Pharmacological Management Of Stable And Variant Angina
The aim of treatment of stable angina is twofold: to control symptoms and to halt the progression of underlying coronary heart disease. Anti-anginals control symptoms and work by restoring the balance between myocardial O2 demand and supply. Patients whose stable angina is refractory to pharmacological agents should be considered for revascularization with coronary artery angioplasty or bypass grafting. The treatment of variant angina is primarily directed at reversing coronary vasospasm.
First line treatment for stable angina consists of either a β- adrenergic receptor blocker (β-blocker), or a calcium-channel blocker (CCB) together with a short-acting nitrate. If the patient’s symptoms are inadequately controlled on one sole agent, and if comorbidities permit, a combination may be used. If in spite of optimal doses of both β-blocker and CCB, the patient still reports anginal pain, other drugs could be added such as ivadrabine, nicorandil, ranolazine and a long-acting nitrate. The initial choice between a β-blocker or a CCB is influenced by coexisting conditions and contraindications. For example, a CCB is preferable if the patient has moderate or severe asthma or hypertension, and a β-blocker may be the choice if rate control is also required (i.e. if atrial fibrillation is also present). If the patient cannot tolerate either of these agents, then monotherapy with a long-acting nitro- vasodilator should be commenced. Some patients need to take multiple classes of anti-anginal to control their symptoms.
β-Adrenergic receptor blockers
As Figure 41 illustrates, myocardial ischaemia creates a vicious cycle by activating the sympathetic nervous system and increasing ventricular end-diastolic pressure; both these effects then trigger ischaemia and anginal pain. β-Blockers help to block this cycle, thereby decreasing O2 demand.They reduce O2 demand by decreasing myocardial contractility and wall stress. The resting and exercising heart rate also falls. This increases the fraction of time the heart spends in diastole, thus enhancing perfusion of the coronary arteries, which occurs predominantly during diastole. The main therapeutic action of these drugs is on cardiac β1-receptors, but both β1-selective and (β1/β2) non-selective blockers are used.
Potential adverse effects of β-blockers include fatigue, reduced left ventricular function and severe bradycardia. Impotence may be a concern in men. β-Blockers can precipitate asthma by blocking β2-receptors in the airways, and therefore even β1-selective agents are contraindicated in this condition. Lipid-soluble β- blockers (e.g. propranolol) can enter the central nervous system and cause depression or nightmares. β-Blockers can also worsen insulin-induced hypoglycaemia in diabetics.
CCBs act by blocking the L-type voltage-gated Ca2+ channels that allow depolarization-mediated influx of Ca2+ into smooth muscle cells, and also cardiac myocytes (see Chapters 11, 13 and 35). As described in Chapter 35, dihydropyridine CCBs such as amlodipine, nifedipine and felodipine act selectively on vascular L-type Ca2+ channels, while the phenylalkylamine verapamil and the benzothiazepine diltiazem block these channels in both blood vessels and the heart.
CCBs prevent angina mainly by causing systemic arteriolar vasodilatation and decreasing afterload. They also prevent coronary vasospasm, making them particularly useful in variant angina. Their use is theoretically advantageous in variable threshold angina, in which coronary vasoconstriction contributes to reduced coronary artery perfusion (see Chapter 40). The negative inotropic and chronotropic effects of verapamil and diltiazem also contribute to their usefulness by reducing myocardial O2 demand. The vasodilatation caused by CCBs can cause hypotension, headache and peripheral oedema (mainly dihydropyridines). On the other hand, their cardiac effects can elicit excessive cardiodepression and atrioventricular (AV) node conduction block (mainly verapamil and diltiazem). CCBs are contraindicated in acute cardiac failure. Caution is required before prescribing CCBs and β-blockers together as the combination can cause dangerous bradycardia.
Nitrovasodilators include glyceryl trinitrate (GTN), isosorbide mononitrate, isosorbide dinitrate, erythrityl tetranitrate and pentaerythritol tetranitrate. Rapidly acting nitrovasodilators are used to terminate acute attacks of angina, while longer-acting preparations provide long-term reduction in angina symptoms.
Nitrovasodilators are metabolized to release nitric oxide (NO), thus acting as a ‘pharmacological endothelium’. The mechanisms of metabolism are unclear, although nitroglycerin is thought to be metabolized mainly by the enzyme mitochondrial aldehyde dehydrogenase. NO stimulates guanylate cyclase to elevate cGMP, thereby causing vasodilatation (see Chapter 24). At therapeutic doses, nitrovasodilators act primarily to dilate veins, thus reducing central venous pressure (preload) and as a consequent ventricular end-diastolic volume. This lowers myocardial contraction, wall stress and O2 demand. Some arterial dilatation also occurs, diminishing total peripheral resistance (afterload). This allows the left ventricle to maintain cardiac output with a smaller stroke volume, again decreasing O2 demand.
Nitrovasodilators can also increase the perfusion of ischaemic myocardium. They dilate larger coronary arteries (those >100 µm in diameter). These give rise to collateral vessels (see Chapter 3) which can bypass stenotic arteries. Collaterals increase in number and diameter in the presence of a significant stenosis, providing an alternative perfusion of ischaemic tissue which is then enhanced by the nitrovasodilators. Nitrovasodilators also relieve coronary vasospasm, and may diminish plaque-related platelet aggregation and thrombosis by elevating platelet cGMP.
GTN taken sublingually relieves angina within minutes; this route of administration avoids the extensive first-pass metabolism of these drugs associated with oral dosing. Nitrovasodilators can also be given in slowly absorbed oral, transdermal and buccal forms for sustained effect.
Continuous exposure to nitrovasodilators causes tolerance. This is caused in part by increased production within blood vessels of reactive oxygen species, which may inactivate NO and also interfere with nitrovasodilator bioconversion. Reflex activation of the renin–angiotensin–aldosterone system by nitrovasodilatorinduced vasodilatation may also contribute to tolerance. Tolerance is irrelevant with short-acting nitrovasodilators, but long-acting preparations become ineffective within hours. Tolerance can be minimized by ‘eccentric’ dosing schedules that allow blood concentrations to become low overnight. The most important adverse effect of nitrovasodilators is headache. Reflex tachycardia and orthostatic hypotension may also occur.
Drugs used less frequently for angina include nicorandil, a vasodilator that has nitrate-like effects and also opens potassium channels; ivabradine, which reduces cardiac ischaemia by inhibiting the cardiac pacemaker current If (see Chapter 11) and slowing the heart; and ranolazine, which protects against ischaemia by increasing glucose metabolism compared to that of fatty acids.
Management of variant angina
CCBs and nitrovasodilators are also used to treat variant angina, but β-blockers are not, as they may worsen coronary vasospasm by blocking the β2-mediated (vasodilating), but not α1-mediated (vasoconstricting) effects of sympathetic stimulation.
Drugs for secondary prevention of cardiovascular disease
The reduction of risk factors that contribute to the further progression of coronary artery disease is a key aim of angina management. Patients should be treated with 75 mg/day aspirin, which sup- presses platelet aggregation and greatly reduces the risk of myocardial infarction and death in patients with both stable and unstable angina. Patients should be offered a statin (e.g. 10 mg atorvastatin; see Chapter 36) to reduce their plasma LDL levels. The 2001 HOPE trial showed that the angiotensin-converting enzyme inhibitor (ACEI) ramipril reduced the progression of atherosclerosis and enhanced survival over a period of 5 years, in a group with coronary artery disease or diabetes, and ACEI are recommended for patients with stable angina who also have other conditions (e.g. hypertension or heart failure) for which these drugs are indicated.