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.
Other anti-anginals
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.
