Many drugs have the potential to cause adverse effects on the cardiovascular system and the resulting problems are often serious or potentially life-threatening. This article reviews the most common, potentially serious drug-induced disorders
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Adverse reactions affecting the cardiovascular system are common: yellow card reports to the Committee on Safety of Medicines (CSM) involving cardiovascular disorders accounted for approximately 10 per cent of all reports received in 1997. There are some predictable, type A reactions, for example the undesirable cardiac effects of cardioactive drugs such as digoxin and antiarrhythmics, but many of these reactions are less predictable and they are not unique to cardiovascular drugs. For example, the cytotoxic agent doxorubicin can cause heart failure and appetite suppressants can cause heart valve disorders.
Pharmacists should be aware of the drugs most likely to have adverse effects on the cardiovascular system and the patient groups at greatest risk of these problems. Factors predisposing to cardiovascular toxicity include heart disease, uncorrected electrolyte abnormalities, and poor renal function. The potential contribution of over-the-counter medicines should also be considered.
ARRHYTHMIAS
There is increasing awareness of the problem of drug-induced cardiac arrhythmias. Terfenadine was returned to prescription only status in 1997 following reports of serious cardiac arrhythmias, and the CSM has recently warned about the risk of problems with cisapride and sertindole.
A cardiac arrhythmia is defined as any abnormal cardiac rhythm, whether the abnormality is one of rate, regularity or origin of the impulse initiating each heart beat.
Drug-induced arrhythmias may be an adverse effect of a non-cardiac drug, a pro-arrhythmic complication of an anti-arrhythmic drug, or may arise from a drug overdose. The associated mortality is unknown.
Predisposing factors include underlying rhythm disturbances (especially ventricular tachycardia or fibrillation), impaired left ventricular function, pre-existing heart disease, high plasma levels of antiarrhythmic drugs and electrolyte abnormalities, especially hypokalaemia and hypomagnesaemia.
Effects on the QT interval The QT interval on the electrocardiogram (ECG) is an indirect measure of the duration of the ventricular action potential and ventricular repolarisation. Prolongation of ventricular repolarisation can cause arrhythmias, the most characteristic of which is torsades de pointes (twisting of the points), a specific form of ventricular tachycardia. The name describes the characteristic “twisting” of the electrical axis on the ECG. While this is usually a self-limiting arrhythmia which causes dizziness or syncope, it may lead to ventricular fibrillation and sudden death. Causes include bradycardia, certain inherited disorders, biochemical disturbances such as hypokalaemia, and acquired heart disease. Some drugs that can prolong the QT interval are shown in Panel 1.
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PANEL 1: SOME DRUGS THAT MAY CAUSE QT INTERVAL PROLONGATION
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Ventricular repolarisation occurs by outward movement of potassium through specific channels in myocardial cell membranes. Drugs are thought to prolong repolarisation either by blocking potassium channels and thus delaying potassium outflow, or by enhancing inward sodium or calcium currents.
QT prolongation is usually assumed to be present when the QT interval corrected for changes in the heart rate (QTc) is greater than 440 milliseconds (ms), although arrhythmias are most often associated with values of 550ms or more.
Some patients with torsade de pointes may be asymptomatic while others experience dizziness, light-headedness, syncope, collapse, irregular heart beat and palpitations.
Drugs that prolong the QT interval should be stopped immediately in patients developing any of these symptoms and an ECG recorded. The arrhythmia should be controlled by increasing the heart rate, either by atrial pacing or by an isoprenaline infusion. Electrolyte abnormalities should be corrected and magnesium sulphate infusion may effectively terminate the arrhythmia, even in the presence of normal magnesium levels. Antiarrhythmic drugs may worsen the problem and should be avoided.
Antiarrhythmic agents All antiarrhythmic drugs may exacerbate pre-existing arrhythmias or cause new ones; they have been estimated to cause arrhythmias in 5 to 10 per cent of patients. The risks of antiarrhythmic therapy in patients with one or more predisposing factors may be deemed too high; however, the clinical decision involves balancing therapeutic benefits against the potential risks. Patients should be carefully selected and monitored and doses should not be escalated rapidly.
Amiodarone appears to be associated with a low frequency of arrhythmias (less than 3 per cent).
Antihistamines Torsade de pointes was first reported with terfenadine overdose in 1989 and subsequently after concomitant treatment with ketoconazole. Terfenadine is almost completely converted into an active metabolite by the liver. In patients with severe liver disease or those taking drugs inhibiting its metabolism, plasma levels of the parent drug can increase sufficiently to disturb ventricular repolarisation. Despite warnings about the seriousness of the reaction and the inclusion of precautions in product information, problems persisted, and the drug reverted to prescription-only status in 1997. Astemizole has also been shown to cause arrhythmias by the same mechanism. Predisposing factors include cardiac disease, liver dysfunction, electrolyte imbalance and overdose. Panel 2 lists some drugs which should not be taken concurrently with these agents.
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PANEL 2: SOME DRUGS THAT SHOULD NOT BE TAKEN WITH TERFENADINE OR ASTEMIZOLE
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Psychiatric drugs Phenothiazines and antidepressants have been associated with torsade de pointes and sudden cardiac death. Doses of 100mg or more of thioridazine have been reported to cause QT interval abnormalities.
The atypical antipsychotic sertindole has been associated with QT interval prolongation. Sertindole’s marketing was recently suspended in the UK pending an investigation of cases of sudden death which may have been drug-induced.
Tricyclic antidepressants slow cardiac conduction velocity and may increase cardiac mortality in patients with heart disease, such as the elderly. They should be avoided in patients with underlying cardiac disease.
Cisapride Cisapride is metabolised by the cytochrome P450 enzyme system CYP3A4. Inhibition of this enzyme by concomitant drug therapy can increase cisapride blood levels, leading to potentially fatal ventricular arrhythmias. Drugs known to increase cisapride blood levels include macrolides, azole antifungals and protease inhibitors. The CSM recommends that cisapride is not taken with preparations known to inhibit its metabolism and should be used with caution in patients taking other drugs known to prolong the QT interval or with conditions known to be associated with QT prolongation. In addition, a dose of 40mg cisapride daily should not be exceeded.
Patients should be warned not to take more than the recommended dose of any drug that can prolong the QT interval. As terfenadine was recently reclassified as a prescription-only medicine, some patients may have old supplies at home. Patients taking terfenadine or cisapride should be advised to avoid concomitant grapefruit juice. Any changes in symptoms which may indicate a drug-induced arrhythmia should be reported to their GP.
ATRIAL FRIBRILLATION
Atrial fibrillation is the most common important cardiac arrhythmia. It is characterised by irregular, disordered and unsynchronised electrical activity of the atria, resulting in an irregular ventricular response. Fatigue, angina, dyspnoea and palpitations are possible symptoms although the condition may be asymptomatic and only diagnosed by monitoring the pulse. Causes include thyrotoxicosis, ischaemic heart disease, hypertension, rheumatic heart disease and drug therapy.
Alcohol is a common cause, accounting for as many as two-thirds of cases of new-onset atrial fibrillation in patients under 65 years. Electrolyte disturbances, a direct effect on the myocardium and excess circulating catecholamines may be responsible.
Drugs are an infrequent cause of atrial fibrillation. Case reports implicate tricyclic antidepressants, trazodone and fluoxetine. Serotonin re-uptake inhibitors are relatively safe with respect to the cardiovascular system; however, serotonin is involved in conduction processes in the heart and caution is still required when prescribing these antidepressants to patients with concomitant heart disease. Atrial fibrillation has also been reported after the administration of repeated large intravenous pulses of corticosteroids for conditions such as rheumatoid arthritis or systemic lupus erythematosus.
Management depends on the type and cause of atrial fibrillation and may require hospital admission. If drug therapy is thought to be responsible the suspected drug should be stopped. If alcohol excess is suspected, lifestyle interventions will be required. Restoration of sinus rhythm may require electrical cardioversion or drug therapy. If sinus rhythm cannot be maintained, drugs that block atrio-ventricular (AV) node conduction, such as digoxin, verapamil or a beta-blocker may be used.
BRADYCARDIA
radycardia is a slowing of the heart rate to less than 60 beats per minute. It is usually asymptomatic unless the rate is very low. Dizziness, syncope and fatigue are possible features. Drug-induced bradycardia has been extensively reported in the literature (Panel 3). Mechanisms include effects on cardiac impulse generation and conduction. In some cases the underlying mechanism is not known.
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PANEL 3: SOME DRUGS THAT MAY CAUSE BRADYCARDIA
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Sinus bradycardia, where the rate of sinus node discharge is slowed, occurs with b-blockers due to the blockade of sympathetic stimulation of the b-receptors in the heart. Atrio-ventricular block occurs when impulses are delayed as they pass through the AV node into the ventricles and can be caused by verapamil, diltiazem, digoxin and also b-blockers. The interaction between b-blockers and verapamil/diltiazem is well recognised and can result in serious bradycardia. If used together, the patient must be carefully monitored. An interaction between topical ophthalmic b-blockers and verapamil has also been reported. Treatment depends on the heart rate and may require discontinuation of the causative drug. If the heart rate is less than 50 beats per minute and the patient is hypotensive, intravenous atropine is given. If this is unsuccessful, cardiac pacing may be required.
Prevention of drug-induced arrhythmias is multifactorial. Polypharmacy should be avoided where possible and consideration given to potential adverse effects before initiating drug therapy. Drugs with known adverse effects on the cardiovascular system should be used with caution in patients with pre-existing heart disease and in those taking drugs which may cause electrolyte abnormalities. Treatment of drug-induced arrhythmias involves stopping the causative agent and correcting any electrolyte imbalance. Hospital admission is generally required to allow for intensive ECG monitoring and drug therapy or pacing if needed.
Case StudyA local GP telephones to ask your advice about one of her patients, Mrs L, a 56-year-old woman with chronic urticaria who takes intermittent terfenadine, prescribed initially by a local dermatologist, to control her symptoms. The patient has recently become alarmed after reading in a health magazine that grapefruit juice can interact with terfenadine causing heart problems. The only other medication she takes is HRT. As part of a weight reducing diet, Mrs L has recently been drinking lots of fruit juice and eating fresh and tinned grapefruit. She now thinks she may have done some damage to her heart as she has experienced a feeling like palpitations a few times over the past couple of months. The GP is aware that the British National Formulary warns against drinking grapefruit juice while taking terfenadine, but is not quite sure of the risks involved and would like more information.
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CARDIAC FAILURE
Cardiac failure is a syndrome which occurs when the heart fails to pump sufficient amounts of blood to meet the metabolic demands of the body. Features of acute cardiac failure include dyspnoea, tachycardia, hypotension and confusion. These arise due to a combination of salt and water retention, increased venous pressure and inadequate organ perfusion. Chronic cardiac failure is characterised by dyspnoea, fatigue, ankle oedema, dizziness, palpitations, wheeze, chest discomfort and cough.
Drugs can induce or exacerbate cardiac failure. This can occur through an increase in preload (volume overload), an increase in afterload (resistance), or cardiac dysfunction. Drugs that cause circulatory overload will increase the preload; intravenous infusion of excessive fluid is the most frequent iatrogenic cause.
Drugs implicated include carbenoxolone, mineralocorticoid steroids such as fludrocortisone, and non-steroidal anti-inflammatory drugs (NSAIDs). Clinically detectable oedema can be seen in 3 to 5 per cent of patients treated with NSAIDs and this could exacerbate heart failure. Selective b2-adrenoceptor agonists used as tocolytics in the prevention of premature delivery may cause pulmonary oedema as a consequence of fluid overload. Prolonged treatment with high doses of ritodrine has been reported to cause cardiac failure.
Drugs with negative inotropic, cardiotoxic or arrhythmogenic effects may cause cardiac dysfunction. Drug-induced arrhythmias have already been discussed.
The role of b-blockers in cardiac failure has changed dramatically in recent years. Historically, the drugs have been contraindicated due to their negative inotropic action which weakens cardiac contractility provements in left ventricular function, suggesting that they may have a role in carefully selected patients.
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PANEL 4: SOME DRUGS THAT MAY CAUSE OR WORSEN CARDIAC FAILURE
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Other drugs reported to cause or worsen cardiac failure include intravenous amiodarone and other antiarrhythmic drugs. Some calcium channel blockers have negative inotropic effects; verapamil is the most cardiodepressant followed by diltiazem then nifedipine. The newer calcium antagonists have reduced cardiodepressant actions and may be used cautiously in patients with cardiac failure. Therapy should be withdrawn if symptoms appear.
If cardiac failure is believed to be drug-induced the agent responsible should be stopped. Management involves lifestyle modification and treatment with diuretics and ACE inhibitors. Over-the-counter medicines which should be discouraged in patients with heart failure include some antacids, effervescent preparations with a high sodium content, and NSAIDs. Panel 4 shows some drugs which may cause or worsen cardiac failure.
HYPERTENSION
Sympathomimetic drugs such as adrenaline, noradrenaline, dobutamine, dopamine and phenylephrine can all cause systemic hypertension.
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PANEL 5: SOME DRUGS THAT MAY CAUSE HYPERTENSION
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MYOCARDIAL TOXICITY
Some drugs may cause direct injury to the heart resulting in cardiomyopathy, contractile function abnormalities or conduction defects. Myocytolysis, in which the number of viable myocardial cells is reduced, can occur. Myocardial toxicity is difficult to diagnose and establishing causality can be difficult. Diagnosis may be based on histological identification of cellular changes; however, it is difficult to categorise injury into early, late, reversible or irreversible patterns.
The cardiotoxicity of anthracycline cytotoxic drugs has been recognised for more than 20 years. It can present acutely as arrhythmias or chronically as dose-related cardiomyopathy.
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PANEL 6: SOME CYTOTOXIC DRUGS THAT MAY CAUSE MYOCARDIAL TOXICITY
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Anthracycline-induced congestive heart failure is associated with a high reported incidence of morbidity and mortality. Many affected patients (about 60 per cent) recover, but their cardiac reserve is limited and they may require careful medical or surgical management during other illnesses or surgical procedures. Doxorubicin and daunorubicin cardiotoxicity is dose-dependent though somewhat unpredictable. The cumulative dose of doxorubicin should not exceed 450-550mg/m2 although the problem has been reported with lower doses despite serial monitoring of cardiac function. Severe doxorubicin toxicity is generally irreversible.
Predisposing factors to doxorubicin toxicity include mediastinal radiotherapy, female sex, the elderly or young, pre-existing heart disease and hypertension.
Cytotoxic drugs which may cause myocardial toxicity are shown in Panel 6.
Dose-dependent cardiotoxicity has been reported with interferon alfa in 5-15 per cent of patients within the first days of therapy. Severe but reversible cardiomyopathy has occurred in patients with no previous history of cardiac disease. Interferon should be used with extreme caution in patients with cardiac disease as further impairment in function may be critical.
MYOCARDIAL ISCHAEMIA
Ischaemia occurs when there is a mismatch in the cell between oxygen demand and supply. A metabolic disorder results in which anaerobic glycolysis produces lactic acid causing a lowered intracellular pH and impaired contractile function of the heart muscle. Angina is the pain resulting from myocardial ischaemia. It is typically described as choking or tightness and may radiate to the arms, back, neck or jaw. It is often confused with indigestion.
The mechanism of drug-induced myocardial ischaemia depends on the causative agent. Abrupt withdrawal of b-blockers may lead to unstable angina, myocardial infarction and sudden death. This is thought to be due to an increased myocardial oxygen consumption caused by an increase in heart rate subsequent to the removal of b-blockade. This effect is more commonly seen after short-acting b-blockers are stopped.
All calcium channel blockers cause vasodilation. Short-acting nifedipine can cause abrupt vasodilation and exacerbation of angina has been widely reported with these formulations. The mechanism involves reflex tachycardia precipitated by vasodilation, increasing myocardial oxygen consumption. There have been concerns voiced about the safety of short-acting nifedipine as an increased mortality rate has been reported in some studies. Patients prescribed short-acting nifedipine for hypertension should probably be switched to a long-acting preparation. Isolated reports of rebound angina after doses have been missed or therapy withdrawn have also been reported for verapamil and diltiazem.
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PANEL 7: SOME DRUGS THAT MAY CAUSE MYOCARDIAL ISCHAEMIA
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Myocardial ischaemia with the antimetabolite cytotoxic fluorouracil was first reported in 1969. Symptoms ranged from chest pain typical of mild angina to myocardial infarction. In 80 per cent of cases the symptoms were accompanied by ECG changes. Symptoms occured within a few hours of starting the infusion to up to 18 hours after its completion. The pain resolved within a few hours of stopping fluorouracil or was relieved by analgesics and/or nitrates. The mechanism is not known. It has been estimated that about 10 per cent of patients who receive fluorouracil will experience cardiac effects which appear to be more common with intravenous infusions than boluses. Predisposing factors include a history of coronary heart disease and radiotherapy. Prophylactic nitrates or calcium channel blockers have been ineffective.
Both thyroxine administration and hyperthyroidism have been reported to cause anginal pain. Sudden thyroid substitution in patients with hypothyroidism and cardiovascular disease may result in severe angina pectoris, myocardial infarction or sudden death. The initial dose should be low (25mg daily or 50mg on alternate days) and increased every four weeks to the required maintenance dose. There is no increase in mortality or morbidity in patients on long-term thyroxine replacement. Panel 7 shows some drugs which may cause myocardial ischaemia.
THROMBOEMBOLIC DISORDERS
Thromboembolic disorders result from the sudden occlusion (embolism) of a blood vessel by a blood clot (thrombus) in the arterial or venous circulation. Venous thromboembolism is common and is associated with a mortality of 1-2 per cent. Deep vein thrombosis (DVT) usually arises in the veins of the lower limbs or pelvis. Clinical features include pain involving the calf or thigh associated with swelling, redness and warmth. Management involves restoring normal circulation and anticoagulation. If part of a venous thrombus breaks off it can lodge in the pulmonary circulation, causing pulmonary embolism (PE). This can present with breathlessness, chest pain and collapse. In the arterial circulation, a thrombus may result in peripheral arterial occlusion, either in the lower limbs or in the cerebral circulation, where it may result in stroke.
Epidemiological studies have demonstrated that combined oral contraceptives (COCs) increase the risk of cardiovascular disease. Oral contraceptives have complex effects on blood pressure, platelet function, blood coagulation, carbohydrate metabolism and lipid metabolism. Since their introduction in the UK in the 1960s the presentations available and populations using them have changed dramatically. The first preparations contained at least 50mg of oestrogen and a progestogen. Preparations containing more than 50mg of oestrogen were withdrawn in the United Kingdom in 1984 due to the association with thromboembolic disorders.
The precise cardiovascular risk of oral contraceptives is poorly known because of a lack of reliable clinical studies and the numerous potential biases in epidemiological studies. Almost all epidemiological studies have shown an increased risk of DVT and/or PE in women on combined contraceptives although the risk remains moderate. In four recent European studies the risk of DVT was multiplied by 2.7 to 4.5 with oral contraception. The risk is higher in women with other risk factors such as smoking, obesity, a family history of DVT, and hereditary clotting disorders. Mortality due to pulmonary embolism was very low in these studies.
Newer progestogens which were believed to have a lower risk of cardiovascular disease were introduced. However, in October, 1995, the CSM warned of a potentially increased risk of thromboembolic disease in users of oral contraceptives containing the third generation progestogens desogestrel or gestodene. Epidemiological studies suggested that the risk of venous thrombosis with these progestogens was twice as high as with second generation contraceptives. The risk of non-fatal venous thromboembolism was estimated as 5 to 11 per 100,000 women per year in non-COC users, compared with 30 for preparations containing desogestrel or gestodene. It is currently recommended that women at high risk of venous thromboembolism should not be prescribed these preparations and that their use be restricted to women intolerant of other COCs who are prepared to accept the increased risk.
Recent studies have shown a two to four fold increase in risk of venous thromboembolism in hormone replacement therapy (HRT) users. The absolute risk in current HRT users is believed to be small (estimated at 16 to 23 excess cases per 100,000 women per year for all venous thromboembolism). The studies indicated that the risk of venous thromboembolism disappears after HRT is stopped. There appears not to be any clinically significant differences between the different types of HRT preparations available. The risk of venous thromboembolism is thought to be greater in women with predisposing factors including a history (personal or family) of DVT or PE, severe varicose veins, obesity, trauma, surgery or prolonged bed rest. The risks of therapy in these women may outweigh the benefits.
Oral contraceptives have been associated with both haemorrhagic and ischaemic stroke. Data from early studies relate to older COCs containing higher oestrogen doses than those now in use. Although the results of more recent studies have been conflicting, there is thought to be an up to two-fold increase in the risk of stroke in women taking COCs. The risk is higher in women with other risk factors, particularly hypertension, but also diabetes and a history of thromboembolic events.
There have been several reports of cerebrovascular events in patients taking bromocriptine for postpartum milk suppression. This may be due to vasospasm of cerebral blood vessels and may be associated with pre-existing hypertension and use in association with other ergot derivatives. Blood pressure should be carefully monitored in postpartum women taking bromocriptine, and particular care should be taken in women on antihypertensives.
VALVULAR DISORDERS
In 1988, cardiac murmurs suggestive of aortic valve disease were reported in a patient known to ingest excessive amounts of the serotonin antagonist ergotamine. Further reports described two patients who had taken ergotamine tartrate for migraine and who developed cardiac valve disease, requiring surgery for valve replacement.
More recently, valvular heart disease involving the mitral, aortic and/or tricuspid valves has been reported in association with appetite suppressants. Regurgitation and thickening of the valve leaflets was described in US patients who had been prescribed fenfluramine-phentermine in combination. The mitral valve was elongated, thickened, white and shiny and resembled the features of long-term ergotamine administration. The precise mechanism responsible for this type of cardiac injury has not been identified, although effects on serotonin are thought to be involved. Several studies have supported an association between anorectics and cardiac valve disease. Both fenfluramine and dexfenfluramine have been withdrawn in the UK.
ACKNOWLEDGMENTS We would like to thank Dr David Wallbridge (senior registrar in medical cardiology, Glasgow Royal Infirmary) for his helpful comments.
A fully referenced copy of this article is available on request. Please send an A4 stamped and addressed envelope to: The Pharmaceutical Journal, 1 Lambeth High Street, London SE1 7JN.
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FURTHER READING
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Miss MacLean is information pharmacist, and Mrs Lee is principal pharmacist, area drug information centre, Glasgow Royal Infirmary