Mechanism of action GTN works by relaxing vascular smooth muscle. It is metabolized 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 messenger cGMP. cGMP causes sequestration of Ca 2� within 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 ‘endotheliumderived relaxing factor’. This endogenous NO is responsible for the resting vasodilator tone present in human resistance arterioles under basal conditions. Nitrovasodilator drugs provide 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 GTN is 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 relationship), 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 potential 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 minimized by omitting the evening dose of isosorbide mononitrate (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). DRUGS USED IN ISCHAEMIC HEART DISEASE 201 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 failure 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 normal 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 particularly useful in patients in whom beta-blockers are contraindicated. 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. Diltiazem or 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, Ca2� antagonists have not been found to prolong survival when administered early in the course of myocardial infarction. DRUGS THAT INFLUENCE THROMBOSIS ASPIRIN AND CLOPIDOGREL The use of aspirin as a mild analgesic is described in Chapter 25, and the antiplatelet uses of aspirin and clopidogrel are discussed in Chapter 30. There is no evidence that the efficacy of aspirin varies with dose over the range 75–320 mg/day during chronic use, but there is evidence that the adverse effect of peptic ulceration and major upper gastro-intestinal haemorrhage 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 inhibition of platelet TXA2 biosynthesis as opposed to endothelial prostacyclin (PGI2) biosynthesis in blood vessels, thereby
202 ISCHAEMIC HEART DISEASE 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 aspirin from 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 anucleate) 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 aspirin is administered every 24 or 48 hours. FIBRINOLYTIC DRUGS Several fibrinolytic drugs are used in acute myocardial infarction, including streptokinase, alteplase, reteplase and tenecteplase. Streptokinase works indirectly, combining with plasminogen to form an activator complex that converts the remaining free plasminogen to plasmin which dissolves fibrin clots. Alteplase, reteplase and tenecteplase are direct-acting plasminogen activators. Fibrinolytic therapy is indicated, when angioplasty is not available, for STEMI patients with STsegment 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, reteplase and tenecteplase, which do not produce a generalized fibrinolytic state, but selectively dissolve recently formed clot, are also safe and effective; reteplase and tenecteplase can be given by bolus injection (two injections intravenously separated by 30 minutes for reteplase, one single intravenous injection for tenecteplase), whereas alteplase has to be given by intravenous infusion. Despite their higher cost than streptokinase, such drugs have been used increasingly over streptokinase in recent years, because of the occurrence of immune reactions andof 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 infection is less certain. Such infections (usually in the form of sore throats) are quite common andoften go undiagnosed; the impact that such infections (along with more severe streptococcal infections, such as cellullitis or septicaemia) have on the efficacy of streptokinase treatment 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 perfusion rather than the blood pressure per se, and as long as the patient is warm and well perfused, the occurrence of hypotension 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. 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 Ca 2� -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 Ca 2� -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 (angiotensinconverting enzyme inhibitors, angiotensin receptor blockers and/or eplerenone).
Soliman s Auricular Therapy Textbook: New Localizations and Evidence Based Therapeutic Approaches was created ( M.D. Nader Soliman )
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Soliman s Auricular Therapy Textbook This textbook is considered the finest ever written in the field of auricular therapy. The auricular acupuncture microsystem is one of the most widely used special acupuncture techniques. This textbook is dedicated to teaching the sound foundations of this unique approach as introduced by its founder Dr. Paul Nogier of France. The scientific bases of the acupuncture microsystem with its three dime... Full description
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