Anti-anginal and beta-adrenoceptor blocking drugs

M. N. G. Dukes

17b

anti-anginal and betaadrenoceptor blocking drugs

HOWSAFE ARE BETA-BLOCKERS? The question discussed in the second Side Effects of Drugs Annual as to the long-term safety of beta-adrenergic receptor drugs is far from being answered; indeed, the question has become increasingly complex. Whilst on the one hand there is still no reason to conclude that any of the newer beta-blockers so far marketed has produced the classic 'practolol syndrome', one must express alarm at the rate at which new products of this type, for which there is little need, continue to appear. Potentially, each one could produce complications at least as grave as those elicited by practolol, and the published material on many of these compounds is so sparse as to suggest that the clinicalevidence o f long-term safety available at the time o f marketing is minimal. The 'practolol syndrome' is not the only reason for concern. Rare but unpleasant conditions such as Peyronie's disease continue to emerge as complications o f beta-blockade; the effects of these drugs on triglyceride concentrations (particularly when used alongside the thiazides) could adversely affect the longterm prognosis of some heart patients; even animal studies - such as a recent paper b y Vaughan Williams e t al. showing that betablockade can impair the growth of the young heart (89) raise questions which the clinic at present simply cannot answer. Various of these points are dealt with in the Chapter which follows. Much o f the new literature is repetitive and need not be quoted at all. Where new phenomena are reported one is commonly in doubt as to whether these reflect the specific effects of a particular drug or newly identified problems involving this class of compounds as a whole. THE PRACTOLOL SYNDROME AND HYPERSENSITIVITY REACTIONS The 'practolol syndrome' has been amilyzed at length in earlier volumes in this series.

Newer reports provide a retrospective review o f the nature and incidence o f this complication (90 C, 91c). Of greater current interest is however the question as to whether theoculomucocutaneous syndrome observed with this one beta-blocking drug can in fact develop with others. Up to the present, the answer is negative. Particularly reassuring is the fact that whereas most of the patients with typical practolol reactions developed antinuclear antibodies,generallyprior t o t h e onset of clinical symptoms, other beta-blocking drugs have been found not to induce formation of such antibodies (92 C, 93c). Amos e t al. (94), using an in vitro model, have succeeded in demonstrating the formation of antibodies highly specific to a practolol metabolite. Finally, Mackie e t aL (95 c ) have shown that whereas various beta-blockers may have a pharmacological effect on the lachrymal glands, practolol is the only one to reduce tear lysozyme secretion drastically and to produce high titres of antibody to intracellular cement substance. 'Dry eyes' are occasionally described in patients using betablockers of various types, but a 'practolol'type change in the cornea and conjunctiva does not seem to have been described with any other drug. The same probably applies with respect to sclerosing peritonitis, subject to the reservation that this condition can also occur spontaneously (96r). A finding of this type has been described once with timolol (97c), but it was no more typical as regards its histology (98r), than was an earlier case of'sclerobing peritonitis' attributed to oxprenolol. Also reassuring is a study by Barclay e t al. (99 C) of 59 patients treated in the past with practolol, and directed to the identification of any late onset effects subsequent to withdrawal of the drug. No such effects were found. Despite this, not every detail of the practolol syndrome is yet known; recent papers

162 have documented deafness (100 C) and biliary cirrhosis (101 C) as manifestations of the condition, and new cases of a respiratory syndrome in patients earlier operated on for sclerosing peritonitis have been described (102c). EFFECTS ON THE CENTRAL NERVOUS SYSTEM Vivid dreams, nightmares, illusions and tiredness have all been reported on occasion with beta-blockers (SEDA-2/169-170) and a paper by Fleminger, who systematically interviewed patients taking these drugs to trace evidence of this type of complication, suggests that it may be quite c o m m o n ; 17.5% of a series of 64 patients recalled having experienced visual hallucinations, illusions or both, sometimes related to disorders of sleep (78c). Of greater concern is the acute brain syndrome again twice reported in recent months with propranolol. Topliss and Bond reported the first of these (79 C) in a 71-year-old woman treated as an in-patient and given up to 40 mg of propranotol every six hours. The complication was characterized by agitation and confusion, followed by rigidity with involuntary movements. The second case involved a 12-year-old girl in whom doses up to 15 mg every eight hours led to disorientation, agitation, perseveration and finally coma with hyperreflexia; the symptoms did not begin to resolve until the drug had been withdrawn for more than three days (80c). Headache or migraine can occur as an adverse reaction to propranolol, or may be relieved by it ; occasionally one finds a patient in whom successful treatment of migraine with a beta-blocker is followed by a rebound aggravation of symptoms when the drug is withdrawn (81 c, 82e). METABOLIC EFFECTS Effects of beta-blockers on carbohydrate metabolism have been reviewed earlier in this series. There is little to add, though the serious character of the hypoglyeaemic reaction which can occur in young children should be noted in the light of a recent report on six cases seen by Br6vi~re et al. in France (83c). Beta-blockers that are highly beta-specific and without membrane-stabilizing activity may well be safer than non-selective drugs in diabetic patients at risk from hypoglycaemia (84c). Hyperkalaemia can occur suddenly and par-

M. iV. G. Dukes adoxically during cardiopulmonary bypass in patients receiving beta-blockers (86Cr). It is k n o w n that beta-blockade can cause a more gradual increase in total body potassium and serum levels and the renal handling of potassium may be altered, but in the case of cardiopulmonary bypass now reported it would seem likely that the non-selective beta-blocker employed modified the adrenergic response induced by the bypass itself. Here too, it may be wiser to use a cardiospecific blocker. Effects on lipid metabolism have come under scrutiny particularly since the publication of an analysis by Helgeland et al. (87 C) of lipid concentrations in 145 Norwegian men receiving antihypertensive treatment over a long period of time. Thiazides, which were being given to all patients, have long been known to result in an increase in serum lipids; what emerged from this series was that whereas the effect on cholesterol over a three-year period was not significant, the triglyceride concentrations rose by some 33% provided propranolol was given concurrently. In the absence of propranolol, the effect of the thiazide on triglyceride levels was not of importance. Propranolol was also found to potentiate the thiazide-induced increase in urate levels. Shaw e t a l . in Australia (88c), found that when 17 patients were treated in random order with pindolol, atenolol and propranolol in single daily doses, each drug being given for four weeks, there was a clear rise in triglycerides; although the increase was greatest with atenolol (50% above placebo levels) all the drugs produced a similar effect, and a subsequent test with metoprolol showed the same pattern of activity. If, as these authors put it, plasma triglyceride levels remain elevated during long-term treatment of hypertension with these drugs, do the benefits outweigh the risks? WITHDRAWALEFFECTS Sudden withdrawal of beta-adrenergic blockers can lead to a rebound effect, with an aggravation of cardiac symptoms and in some cases myocardial infarction (SEDA2/167). Although this effect was very fully reviewed in the previous Annual, a number of new aspects have now come to the fore. The frequency of this event has been studied by Shiroff et al. in a retrospective study of 55 patients in whom propranolol was abruptly withdrawn in order to perform cardiac

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catheterization (65c). Under these special conditions rebound was rare, only one patient suffering a change in the pain pattern and one a myocardial infarct. On the other hand, these were hospitalized patients with reduced activity; older work shows that in out-patients the incidence o f rehound phenomena can be as high as 50%(65r). The mechanism of the rebound effect is not dear. Boudoulas et al. (66 r detected a hypersensitivity to isoproterenol 2 4 - 2 8 hr after withdrawal of propranolol, perhaps attributable to activation of adrenergic receptors during long-term blockade. However, Kristensen et al. (67 C, 68 CR) found that there was a clear increase in triiodothyronine levels in the serum after withdrawal of propranolol, and they have suggested that this change may at least in part be responsible for withdrawal symptoms. Other s y m p t o m s and signs can occur following sudden withdrawal of a beta-blocker, including tachycardia, sweating and tremor (68 r) and these indeed suggest the involvement of the thyroid. Frishman et al. (69 C) have also noted that rebound hyperaggregability of the platelets at this time can be associated with the increased frequency of angina and impaired exercise tolerance.

history in this case had been exceptionally unfavourable. However, when Stirrat and Lieberman (26 c R ) retrospectively analyzed cases of propranolol-treated hypertension in pregnancy they found that whilst 7 of 9 propranolol-treated pregnancies ended in foetal death, only 3 of 15 pregnancies where the hypertension was treated with other drugs resulted in the death o f the foetus. Analysis of the individual cases suggested that in those pregnancies where placental insufficiency is already a hazard, propranolol may reduce the chances o f foetal survival; the more favourable conclusions of some earlier workers probably reflect the fact that in their cases the placentae were functioning normally. A series of six cases described by Habib and McCarthy confirms earlier evidence that if propranolol is given within the last week before delivery even infants who are delivered satisfactorily and have a good Apgar score at birth can shortly after birth develop respiratory distress or hypoglycaemia; hyperbilirubinaemia and bradycardia were generally observed (27CR). Complementary to this is a report from Cottrill et aL showing that the neonate has some difficulty in disposing o f the propranolol which has passed the placenta (28); this is not surprising since propranolol is strongly bound to protein and is removed mainly by hepatic metabolism; in the neonate (and especially the prematureinfant) albumen levels are lower than in the adult and hepatic metabolism is less efficient. Habib's suggestion to withdraw propranolol, if at all possible, during the last week before delivery should be taken seriously, and in view of the other data presented above beta-blockers should not be regarded as innocuous in pregnancy. Propranolol has long been known to enter the breast milk; no resultant complications have been described, but in theory bradycardia and hypoglycaemia might occur.

EFFECTS IN PREGNANCY, LABOUR AND LACTATION Most of the literature concerning the effects of beta-blockers during pregnancy, labour, and lactation relates to the use of propranolol. Concern has centered primarily around the evidence, to be found in the earliest literature on beta-blockers, that they might stimulate uterine contractions and could also have a direct pharmacological effect on the foetus (25r). In the meantime, a substantial number of women have been treated with propranolol during pregnancy. The conclusions are variable, but they do point to the existence of some risk situations, and to the need for careful observation o f the neonate. Tcherdakoff et al. (25 C) have reported on nine cases of hypertension treated with propranolol during the whole of pregnancy or a large part thereof; they concluded that this series provided no evidence that the drug caused congenital malformations, abortion, premature labour or foetal or maternal distress; there was one case in which foetal distress led to an early caesarean section, followed by fatal hyaline membrane disease, but the prior obstetric

PEYRONIE'S DISEASE Peyronie's disease of the penis - characterized by fibrous plaques at the base of the shaft and pain and deformity on erection has now been observed several times in patients taking beta-adrenergic blockers. Two cases described by Osborne (59 c) and one reported by Wailis et al. (60 c) had been taking propranolol; the response to withdrawai o f the drug is not specified in their reports. However, a further case has been seen b y Yudkin (61 c) in which metoprolol

164 was involved, and here the symptoms disappeared after the patient had been transferred to methyldopa. Coupland (103 e) has described both a case of Peyronie's disease and one of Dupuytren's contracture apparently associated with propranolol; it may be that propranolol is in a small minority of cases capable of eliciting these and other conditions in which fibrosis plays a role, e.g. retroperitoneal fibrosis. EFFECTS ON PERIPHERAL C I R C U L A T I O N

Raynaud-like phenomena have been described in the past in patients taking betablockers of various types and they continue to be reported. There is evidence that alphaadrenergic sympathetic dominance may produce disturbances of the peripheral haemodynamics, probably by eliminating the capacity of the muscular vessel bed for beta 2-mediated vasodilatation. It is not clear, however, whether this can also affect percutaneous blood flow and hence skin temperature (62CR). Exceptionally, the peripheral effects can lead to gangrene, which has now been reported for the second time with metoprolol (63cr). SELF-POISONING WITH BETA-ADRENERGIC BLOCKING D RUGS (15 R) (SEDA-2/1711

Most ,marketed beta-blockers have on occasion been used in attempted suicide; the great majority o f the subjects involved have recovered, despite the rapid absorption of these drugs. The main features o f grosr overdosage are cardiovascular; one usually encounters bradycardia and hypotension, which may proceed to low-output cardiac failure and cardiogenic shock; in severe cases the myocardium becomes unreactive to pharmacological or electrical stimuli and death occursin asystole. The ECG tends to show bradycardia and disappearance of atrial activity; less commonly there is prolongation of the PR interval and auriculoventricular block or bundle branch block (18r). The cardiac symptoms are likely to be more serious in patients with pre-existing cardiac failure, in whom even mild overdosage can prove fatal. Secondary symptoms can include hypoglycaemia and respiratory difficulty (due to bronchospasm, central respiratory depression or cardiac failure). The patients are likely to be conscious unless there is severe hypoglycaemia.

M. N. G. Dukes

It is difficult to generalize about the doses likely to be tolerated, or to compare the various drugs in this respect, particularly since one first has to exclude from consideration the many reports of cases in which other drugs were taken at the same time. One must also bear in mind that some patients may already have been receiving very high therapeutic doses of the same betablocker; one can point in the literature to patients who have been taking as much as 600 mg oxprenolol, 4000 mg propranolol, 80 mg pindolol or 4000 mg sotalol under medical supervision. Patients have been described who recovered after taking with suicidal intent doses of 5100 mg propranolol, 9000 mg practolol, 500 mg pindolol and 10,000 mg metoprolol (18R); a recent report from Ireland describes a patient who took 1200 mg atenolol and developed virtually no complications (17c). On the other hand there are fatal cases in the literature involving oxprenolol (16 c , 18R), and one of these was known to have taken 4480 mg (18R). Since absorption is so rapid, gastric lavage (whilst diagnostically useful) is therapeutically of little use; haemodialysis may succeed in removing some drugs, but only those which are more soluble in water and less protein-bound than is propranolol. Drugs likely to be of use include atropine (e.g. 3 g) (20r), isoprenaline (or other catecholamines, especially noradrenaline) calcium, orglucagon ( 2 - 1 0 mg to activate myocardial adenylcyclase).

INDIVIDUAL BETA-ADRENERGIC BLOCKING DRUGS PROPRANOLOL (see also general section# The skin and mucosae may be affected in various ways by propranolol. Rash is uncommon but Van Ketel et al. (70 C) have described a major skin disorder closely resembling Lyell's syndrome which was traced to a Type IV allergic reaction to propranolol. Tangsrud and Golf (71) have reported from Sweden on a woman of 65 in whom dryness and ulceration of the lip accompanied by inflammatory leukoplakial changes in the buccal mucosae, were apparently induced by propranolol; the condition subsided when the drug was withdrawn but returned on challenge. Alopecia during propranolol therapy, improving when treat-

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ment was stopped, has been described in a 55-year-old woman treated by Scribner (72 e). Dystonic reactions, sometimes involving acute episodes of acute muscular contraction, have been reported on several occasions and are unlikely to be merely coincidental (73 c, 74 r, 75c). Pulmonary oedema has been described in two cases of phaeochromocytoma in which beta-blockade was induced with propranolol without concomitant alpha blockade. In both the sequence of events was suggestive of a causal relationship, and in one the ECG and enzyme evidence pointed to the presence of myocardial necrosis. It is possible that in these patients the lung oedema resulted from interruption of the beta-adrenergic drive to the heart associated with vasoconstriction mediated by unopposed alpha-adrenergic stimulation (76r Pulmonary oedema, associated with cardiac failure and followed by fatal cardiac arrest, has also been reported in a child treated with propranolol for tetanus in order to counter the sympathetic overactivity (77c).

PENBUTOLOL Penbutolol is a non-selective beta-blocker. Its side effects are closely similar to those o f propranolol and it should be used with caution in asthmatic patients (31 c, 32e), bronchospasm having been observed.

TIMOLOL The manufacturer's literature makes reference to very occasional reports of nonpsoriatic rash and pruritus and of a single case of exfoliative dermatitis. It is clear that such events may have been purely coincidental. At the time of writing, approval of timolol for release in the USA is delayed pending a further analysis of rat studies in which the females in the high dose group showed a significantly higher incidence of mammary fibroadenoma than did the controls. Is has been pointed out that even control series of rats sometimes exhibit such a high incidence of fibroadenomata. There is no clinical evidence that timolol is a tumorogen (29r), but since timolol has also been thought to induce liver tumours in mice (37r), further safety investigations are currently in progress. METOPROLOL As pointed out in SEDA-2 (p. 169) metoprolol is relatively cardioselective and can be cautiously used in asthmatic patients requiring a beta-blocker. The United States FDA recommends that in the latter situation the lowest possible dose of metoprolol be used and a beta-stimulant given at the same time (3or).

ATENOLOL Atenolol is relatively cardioselective. A review of 2600 patients who had taken the drug for periods ranging from one month to nearly four years suggests that its pattern o f adverse reactions is closely similar to that of other beta-blockers (33 R). L-BUNOLOL L-Bunolol is again a typical beta-blocker of a non-selective type (34c). ACEBUTOLOL Claims that acebutolol is cardioselective have been challenged in the German literature on the grounds that the clinical evidence for such a claim is meagre, that the drug has been shown to impair lung function and induce bronchospasm in asthmatic patients, and that it has a greater effect on the beta-2 receptors in the peripheral vessels than does practolol (35 R). Ashford et al. (36 C) have described a 60year-old woman in whom severe cutaneous vasculitis with arthralgia developed within two weeks o f starting treatment with acebutolol 100 rag/day. The condition regressed within three days but an accompanying splenomegaly persisted somewhat longer. Prick testing with acebutolol was positive in the patient but negative in controls. During animal studies it was subsequently found that intradermal injections of acebutolol in the rhesus monkey resulted in direct vascular damage. The patient did not react to rechallenge with acebutolol o r other beta-blockers, but this situation has been encountered earlier with other drugs known to cause allergic reactions, and there seems no reason to doubt the conclusion o f these investigators that in the woman concerned acebutolol had indeed caused a severe immunological reaction. NADOLOL Nadolol is non-cardioselective and is structurally very closely related to propranolol. Recommendations that the drug can be given once daily reflect the relatively long half-life. Absorption may not be con-

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M. N. G. Dukes

stant; work by Dreyfuss et al. (38 C) showed that of four patients given 2 mg of radioactively labelled nadolol three showed absorption percentages of between 24.3 and 40.9%, calculated on areas under the plasma concentration-versus-time curves, whereas the fourth showed absorption of 72.5%. It is not clear what these findings mean, particularly since the recommended clinical dose is 2 0 - 8 0 times higher than that employed in this experiment and the kinetics could be dose-dependent; this latter possibility is suggested by work with 10 mg tablets which Dreyfuss reports more briefly, and by statements elsewhere in the literature to the effect that the half-life of clinical doses approaches 24 hours (39Cr). Most of the work on nadolol is apparently unpublished, and until more evidence becomes available in print one can only speculate as to whether there may not be a considerable range of variation in the response (both desired and undesired) to this drug. OXPRENOLOL Of the various beta-blockers sometimes suspected of inducing a practolol syndrome, oxprenolol has received particular attention. There is no doubt that this compound does from time to time induce reactions involving the skin, eyes or serous membranes, but a true practolol reaction has never been observed, as pointed out above. Harrower and Strong have described a 62year-old woman who developed skin pigmentation resembling that of Addison's disease during treatment with the drug, which regressed when oxprenolol was withdrawn; there was no increase in ~irculating MSH or ACTH (40c). Levene and Gange have briefly reported on four cases developing rashes

with lichenoid changes and (in one patient) psoriasiform features (41cr); at least one similar case has been reported earlier. Young et al. have observed an elderly patient who during treatment with oxprenolol developed vomiting, weight loss, constipation and a (transient) upper abdominal mass; following death in renal failure an autopsy was performed and the findings included generalized ileus of the duodenum and jejunum; there was no peritonitis (42c). Dilatation of the small bowel has been observed/ earlier in patients receiving betablockers, including oxprenolol (42r), the mechanism of this complication being unknown. Thrombocytopenia during oxprenolol treatment has been reported four times to the British Committee on Safety of Medicines (43 r) and'one such case (following treatment with the drug in a long-acting form) has been published (43c). The condition recurred on rechallenge with oxprenolol and the patient was succesfully transferred to propranoloL LABETALOL Labetalol, as might be expected, produces adverse reactions reflecting both its betaand its alpha-receptor blocking activity, though the latter type of side effect (dizziness and postural hypertension) involves only a minority of patients. A general overview of the adverse reactions to labetalol at various (though low) dosage levels and after varying periods of treatment has been provided by the manufacturer (44 r) and is reproduced in Table I. Structural variants

Structurally, labetalol has two centres of

Table 1. Side effects of labetalol (percentages} Side effect

Lethargy Dizziness Headache Upper gastrointestinal tract symptoms (including nausea) Postural hypotension Depression Dyspnoea Tingling sensation in skin/scalp

Three months

Six months

~;400 mg 401-600mg (n=1061) (n=280)

<400 mg 401-600mg (n=317) (n=110)

3.9 4.5 1.9 2.6

5.0 3.2 5.7 2.1

2.5 2.5 1.6 1.3

3.6 3.6 2.7 0.9

0.7 0.7 1.4 1.0

1.4 0.7 1.4 1,1

0.6

2.7

0.9 0.3

2.7 1.8

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chirality, which means that four isomers exist. As currently manufactured, the drug appears to be a mixture of all four, in roughly equal quantities; the alpha- and beta-blocking properties seem to reside in different isomers. So long as the mode of synthesis remains constant and the drug is produced by only one manufacturer this is not likely to raise problems, but it is clear that with such a product one must be wary of a 'generic' product emanating from another supplier, since the isomers might under these circumstances he present in quite different proportions, resulting in a different pattern of effects and side effects.

fled that levels of free urinary catecholamines were considerably increased in some patients following oral labetalol and that the effect might persist for some ten days after withdrawal of the drug; in one patient this effect had led to a false diagnosis of phaeochromocytoma for which an operation was performed (52r). Whether labetalol actually does increase excretion of urinary catecholamines is in fact doubtful; work by Hamilton et al. (53 Cr) appears to have excluded such an effect in the ten patients whom they studied; they have suggested that a metabollte of labetalol may simply interfere with the fluorimetric and spectrophotometric determination of urinary catecholamines and metanephrines.

Metabolic considerations Labetalol is largely metabolized in the liver, and the bio-avaffability will increase in liver disease, though the plasma half-life is apparently not greatly changed. If overdosage is to be avoided, patients with chronic hepatic disease should receive lower doses of the compound than other patients (45Cr). Effects on blood pressure As is evident from Table 1, postural hypotension occurs in less than 3% of patients receiving up to 600 mg daily. However, the recommended daffy dose is up to 2400 rag, and at the higher dose levels postural hypertension is much more common (46 r, 47r). The actual incidence varies from series to series, apparently because certain individuals are extraordinarily sensitive to this effect. Louis et al. (48 c) noted postural hypertension in 20 of 57 cases given 200-2400 mg daily; in five of these the effect was sufficiently severe to warrant reduction in dosage. These workers found that postural hypotension was rather less common ff initial doses were kept to a minimum (a thiazide diuretic being added if needed) and the drug was given in three rather than two divided doses daffy. Two patients proved very liable to this particular adverse reaction when suddenly started on 200 mg doses, weakness and tachycardia setting in 15-180 minutes after the first tablet. Pressor responses to intravenous labetalol have been reported on several occasions (49 C, 50r) inter alia when an attempt was made to use this drug in the treatment of phaeochromocytoma (5 lr). Effect on urinary catecholamines Late in 1977 the manufacturer was noti-

Cutaneous and ocular effects Gange and Wilson-Jones (54 C) have reported on a case of bullous lichen planus with blister information that occurred during treatment with labetalol, resolved after withdrawal and recurred on rechallenge; a similarly well-documented lichenoid eruption has also been described by Savage et al. (55c). Unpleasant paraesthesiae or fornication, primarily affecting the scalp, have now been described several times in patients taking labetalol (56 r) and occurred in four out of eight healthy volunteers undergoing a doseresponse study in Sweden (57c). Perioral numbness and tingling has also been described, persisting until the patient was given alternative therapy (58 r ). There have been no reports of ocular effects with labetalol, and in studies where specific attention was paid to the eyes such effects were found to be absent (47r).

MISCELLANEOUS ANTI-ANGINAL DRUGS NIFEDIPINE(BAY A-1040, ADALAT) This verapamil-like calcium antagonist has earlier been reported to cause unpleasant subjective sensations and occasional oedema (SEDA-2/174-5). Bridgman has more recently reported briefly on two women in their early sixties who, after receiving 10 mg nffedipine three times daffy for a week, developed a well-marked erythema of both legs and ankles, which subsequently became oedematous and very painful. The causal association would seem clear, particularly since the condition receded within some

168

three days of withdrawing the drug, and recurred in the one patient who was later rechallenged. The complication was ascribed by Bridgman to the marked increase in peripheral blood flow which nffedipine induces (21cr). Ischaemic cardiac pain Nifedipine tends to increase the heart rate ( 2 2 0 and has earlier been reported to cause palpitations (23 c) in occasional subjects. Jariwalla and Anderson have reported three cases in whom administration o f 10 mg nifedipine was followed within 3 0 - 6 0 minutes by severe chest pain simulating a myocardial infarction or severe angina; the symptoms lasted for up to three hours and did not recur after withdrawal of the drug. In two o f the three cases the pulse rate was recorded and was not found to be increased (22c). A similar incident has also been recorded by Rodger and Stewart (24c), this one involving a man who was receiving 20 mg three times daily; the reaction occurred within 15 minutes and was accompanied by agitation and sweating, but there was no palpitation and no dyspnoea. Similar symptoms occurred following subsequent doses of nifedipine and ceased only when the drug was finally withdrawn. The published material is too sparse to provide an estimate of the incidence of this adverse reaction, but it appears to be a consequence o f an inherent effect of the drug on cardiovascular function and can (as in the case of Rodger and Stewart) occur in a patient who has already been taking the drug for some time. Tremor In one of the above cases (24 r a fine tremor developed within 30 minutes o f taking nifedipine and lasted for up to two hours; it occurred both at the 20 mg and 10 mg dose levels and involved particularly the upper limbs. PERHEXILINE In considering the adverse reactions to perhexiline it is very necessary to keep a sense of proportion. It is true that about 50% o f patients do exhibit adverse effects, but these are often limited to dizziness, unsteadiness or gastrointestinal symptoms. Neuropathies continue to be reported but they are almost always reversible. Severe

M. N. G. Dukes liver damage is less c o m m o n than the number of reports would suggest, some patients having been the subjects of more than one publication. Neurological The characteristics of this type o f complication were described in SEDA-2 (p. 173). The mechanism remains unclear. Both sensory and m o t o r nerves are involved; the CSF is usually abnormal, with a raised protein content but no hypercytosis. Histologically one finds demyelinization and Schwannian (or Wallerian) degeneration. The whole picture is that of a polyradiculoneuritis an unusual pattern for a drug reaction - and the fact that it tends to be associated with emaciation and a general deterioration of health suggests that one is faced here with a general metabolic disturbance which has particularly severe repercussions for the peripheral nerves (1 c R). Bousser et al. ( l r ) , citing a personal communication from Singlas, have pointed out that 14 o f a series of 20 cases were found to be 'slow metabolizers' o f drugs, whereas such individuals do not constitute more than about a fifth of the general population. It is quite possible that a latent effect on the nerves is much more common, and that this only becomes clinically manifest in slow inactivators of the drug. Sebille (2 c ) examined 35 patients taking perhexiline and found electrophysiological changes in the peripheral nerves in some two-thirds of them, irrespective of the dose or the duration of treatment, and despite the fact that none o f them exhibited clinical signs of neuropathy. Although clinical recovery from perhexiline neuropathy may be complete within 3 - 8 months, electrophysiological changes can persist much longer (3c). Hepatic Whilst functional and histological changes in the liver are now well recognized (SEDA2/173) and continue to be reported, severe jaundice has also been described ( 4 c ) , as has cirrhosis after two years of treatment (5c); in neither case were other aetiological factors in evidence. Hypoglycaema Hypoglycaemia is a known hazard of perhexiline; since the same complication can occur with beta-blockers, there may be particu-

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lar risks in using b o t h types o f treatment simultaneously. Bourmayan e t a l . (6 c ) have described a series of hypoglycaemic incidents in a man of 67 receiving both perhexiline and pindolol, a combination which has been incriminated before on this score (SEDA2/170). Although it has been suggested that hyperinsulinism m a y be involved in perhexiline hypoglycaemia, no hyperinsulinism was found in a case studied by Houdent etal. (7c), nor was there a liver disturbance o f the glycogenosis type.

sion bodies not only in nerve cells but also in the vascular (endothelial) wall (1 or).

Papilloedema Stephens e t a l . (8 c) have described three cases of papilloedema occurring during perhexiline treatment; in one of them, some impairment o f visual acuity persisted after the drug was withdrawn. Since all three patients presented initially with headache, it was concluded that raised intracranial pressure was involved, although no direct measurements were made. This conclusion has been challenged (gcr), particularly since older reports of perhexiline papilloedema in the literature, as well as one newer case, suggest that the condition may reflect a peripheral neuropathy and can occur when the intracranial pressure is normal (or only intermittently raised), but there seems little d o u b t that perhexiline does on occasion increase intracranlal pressure sufficiently to induce symptoms (10c). Thrombosis Poisson et al. (10 c) have reported on two patients with perhexiline neuropathy and central nervous involvement (including raised intracranial pressure) in whom carotid arteriography using methyiglucamine ioxitalamate was performed to exclude an organic disorder. Arteriography was followed b y thrombosis of the ophthalmic veins with severe symptoms. This is such an unusual complication that a predisposing role o f perhexiline has been postulated, particularly since the drug induces polymorphous inclu-

Mixed and paradoxical syndromes The metabolic, neurological and hepatic complications o f perhexiline therapy can occur together, and may be accompanied b y gastrointestinal symptoms, loss of weight and even frank wasting. The resulting picture may be complex (11 C) and the onset can be sudden and occur early in treatment, sometimes even during the first few days (12c). If the patient is not transferred to alternative therapy in good time, fatalities can result (13c). In a case described by Dawkins and O'Connor (14c), a 63-year-old man was diagnosed as having bronchial carcinoma with non-metastatic neurological complications; only following death from an overwhelming chest infection and the performance of an autopsy did it become apparent that no malignancy was present; the patient had apparently been suffering from a range of complications attributable to perhexiline, which he had been taking (together with oxprenolol) for some 12 months. EACH (ETHYL-ADENOSINE-5-.CARBOXYLATE HYDROCHLORIDE) E A C H is an adenosine analogue which was synthesized in the hope that it would possess the coronary vasodilator effects of the adenosine nucleotides but would also prove suitable (in view of its ability to resist hydrolysis) for oral administration. Irshad etal. (64 c) assessed the anti-anginalpotential of the drug in nine patients during exercise tests, employing doses of 9, 26 or 33 mg. No anti-anginal effect was demonstrated, but at the highest dose, employed in six subjects, one patient developed nausea and diffuse numbness and three others developed angina (in two cases after exercise had been completed). It is possible that EACH may have generated an undesirable redistribution of the coronary blood flow, hence inducing angina.

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