Ischaemic Heart Disease
Angina pectoris is the most common symptom of ischaemic heart disease. It is the consequence of an imbalance between myocardial supply and demand arising either as the result of narrowing of the coronary arteries through atherosclerosis or as the result of coronary artery spasm.
Stable angina is the result of a fixed atherosclerotic obstruction and is precipitated by an increase in myocardial oxygen requirements occurring during exercise or excitement. It can be reproduced predictably each time the patient exerts himself/herself to the same degree. Unstable angina occurs unpredictably, often at rest, as well as during physical exertion. It is a condition which deteriorates rapidly, being brought on by lower and lower levels of exercise over a period of time. It is believed to be caused by a transitory obstruction of a coronary artery possibly due to platelet aggregation or an embolus.
Variant, vasospastic or Prinzmetal's angina is unpredictable and may be experienced even when the patient is resting. It arises due to the spasm of the smooth muscle in the walls of the coronary arteries which produces vasoconstriction and reduces blood flow.
Treatment: The aim of treatment is to restore the balance of myocardial oxygen supply and demand. The three classes of compound employed are the nitrates, beta-blockers and the calcium antagonists.
Nitrates relieve both exertional (stable and unstable) and vasospastic angina. Their exact mechanism of action in the relief of angina has not been fully elucidated, but appears to depend on their conversion to the nitrite ion (NO) which is considered to generate nitric oxide (NO). This is possibly the same molecule as 'endothelium derived relaxant factor (EDRF) the "endogenous nitrate" responsible for vasodilatation in hypoxia.
The predominant effect of the nitrates is the venodilatation of the venous capacitance vessels. This allows venous pooling of blood and reduces venous return to the heart. The lower venous filling pressure (preload) reduces the pressure in the ventricles which in turn reduces wall tension and hence oxygen requirements. The reduction in afterload achieved through dilatation of the arteriolar resistance vessels also contributes by reducing the amount of work the heart has to do. In addition, although the nitrates do not increase total coronary blood flow in patients with angina, they do appear to redistribute the blood to ischaemic regions, particularly the subendocardial regions which are subject to the greatest amount of extravascular compression during systole. Nitrates are available in a wide range of formulations. The choice of product depends upon the onset and duration of action required. The short-acting nitrates such as glyceryl trinitrate are generally used to abort angina attacks which have already begun. Glyceryl trinitrate can be administered lingually, sublingually or buccally in the form of sprays, or sublingual, buccal and chewable tablets. Absorption from the oral mucosa is rapid (sublingual absorption being the fastest), and haemodynamic effects and relief from pain are almost immediate. In the long term prophylactic management of angina attacks the nitrates with a long duration of action are used. These include sustained release formulations of glyceryl trinitrate, and oral forms of pentaerythritol tetranitrate, isosorbide dinitrate and isosorbide mononitrate. Glyceryl trinitrate is also well absorbed through the intact skin, and can be applied in the form of an ointment or as a transdermal patch.
The vasodilator action of the nitrates is responsible for their most common side effects of headache and facial flushing. The incidence of both is greatest at commencement of treatment and diminishes with time. It can be reduced or avoided if the dose is slowly titrated to the needs of the patient. Tolerance and cross tolerance may develop with repeated prolonged use of nitrates.
b-BLOCKERS are effective in reducing the frequency and severity of exertional angina. They are not useful for vasospastic angina and may on occasion exacerbate the condition by allowing unopposed alpha-mediated vasoconstriction of the coronary arteries. The basis of their use in exertional angina is to reduce the work the heart is allowed to perform to a level below that which would provoke an angina attack. They block the sympathetic drive to the heart, reducing the chronotropic and inotropic responses during exercise or stress, and so limiting the oxygen requirements.
The beta-blockers are used for the prophylaxis of angina. There are a number of products available and choice will usually depend upon the patient's response or the dosage frequency required. Cardioselective b -blockers (acebutolol, atenolol, bisoprolol, metoprolol) may be less prone to precipitating bronchospasm than the non-cardioselective types (nadolol, oxprenolol, pindolol, propranolol, timolol) but care is still necessary in patients with a history of respiratory problems. They may precipitate heart failure in those with a poor cardiac reserve. In patients who do not respond adequately to maximal, dosages of a nitrate or beta-blocker, concurrent use of the two compounds may be beneficial. The additive effect is principally the result of one agent blocking the adverse effects of the other. Beta-blockers block the reflex tachycardia and positive inotropic effects of the nitrates, while the nitrate attenuates the increase in left ventricular end diastolic volume of the beta-blocker by increasing venous capacitance.
Ca++ANTAGONISTS can be used to treat both exertional and vasospastic angina. In exertional angina, their clinical efficacy relates to their ability to decrease afterload, improve myocardial efficiency, reduce heart rate and to increase coronary blood flow. They act by blocking the inward movement of Ca++ ions into the cells. In the heart, this results in less free intracellular calcium which in turn reduces the breakdown of ATP stores.
The result is a more controlled and efficient contraction of the cardiac muscle, consuming less energy and requiring less oxygen. In the vasculature, vasodilatation reduces afterload and hence oxygen requirements, while coronary vasodilatation allows more oxygenated blood to perfuse the myocardium. Once the balance of oxygen supply and demand has been restored the patient is able to exercise harder and for longer periods.
In vasospastic angina, inhibition of smooth muscle contraction relieves the coronary artery spasm. Unlike the beta-blockers, the Ca++ antagonists are a heterogeneous group of compounds with multiple and differing haemodynamic effects. In vitro, they are all potent dilators of coronary and peripheral arteries and all exert potent negative inotropic and chronotropic effects. In vivo, however, the vasodilatation and hypotensive effects trigger the baroreceptor reflex which opposes the negative cardiac effects. The net haemodynamic and electrophysiological effect of each agent therefore results from a complex interplay of direct and reflex effects. The WHO has classified Ca++ antagonists according to their pharmacological and clinical effects. In vivo, class I agents (eg. verapamil), have the most potent negative inotropic effect. Their depressant effect on cardiac conduction may precipitate heart failure if there is AV or SA node dysfunction, or if b-blockers are prescribed concurrently. Class II agents (eg. amlodipine, felodipine, nicardipine, nifedipine, nisoldipine), do not depress conduction or contractility and therefore the risk of precipitating cardiac failure in patients with conduction disorders is reduced.
In fact, they may reverse some of the negative inotropic effects of b-blockade and may therefore be prescribed together provided the patient is monitored in case severe hypotension ensues.
The class III agent, diltiazem, has a negligible or slightly negative inotropic effect and causes virtually no reflex tachycardia. Combining a nitrate with a Ca++ antagonist may be beneficial since the former reduces preload and the latter afterload. Excessive vasodilatation may occur. A nitrate with a Class II agent may be useful in patients with exertional angina with heart failure, sick sinus syndrome or AV conductiondisturbances.
Sustained-release preparations containing the same quantity of a given calcium antagonist are unlikely to have the same pharmacokinetic profiles. It is therefore essential that such preparations are prescribed by brand name and patients are not transferred from one preparation to another without full clinical assessment and retitration.
Potassium Channel Activators represent a novel class of antianginal agents. They act by increasing membrane conductance to K+ions, which causes hyperpolarisation of vascular smooth muscle membranes, reducing their excitability and leading to arteriolar vasodilatation.
Nicorandil, is also considered to exert a "nitrate-' like" action to promote venodilatation but, unlike nitrates, tolerance does not appear to develop. Nicorandil reduces afterload and preload, while in the coronary circulation it dilates both the large epicardial and smaller resistance vessels. It increases coronary blood flow and perfusion of post-stenotic regions of the mycocardium without causing a coronary "steal effect", thereby restoring the balance between oxygen supply and demand in the ischaemic myocardium to relieve angina.
Nicorandil can be used as monotherapy or in combination with other anti-anginal agents. It does not 1-depress myocardial contractility or have a clinically significant effect on heart rate or blood pressure in patients with angina.
Additional resources on internet:
- What is Ischaemic Heart Disease? (IHD) : Department for work and pensions (DWP)
- European union public health information system : Ischaemic heart disease
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