Antianginal and β-adrenoceptor antagonists

J.R. Lawrence

19

Antianginal and fl-adrenoceptor antagonists

BETA-BLOCKERS (SED-IO, 317;

SEDA-9, 171; SEDA-IO, 158) Accurate information about the nature, frequency and severity of drug side effects is difficult to obtain. In the case of side effects to fl-adrenoceptor blocking drugs recent attempts to quantitate side effects accurately involved the use of visual analog scales (1 c, 2c) which proved superior to numerical scales (3c). Inevitably much of the information which follows on fl-adrenoceptor blocker side effects is less accurate in quantitative terms but no less important from the viewpoint of extending our knowledge about this widely used group of drugs.

Cardiovascular Considering the propensity for beta-blockade to produce br,adyarrhythmias and cardiacfailure the safety of fl-adrenoceptor blockers in acute myocardial infarction is impressive. Recently published trials and reviews support the conclusions reached in previous editions of this Annual about the low incidence of side effects, in patients with acute myocardial infarction, in both delayed entry (SEDA-6, 186) and early entry (SEDA-10, 172) trials. One comprehensive review of the subject by Yusuf et al (4R) included assessment of further early-intervention trials using metopro1ol (5c-7c). The authors noted that almost all trials of this type have reported an excess of sinus bradycardia and hypotension, particularly in the hours soon after the start of therapy. Only infrequently has atropine or a flladrenoceptor agonist been required in this setting, interruption of fl-adrenoceptor blocker therapy usually being sufficient on its own. With regard to heart failure, Yusuf et al (4c) concluded that there was a slight aggravation of failure during the acute stage, but that this was significant at a low level only in the lateSide Effects of Drugs Annual 11 M.N.G. Dukes, editor 9 Elsevier Science Publishers B.V., 1987

entry, long-term trials. As has been pointed out previously, however, most of these studies have excluded patients with any evidence of heart failure at entry, although in two which did not (8c, 9c) there was no increase in deaths or subsequent heart failure. Yusuf (4a) reminds us that it is, nonetheless, important to consider the benefit which might ensue if patients with cardiac failure at entry, and its associated poor prognosis, could tolerate fl-adrenoceptor blocker therapy. For cardiogenic shock the number of cases in published trials was so small that no accurate inferences about risk could be drawn (4R). Pooled information on heart block (degree unspecified) was classified by the reviewers (4R) as 'uninformatively inadequate' but did allow calculation of 95% confidence limits for aggregated data from the short-term trials, suggesting that the risk was, at most, 1% of all patients. In recently reported, earlyintervention metoprolol trials (5c-7c), the results conformed to the general pattern outlined above, but in one study (6c, 7c) temporary or permanent withdrawal from the trial because of cardiac failure was significantly more common in metoprolol-treated subjects than in controls, although the overall incidence of cardiac failure was the same in both groups. One unusual result in the other trial (5c) was a significantly lower incidence of atrioventricular block in the metoprolol-treated patients. Another metoprolol trial (10c) which has been reported recently looked at 3-year morbidity/ mortality following myocardial infarction and in common with other such studies was associated with a significantly higher incidence of cardiac failure in fl-adrenoceptor-blockertreated patients. In view of the acceptance of untreated cardiac failure as a contraindication to fl-adrenoceptor blocker therapy (SEDA10, 324), the apparent efficacy (11 c) of betablockade in carefully selected patients with dilated cardiomyopathy is surprising. Only one of 21 subjects proved intolerant of metoprolol, the others showing significantly increased exercise tolerance and improved functional

Chapter 19 J.R. Lawrence

162 classification during a 12-month treatment period. Reduced peripheral circulation is considered a well-established side effect of fl-adrenoceptor blocker therapy, but it was suggested previously (SEDA-8, 184) that patients with intermittent claudication should not be denied possible benefits from the use of such therapy. An extremely comprehensive study (12cR) of fladrenoceptor blocker effects in patients with intermittent claudication concluded that betablockade appeared not to be an independent risk factor for intermittent claudication. That conclusion was reached following a series of case-controlled, open and placebo-controlled double-blind crossover studies in patients with intermittent claudication evaluated by treadmill exercise and strain-gauge plethysmography. Walking capacity was unaffected by betablockade: the degree of obliterative arterial disease modulated the lower limb hemodynamic responses to beta-blockade so that in limbs with severe and extensive disease fladrenoceptor blocker therapy appeared to lose its effect on the peripheral circulation. Pindolol was associated with higher resting and hyperemic flow than propranolol or labetalol and the author suggested an advantage of intrinsic sympathomimetic activity (ISA) in mildly diseased limbs in keeping with a previous suggestion that this property is associated with maintained skin blood flow (13c). Provocation of vasospastic angina (SEDA-8, 184) is occasionally seen following start of fladrenoceptor blocker therapy. In one patient (14c) unstable angina followed the start of betaxolol therapy for hypertension. Torsade depointes is a well-known complication of sotalol therapy and has been reported in patients receiving conventional doses of the drug. A patient has been reported recently (15 c) in whom torsade de pointes necessitating cardioversion occurred at drug plasma levels within the 'therapeutic range'. Certainly plasma concentrations attained and drug halflife were, in that patient, comparable to measures obtained in healthy subjects receiving similar doses of the drug. The patient described, however, had been receiving maprotiline which might have contributed to prolongation of the QT-interval.

Respiratory Increased airways resistance is an inevitable consequence of fl2-adrenoceptor blockade. Agents with fll-adrenoceptor selectivity are therefore preferred in patients with any tendency to bronchospasm who should in

any case only receive a fl-adrenoceptor blocking drug if no suitable alternative exists (SED-10, 320; SEDA-8, 185). A comparison of atenolol, oxprenolol and acebutolol in patients with chronic obstructive airways disease (16 c) underlined this broad conclusion and adduced no evidence that the partial agonist activity of acebutolol and oxprenolol produced benefit in terms of a lesser degree of bronchoconstriction. The extent to which even cardioselective agents are poorly tolerated by patients with asthma was shown by another piece of recent work (17 c) on metoprolol and bevantolol, two flladrenoceptor selective blocking agents. In that dose-ranging study maximum tolerated doses of both drugs were said to be much lower than those usually required for therapeutic activity. Pulmonary fibrosis and pleurisy have been described in association with practolol, pindoIol and acebutolol therapy (SED-10,321; SEDA-8, 186) and a pneumonitic reaction to acebutolol has also been reported previously (18c). Details of another case of hypersensitivity 'pneumopathy' attributed to acebutolol have recently been published by the same group (19cr). This second case occurred in a 49year-old man receiving acebutolol for hypertension who developed interstitial pneumonitis some 13 months after the start of therapy. Bronchoalveolar washings revealed lymphocytosis and no other cause of pulmonary inflammation was found: complete resolution occurred within 3 weeks of withdrawal of therapy. The authors firmly implicated acebutolol in the production of this reaction because of a positive leukocyte-migration inhibition test in the presence of low concentrations of acebuto1ol.

Nervous system

An interesting account of the possible neuropharmacological mechanisms involved in the minor psychological symptoms commonly associated with fl-adrenoceptor blocker therapy has recently appeared (20R). The author concluded that the commonly occurring sleep disturbance associated, in particular, with lipophilic fl-adrenoceptor blockers is probably of complex etiology, but other recently published work has extended our knowledge of this side effect a little. Thus, one randomized crossover comparison (21 c) of atenolol and pindolol in hypertension yielded the expected lower incidence of sleep disturbances with the hydrophilic atenolol compared with pindolol. In addition, however, that trial also showed that the incidence of sleep disturbance actually decreased significantly during

Antianginal and fl-adrenoceptor antagonists Chapter19 atenolol treatment compared with a 2-week pre-trial washout period. Two recent pieces of evidence support the contention that sleep disturbance associated with fl-adrenoceptor blockade can be improved by changing the patient to a hydrophilic agent such as atenolol. In one double-blind study 14 patients with a previous history of nightmares or hallucinations when treated with lipophilic betablockers experienced very many fewer episodes during 4 weeks of atenolol compared with propranolol or metoprolol therapy (22c). Metoprolol is in fact a compound of intermediate lipophilicity which was also associated with significantly more sleep disturbance and restlessness at night than atenolol in another double-blind study conducted in 17 patients, all of whom had experienced CNS effects of more lipophilic agents (23c). Finally a detailed placebo-controlled crossover comparison of atenolol, propranolol, metoprolol and pindolol in 10 female volunteers studied under sleep laboratory conditions has also been published recently (24c). The study showed that although dreaming, equated with REM sleep, was reduced, recollection of dreaming was increased by the 3 lipophilic drugs. Analysis of the physiological records confirmed subjects' reports that wakening was increased. Dreaming was also reduced by atenolol, but atenolol had no effect on subjective measures of sleep. fl-Adrenoreceptor blocker therapy may disturb psychomotor function (SED-10, 321; SEDA-10, 159) and affect specialized skills such as car-driving. Recently published evidence on beta-blockade and psychomotor function includes a report that acute or chronic administration of atenolol in a dose of 100 mg daily did not impair visual reaction time in 30 healthy subjects (25c~). Another volunteer study using a saccadic eye movement reaction time task showed improved performance with both atenolol and metoprolol which did not however attain conventional levels of statistical significance (26c). A consistent effect of fladrenoceptor blocker therapy on specialized skills has not been demonstrated (SED-10, 321; 27r), but one recent double-blind placebocontrolled trial showed a clearly beneficial effect of atenolol 50 mg on subjective driving performance in an amateur car rally (28c). In that trial complaints of stress were markedly reduced in the atenolol group in keeping with the efficacy of this hydrophilic compound in controlling somatic and affective symptoms of anxiety (29c). Tardive dyskinesia appeared to be 'induced'

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by propranolol in a 53-year-old man with akathisia following haloperidol therapy for aggressive behavior (30c). Propranolol usage controlled akathisia, but severe orobuccal dyskinesia appeared within 48 hours and mild parkinsonian features were also seen. Resolution of these features with reappearance of akathisia occurred on propranolol withdrawal and the whole sequence was repeated after an interval of I month. The author speculated that blockade of central noradrenergic receptors might cause increased dopamine receptor sensitivity and it certainly seems likely that propranolol should be regarded as facilitative rather than causal in this reaction.

(SED-IO, 322; SEDA-9, 173; SEDA-IO, 160) Blood lipids That fl-adrenoceptor blocking Endocrine, metabolic

drugs reduce the plasma concentration of HDL cholesterol is well known, but whether or not that change is of any prognostic significance has been unclear to date. The effect of longterm fl-adrenoceptor blocker treatment on plasma iipids in cohorts of the Norwegian timolol multicenter study has recently been reported (31cR). One year's timolol treatment was associated with a significant reduction in H D L cholesterol from 1.32 to 1.26 mmol/1 and at the end of the treatment period H D L cholesterol levels were lower in timolol than placebo-treated patients. These H D L cholesterol levels, however, were of no prognostic significance in either placebo- or timololtreated patients. The reassuring conclusion, therefore, was that any deleterious effect of timolol on serum lipids did not attenuate the protective effect of the drug. Hypertriglyceridemia is the other consistent lipid abnormality associated with fl-adrenoceptor blocker therapy and some recent observations on metoprolol (32cR) may be relevant to the mechanisms involved in producing that change. Metoprolol treatment at a level associated with 'adequate' beta-blockade and antihypertensive effect was associated with a significant increase in binding of the fl-adrenergic antagonist (-)-3H-dihydroalprenolol to subcutaneous adipocytes and a 50% increase in the maximum lipolytic response to the fl-adrenoceptor agonist, isopropylnoradrenaline (32CR). The authors postulated that the observed increase in lipolytic response might in some measure account for the increased plasma trigiyceride level observed, although no parallel could be drawn between observed receptor change and lipolytic response.

164 Thyroid The complex changes which fladrenoceptor blocker therapy produces in concentrations of circulating thyroid hormones have been summarized previously in these pages (SED-10, 322): similar changes to those produced by propranolol have been described recently following celiprolol therapy (33c). Other Excess 5-hydroxyindole acetic acid (5-HIAA) excretion in urine is the hallmark of the carcinoid syndrome and it appears that fladrenoceptor blocker therapy should now be added to the list of drugs increasing the excretion of that serotonin metabolite or interfering with its assay. Oral therapy with both atenolol and pindolol increased apparent urinary 5-HIAA excretion, some of this effect, in the case of pindolol, being attributable to chemical interference with the colorimetric assay used (34c).

Skin lesions (SED-IO, 323; SEDA-9, 177; SEDA-IO, 160) Little new information has appeared in recent reviews (35 R, 36~) on the psoriasiform, eczematous, lichenoid and other skin lesions attributed to /~-adrenoceptor blocker therapy. In support of an immunological mechanism, induction of Class III MHC antigens on psoriatic keratinocytes by betablockers has recently been described (37c).

Arthralgia associated with betablockade Arthropathy is o f course occasionally seen as part o f a drug-induced lupus syndrome, but o f fladrenoceptor blockers in common use only acebutolol is associated with antinuclear factor formation at all commonly (SEDA-8, 187; SEDA-9, 176; SEDA-IO, 160). Recently, however, Savola (38 ~r) has suggested that arthralgia is a not uncommon side effect o f fl-adrenoceptor blocker therapy, metoprolol being particularly implicated. Joint symptoms were noted, by that author, to involve the shoulder joint in 15 o f 18 patients: 9 o f the group had involvement o f a second joint - most commonly the knee - 5 had polyarthritis, and in 2 the small finger joints were affected. Occasional accompaniments o f the arthropathy were eye symptoms, dry mouth and Raynaud's phenomenon. The author claimed that as joint symptoms were not uncommon in patients o f the age group receiving fl-adrenoceptor blocking therapy the specific arthropathy he described might well have been overlooked previously, His claim that arthropathy should be regarded as a specific side effect has not,

Chapter 19 J.R. Lawrence however, remained unchallenged. Thus, it was pointed out (39") that tests for antinuclear factor were not carried out in all the patients described (38 c') and in no case was the association confirmed by rechallenge. Furthermore, a recently published case-control study identified 127 patients, attending a hypertension clinic, with arthropathy and showed no significant association between arthropathy o f all types and the use o f beta-blockers (40c). The 42 patients with arthritis o f undiagnosed cause were, moreover, no more likely to be taking a beta-blocker than their controls and arthritis had developed during beta-blocker treatment in only 5 o f that group. An association between the use o f beta-blockers and arthropathy could not be completely excluded because o f insufficient power in that case-control study, but the results did not support the suggestion that arthritis was a common reaction to beta-blockers. On the other hand, several adverse drug reaction reports, summarized by Sills and her colleague from the FDA (41c), have appeared in support o f Savola's suggestion. It appears that 5 cases of metoprolol-associated arthralgia, most o f whom had negative serological tests for collagenoses, had been reported to the FDA up to January, 1986:2 o f these patients experienced an exacerbation o f symptoms when rechallenged with the drug. Seven cases o f arthralgia had also been reported as associated with other fl-adrenoceptor blocker drugs, 6 o f these being attributed to propranolol and I to atenolol (41c). An unusual reaction to pindolol therapy which might conceivably have been mistaken for arthralgia was painful muscle cramps in the legs o f a 67-yeae, oM man on pindolol treatment for hypertension (42c). The reaction was associated with a rise in serum creatinine phosphokinase (CPK) levels and a mild neuropathic pattern seen on EMG might have been a predisposing factor: pindolol rechallenge confirmed the association. The novel compound, bucindolol, was associated with generalized malaise, arthralgia, myalgia and a raised C P K level in 1 o f 8 patients receiving the drug over 6 months; another 5 patients showed only a rise in serum C P K levels (43c). Myalgia with raised plasma CPK and toxic myopathy features on muscle biopsy has also previously been attributed to labetolol (44c).

In relation to mechanisms thought to be important in leading to the withdrawal syndrome (SED-10, 325), it is of interest that acebutolol 400 mg/day for 20 days Miscellaneous

Antianginal and fl-adrenoceptor antagonists Chapter19 was associated with a decrease rather than an increase in fl-adrenoceptor density of human mononuclear leukocytes (45c). There is no clinical evidence, however, that the observed receptor down-regulation would be associated with a lower incidence of withdrawal effects. While the role of fl-adrenoceptor blocking drugs in the prevention of bleeding from esophageal varices in patients with cirrhosis is still being evaluated, hepatic encephalopathy has, in a few patients, been attributed to their use (SEDA-8, 185; SEDA-9, 173). Recently, during a trial of propranolol in 30 cirrhotic patients (46c), two subjects had the therapy withdrawn because of hepatic encephalopathy, hut the exact relationship of propranolol to this not uncommon manifestation of severe liver disease remains unclear. In another trial of propranolol in 174 patients with cirrhosis, drug withdrawal was, for a variety of reasons, necessary in 25 and that subgroup did uniformly badly (47c). It is therefore not surprising that a recent reviewer (48 R) emphasized the need for extreme caution when fl-adrenoceptor blockers were used in cirrhosis. That author emphasized the possible difficulty of resuscitation in the presence of bleeding as well as the possibility of encephalopathy. Consistent with previously published evidence (SEDA-8, 189) that nadolol produces less depression of renal function than other fladrenoceptor blockers, a crossover trial in 20 hypertensive patients with moderately impaired renal function showed increased creatinine clearance and decreased serum fl2-microglobulin concentrations in patients on nadolol compared with propranolol (49c). A comprehensive review offibrotic reactions to drug therapy has recently appeared (50R). The author agreed, in general, with views previously expressed on these pages about the lack of hard evidence implicating beta-blocker therapy in production of Peyronie's disease (SED-10, 323) or retroperitoneal fibrosis (SEDA-9, 175). As far as sclerosing peritonitis is concerned, the verdict on a causal association with fl-adrenoceptor blockers other than practolol remains 'not proven' (SED-10, 323; 50~).

Second-generation effects Among recent anecdotal reports of deleterious effects arising from fl-adrenoceptor blocker usage in pregnancy there have been putative cases of propranolol teratogenicity (51c~), neonatal cardiorespiratory depression with hypoglycemia and growth retardation following nadolol (52c), and intra-

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uterine death after labetalol combined with other hypotensive therapy (53c). Notwithstanding the increasing weight of evidence on the safety and efficacy (SED-10, 325; SEDA-8, 187; SEDA-9, 174; 54c) of fl-adrenoceptor blocking drugs in pregnancy hypertension a recent reviewer (55 R) who summarized the pros and cons still maintained that these drugs should remain second-line agents.

Overdosage (SED-IO, 326; SEDA-9, 177; SEDA-IO, 161) Little new clinical information on this subject has been published since the last edition of this Annual. The picture following acute intoxication with talinolol seems similar to that after propranolol overdose, cardioselectivity being predictably lost at high-dose level. Six of the 16 patients described who had taken talinolol died (56~ One unusual feature seen after sotalol overdose was widespread symmetrical T-wave inversion, simulating the changes of non-transmural infarction, in the ECG (57c). These changes followed ingestion of 1.2 g of the drug, were not associated with any change in cardiac enzymes, and resolved within 72 hours. Of possible toxicological effects in man which might be evident at the high betablocker serum levels found after overdose Langemeijer (58') has drawn attention to the occurrence of central respiratory depression in rats administered overdoses of propranolol, timolol or sotalol. Respiratory arrest was preceded by diminished respiratory frequency with no reduction in tidal volume and artificial ventilation significantly increased survival time in that model; intraventricular low-dose drug administration also caused respiratory arrest. Interactions (SED-IO, 326; SEDA-9, 178; SEDA-IO, 161) Calcium antagonists Combinations of fladrenoceptor blocking agents and calcium antagonists are gaining popularity in the treatment of refractory angina. The pathophysiological implications, indications and dangers of these drug combinations have been recently reviewed (59~t). There is no doubt about the efficacy of this approach, as shown, for example, by the superiority of diltiazem and propranolol in combination compared with either drug alone (60Cr); in that particular study, congestive failure developed in 2 of 24 patients while on propranolol and in one of these subjects when receiving combined therapy in more than minimal doses. When severe hypotension arises during combined drug use

Chapter 19 J.R. Lawrence

166 of this type, intravenous calcium can be extremely effective, as in 2 recently reported cases (61cr). These were a previously healthy young woman who had taken an overdose of verapamil with atenolol and a patient with ischemic heart disease tolerant of diltiazem and atenolol in combination until a further episode of myocardial infarction occurred. Further complexities of the interaction between these drug classes have also been described. Thus, an impressive pharmacokinetic interaction was observed between oral verapamil and metoprolol but not verapamil and atenolol (62c). Metoprolol plasma concentrations and consequently area-under-the-curve were doubled during verapamil co-administration, presumably secondary to inhibition of metoprolol metabolism by verapamil. Finally, an intriguing account has appeared of reduced regional myocardial blood flow in patients with significant left anterior descending artery stenosis, but not those without, during cold pressor testing while receiving propranolol and nifedipine in combination (63c). These complexities do, it seems, underline the need for caution whenever these drug types are used in combination. Other drugs The relative contributions of reduced hepatic blood flow and inhibition of drug metabolism to the well-recognized propranolol-lidocaine interaction have been further explored by Bax et al (64cR). They tested, in 6 healthy volunteers, their postulated model which called for 25% reduction in hepatic blood flow and 50% reduction in intrinsic metabolic clearance of lidocaine (64ca). Good agreement was obtained between predicted and observed results, so that as far as propranolol is concerned, enzyme inhibition is certainly quantitatively more important than reduced liver blood flow. Perhaps particularly important in relation to the previous description of asystole following propranolol pre-administration for electroconvulsive therapy (SEDA-9, 178) is a recent report of the efficacy of propranolol and atropine in maintaining sinus rhythm in that setting (65c). Propranolol has been shown, in a volunteer study, to impair clearance of the antituberculous drug, isoniazid (66c). It was unclear whether the reduction in isoniazid clearance of approximately 20% was due to inhibition of Nacetyltransferase activity or reduction of hepatic acetyl-coenzyme A availability. Mechanisms involved in the previously described (67c) reduction of theophylline clearance

by propranolol have been explored in a volunteer metabolic study (68cr). The data were consistent with a dose-dependent and selective inhibitory effect of propranolol on the separate forms of cytochrome P-450 involved in theophylline demethylation and 8-hydroxylation. I)ebrisoquine oxidation status and ~-adrenocepmr blockers (SEDA-8, 190) The oxidative clearance of metoprolol, timolol and bufuralol is influenced by the debrisoquine hydroxylation gene locus, so that metabolism of these lipophilic agents exhibits polymorphic characteristics. Reviewing the subject recently, Smith concluded that objective evidence was lacking for an association between poor metabolizer phenotype and adverse beta-blocker effects (69•). However, extensive metabolizers of metoprolol studied with conventional and sustained-release formulations would require twice-daily dosing with the latter to produce an optimum hypotensive effect over 24 hours (70Cr). Exercise heart rate over 24 hours following a single dose of timolol also showed the predicted pattern with a greater degree of beta-blockade at 12 and 24 hours in poor metabolizers (71cr). The practical importance of such observations awaits elucidation. I N D I V I D U A L fl-ADRENOCEPTOR BLOCKING D R U G S A N D NEWER AGENTS Labetalol The curroat status of this combined alphaand beta-blocker has been recently reviewed (72a). That overview recalled the rather high incidence of antinuclear and antimitochondrial antibodies - seen in some 15% of patients during labetalol use at doses of 100 to 2400 mg/d for up to 6.5 years (73 c) - although a lupus-like syndrome has been rare. In spite of potential benefits of the compound with regard to the peripheral circulation (SEDA-9, 178) in a recent appraisal of the drug in angina 5 of 10 patients complained of leg fatigue and 3 were said to develop intermittent claudication (74c). A recent report describes 2 cases of fever attributed to labetalol. In both cases fever settled on withdrawal of the drug and recurred on rechallenge. The authors state that the manufacturer had received 2 further reports of fever possibly due to labetalol, in one of which fever was associated with a rash. They postulate an immunoaUergic mechanism on the

Antianginal and fl-adrenoceptor antagonists Chapter 19 basis of lack of dose dependency and a sensitization period of 3-4 weeks (170c).

Betaxolol and bisoprolol These newer cardioselective agents with long half-lives have, in general, been well tolerated. Use of betaxolol was associated with minor symptoms such as tiredness, sleep disturbance, impotence and cold extremities seen with other fl-adrenoceptor blockers (75R). Bisoprolol was comparable to atenolol, with respect to the minor side effects produced, in 20 patients with stable angina (76c).

Esmolol This new ill-selective agent has an extremely short half-life (ca. 10 min) due to extensive metabolism by blood, tissue and hepatic esterases. It has been suggested that its short duration of action might make it useful for a trial of beta-blocker therapy in clinical situations, such as asthma and congestive heart failure (77~). Esmolol is certainly an effective agent in the control of supraventricular tachycardia (78c-80c), but impressive transient hypotension may follow its use. In general that side effect was not associated with symptoms (78c, 79c) and reversed rapidly on cessation of esmolol infusion. Hypotension 'did, however, occur in a high proportion of patients studied (78c, 79c) and was on occasion symptomatic (80c). Increased risk factors for the occurrence of hypotension were recent operation, atrial fibrillation and age > 6 5 years (79c). Other reasons for drug withdrawal in those trials were the occurrence of junctional rhythm and increased pulmonary artery pressure (80c). Marked hypotension (systolic blood pressure < 50 mmHg) was also seen in one of 12 patients with hypertension who received the drug (81c). Serum digoxin levels in healthy volunteers were increased by 10-20% during esmololdigoxin treatment compared with digoxin therapy alone (82cr) and total area under the digoxin concentration-time curve was accordingly significantly higher in the presence of esmolol. Morphine, when coadministered with esmolol, may on occasion increase steady-state blood levels of esmolol (82cr).

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particularly in patients receiving drugs such as clonidine and propranolol which act on the cardiovascular system (SEDA-8, 190). Increased vagal activity was the presumed mechanism for appearance of complete atrioventricular block with a short episode of asystole after sublingual isosorbide dinitrate in a 7 l-year-old patient who was receiving lignocaine by infusion (83r). The authors stressed the possible importance of an additive interaction between the drugs and recalled a previously reported case (84c), but it remains possible that nitrate syncope alone was to blame. Another case of coronary artery vasospasm (see SEDA-10, 163) occurred during cardiac catheterization while the patient was receiving substantial doses of intravenous glyceryl trinitrate (nitroglycerin) (85c). Vasospasm was observed to continue, in that individual, despite resolution of chest pain but did respond to intracoronary glyceryl trinitrate. Recently another example of ventricularfibrillation following nitrate use has been reported. The arrhythmia appeared immediately after intracoronary injection of glyceryl trinitrate, in a 46-year-old man undergoing angiography in preparation for coronary angioplasty (86cr). The marked resistance to defibrillation made the authors particularly confident in their assertion that the high potassium content of the preparation used ('Tridil') was the cause of the arrhythmia. Ventricular fibrillation has however also been documented immediately after sublingual glyceryl trinitrate use (87c).

N I T R A T E DERIVATIVES (SED-IO, 328; SEDA-9, 178; SED.4-10, 162)

Nitrate tolerance In the past we have briefly discussed this subject from the viewpoint of regarding loss of drug efficacy as a side effect (SEDA-10, 164). A recent review of a transdermai nitrate system ascribed the disappointing duration of action of the formulation to development of tolerance (88x). Another assessment of how nitrate tolerance might be avoided compared the efficacy of thrice-daily buccal glyceryl trinitrate with 4 times a day oral isosorbide dinitrate (89c). Over 2 weeks prolonged antianginal efficacy was maintained only with thrice-daily buccal administration. Nonetheless, in another study transdermal glyceryl trinitrate seemed to offer a sufficiently prolonged effect to wean patients with unstable angina from intravenous nitrate therapy (90c). Two more cases of severe contact dermatitis following use of glyceryl trinitrate patches have been recorded (91c).

Cardiovascular effects Vasovagal syncope is a well-recognized risk of sublingual nitrate use

Interactions Disopyramide therapy interfered with sublingnal isosorbide dinitrate efficacy by

168 an unusual mechanism in a 75-year-old man with post-infarction angina (92c). He found that sublingual isosorbide would not dissolve if taken within some hours of disopyramide due to the xerostomia associated with the latter drug. The authors pointed out the potential for interaction of this type with other drugs showing anticholinergic effects. While undue dizziness or faintness has been claimed to follow sublingual nitrate use in patients on the beta-blocker, metoprolol (93c), a potential advantage during exercise was shown recently for a propranolol+ glycerylnitrate combination (94c). Pulmonary capillary wedge pressures were lower on combination therapy and the authors concluded that the potential hazard of giving beta-blockers to patients with left ventricular dysfunction might be reduced by adding glycerylnitrate. CALCIUM ANTAGONISTS (SED-IO, 330;

SEDA-8, 179; SEDA-IO, 164)

Diltiazem Nifedipine Verapamil A recently published review of diltiazem's efficacy and safety (95 R) has emphasized that the compound is well tolerated, and overall patient acceptability of these drugs still seems better for verapamil and diltiazem than for nifedipine (9C). Some minor side effects such as cutaneous flush, headaches and palpitation due to nifedipine may however be improved by use of a slow-release formulation (97c). Cardiovascular While the propensity for verapamil and diltiazem to depress sinoatrial and atrioventricular nodalfunction is well recognized, nifedipine too can, on occasion, cause troublesome bradyarrhythmia. One example occurred in a 79-year-old woman who developed syncope, complete heart block and ventricular standstill during periods of increased vagal tone following sublingual nifedipine for hypertension (98cr). The authors stressed the importance, in that reaction, of elevated vagal tone associated with micturition and vomiting. In another patient, sinoatrial block was observed after a single oral dose of nifedipine (99c). No contributory factor was observed, although a parasympatheticomimetic action was postulated in view of a ready response to atropine. A recent report detailed 3 cases of 'cardiac decompensation' (cardiovascular collapse and

Chapter 19 J.R. Lawrence respiratory arrest) following use of verapamil in infants given the drug intravenously for supraventricular tachycardia (100c). In that cardiac failure was present at treatment, the reaction is perhaps not particularly surprising: the severity of cardiac decompensation observed certainly justifies the author's recommendation that DC cardioversion would have been the preferred treatment. Notwithstanding the occasional appearance of depressed sinoatrial or atrioventricular function (101 ~) following calcium antagonist use in hypertrophic cardiomyopathy (HOCM) a recent article has concluded that these drugs now represent the treatment of choice in this condition (102c). An unusual response to the use of intravenous verapamil for recurrent supraventricular tachycardia was the appearance of an atypical ventricular tachycardia which converted spontaneously to sinus rhythm (103c). Further examples of paradoxical myocardial ischemia (SEDA-8, 191) attributed to nifedipine have been described. Of 3 patients described by one group the recognized pattern of reversible symptoms within a short time of the initial nifedipine dose (104cr) was seen in only a single patient. In another, nifedipine appeared to worsen unstable angina which led to asystole, and in the third myocardial infarction was produced. Three more cases of myocardial infarction closely related in time to the first dose of nifedipine were described in another paper (105c). Given the unpredictability of the outcome in unstable angina, however, the exact relationship of nifedipine use to the subsequent appearance of myocardial infarction must remain uncertain. The results of a recent study are of interest in relation to the possible occurrence of a calcium antagonist withdrawal syndrome (SEDA-8, 191). Nifedipine withdrawal was studied in a double-blind randomized fashion in 81 patients before coronary artery bypass surgery: rest angina appeared in some subjects, but only those previously experiencing occasional rest angina, and there were no early untoward effects of drug withdrawal (106cr). In another interesting review of the calcium antagonists (107R), the author draws attention to the possibility of rebound coronary vasospasm following sudden diltiazem withdrawal. A rather worrying comment on the toxicity of calcium antagonists was the account of cardiovascular collapse following uncomplicated coronary artery bypass in patients receiving nifedipine preoperatively (108c). Three of

Antianginal and fl-adrenoceptor antagonists Chapter19 the 4 individuals responded to large doses of calcium chloride and adrenaline by infusion but the fourth died. Goiti, who documented these cases, recalled a report by Palatianos and co-workers to the American Heart Association in 1983 about 11 episodes of apparently unexplained cardiovascular collapse perioperatively out of 80 consecutive patients who had received preoperative nifedipine. Goiti also mentioned that 13 of 57 consultant surgeons performing coronary artery surgery expressed, in reply to a questionnaire, concern about possible morbidity related to calcium antagonist treatment preoperatively. Respiratory A brief account has appeared suggesting that nifedipine can cause marked deterioration of respiratory function in asthmatic patients (109c). On the other hand, another reviewer has concluded that published work substantiates a small, though variable, protective effect of calcium antagonists, particularly nifedipine, against bronchoconstriction provoked by exercise, cold air, allergen and methacholine challenge (IIOR). There is also further evidence for an effect of nifedipine on subjective measures of bronchospasm (11 lC), so objective assessment of airways function seems important when considering the overall acceptability of calcium antagonists in asthmatic patients. Nervous system While nifedipine, in particular, is regarded as a safe and effective drug in hypertensive emergencies (112 cr) neurological deficit has occasionally been reported following its use (SEDA-10, 331). Rapidly progressive hemiparesis, aphasia and confusion attributed to stroke in evolution and coincidental with a blood pressure fall from 230/136 to 167/100 mmHg appeared in 1 of 30 patients whose hypertensive crises were treated by means of sublingu~d nifedipine (113cr). Bertel and Connen (112c~) also refer to a further case of retinal ischemia (see SEDA-9, 181) attributed to its use. Considering the increased evidence for the efficacy of various calcium antagonists in migraine (114'), the potential for worsening of cerebral ischemia should perhaps also be borne in mind in that particular setting. Recently, myoclonic dystonia was described in a 70-year-old man treated with verapamil for supraventricular tachycardia (115c). That patient developed both myoclonic and dystonic movements after 10 months of maintenance verapamil therapy in a dose of 80 mg thrice daily: abnormal movements disappeared

169

within 3 weeks of substituting diltiazem for verapamil. The authors proposed a possible central action of verapamil, at the level of the basal ganglia, to explain this reaction and claimed that a cause-effect relationship with drug therapy was likely as idiopathic cases of the disorder rarely improve spontaneously. Miscellaneous Gingival hyperplasia ( SEDA-9, 181, SEDA-IO, 166), by now a well-recognized side-effect of nifedipine, has now also been reported in 2 patients receiving verapamil for angina pectoris (116c). In one of these patients the feature resolved on withdrawal of the drug. As in the nifedipine-associated cases, the reaction closely resembles that seen with phenytoin. Four more cases associated with nifedipine have been reported (117 c, 118c) and the Committee on Safety of Medicines in the UK has received 7 reports of gum hyperplasia with 3 reports of gingival bleeding or gingivitis following nifedipine use. The similarity to phenytoin-induced gingival hyperplasia extended to the microscopic appearance of the lesion in the experience of one group (117 c) who described increased numbers of fibroblasts containing strongly sulfated mucopolysaccharides. The other workers (118 c) noted an abundant inflammatory exudate rich in plasma cells and likened the reaction microscopically to that seen occasionally with cyclosporin A. Mild hepatitic reactions have been observed in association with use of these 3 calcium antagonists (SED-10, 331; SEDA-8, 192; SEDA-9, 181; SEDA-10, 166) and further cases showing mild biochemical evidence of hepatic dysfunction have been described during diltiazem (119c) and nifedipine (120cr) therapy. The elevation in liver enzyme concentrations was generally transient, although mild persistent abnormalities were seen in 3 of the patients (119 c) receiving diltiazem. Overall abnormal liver function associated with diltiazem has been reversible, as emphasized by a recent review article on the drug (95 R) which did, however, note 1 or 2 cases of extreme elevation in hepatic enzyme levels reported to the manufacturers. Of renal effects associated with these drugs the matter of increased urine flow (SEDA-9, 181) has again been raised by the observation, in 9 patients, of nocturia attributed to nifedipine which ceased or improved markedly on withdrawal of therapy (121c). Nifedipine has been previously reported to cause renal dysfunction (SEDA-10, 165) but a recent study showed significant improvement

170 in indices of renal function during its use for essential hypertension; in patients with 'renoparenchymal' hypertension, however, renal blood flow, glomerular filtration rate and urinary volume decreased in some patients (122c). In relation to these findings and previous suggestions of a protective effect on renal function mediated by calcium antagonists a retrospective study of patients who had cardiac surgery showed an apparently increased incidence of postoperative acute renal failure in patients who had received these drugs before surgery (123c). That observation is, of course, in no way controlled and patients requiring preoperative calcium antagonists may well have had more severe disease. A possible hematological complication increased bleeding time - was regarded as a possible side effect of diltiazem in 3 patients (124c). These were, respectively, 37- and 23year-old males with subarachnoid hemorrhage discovered to have prolonged bleeding times at preoperative hemorrhagic screening and a 38year-old woman with migraine, showing the same abnormality, who had been screened because of spontaneous bruising and heavy menses. In the men normal bleeding times were restored within 48 hours of diltiazem withdrawal; the clinical problem ceased in the young woman following cessation of drug therapy, but it was not recorded that the prolonged bleeding time did in fact return to normal. Other authors have noted no alteration in bleeding time, or other measures of coagulation, with diltiazem use (125c). Verapamil, but not nisoldipine, inhibited platelet aggregation in vivo and in vitro, an effect seen by the authors (126 c) as potentially beneficial. Agranulocytosis has previously been reported with nifedipine (127 c) and a case of leukopenia has apparently been reported to the manufacturers of diltiazem (95a). That was in a 60-year-old male whose white count fell to 1500 per cmm 3 weeks after the start of diltiazem but recovered on drug withdrawal, only to fall again when he was rechallenged with the drug. The patient also had scleroderma, active rheumatoid disease and pulmonary fibrosis. Apart from minor flushing and leg erythema associated with edema, skin reactions seem surprisingly rare with the calcium antagonists in common use. Recently a photosensitivity reaction was attributed to nifedipine in 2 patients, 60 and 65 years old, who were receiving 10 and 30 mg of the drug daily (128c). One of these patients had also been taking

Chapter 19 J.R. Lawrence diuretics, but rechallenge with these agents was without effect; nifedipine rechallenge was not attempted owing to the severity of the reaction. In another 80-year-old man a generalized bullous eruption was almost certainly attributable to nifedipine in that the rash reappeared when the patient later restarted the drug of his own accord (129c). Mild erythema multiforme and the more ominous Stevens-Johnson syndrome have apparently been reported to the drug manufacturers (95 t) as probable reactions to diltiazem; the most severe cases occurred within weeks of initiation of therapy and all patients recovered. In one recently reported trial of nifedipine, acne rosacea worsened in one patient while on the drug (130c). A 50-year-old man is reported (131 r who was being treated for hypertension and generalized vascular disease with a number of drugs. He was started on diltiazem 60 mg q.i.d, and, 4 days later, developed generalized swellings and, subsequently, a rash. He also became anorexic and complained of night sweats. On examination, he was febrile and had generalized rubbery lymphadenopathy, hepatosplenomegaly and an erythematous maculopapular rash over his trunk and arms. Clinical laboratory testing revealed an eosinophilia, a high ESR and, 1 week later, an elevation of hepatic transaminase levels in serum. Lymph node biopsy revealed a pleomorphic lymphoid infiltrate. Tests for possible infections and lymphomas were all negative. The syndrome settled when diltiazem was stopped and the patient was not rechallenged. This case was reported briefly in SEDA-10 (p. 166). There is a very brief report of a 73-year-old man (1320 treated with 270 mg daily. He presented with profound losses of both taste and smell which resolved despite continued medication with diltiazem. A small placebo-controlled study of diltiazem 160 mg b.d. is reported (1330. Symptoms which occurred in association with diltiazem therapy include dizziness, edema, constipation, dyspnea and dyspepsia. Diltiazem appears in breast milk in the same concentrations as in plasma (1340. The potential risk to the suckling infant is not yet known. An unreviewed report has appeared of unilateral gynecomastia in 3 men, whose ages ranged from 57 to 71 years, receiving nifedipine in daily doses of 10-80 mg (135c). This appeared gradually over 4-26 weeks of initiating therapy and some regression had occurred within 2 months of drug withdrawal in 1 subject.

Antianginal and fl-adrenoceptor antagonists Chapter 19 OTHER CALCIUM ANTAGONISTS Bepridil (SEDA-8, 193; SEDA-9, 182; SEDA-IO, 166) Elevated hepatic enzymes were noted previously as a reason for early crossover from bepridil in one double-blind study (136 c) and clinical details of another example of this reaction have been published recently (137c). The patient, a 54-year-old man with angina, had minimal elevation in transferase levels, suggesting mild alcoholic liver disease, before the start of bepridil treatment and developed marked elevation in both aspartate and alanine transferase levels within 3-4 days of the start of therapy. Rapid improvement followed cessation of bepridil and the authors noted briefly another similar case reported to the manufacturers.

Felodipine ( S E D A- 9, 196) This dihydropyridine derivative has a pharmacological spectrum perhaps more suited to use in hypertension and cardiac failure than angina. Flushing and headache were reported by all of 8 healthy subjects receiving the drug as part of a pharmacokinetic study (138c). Another side effect, related to vasodilatation and reminiscent of nitrate hypoxemia, was decreased arterial oxygen saturation in patients infused with felodipine for pulmonary hypertension secondary to chronic obstructive airways disease (139c). In a small single-blind study in hypertensive patients felodipine was given in 5 or 10 mg doses daily. After 5 mg, patients reported headaches and 1 reported palpitations. After 10 mg, severe headaches, 1 case of flushing and 1 paranoid reaction (thought to be related to treatment) were reported (140c).

Gailopamil This methoxy derivative of verapamil caused profound bradycardia after ingestion of a single 50 mg dose in a 75-year-old female patient who required intensive resuscitation including external cardiac pacing (141c).

Nimodipine Because of its predilective effects on cerebral vessels this drug, which has some potential for antianginal efficacy, has been assessed primarily in subarachnoid hemorrhage. Changes in heart rate with hypotension were noted in one

171

such study and the organic solvent of the parenteral formulation caused reversible increases in liver enzyme concentrations (142c). No interactions with a variety of coadministered drugs were noted in that study and another report of the drug's efficacy in migraine noted no change in 3-hour glucose tolerance tests with nimodipine use (143c).

Nisoidipine No important side effects have, to date, been ascribed to this newer dihydropyridine derivative. Although causing headache and flushing as often as nifedipine in one crossover study the incidence of ankle edema was less with nisoldipine (144c).

Nitrendipine Interest has mainly centered on the coronary and systemic vasodilator properties of this dihydropyridine derivative. The spectrum of minor side effects seen after use of the compound was clearly set out in a review of 85 clinical studies covering 967 patients (145R). Headache, flushing, ankle edema, dizziness and palpitations were commonly documented and could be easily explained in terms of the pharmacology of the compound.

Overdosage with calcium antagonists (SED-IO, 332; SEDA-9, 181; SEDA-IO, 167) Fatal verapamil intoxication has been described previously. One recently documented example occurred in a 21-year-old man who showed hypotension, severe metabolic acidosis, generalized convulsions and atrioventricular dissociation unresponsive to calcium gluconate, pressor amines, artificial ventilation and cardiac pacing (1466"). In another 60-year-old woman, who ingested 2.4 g verapamil in retard form, coma due to circulatory collapse was followed by death after 44 hours of intense resuscitative efforts: plasma verapamil levels rose progressively during this fatal illness (147c). Continued drug absorption in that case was considered due to small-intestine deposits of the drug, arising no doubt from the retard formulation, found at autopsy. It is of considerable interest, in relation to these fatal outcomes following verapamil intoxication, to record the apparent efficacy of 4-aminopyridine in reversing features of a modest accidental overdose of the drug by a patient on maintenance hemodialysis (148cr). The rationale for that treatment, supported by prior animal experimentation,

172 was the enhancement of transmembrane calcium flux and facilitation of synaptic transmission associated with the use of 4-aminopyridine, an antagonist of non-depolarizing neuromuscular blocking agents. Interactions of calcium antagonists (SED-IO, 332; SEDA-9, 181; SEDA-IO, 167) The increasing use of calcium antagonists in clinical practice has, inevitably, increased the potential for interaction with other drugs. Comprehensive review articles published recently have covered kinetic (149 x) and more general (150R) aspects of interactions involving this class of agent. While interactions between calcium antagonists and an increasing number of drug groups have been described, it must be emphasized that the greatest potential for serious mishap still arises from interactions of calcium antagonists, especially verapamil and related compounds, with [J-adrenoceptor blockers (150~). Numerous examples of such interactions have been detailed in past editions of this Annual and while the risk is considerably less with nifedipine, caution should be advised whenever these groups of drugs are used together. Certainly a drug like tiapamil, which closely resembles verapamil in its pharmacological profile, might be expected to carry a high risk of serious interaction with fl-adrenoceptor blockers (151c). On the other hand, intravenous use of a pharmacologically intermediate drug like diltiazem in patients treated chronically with propranolol was without deleterious hemodynamic effect; indeed, a relatively prolonged increase in cardiac index was noted (152c). Although the true clinical importance of interaction between cardiac glycosides and calcium antagonists is still unclear, there is an increasing amount of information on the subject (149x, 150R). As far as the combination of digoxin and verapamil is concerned, it seems clear that the end-result of the complex interaction (SEDA-8, 192) is an increase in plasma digoxin levels, so patients receiving the combination should be carefully monitored (150a). Nifedipine, on the other hand, has been variously reported to reduce, increase or not affect digoxin clearance (150R). One recent study of the effect of adding nifedipine (40 mg daily) to the digoxin therapy of 9 patients in atrial fibrillation (153 cr) revealed a modest 15% increase in plasma digoxin levels which was unaccompanied by any change in heart rate. Another study in volunteers revealed a

Chapter 19 J.R. Lawrence

similar slight but significant increase in plasma digoxin level of 15% which was independent of the nifedipine dose used (154c). In patients with chronic atrial fibrillation diltiazem caused an increase in steady-state digoxin concentration of from 36 to 50% (155c), whereas previous volunteer work suggested a lesser effect (150R). Increased steady-state digoxin levels of about 20% were noted in a more recent study in normal subjects (156r). Careful monitoring would seem justified, therefore, when digoxin and diltiazem are used in combination. In a review article, attention is also drawn to the potential for interactions between diltiazem and digoxin (inhibition of digoxin clearance) and quinidine (suppression of quinidine plasma levels) (107R). Less work has been done on interactions of other calcium antagonists with digoxin, but nitrendipine did lead to marked increase in digoxin plasma levels in some volunteers (157c) and mean serum digoxin levels were increased by more than 25% during bepridil treatment in another large volunteer study (158c). Finally a careful patient study has shown verapamil to increase steady-state plasma digitoxin levels by a mean of 35% and diltiazem by 21% whereas nifedipine co-therapy was without significant effect (159cr). It does seem, as far as pharmacokinetic interaction with cardiac glycosides is concerned, that verapamil-like substances and diltiazem produce more effect than dihydropyridine (nifedipine-like) compounds. A case of ventricular fibrillation which followed intravenous verapamil administration in a patient on digoxin was attributed to interaction (160c), though the ~echanism is unclear. Other rhythm disturbances attributed to drug interactions involving calcium antagonists were ventricular tachycardia precipitated by sodium iotalamate (Conray 420) injection during prenylamine treatment (161 c) and sinus arrest with hypotension during combined amiodarone + diltiazem therapy (162c). In addition to interaction with prenylamine leading to arrhythmia, contrast media especially ionic agents - have been associated with a significantly greater hypotensive effect in patients on nifedipine and diltiazem at the time of left ventriculography (163c). Anticonvulsant neurotoxicity has been observed as a result of pharmacokinetic interaction between carbamazepine and calcium antagonists (164c, 165c). Verapamil in a dose of 360 mg/d was administered to 6 patients with partial epilepsy stabilized on carbamazepine and resulted in a 46% rise in total carbamazep-

Antianginal and fl-adrenoceptor antagonists

Chapter 19

ine levels with resulting neurotoxicity (164c). Withdrawal of verapamil in another patient receiving both verapamil and carbamazepine resulted in a marked fall in anticonvulsant serum level and seizure breakthrough (164c). This same patient was later followed on carbamazepine + nifedipine and carbamazepine + diltiazem combinations: nifedipine did not upset steady-state carbamazepine levels, but they rose by 50% within 48 hours of starting diltiazem with resulting dizziness, nausea, ataxia and diplopia (165c). A fall in the level of the metabolite, carbamazepine 10,11-epoxide appeared to confirm the authors' suggestion that inhibition of carbamazepine metabolism was the cause of the interaction (164c). Animal experiments have suggested that myocardial contractility might be excessively depressed by the combination of calcium antagonists and volatile anesthetics (149 R, 150R, 166c), but the clinical importance of the interaction is unclear. Verapamil and diltiazem

173

(167c) increased the arrhythmogenic threshold in animal studies of halothane and catecholamines in combination and the protective effect of diltiazem was demonstrated in patients with atrial fibrillation preoperatively who had suffered tachyarrhythmias during anesthesia prior to diltiazem administration (167c). Calcium antagonists have no antitumor activity but have been found to potentiate the effects of cytotoxic agents such as Vinca alkaloids and anthracyclines in vitro and in vivo (150R, 168c). The clinical relevance of these potentially useful interactions is however unknown. An unusual example of apparent tachyphylaxis to the effects of verapamil, taken for suppression of supraventricular tachycardia, occurred in a 68-year-old man who required increased doses, and subsequently amiodarone, for arrhythmia control during treatment with intravenous gentamicin and carbenicillin (169c). The mechanism of that possible verapamilantibiotic interaction was not explored.

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Chapter 19 J.R. Lawrence thy induced by beta-blockade. Br. Med. J., 288, 237. 40. Waller PC, Ramsay LE (1985) Do//-blockers cause arthropathy? A case controlled study. Br. Med. J., 291, 1684. 41. Sills JM, Bosco L (1986) Arthralgia associated with beta-adrenergic blockade. J. Am. Med. Assoc., 255, 198. 42. Kohara N, Fujimori S, Nagura H et al (1986) Frequent painful muscle cramps and elevated serum CK induced by pindolol. Clin. Neurol., 26, 66. 43. Reid JL, Curzio J, Vincent J (1985) Bucindolol in essential hypertension. Int. J. Clin. Pharm. Res., 5, 293. 44. Teicher A, Rosenthal T, Kissin E et al (1981) Labetalol induced toxic myopathy. Br. Med. J., 282, 1824. 45. Basso A, Piantanelli L, Cognini G et al (1985) Acebutolol-induced decrease of mononuclear leucocyte//-adrenoreceptors in hypertension. Pharmacology, 31, 278. 46. Bardot-Tassin P, Levy V-G (1985) Propranolol et hrmorragies des cirrhoses. Gastroentirol. Clin. Biol., 9, 745. 47. Pagliaro L, Pasta L, D'Amico G et al (1986) A randomized clinical trial of propranolol for the prevention of initial bleeding, in cirrhosis with portal hypertension. N. Engl. J. Med., 314, 244. 48. Editorial (1985) //-Adrenergic blockers in cirrhosis. Lancet, 1, 1372. 49. Pun KK, Yeung CK, Chan MK (1985) Effects of nadolol and propranolol on renal function in hypertensive patients with moderately impaired renal function. Br. J. Clin. Pharmacol., 20, 401. 50. Castle WM (1985) Drugs and fibrotic reactions. I. Adverse Drug React. Bull., 113, 420. 51. Campbell JW (1985) A possible teratogenic effect of propranolol. N. Engl. J. Med., 313, 518. 52. Fox RE, Marx C (1985) Neonatal effects of maternal nadriol therapy. Am. J. Obstet. Gynecol., 152, 1045. 53. Edwards IR (1984) Medicine adverse reactions committee: eighteenth annual report 1983. N Z Med. J., 97, 729. 54. Gallery EDM, Ross MR, Gyory AZ 0985) Antihypertensive treatment in pregnancy: analysis of different responses to oxprenolol and methyldopa. Br. Med. J., 291, 563. 55. De Swiet M (1985) Antihypertensive drugs in pregnancy. Br. Med. J., 291, 365. 56. Von Oltmanns G, Schwela H, Kulich B e t al (1985) Akute fl-Blocker-Intoxikationen. Z. Ges. Inn. Med. Ihre Grenzgeb., 40, 546. 57. Baliga BG (1985) Beta-blocker poisoning: prolongation of Q-T interval and inversion of T-wave. J. Ind. Med. Assoc., 83, 165. 58. Langemeijer JJM (1986) Centrally induced respiratory arrest: main cause of death in fladrenoreceptor antagonist intoxication. Hum. Toxicol., 5, 65. 59. Leon MB, Rosing DR, Bonow RO et al (1985) Combination therapy with calcium-channel block-

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ers and beta-blockers for chronic stable angina pectoris. Am. J. Cardiol., 55, 69B. 60. Strauss WE, Parisi AF (1985) Superiority of combined diltiazem and propranolol therapy for angina pectoris. Circulation, 71, 951. 61. Henry M, Kay MM, Viccellio P (1985) Cardiogenie shock associated with calcium channel and beta blockers: reversal with intravenous calcium chloride. Am. J. Emergency Med., 3, 334. 62. McLean A, Knight R, Harrison PM et al (1985) Clearance-based oral drug interaction between verapamil and metoprolol and comparison with atenolol. Am. J. Cardiol., 55, 1628. 63. Kern MJ, Petrn MA, Ferry DR et al (1985) Regional coronary vasoconstriction after combined beta-adrenergie and calcium channel blockade in patients with coronary artery disease. J. Am. Coll. Cardiol., 5, 1438. 64. Tucker GT, Bax NDS, Lennard MS et al (1984) Effects of beta-adrenoreceptor antagonists on the pharmacokinetics of lignocaine. Br. J. Clin. Pharmacol., 17, 21S. 65. London SW, Glass DD (1985) Prevention of electroconvulsive therapy-induced dysrrhythmias with atropine and propranolol. Anaesthesiology, 62, 819. 66. Santoso B (1985) Impairment of isoniazid clearance by propranolol. Int. J. Clin. Pharmacol. Ther. Toxicol., 23, 134. 67. Conrad KA, Nyman DW (1980) Effects of metoprolol and propranolol on theophylline elimination. Clin. PharmacoL Ther., 28, 463. 68. Miners JO, Wing MH, LiUywhite KJ et al (1985) Selectivity and dose-dependency of the inhibitory effect of propranolol on theophylline metabolism in man. Br. J. Clin. Pharmacol., 20, 219. 69. Smith RL (1985) Polymorphic metabolism of the//-adrenoreeeptor blocking drugs and its clinical relevance. Eur. J. Clin. Pharmacol., 28, Suppl, 72. 70. Silas JH, McGourty JC, Lennard MS (1985) Polymorphic metabolism of metoprolol: clinical studies. Eur. J. Clin. Pharmacol., 28, Suppl, 85. 71. McGourty JC, Silas JH, Fleming JJ (1985) Pharmaeokinetics and beta-blocking effects of timolol in poor and extensive metabolizers of debrisoquin. Clin. Pharmacol. Ther., 38, 409. 72. Kanto JH (1985) Current status of labetalol, the first alpha- and beta-blocking agent. Int. J. Clin. PharmacoL Ther. Toxicol., 23, 617. 73. Waal-Manning H J, Simpson FO (1982) Review of long-term treatment with labetalol. Br. J. Clin. Pharmacol., 3, Suppl, 65S. 74. Quyyumi AA, Wright C, Mockus Let al (1985) Effects of combined alpha- and beta-adrenoreceptor blockade in patients with angina pectoris. Br. Heart J., 53, 47. 75. Beresford R, Heel RC (1986) Betaxolol: a review of its pharmacodynamic and pharmacokinetic properties and its therapeutic efficacy in hypertension. Drugs, 31, 6. 76. Kohii RS, Khurmi NS, Kardash MM et al (1985) Efficacy of once daily bisoprolol in stable

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angina pectoris: an objective comparison with atenolol and long-term follow-up. Eur. Heart J., 6, 845. 77. Kloner RA, Kirshenbaum J, Lange R et al (1985) Experimental and clinical observations on the efficacy of esmolol in myocardial ischaemia. Am. J. Cardiol., 56, 4OF. 78. Gray RJ, Bateman TM, Czer LSC et al (1985) Esmolol: a new ultrashort-acting beta-adrenergic blocking agent for rapid control of heart rate in post-operative supraventricular tachycardia. J. Am. Coll. Cardiol., 5, 1451. 79. Morganroth J, Horowitz LM, Anderson J e t al (1985) Comparative efficacy and tolerance of esmolol to propranolol for control of gupraventricular tachyarrhythmia. Am, J. Cardiol., 56, 33F. 80. The Esmolol vs Placebo Multicentre Study Group (1986) Comparison of the efficacy and safety of esmolol, a short-acting beta blocker with placebo in the treatment of supraventricular tachyarrhythmias. Am. Heart J., 111, 42. 81. Gray RJ, Bateman TM, Czer LSC et al (1985) Use of esmolol in hypertension after cardiac surgery. Am. J. Cardiol., 56, 49F. 82. Lowenthal DT, Porter S, Saris SD et al (1985) Clinical pharmacology, pharmacodynamics and interactions with esmolol. Am. J. Cardiol., 56, 14F. 83. Antonelli D, Barzilay J (1986) Complete atrioventricular block after sublingual isosorbide dinitrate. Int. J. Cardiol., 10, 71. 84. Lancaster L, Fenster PE (1983) Complete heart block after sublingual nitroglycerin. Chest, 84, 111. 85. Horn GA, Brent BN (1985) Coronary artery vasospasm during treatment with intravenous nitroglycerin. Catheter. Cardiovasc. Diagn., 11, 423. 86. Quigley PJ, Maurer BJ (1985) Ventrieular fibrillation during coronary angiography: association with potassium-containing glyceryl trinitrate. Am. J. Cardiol., 56, 191. 87. Berisso MZ, Cavallini A, Iannetti M (1984) Sudden death during continuous holter monitoring out of hospital after nitroglycerin consumption. Am. J. Cardiol, 54, 677. 88. Anonymous (1986) Transdermal glyceryl trinitrate patches (Transiderm-Nitro). Drug Ther. Bull., 24,5. 89. Parker JO, Vankoughnett KA, Farrell B (1985) Comparison of buccal nitroglycerin and oral isosorbide dinitrate for nitrate tolerance in stable angina pectoris. Am. J. Cardiol., 56, 724. 90. Lin S-G, Flaherty JT (1985) Crossover from intravenous to transdermal nitroglycerin therapy in unstable angina pectoris. Am. J. CardioL, 56, 742. 91. Fisher RG, Tyler M (1986) Severe contact dermatitis due to nitroglycerin patches. South. Med. J., 78, 1523. 92. Barletta MA, Eisen H (1985) Isosorbide dinitrate-disopyramide phosphate interaction. Drug Intell. Clin. Pharm., 19, 764. 93. Hyldstrup L, Mogensen NB, Nielsen PE (1983) Orthostatic response before and after nitroglycerin

176 in metoprolol- and verapamil-treated angina pectoris. Acta Med. Scand., 214, 131. 94. Haerem JW, Westheim A, Fonstelien E (1985) Acute hemodynamic effects of propranolol, glycerylnitrate and exercise in coronary patients with left ventricular dysfunction. Int. J. Cardiol., 9, 465. 95. Quigiey MA, White KL, McGraw BF (1985) Interpretation and application of world-wide safety data on diltiazem. Acta Pharmacol. Toxicol., 57, Suppl II, 61. 96. Conti CR, Pepine CJ, Feldman RL (1985) Calcium antagonists. Cardiology, 72, 297. 97. Svetoni M, Spargi J, Casini M (1985) Effeto antiipertensive di un preparato ad azione ritardata di nifedipina. Clin. Ter. Cardiovasc., 2, 143. 98. Zangerle KF, Wolford R (1985) Syncope and ' conduction disturbances following sublingual nifedipine for hypertension. Ann. Emergency Med., 14, 1005. 99. Villani GQ, Del Giudice S, Arruzzoli S (1985) Blocco seno-atriala dopo somministrazione orale di nifedipina. Minerva CardioangioL, 33, 557. 100. Epstein ML, Kid EA, Victorica BE (1985) Cardiac decompensation following verapamil therapy in infants with supraventricular tachycardia. Pediatrics, 75, 737. I01. Lorrell BH (1985) Use of calcium channel blockers in hypertrophic cardiomyopathy. Am. J. Med., 78, Suppl 2B, 43. 102. Hopf R, Rodrian S, Kaltenbach M (1986) Behandlung der hypertrophen Kardiomyopathie mit Kalziumantagonisten. Therapiewoche, 36, 1433. 103. Winters SL, Schweitzer P, Kupersmith J (1985) Verapamil induced polymorphous ventricular tachycardia. J. Am. Coll. Cardiol., 6, 257. 104. Benjamin Sia ST, Macdonald PS, Triester Bet al (1985) Aggravation of myocardial ischaemia by nifedipine. Med. J. Aust., 142, 48. 105. Siebert J, Skarzynski P (1984) Zawal miesnia serca po pierwszej dawce nifedypiny. Wiadomosei Lekar., 37, 669. 106. Gottlieb SO, Gerstenblith G (1985) Safety of acute calcium antagonist withdrawal: studies in patients with unstable angina withdrawn from nifedipine. Am. J. Cardiol., 55, 27E. 107. Piepho RW (1985) Individualization of calcium-entry-blocker dosage for systemic hypertension. Am. J. Cardiol., 56, 1054. 108. Goiti JJ (1985) Calcium channel blocking agents and the heart. Br. Med. J., 291, 1505. 109. Rotrekl P, Lupinek Z, Ohnutkova E et al (1985) Is nifedipine administration safe in asthmatic patients. Vnitrni Lekars., 31, 555. 110. Barnes PJ (1985) Clinical studies with calcium antagonists in asthma. Br. J. Clin. Pharmacol., 20, 289S. 111. Ozenne G, Moore ND, Leprevost A et al (1985) Nifedipine in chronic bronchial asthma: a randomized double-blind crossover trial against placebo. Eur. J. Respir. Dis., 67, 238. 112. Bertel O, Conen LD (1985) Treatment of

Chapter 19 J.R. Lawrence hypertensive emergencies with the calcium channel blocker nifedipine. Am. J. Med., 79. Suppl 4A, 31. 113. Ellrodt AG, Ault MJ, Riedinger MS et al (1985) Efficacy and safety of sublingual nifedipine in hypertensive emergencies. Am. J. Med., 79, Suppl 4A, 19. 114. Solomon GD (1985) Comparative efficacy of calcium antagonist drugs in the prophylaxis of migraine. Headache, 25, 368. 115. Hicks CB, Abraham K (1985) Verapamil and myoclonic dystonia. Ann. Intern. Med., 103, 154. 116. Cucchi G, Giustiniani S, Robustelli F (1985) Gengivite ipertrofica da verapamil. G. Ital. Cardiol., 15, 556. 117. Lucas RM, Howell LP, Wall BA (1985) Nifedipine-induced gingival hyperplasia: a histochemical and ultrastructural study. J. Periodontol., 56, 211. 118. Bencini PL, Crosti C, Sala F et al (1985) Gingival hyperplasia by nifedipine: report of a case. Acta Derm.-venereol. (Stockholm) 65, 362. 119. Schroeder JS, Beier-Scott L, Ginsburg R et al (1985) Efficacy of diltiazem for medically refractory stable angina: long-term follow-up. Clin. Cardiol., 8, 480. 120. Abramson M, Littlejohn GO (1985) Hepatic reactions to nifedipine. Med. J. Aust., 142, 47. 121. William G, Donaldson RM (1986) Nifedipine and nocturia. Lancet, 1, 738. 122. Yokoyama S, Moil N, Takayama S et al (1985) Renal effects of nifedipine, a calcium antagonist, administered as an antihypertensive drug. Jpn. J. Nephrol., 27, 107. 123. Hull RW, Hasbargen JA (1985) No clinical evidence for protective effects of calcium-channel blockers against acute renal failure. N. Engl. J. Med., 313, 1477. 124. Saunders FW, Shedden P (1986) Diltiazem: possible haematologic complications. Surg. Neurol., 25, 82. 125. Cremer KJ, Joyal M, Pieper JA et al (1984) Does dilttazem or dipyridamole alone or in combination alter haemostasis? Clin. Pharmacol. Ther., 35, 233. 126. Jones CR, Pasanisi F, Elliott HL et al (1985) Effects of verapamil and nisoldipine on human platelets: in vivo and in vitro studies. Br. J. Clin. PharmacoL, 20, 191. 127. Voth AJ, Turner RH (1983) Nifedipine and agranulocytosis. Ann. Intern. Med., 99, 882. 128. Wood TML (1986) Photosensitivity reaction associated with nifedipine. Br. Med. J., 292, 992. 129. Alcalay J, David M (1986) Generalised fixed drug eruption associated with nifedipine. Br. Med. J., 292, 450. 130. Corbin DOC, Wood DA, Macintyre CCA (1986) A randomized double blind cross-over trial of nifedipine in the treatment of primary Raynaud's phenomenon. Fur. Heart J., 7, 165. 131. Scolnick B, Brinberg D (1985) Diltiazem and generalized lymphadenopathy. Ann. Intern. Med., 102, 558.

Antianginal and fl-adrenoceptor antagonists

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132. Berman JL (1985) Dysosmia, dysgeusia, and diltiazem. Ann. Intern. Med., 102, 717. 133. Pool PE, Shirley C, Seagram BA et al (1985) Effects of diltiazem on serum lipids, exercise performance and blood pressure: randomised, double-blind placebo controlled evaluation for systemic hypertension. Am. J. Cardiol., 56, 864. 134. Okada M, Inoue H, Nakamura Y e t al (1985) Excretion of diltiazem in human milk. N. EngL J. Med., 312, 992. 135. Clyne CAC (1986) Unilateral gynaecomastia and nifedipine. Br. Med. J., 292, 380. 136. Hill JA, O'Brien JT, Alpert JS et al (1985) Effect of bepridil in patients with chronic stable angina: results of a multicenter trial. Circulation, 71, 98. 137. Sre A, Bellorini M, Bouvry M (1985) Hrpatique aiguE chez un homme prenant de brpridil (cardium). Gastroentbrol. Clin. BioL, 9, 948. 138. Edgar B, Reg~rdh CG, Johnsson G et al (1985) Felodipine kinetics in healthy men. Clin. Pharmacol. Ther., 38, 205. 139. Bratel T, Hodenstierna G, Nyquist O et al (1985) The effect of a new calcium antagonist, felodipine, on pulmonary hypertension and gas exchange in chronic obstructive lung disease. Eur. J. Respir. Dis., 67, 244. 140. Mace PJE, Stallard TJ, Littler WA (1985) Felodipine in hypertension. Eur. J. Clin. Pharmacol., 29, 383. 141. Janekovic V (1985) Lebensbedrohliche Bradykardie nach Gallopamil. Notfall Med., 11, 1091. 142. Koos WT, Perneczky A, ]kuer LM (1985) Nimodipine treatment of ischaemic neurological deficits due to cerebral vasospasm after subarachnoid haemorrhage. Neurochirurg, 28, Suppl 1, 70. 143. Moyer JS, Nance M, Walker M e t al (1985) Migraine and cluster headache treatment with calcium antagonists supports a vascular pathogenesis. Headache, 25, 358. 144. Rosendorff C, Goodman C (1985) Doubleblind double-dummy cross-over study of the efficacy and safety of nisoldipine (BAYR 5552) versus nifedipine. Curr. Ther. Res., 37, 912. 145. Stoepel K, Deck K, Corsing C (1984) Safety aspects of long-term nitrendipine therapy, J. Cardiovasc. Pharmacol., 6, Suppl 7, SI063. 146. Borkje B, Omvik P, Storstein L (1986) Fatal verapamil poisoning. Tidsskr. Norske Laegoforen., 106, 433. 147. Mayer U, Buhl N, Sachs H et al (1985) Trdliche Vergiftung mit Verapamil im Retardform. Dtsch. Med, Wochenschr., 110, 1293. 148. Ter Wee PM, Kremer Hovinga TK, Uges DRA et al (1985) 4-Aminopyridine and haemodialysis in the treatment of verapamil intoxication. Hum. Toxicol., 4, 327. 149. McAllister RG, Hamann SR, Blouin RA (1985) Pharmacokinetics of calcium-entry blockers. Am. J. Cardiol., 55, 30B. 150. Klieman RL, Stephenson SH (1985) Calcium

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178 thane anaesthesia in dogs and humans. Anesth. Analg., 64, 964.

168. Scheid W, Traut H (1985) Synergistic enhancement of the bleomycin and peplomycin induced mitotic index reduction by verapamil. Arzneim.- Forsch. , 35, 1717.

Chapter 19 J.R. Lawrence

169. Aderka D, Levy A, Pinkhas J (1986) Tachyphylaxis to verapamil. Arch. Intern. Med., 146, 207. 170. Stricker BHCh, Heijermans HSF, Braat H, Norg J (1986) Fever induced by labetalol. J. Am. Med. Assoc., 256, 619.