Drugs that are used to influence atherosclerosis are described in Chapter 27. In the present chapter, we briefly describe those drugs that are used to treat ischaemic heart disease either because of their haemodynamic properties or because they inhibit thrombosis.
DRUGS THAT INFLUENCE HAEMODYNAMICS ORGANIC NITRATES
Use and administration
GTNis used to relieve anginal pain. It is generally best used as ‘acute’ prophylaxis, i.e. immediately before undertaking strenuous activity. It is usually given sublingually, thereby ensuring rapid absorption and avoiding presystemic metab- olism (Chapter 5), but in patients with unstable angina it may be given as an intravenous infusion. The spray has a some- what more rapid onset of action and a much longer shelf-life than tablets, but is more expensive. GTN is absorbed trans- dermally and is available in a patch preparation for longer prophylaxis than the short-term benefit provided by a sublin- gual dose. Alternatively, a longer-acting nitrate, such as isosorbide mononitrate, may be used prophylactically to reduce the frequency of attacks; it is less expensive than GTN patches and is taken by mouth. In patients whose pattern of pain is predominantly during the daytime, it is prescribed to be taken in the morning and at lunch-time, thereby ‘covering’
the day, but avoiding development of tolerance by omitting an evening dose. Longer-acting controlled-release preparations are available for once daily use, and these usually provide nitrate cover during most of the day, but leave a small ‘nitrate- free’ window of a few hours, thereby again preventing the development of nitrate tolerance. Long-acting nitrates are also used in combination with hydralazinein patients with heart failure who are unable to take ACE inhibitors and, especially, in patients of African origin (Chapter 31).
GTN is volatile, so the tablets have a limited shelf-life (around six weeks after the bottle is opened) and they need to be stored in a cool place in a tightly capped dark container, without cotton wool or other tablets. Adverse effects can be minimized by swallowing the tablet after strenuous activity is completed (a more genteel alternative to spitting it out!), because of the lower systemic bioavailability from gut than from buccal mucosa.
200 ISCHAEMIC HEART DISEASE
DRUGSUSED INISCHAEMICHEARTDISEASE 201
Mechanism of action
GTNworks by relaxing vascular smooth muscle. It is metabo- lized by smooth-muscle cells with generation of nitric oxide (NO). This combines with a haem group in the soluble isoform of guanylyl cyclase, activating this enzyme and thereby increasing the cytoplasmic concentration of the second mes- senger cGMP. cGMP causes sequestration of Ca2within the sarcoplasmic reticulum, thus relaxing smooth muscle. NO is also synthesized from endogenous substrate (L-arginine) under physiological conditions by a constitutive enzyme in vascular endothelial cells and is Furchgott’s ‘endothelium- derived relaxing factor’. This endogenous NO is responsible for the resting vasodilator tone present in human resistance arterioles under basal conditions. Nitrovasodilator drugs pro- vide NO in an endothelium-independent manner, and are therefore effective even if endothelial function is severely impaired, as in many patients with coronary artery disease.
Haemodynamic and related effects
GTNis relatively selective for venous rather than arteriolar smooth muscle. Venodilatation reduces cardiac preload.
Reduced venous return reduces ventricular filling and hence reduces ventricular diameter. Ventricular wall tension is directly proportional to chamber diameter (the Laplace rela- tionship), so ventricular wall tension is reduced by GTN. This reduces cardiac work and oxygen demand. Coronary blood flow (which occurs during diastole) improves due to the decreased left ventricular end-diastolic pressure. Spasm is opposed by NO-mediated coronary artery relaxation.
Reduced arterial tone reduces diastolic blood pressure and arterial wave reflection hence reducing cardiac afterload and myocardial oxygen demand. Nitrates relax some non-vascular smooth muscles and therefore sometimes relieve the pain of oesophageal spasm and biliary or renal colic, causing poten- tial diagnostic confusion.
Adverse effects
Organic nitrates are generally very safe, although they can cause hypotension in patients with diminished cardiac reserve. Headache is common and GTN patches have not fared well when evaluated by ‘quality of life’ questionnaires for this reason. Tolerance is another problem. This can be min- imized by omitting the evening dose of isosorbide mono- nitrate (or by removing a patch at night).
β-ADRENOCEPTOR ANTAGONISTS
For more information, see also Chapters 28, 31 and 32.
Use in ischaemic heart disease
The main uses of beta-blockers in patients with ischaemic heart disease are:
• prophylaxis of angina;
• reduction of the risk of sudden death or reinfarction following myocardial infarction (‘secondary prevention’);
• treatment of heart failure (Chapter 31).
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS (ACEI) AND ANGIOTENSIN RECEPTOR BLOCKERS Use in ischaemic heart disease
As well as their well established uses in hypertension (see Chapter 28) and in heart failure, including chronic heart fail- ure caused by ischaemic heart disease (see Chapter 31), there is also substantial evidence to support the use of ACEI and angiotensin antagonists in the early stages of myocardial infarction (see above). The evidence suggests that any benefit is very small (or non-existent) in patients with completely nor- mal ventricular function, but that with increasing ventricular dysfunction there is increasing benefit. Treatment should be started with small doses with dose titration up to doses that have been demonstrated to improve survival.
CALCIUM ANTAGONISTS Use in ischaemic heart disease
Apart from their use in hypertension (Chapter 28) and in the treatment of cardiac dysrhythmias (see Chapter 32), the main use of calcium-channel antagonists in patients with ischaemic heart disease is for the prophylaxis of angina. They are partic- ularly useful in patients in whom beta-blockers are con- traindicated. Disappointingly, despite having quite different pharmacological actions to beta-blockers, these classes of drugs do not appear to act synergistically in angina and should not be routinely co-administered as prophylaxis to such patients. They may be particularly useful in the rare patients in whom spasm is particularly prominent (spasm can be worsened by β-blockers). Short-acting dihydropyridines should be avoided because they cause reflex tachycardia.
Diltiazemor a long-acting dihydropyridine (e.g. amlodipine or a controlled-release preparation of nifedipine) are often used in this setting. Unlike β-adrenoceptor antagonists and ACEI, Ca2antagonists have not been found to prolong sur- vival when administered early in the course of myocardial infarction.
DRUGS THAT INFLUENCE THROMBOSIS ASPIRIN AND CLOPIDOGREL
The use of aspirinas a mild analgesic is described in Chapter 25, and the antiplatelet uses of aspirinandclopidogrelare dis- cussed in Chapter 30. There is no evidence that the efficacy of aspirinvaries with dose over the range 75–320 mg/day dur- ing chronic use, but there is evidence that the adverse effect of peptic ulceration and major upper gastro-intestinal haemor- rhage is dose related over this range. Accordingly, the lower dose should be used routinely for chronic prophylaxis. At the onset of ACS it is appropriate to use a higher dose (e.g.
300 mg) to obtain rapid and complete inhibition of platelet cyclo-oxygenase (COX). There has been considerable interest in the possibility that very low doses of aspirin(40 mg/day or less) may provide the highest degree of selectivity for inhibi- tion of platelet TXA2biosynthesis as opposed to endothelial prostacyclin (PGI2) biosynthesis in blood vessels, thereby
maximizing its cardiovascular benefits. Aspirin acetylates platelet COX as platelets circulate through portal venous blood (where the acetylsalicylic acid concentration is high during absorption of aspirinfrom the gastro-intestinal tract), whereas systemic endothelial cells are exposed to much lower concentrations because at low doses hepatic esterases result in little or no aspirin entering systemic blood. This has been demonstrated experimentally, but the strategy has yet to be shown to result in increased antithrombotic efficacy of very low doses. In practice, even much higher doses given once daily or every other day achieve considerable selectivity for platelet vs. endothelial COX, because platelets (being anucle- ate) do not synthesize new COX after their existing supply has been irreversibly inhibited by covalent acetylation by aspirin, whereas endothelial cells regenerate new enzyme rapidly (within six hours in healthy human subjects). Consequently, there is selective inhibition of platelet COX for most of the dose interval if a regular dose of aspirinis administered every 24 or 48 hours.
FIBRINOLYTIC DRUGS
Several fibrinolytic drugs are used in acute myocardial infarction, including streptokinase,alteplase,reteplase and tenecteplase.Streptokinaseworks indirectly, combining with plasminogen to form an activator complex that converts the remaining free plasminogen to plasmin which dissolves fibrin clots.Alteplase,reteplaseandtenecteplaseare direct-acting plasminogen activators. Fibrinolytic therapy is indicated, when angioplasty is not available, for STEMI patients with ST- segment elevation or bundle-branch block on the ECG. The maximum benefit is obtained if treatment is given within 90 minutes of the onset of pain. Treatment using streptokinase with aspirin is effective, safe and relatively inexpensive.
Alteplase,reteplaseandtenecteplase, which do not produce a generalized fibrinolytic state, but selectively dissolve recently formed clot, are also safe and effective; reteplaseand tenecteplasecan be given by bolus injection (two injections intravenously separated by 30 minutes for reteplase, one sin- gle intravenous injection for tenecteplase), whereas alteplase has to be given by intravenous infusion. Despite their higher cost than streptokinase, such drugs have been used increas- ingly over streptokinase in recent years, because of the occurrence of immune reactions and of hypotension with streptokinase. Being a streptococcal protein, individuals who have been exposed to it synthesize antibodies that can cause allergic reactions or (much more commonly) loss of efficacy due to binding to and neutralization of the drug. Individuals who have previously received streptokinase(more than a few days ago) should not be retreated with this drug if they reinfarct. The situation regarding previous streptococcal infec- tion is less certain. Such infections (usually in the form of sore throats) are quite common and often go undiagnosed; the impact that such infections (along with more severe strepto- coccal infections, such as cellullitis or septicaemia) have on the efficacy of streptokinasetreatment is uncertain, but likely to be significant. Hypotension may occur during infusion of streptokinase, partly as a result of activation of kinins and
other vasodilator peptides. The important thing is tissue per- fusion rather than the blood pressure per se, and as long as the patient is warm and well perfused, the occurrence of hypoten- sion is not an absolute contraindication to the use of fibrinolytic therapy, although it does indicate the need for particularly careful monitoring and perhaps for changing to an alternative (non-streptokinase) fibrinolytic agent.
202 ISCHAEMIC HEART DISEASE
Key points
Ischaemic heart disease: pathophysiology and management
• Ischaemic heart disease is caused by atheroma in coronary arteries. Primary and secondary prevention involves strict attention to dyslipidaemia, hypertension and other modifiable risk factors (smoking, obesity, diabetes).
• Stable angina is caused by narrowing of a coronary artery leading to inadequate myocardial perfusion during exercise. Symptoms may be relieved or
prevented (prophylaxis) by drugs that alter the balance between myocardial oxygen supply and demand by influencing haemodynamics. Organic nitrates, nicorandil and Ca2-antagonists do this by relaxing vascular smooth muscle, whereas β-adrenoceptor antagonists slow the heart.
• In most cases, the part played by coronary spasm is uncertain. Organic nitrates and Ca2-antagonists oppose such spasm.
• Unstable angina and NSTEMI are caused by fissuring of an atheromatous plaque leading to thrombosis, in the latter case causing some degree of myocardial necrosis.
They are treated with aspirin, clopidogrel and heparin (usually low-molecular-weight heparin nowadays), which improve outcome, and with intravenous glyceryl trinitrate if necessary for relief of anginal pain; most cases should undergo coronary angiography at some stage to delineate the extent/degree of disease and suitability for PCI or CABG, and this should be done early in patients who fail to settle on medical therapy.
• STEMI is caused by complete occlusion of a coronary artery by thrombus arising from an atheromatous plaque, and is more extensive and/or involves a greater thickness of the myocardium than NSTEMI. It is treated by early (primary) angioplasty where this is available;
where not available, fibrinolytic drugs (with or without heparin/low-molecular-weight heparin) should be given. Important adjunctive therapy includes aspirin and clopidogrel, inhaled oxygen and opoids.
Angiotensin-converting enzyme inhibition, angiotensin receptor blockade and aldosterone antagonism (with eplerenone) each improve outcome in patients with ventricular dysfunction; whether the use of all three of these treatment modalities in combination confers additional benefit over maximal dosage with one of these agents remains a matter of debate.
• After recovery from myocardial infarction, secondary prophylaxis is directed against atheroma, thrombosis (aspirin) and dysrhythmia (β-adrenoceptor antagonists, which also prevent re-infarction) and in some patients is used to improve haemodynamics (angiotensin- converting enzyme inhibitors, angiotensin receptor blockers and/or eplerenone).
DRUGSUSED INISCHAEMICHEARTDISEASE 203
FURTHER READING
Carbajal EV, Deedwania P. Treating non-ST-segment elevation ACS.
Pros and cons of current strategies. Postgraduate Medicine2005;118:
23–32.
Opie LH, Commerford PJ, Gersh BJ. Controversies in stable coronary artery disease. Lancet2006;367: 69–78.
Sura AC, Kelemen MD. Early management of ST-segment elevation myocardial infarction. Cardiology Clinics2006;24: 37–51.
Case history
A 46-year-old advertising executive complains of exercise- related pain when playing his regular daily game of squash for the past three months. Ten years ago he had a gastric ulcer, which healed with ranitidine, and he had experi- enced intermittent indigestion subsequently, but was other- wise well. His father died of a myocardial infarct at the age of 62 years. He smokes 20 cigarettes per day and admits that he drinks half a bottle of wine a day plus ‘a few gins’.
Physical examination is notable only for obesity (body mass index 30 kg/m2) and blood pressure of 152/106 mmHg.
Resting ECG is normal and exercise ECG shows significant ST depression at peak exercise, with excellent exercise tol- erance. Serum total cholesterol is 6.4 mmol/L, triglycerides are 3.8 mmol/L and HDL is 0.6 mmol/L. γ-Glutamyl transpep- tidase is elevated, as is the mean corpuscular volume (MCV). Cardiac catheterization shows a significant narrow- ing of the left circumflex artery, but the other vessels are free from disease.
Question
Decide whether each of the following statements is true or false.
Immediate management could reasonably include:
(a) an ACE inhibitor;
(b) GTN spray to be taken before playing squash;
(c) no reduction in alcohol intake, as this would be dangerous;
(d) referral for angioplasty;
(e) isosorbide mononitrate;
(f) a low dose of aspirin;
(g) nicotine patches;
(h) dexfenfluramine.
Answer (a) False (b) False (c) False (d) False (e) True (f) True (g) False (h) False
Comment
This patient has single-vessel disease and should be started on medical management with advice regarding diet, smok- ing and reduction of alcohol consumption. He should con- tinue to exercise, but would be wise to switch to a less extreme form of exertion. Taking a GTN spray before play- ing squash could have unpredictable effects on his blood pressure. A long-acting nitrate may improve his exercise tolerance, and low-dose aspirin will reduce his risk of myocardial infarction. In view of the history of ulcer and indigestion, consideration should be given to checking for Helicobacter pylori(with treatment if present) and/or reinsti- tution of prophylactic acid suppressant treatment. His dys- lipidaemia is a major concern, especially the low HDL despite his high alcohol intake and regular exercise. It will almost certainly necessitate some form of drug treatment in addition to diet. His blood pressure should improve with weight reduction and reduced alcohol intake. However, if it does not and if the angina persists despite the above measures, a β-adrenoceptor antagonist may be useful despite its undesirable effect on serum lipids. If angina is no longer a problem, but hypertension persists, a long- acting α-blocker (which increases HDL) would be worth considering.
Because of the risks of haemorrhage, patients are not gener- ally treated with fibrinolytic drugs if they have recently (within the last three months) undergone surgery, are preg- nant, have evidence of recent active gastro-intestinal bleeding, symptoms of active peptic ulcer disease or evidence of severe liver disease (especially if complicated by the presence of varices), have recently suffered a stroke or head injury, have severe uncontrolled hypertension, have a significant bleeding diathesis, have suffered recent substantial trauma (including vigorous chest compression during resuscitation) or require invasive monitoring (e.g. for cardiogenic shock). The position regarding diabetic or other proliferative retinopathy is contro- versial. If ophthalmological advice is locally and immediately available, this is no longer universally regarded as an absolute contraindication to fibrinolysis.
●Introduction 204
●Pathophysiology of thrombosis 204
●Anticoagulants 205