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Drugs Used in Heart Disease

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VOL: 98, ISSUE: 18, PAGE NO: 43

ROMAN LANDOWSKI, BSc(Hons), MRPharmS, DipClinPharm, Senior Pharmacist, Medicines Information, UCL Hospitals, London;ROB SHULMAN, BScPharm(Hons), MPharmS, DipClinPharm, ICU Principal Pharmacist, UCL Hospitals, London;RHIAN DAVIES, BSc(Hons), MRPharmS, DipClinPharm, Cardiac Directorate Pharmacist, The Heart Hospital, London

Sponsored by Pfizer

Over the past 20 years there have been major advances in the development of drugs for the treatment of heart disease. By understanding how these drugs work it is easier to follow the rationale for their use and their associated side-effects. In Parts 1 and 2 of this three-part series, the pharmacology of the many classes of drugs used in heart disease is explained. In Part 3 the focus switches to the main heart diseases and how drugs are used in their management. The diseases covered include acute coronary syndromes, myocardial infarction, atrial fibrillation, stable angina and heart failure. The drugs described in Part 1 include beta-blockers, digoxin, amiodarone, loop diuretics and spironolactone.


Over the past 20 years there have been major advances in the development of drugs for the treatment of heart disease. By understanding how these drugs work it is easier to follow the rationale for their use and their associated side-effects. In Parts 1 and 2 of this three-part series, the pharmacology of the many classes of drugs used in heart disease is explained. In Part 3 the focus switches to the main heart diseases and how drugs are used in their management. The diseases covered include acute coronary syndromes, myocardial infarction, atrial fibrillation, stable angina and heart failure. The drugs described in Part 1 include beta-blockers, digoxin, amiodarone, loop diuretics and spironolactone.



Since their discovery in the 1960s, beta-blockers have found a wider range of uses in heart disease than any other therapeutic group. They are the most effective single agents for stable angina and several are also used in hypertension, arrhythmias, post-myocardial infarction and, most recently, in heart failure (Box 1.)



Mode of action



The mode of action of beta-blockers is to block the beta-adrenoreceptors in the sympathetic nervous system from stimulation by noradrenaline and adrenaline. Thus in thyrotoxicosis where tissues are sensitised to circulating adrenaline, propranolol is used to reduce the adrenaline-mediated symptoms of tachycardia, tremor and nervousness.



There are two types of beta-receptors: beta1 (B1) and beta2 (B2). Beta1 receptors are found in the myocardium and in the sinoatrial node and atrioventricular node (Fig 1). When the beta receptors are stimulated by adrenaline two effects occur:



1. There is an increase in myocardial contractility resulting in the heart beating more forcefully (a positive inotropic effect). A positive inotrope is a drug, for example dopamine, or a neurotransmitter, such as adrenaline, which increases myocardial contractility so increasing the amount of blood ejected from the heart with each beat.



2.There is an increase in the rate of depolarisation in the sinoatrial node and a decrease in the refractory period of the atrioventricular node, resulting in tachycardia (a positive chronotropic effect). A positive chronotrope can be a drug, for example, isoprenaline, or a neurotransmitter, such as adrenaline, which increases the rate of depolarisation of the sinoatrial node so leading to a faster heart rate (Fig 2).



Effects of beta-blockers on beta-receptors



By blocking b1 receptors in the myocardium, the administration of beta-blockers will result in a reduction in the force of cardiac output. Hall et al. (1995) showed that even low dose metoprolol (6.25mg bd) significantly reduced ejection fraction (the fraction of blood in the left ventricle which is ejected with each beat - in health it is in the region of 55-90%; in heart failure it is usually below 40%). Hall et al. (1995) found that the ejection fraction following administration of metoprolol did not recover to baseline levels until one month of therapy and did not improve significantly above baseline until after three months of therapy.



Cautions when using beta-blockers



Heart failure



Cardiac output can be reduced by 20% when beta-blockers are initiated, which may precipitate heart failure in those with pre-existing low output states. Thus beta-blockers should never be prescribed for patients in acute heart failure. In chronic heart failure the same may occur, but if doses are started low and adjusted upwards slowly, the acute reductions in cardiac output can be kept to a tolerable level.



Heart block and bradycardia



Beta-blockers, by blocking Beta1 receptors in the sinoatrial and atrioventricular nodes, normally reduce the pulse rate. While this may be beneficial in angina or tachyarrhythmias, it is a problem in patients who have pre-existing bradycardia or heart block. In these patients, the excessive slowing of pulse may result in dizziness and fatigue. It follows that beta-blockers should not be used in patients with heart block (unless a pacemaker is in situ) or if their pulse is much below 60 beats a minute (Fig 3).



Think Point: What investigations should be carried out before starting beta-blockers?



Asthma and peripheral vascular disease



Beta2 receptors are found in the smooth muscle of bronchi and in the blood vessels of the skeletal muscles. When stimulated by adrenaline these receptors initiate smooth muscle relaxation. Bronchodilatation and vasodilatation result, which aids the ‘fight or flight’ response with which adrenaline is associated. Nearly all current beta-blockers are potentially capable of blocking beta2 receptors, so causing bronchospasm and vasoconstriction. This makes them potentially harmful in patients with asthma or peripheral vascular disease.



Selectivity of beta-blockers



Beta-blockers vary in their selectivity for blocking beta2 receptors. Propranolol and carvedilol are non-selective, while atenolol and metoprolol are more selective for beta1 receptors and so are termed cardioselective. Nebivolol is the most cardioselective beta-blocker, followed by bisoprolol. The more cardioselective the beta-blocker, the less likely it is to precipitate asthma.



Unfortunately, even beta1 selective beta-blockers may still cause vasoconstriction. This is because circulating adrenaline will stimulate alpha-receptors in the vascular walls which promote vaso- constriction, while compensatory beta2-mediated vasodilatation is blocked. Beta-blockers such as labetalol and carvedilol, which also block alpha-receptors, are vasodilatory. Likewise, celiprolol and pindolol, which have agonist effects on beta2 receptors, are vasodilatory. Finally, nebivolol is vasodilatory by virtue of its additional nitrate-like effects (see Part 2).



Diabetes and beta-blockers
Diabetics utilise Beta2 receptors in the liver during hypoglycaemia. Then, under stimulation from adrenaline, they stimulate glucose production via glycogenolysis and gluconeogenesis. This process alleviates hypoglycaemia. If these beta2 receptors are blocked, a more profound hypoglycaemia may result.



Non-selective beta-blockers such as propranolol are potentially harmful in diabetics prone to hypoglycaemia. Cardioselective beta-blockers are less risky, and indeed atenolol was as safe as captopril (an ACE inhibitor) in the UKPDS 39 study (1998). All beta-blockers can mask the tremor, tachycardia and sweating that warn the diabetic of hypoglycaemia.



Think Point: What advice should patients with diabetes receive before starting beta-blockers?



Effects of long-term therapy with beta-blockers
During long-term therapy with beta-blockers, beta-adrenoreceptor upregulation occurs; that is, the number of beta-receptors present in tissue increases. While beta-blockers are still in the system, no effect is seen. However, if beta-blockers are suddenly stopped, the tissues experience enhanced adrenergic stimulation from even normal amounts of circulating adrenaline. This may result in myocardial ischaemia, angina and even myocardial infarct. The dosage of beta-blockers should therefore always be tapered down before being stopped.



Digoxin and amiodarone
Digoxin and amiodarone are the main drugs used to treat atrial fibrillation (Box 2).






Digoxin was first used over 200 years ago in the treatment of ‘dropsy’ (heart failure). It has two effects on the heart:



1. It increases inflow of calcium into the myocytes (muscle cells) of the myocardium, resulting in increased contractility (positive inotropic effect).



2. It stimulates cholinergic receptors to reduce firing from the sinoatrial node and to prolong the refractory period in the atrioventricular node which slows down heart rate (negative chronotropic effect).



By virtue of digoxin’s modest positive inotropic effect it can help relieve symptoms of heart failure. It is the only positive inotrope that is available orally; others were withdrawn owing to negative effects on mortality. The DIG study (1997) showed that digoxin had a neutral effect on mortality but reduced morbidity and hospital admissions for patients with heart failure.






Increased intracellular calcium can cause arrhythmias. Digoxin increases calcium in the myocytes as a result of its inhibiting the sodium-potassium pump on the cell membrane. Digoxin competes with potassium for space on this pump. If potassium levels are low, the effects of digoxin on this pump are potentiated. Digoxin toxicity resulting in arrhythmias is thus more likely if the patient is hypokalaemic.



By slowing conduction through the atrioventricular node, digoxin can lead to heart block and worsen pre-existing heart block (see Fig 3). This is more likely if digoxin is combined with other drugs that slow conduction through the atrioventricular node. Nevertheless, drugs such as verapamil (a calcium channel blocker) or beta-blockers may be combined with digoxin in order to achieve a more effective slowing of impulses to the ventricles in fast atrial fibrillation.



Digoxin toxicity



About 70% of digoxin is eliminated from the body by the kidneys and levels do rise in renal failure. This may lead to signs of digoxin toxicity such as nausea, colour vision disturbances (seeing green haloes around lights) and arrhythmias. Digoxin levels can also be increased by drugs such as quinine, carbamazepine and amiodarone. Diuretics that reduce potassium levels may cause digoxin toxicity even if digoxin levels are not excessive. In life-threatening digoxin toxicity, infusion of digoxin antibodies (Digibind) will rapidly inactivate circulating digoxin.



Think Point: Find out the normal therapeutic values for digoxin.






Amiodarone is an antiarrhythmic, which is widely used owing to its efficacy and safety record. Since the CAST study in 1989, it has been acknowledged that antiarrhythmic drugs are potentially arrhythmo-genic and can actually worsen mortality. However, amiodarone was shown to reduce arrhythmic mortality in the large CAMIAT (1997) and EMIAT (1997) studies when given post-myocardial infarction.



Mode of action



Amiodarone works on all conducting tissue in the heart and affects all phases of the action potential. It is particularly associated with inhibiting the outflow potassium channels and hence prolongs polarisation and therefore the refractoriness of conducting tissue. It is generally accepted as being the most effective antiarrhythmic.



Amiodarone has a very long half life. Unless a loading dose is given, it may take 10 days to have an effect. Intravenous amiodarone may work within 24 hours owing to a more pronounced beta-blocking effect.






Most antiarrhythmic drugs have negative inotropic effects but this is not so with oral amiodarone and it may be used safely in heart failure. It does, however, have several serious side-effects that necessitate monitoring. Pulmonary fibrosis is reversible if stopped early but is fatal in 10% of those who develop the condition. It affects 17% of patients on daily doses of 400mg but only 2% of those on 200mg a day. Chest X-rays and measurement of transfer factor are recommended at the first sign of pulmonary toxicity.



Amiodarone inhibits the conversion of thyroid hormone T4 to the more active T3, and hypothyroidism is found in 6% of cases. There is a large amount of iodine in amiodarone, and hyperthyroidism is also found in about 1% of cases. Thyroid-stimulating hormone levels should be checked every six months. Reversible blue/grey skin discoloration and photosensitivity are potential long-term problems with amiodarone.



Think Point: What advice would you give a patient taking amiodarone about exposure to sunlight?



Diuretics (Box 4)



Furosemide [frusemide] and bumetanide are loop diuretics used in the treatment of heart failure. They act on the loop of Henle in the nephron to prevent the reabsorption of sodium and chloride ions back into the blood. These ions pull water with them so that there is an increase in excretion of water and sodium and chloride ions from the body. Potassium and magnesium are also lost.



Loop diuretics are potent and short lasting. Typically, diuresis will start within one hour and be complete by six hours after oral dosing. Loop diuretics work from within the renal tubule and higher doses are needed in renal failure. Hypokalaemia and hypomagnesaemia are potential side-effects which may predispose the patient to atrial fibrillation and other tachyarrhythmias. For this reason loop diuretics are often co-prescribed with potassium-sparing diuretics such as amiloride. The effects of loop diuretics on fluid and electrolytes may be potentiated by comb-ining them with thiazide diuretics such as meto-lazone. Normal values for electrolytes are shown in Box 3.



By increasing urine output, loop diuretics can help clear oedema. They also cause the release of atrial natriuretic peptide, which is vasodilatory. It is vasodilatation in the pulmonary veins that relieves pulmonary oedema in heart failure. This relief may be obtained just 10 minutes after injection of furosemide, which is before any diuresis can occur.






High concentrations of furosemide in the otic fluid can damage the cilia there and cause high frequency hearing loss. When furosemide is injected intravenously, the rate should be no faster than 4mg/min. (that is, 20mg over five minutes) in order to avoid ototoxicity. Loop diuretics can also cause hyperglycaemia and gout.



Think Point: What is the recommended method of diluting and administering furosemide in your clinical area?






Spironolactone is an aldosterone antagonist. Since aldosterone is the sodium-retaining hormone, the effect of spironolactone is to retain potassium from the urine in exchange for sodium from the blood. Spironolactone does this by inhibiting the sodium - potassium pump in the distal tubule of the nephron. Thus potassium retention is a feature of spironolactone. The diuretic effect of spironolactone is slow to start and is unlikely to be noticed at the low doses used in heart failure.



Aldosterone is thought to be involved in myocardial fibrosis and it is by inhibiting this effect that spironolactone is thought to improve mortality in heart failure. Spironolactone also inhibits the vasoconstricting effect of aldosterone at doses that are lower than those required to cause diuresis.






Spironolactone has an anti-androgen effect and caused gynaecomastia (breast enlargement) in 10% of men receiving low dose spironolactone (12.5mg - 50mg od) in the RALES trial (1999). Impotence is also a possible side-effect.

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