in the fingers, relieved by immersing the hands in cold water) 3--4 weeks after starting treatment. The symptoms were more frequent in warm weather and bed at night. The diagnosis was made only after a year and the drug was withdrawn, after which the symptoms quickly disappeared (40c). Verapamil ( SED-11, 374)

Liver Mild hepatic reactions are known with Although in this case there was a clear degree of overdosage which undoubtedly raised the risk, 2 other cases in elderly people have been reported in which compliance was adequate (45c); the suggestion of the authors concerned that nifedipine or nicardipine are less likely to cause an interaction with fl-adrenergic blockers must, as pointed out above, be treated with much reserve.

verapamil and seem to be allergic in nature. An unusually severe reaction in a woman of 56 involved 2 episodes of jaundice, pruritus and upper abdominal pain with transaminase elevated up to 6-fold and alkaline phosphatase up to 4-fold when she was inadvertently rechallenged with the drug. The liver biopsy showed marked cholestasis (47c).

Nieardipine ( SED-I1, 378; SEDA-13, 161)

ACKNOWLEDGEMENT

Skin and appendages Levesque et al have described a case of erythromelalgia which was so closely associated in time with the use of nicardipine that the cause and effect relationship seems very likely. The 67-year old hypertensive

The author would like to acknowledge the support which he received in the preparation of this Chapter from a specialized section of the Working Group on Human Toxicological Assessment at the University of Copenhagen.

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Chapter 19 M.N.G. Dukes

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