Unstable angina

Unstable angina occurs if there is incomplete occlusion of the coronary artery following plaque rupture, but with critical reduction in blood flow so that oxygen supply is inadequate at rest or on minimal stress. Angina may then occur at rest or with very little exertion. Unstable angina is distinguished pathologically from other acute coronary syndromes because perfusion of the ischaemic tissue remains sufficient to prevent necrosis of myocytes. Unlike myocardial infarction, symptoms of unstable angina are usually relieved by glyceryl trinitrate (see below), or resolve spontaneously within 30 min.

Following an episode of unstable angina the thrombus may become incorporated into the plaque so that after healing the plaque is substantially larger, leading to greater long-term luminal narrowing.

Myocardial infarction and sudden cardiac death

Myocardial infarction most commonly arises from complete coronary artery occlusion following disruption of an unstable atheromatous plaque. Occlusion often occurs at the site of an atheromatous lesion that previously was only producing minor or moderate stenosis of the artery and may not have caused symptoms prior to disruption. Muscle necrosis begins when the occlusion lasts for longer than 20–30 min.

Myocardial infarction is usually associated with intense, prolonged chest pain and sympathetic nervous stimulation which increases cardiac work. However, about 15% of infarctions do not present with pain, and may go unrecognised (silent infarction). The diagnosis of acute myocardial infarction requires a rise in the plasma concentrations of sensitive biochemical markers, such as cardiac-specific myoglobin or troponin, which are released from necrotic myocytes. Cell death begins in the subendocardial muscle which is furthest from the epicardial blood supply (the endocardium receives its oxygen from the ventricular cavity), and, unless perfusion is restored, it progressively extends across the full thickness of the myocardium (transmurally) over the next few hours. Activation of endogenous fibrinolysis (Ch. 11) and the presence of a good collateral circulation are factors that favour reperfusion of the ischaemic area and naturally limit the size of the infarct. If very early reperfusion occurs the damage is usually confined to the subendocardial myocardium.

A full-thickness (or transmural) myocardial infarction often produces characteristic changes on the electrocardiograph (ECG), with early ST-segment elevation and eventually pathological Q waves. The resulting infarction is referred to as an ST-elevation myocardial infarction (STEMI). A subendocardial infarction often presents without diagnostic ECG changes. In these cases the ECG may show ST-segment depression or T-wave inversion (consistent with myocardial ischaemia), or even be normal. The resulting infarction is classified as a non-ST-elevation myocardial infarction (NSTEMI), because of the absence of the characteristic ST-segment changes usually found with more extensive myocardial damage.

Myocardial infarction principally affects left ventricular muscle, and the amount of muscle lost correlates well with both early and late survival. Infarction of the anterior muscle of the left ventricle (usually resulting from an occlusion in the left coronary artery system) causes greater myocardial loss than does inferior infarction of the ventricle (usually from right coronary artery occlusion). The amount of muscle loss also determines the extent of left ventricular remodelling (a geometrical change in the left ventricle that begins with healing of the infarct), which determines the risk of subsequent heart failure.

Sudden cardiac death results when fatal ventricular arrhythmias arise from ischaemic tissue, or from ventricular rupture.

Mechanism of action and effects

The organic nitrates are vasodilators that relax vascular smooth muscle by mimicking the effects of endogenous nitric oxide (NO). Enzymatic degradation of the nitrate releases NO, which combines with thiol groups in vascular endothelium to form nitrosothiols. Nitrosothiols activate guanylyl cyclase, which generates the second messenger cyclic guanosine monophosphate (cGMP; Fig. 5.3). cGMP activates protein kinase G, which reduces the availability of intracellular Ca²⁺ to the contractile mechanism of vascular smooth muscle, causing relaxation and vasodilation. Vasodilation is produced in three main vascular beds.

 Venous capacitance vessels, leading to peripheral pooling of blood and reduced venous return to the heart. This lowers left ventricular filling pressure (preload), decreases ventricular wall tension and therefore reduces myocardial oxygen demand. Venous dilation is produced at moderate plasma nitrate concentrations, and tolerance to this action occurs rapidly during continued treatment.

 Arterial resistance vessels, leading to reduced resistance to left ventricular emptying (afterload). This lowers blood pressure, decreases cardiac work and contributes to a reduced myocardial oxygen demand. Arterial dilation occurs at higher plasma nitrate concentrations than venodilation, but tolerance arises less readily during long-term treatment.

 Coronary arteries. Nitrates have little effect on total coronary blood flow in angina; indeed, flow may be reduced because of a decrease in perfusion pressure. However, blood flow through collateral vessels may be improved, and nitrates also relieve coronary artery vasospasm. The net effect is increased blood supply to ischaemic areas of the myocardium. Coronary artery dilation occurs at low plasma nitrate concentrations, and tolerance is slow to develop.

Pharmacokinetics

Glyceryl trinitrate (GTN) is the most widely used organic nitrate. It is well absorbed from the gut but undergoes extensive first-pass metabolism in the liver to inactive metabolites. To increase its bioavailability, GTN is given by one of four routes that avoid first-pass metabolism.

 Sublingual: the tablet is placed under the tongue and is absorbed rapidly across the buccal mucosa. The very short half-life of GTN (less than 5 min) limits the duration of action to approximately 30 min. Tablets lose their potency with prolonged storage, and a metered-dose aerosol spray is a more stable delivery method.

 Buccal: a tablet containing GTN in an inert polymer matrix is held between the upper lip and gum, which permits slow release of drug to prolong the duration of action.

 Transdermal: GTN is absorbed well through the skin and can be delivered from an adhesive patch via a rate-limiting membrane or matrix. Steady release of the drug maintains a stable blood concentration for at least 24 h after application of the patch.

 Intravenous: the short duration of action of GTN is an advantage for intravenous dose titration.

Isosorbide 5-mononitrate is well absorbed from the gut and does not undergo first-pass metabolism. It has a half-life of 3–7 h so modified-release formulations are often used to prolong the duration of action.

Unwanted effects

 Venodilation can produce postural hypotension, dizziness, syncope and reflex tachycardia. Tachycardia can be reduced by concurrent use of a β-adrenoceptor antagonist.

 Arterial dilation causes throbbing headaches and flushing, but tolerance to these effects is common during treatment with long-acting nitrates.

 Tolerance to the therapeutic effects of nitrates develops rapidly if there is a sustained high plasma nitrate concentration. Tolerance is therefore a particular problem with delivery of GTN via transdermal patches or with long-acting nitrates. The cause is incompletely understood, but an important mechanism may be increased degradation of NO by oxygen free radicals (e.g. superoxides). There is limited evidence that co-administration of an angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor antagonist or hydralazine (Ch. 6) may reduce nitrate tolerance by impairing superoxide formation. Reflex activation of the sympathetic nervous system and the renin–angiotensin system in response to hypotension may also counteract the vasodilator actions of the nitrates. Tolerance can be avoided by a ‘nitrate-low’ period of several hours in each 24 h. This is preferable to a ‘nitrate-free’ period, which carries a risk of rebound angina. A nitrate-low period is achieved by asymmetric dosing with conventional formulations of isosorbide mononitrate (e.g. twice daily, at 8 a.m. and 1 p.m.) or by using a once-daily formulation that allows plasma nitrate concentrations to fall overnight. Transdermal GTN patches must be removed for part of each 24 h (e.g. overnight) to prevent tolerance.

 Drug interactions are most troublesome with phosphodiesterase inhibitors, such as sildenafil, used in the treatment of erectile dysfunction. These inhibit cGMP metabolism (Ch. 16) and co-administration can result in marked hypotension.

Mechanism of action and effects in angina

All β-adrenoceptor antagonists (often simply referred to as β-blockers) act as competitive antagonists of catecholamines at β-adrenoceptors. They achieve their therapeutic effect in angina by blockade of the cardiac β₁-adrenoceptor with reduced generation of intracellular cAMP. As a result they:

 decrease heart rate (by inhibition of the cardiac I_f pacemaker current in the sinoatrial node; see Ch. 8); this is most marked during exercise, when the rate of rise in heart rate is blunted,

 reduce the force of cardiac contraction (see Ch. 7),

 lower blood pressure by reducing cardiac output (a consequence of both the decreased heart rate and force of myocardial contraction).

The overall effect is to reduce myocardial oxygen demand. The slower heart rate also lengthens diastole and gives more time for coronary perfusion, which effectively improves myocardial oxygen supply.

Certain β-adrenoceptor antagonists have additional properties, which might reduce the incidence of unwanted effects or enhance their blood pressure-lowering actions (see below and also Chs 6 and 8), as follows.

 Cardioselectivity. Some β-adrenoceptor antagonists, for example atenolol, bisoprolol and metoprolol, are selective antagonists at the β₁-adrenoceptor. They are usually called cardioselective drugs since the most important site of action on β₁-adrenoceptors is the heart. Other β-adrenoceptor antagonists, for example propranolol, have equal or greater antagonist activity at β₂-adrenoceptors; these drugs are referred to as ‘non-selective’ β-adrenoceptor antagonists. The cardioselectivity of all β-adrenoceptor antagonists is dose-related, with progressively more β₂-adrenoceptor blockade at higher doses.

 Partial agonist activity (PAA) or intrinsic sympathomimetic activity (ISA). Certain β₁-adrenoceptor antagonists also act as partial agonists at either β₁– or β₂-adrenoceptors. For example, pindolol is a β₁-adrenoceptor antagonist that also has weak agonist activity at β₂-adrenoceptors, and as such it will produce vasodilation in some vascular beds (see Fig. 6.6). Drugs with PAA at the β₁-adrenoceptor have less inhibitory effect on heart rate and force of contraction and may be less effective than full antagonists in the treatment of severe angina, but their PAA means they are less likely to cause a resting bradycardia. Beta-adrenoceptor antagonists with PAA are not widely used.

 Vasodilator activity. Pure β₁-adrenoceptor antagonists do not cause vasodilation. Indeed, the reflex response to β₁-adrenoceptor blockade is vasoconstriction, mediated in part by the reflex sympathetic nervous system stimulation of α₁-adrenoceptors in response to the fall in cardiac output. However, some β-adrenoceptor antagonists have additional properties that produce arterial vasodilation. Mechanisms of vasodilation include β₂-adrenoceptor partial agonist activity (e.g. pindolol; see above), α₁-adrenoceptor blockade (e.g. carvedilol, labetalol) or an increase in endothelial NO synthesis (e.g. nebivolol) (see Fig. 6.6). Vasodilation does not have any proven advantage for the treatment of angina, but may be useful when β-adrenoceptor antagonists are given for the treatment of hypertension (Ch. 6).

Pharmacokinetics

Highly lipophilic β-adrenoceptor antagonists, such as propranolol and metoprolol, are well absorbed from the gut but undergo extensive first-pass metabolism in the liver, with considerable variability among individuals. Reduction in heart rate during exercise is closely related to the plasma concentration of the drug, so dose titration of lipophilic β-adrenoceptor antagonists is usually necessary to achieve an optimal clinical response. Most lipophilic β-adrenoceptor antagonists have short half-lives (see Compendium of drugs used to treat ischaemic heart disease at the end of this chapter), and are often available in modified-release formulations to prolong their duration of action.

Hydrophilic β-adrenoceptor antagonists, such as atenolol, are incompletely absorbed from the gut, and are eliminated unchanged in the urine. The dose range to maintain effective plasma concentrations is narrower than for those drugs that undergo metabolism. The half-lives of hydrophilic β-adrenoceptor antagonists are usually longer than those of lipophilic drugs (see Compendium at the end of this chapter).

Unwanted effects

 Blockade of β₁-adrenoceptors. A large dose of a β-adrenoceptor antagonist can precipitate acute pulmonary oedema if there is pre-existing poor left ventricular function, when high sympathetic nervous activity is necessary to maintain cardiac output. However, there is a paradox that when used at low doses with gradual-dose titration a β-adrenoceptor antagonist is part of the core therapy of heart failure (Ch. 7). A reduction in cardiac output can also impair blood supply to peripheral tissues, which can be detrimental in critical leg ischaemia (Ch. 10) or can provoke Raynaud’s phenomenon (Ch. 10). Excessive bradycardia occasionally occurs, and β-adrenoceptor antagonists should be used with caution or avoided in the presence of advanced atrioventricular conduction defect (heart block). Drugs with partial agonist activity produce less bradycardia or reduction of cardiac output.

 Blockade of β₂-adrenoceptors.

 Bronchospasm can be precipitated in people with asthma (including those with chronic obstructive pulmonary disease and some bronchodilator reversibility). People who are susceptible to this problem can experience bronchospasm even with cardioselective drugs.

 Hypoglycaemia may be prolonged by non-selective β-adrenoceptor antagonists, which may be a problem in people with diabetes mellitus who are treated with insulin (Ch. 40). Gluconeogenesis, a component of the metabolic response to hypoglycaemia, is dependent upon β₂-adrenoceptor stimulation in the liver. Beta-adrenoceptor antagonists also blunt the autonomic response that alerts the person to the onset of hypoglycaemia.

 Central nervous system effects. These include sleep disturbance, vivid dreams and hallucinations, and are more common with lipophilic drugs, which readily cross the blood–brain barrier. Other consequences of CNS action include fatigue and subtle psychomotor effects, for example lack of concentration and sexual dysfunction.

 Effects on blood lipid levels. Most β-adrenoceptor antagonists raise the plasma concentration of triglycerides and lower the concentration of high-density lipoprotein (HDL) cholesterol (Ch. 48). These changes are modest but potentially atherogenic. They are most marked with non-selective β-adrenoceptor antagonists, and least if the drug has partial agonist activity.

 Sudden withdrawal syndrome. Upregulation of β-adrenoceptors (Ch. 1) during long-term treatment makes the heart more sensitive to catecholamines. Palpitation due to a greater awareness of the heart is common on withdrawal. Beta-adrenoceptor antagonists should be stopped gradually in people with ischaemic heart disease, to avoid precipitating unstable angina or myocardial infarction.

 Drug interactions. The calcium channel blocker verapamil and, to a lesser extent, diltiazem (see below) have potentially hazardous additive effects with β-adrenoceptor antagonists, since both reduce the force of cardiac contraction and slow heart rate.

Mechanism of action and effects

Calcium is essential for excitation/contraction coupling in muscle cells. The following mechanisms of regulating intracellular free Ca²⁺ concentration are important pharmacologically (Figs 5.4 and 5.5).