Prescribing Notes


Angina pectoris is the most common symptom of ischaemic heart disease. It is the consequence of an imbalance between myocardial oxygen 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 him/herself to the same degree. Unstable angina occurs unpredictably, often at rest, as well as during physical exertion. It is a condition that 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.

The aim of treatment is to restore the balance of myocardial oxygen supply and demand.

Nitrates Short-acting nitrates such as glyceryl trinitrate are generally used to abort angina attacks that have already begun. Glyceryl trinitrate can be administered lingually, sublingually or buccally in the form of sprays, or sublingual, buccal or chewable tablets. Absorption from the oral mucosa is rapid (sublingual absorption being the fastest), and haemodynamic effects and pain relief are almost immediate. In the long term prophylactic management of angina attacks, nitrates with a long duration of action are used. These include sustained-release formulations of glyceryl trinitrate, and oral forms of isosorbide dinitrate and isosorbide mononitrate. Glyceryl trinitrate is also well absorbed through 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.

β-blockers are used for the prophylaxis of angina and are effective in reducing the frequency and severity of exertional angina. They are not useful for vasospastic angina and may exacerbate the condition by allowing unopposed α-receptor mediated vasoconstriction of the coronary arteries. They are used in exertional angina to reduce the work of the heart to a level that will not provoke an angina attack.

Cardioselective β-blockers (acebutolol, atenolol, bisoprolol, metoprolol) may be less prone to precipitating bronchospasm than the non-cardioselective types (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 β-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. β-blockers block the reflex tachycardia and positive inotropic effects of the nitrates, while the nitrate attenuates the increase in left ventricular end diastolic volume produced by the β-blocker by increasing venous capacitance.

Calcium-channel blockers can be used to treat exercise-induced (stable) angina and vasospastic (variant or Prinzmetal's) angina. The role of calcium-channel blockers in unstable angina is less well established. They do not reduce the risk of MI but are used in patients who continue to have symptomatic myocardial ischaemia during conventional antianginal therapy. Studies show that diltiazem and verapamil may be beneficial but neither should be used in heart failure.

Calcium-channel blockers prevent the inward flow of calcium ions into the cell, reducing the availability of intracellular calcium for muscle contraction. At least six different types of calcium channel have been identified. In the cardiovascular system, the most important is the L-type or long-lasting channel. L-type calcium-channel blockers can be subdivided into three classes:

Class I, the phenylalkylamines, includes verapamil.

Class II, the dihydropyridines, includes amlodipine, felodipine, nicardipine and nifedipine.

Class III, the benzothiazepines, includes diltiazem.

Class I agents 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 β-blockers are prescribed concurrently. Class II agents are relatively selective for the vasculature. They 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 β-blockade and may therefore be prescribed together provided the patient is monitored in case severe hypotension occurs. Class III agents have a negligible or slightly negative inotropic effect and cause virtually no reflex tachycardia.

Note: Sustained-release preparations containing the same quantity of a given calcium-channel blocker are unlikely to have the same pharmacokinetic profiles. Preparations should be prescribed by brand name and patients should not be transferred from one preparation to another without full clinical assessment and retitration.

The potassium-channel activator nicorandil produces arteriolar vasodilatation and is also considered to exert a 'nitrate-like' action. However, unlike nitrates, tolerance to nicorandil does not appear to develop. Nicorandil can be used as monotherapy or in combination with other anti-anginal agents. It does not depress myocardial contractility or have a significant effect on heart rate or blood pressure in angina.

The sinus node If inhibitor ivabradine exerts its effect through selective and specific inhibition of the cardiac pacemaker If current that controls the spontaneous diastolic depolarisation in the sinus node and regulates heart rate, thereby lowering the heart rate and reducing the workload of the heart.

Ranolazine is an add-on therapy for patients inadequately controlled by or intolerant of first-line anti-anginals. While the mechanism of action is largely unknown, it is thought that the drug may exert its effect in part through inhibition of the late sodium current in cardiac cells, thereby reducing intracellular sodium accumulation and subsequently reducing intracellular calcium overload. This reduction in intracellular calcium overload is thought to improve myocardial relaxation and decrease left ventricular diastolic stiffness.