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Transcript
Drugs used in the treatment of Angina Pectoris Introduction • Angina is the pain caused by myocardial ischaemia • It typically presents as sudden, severe, pressing chest pain radiating to the neck, jaw, back, and arms • Occurs due to an imbalance in the myocardial oxygen supply-demand relationship caused by: I. An increase in myocardial oxygen demand II. A decrease in myocardial oxygen supply Causes and consequences of myocardial ischemia: New understanding O2 demand Na+ and Ca2+ overload Heart rate Blood pressure Preload Contractility Electrical instability Myocardial dysfunction Ischemia O2 supply Development of ischemia Consequences of ischemia Belardinelli L et al. Heart. 2006;92(suppl IV):iv6-14. Therapeutic objectives • The major therapeutic are aimed at: 1) Terminating or preventing an acute attack 2) Increasing the patient’s exercise capacity • Can be achieved by: 1) Reducing overall myocardial oxygen demand 2) Increasing oxygen supply to ischemic areas Introduction Types of angina 1. Atherosclerotic or typical angina • The most common form of angina • Caused by the reduction of coronary blood flow produced by coronary atherosclerosis • Symptoms of angina occurs when myocardial oxygen demand increases, as with physical activity, emotional excitement, or any other cause of increased cardiac workload Drugs used in typical angina function principally by reducing myocardial O2 demand by decreasing heart rate, myocardial contractility, and/or ventricular wall stress • Introduction Types of angina 2. Vasopastic or variant angina: • Occurs at rest, even during sleeping and is due to vasospasm of large epicardial coronary vessels or one of their major branches • Symptoms are caused by decreased blood flow to the heart muscles • The principal therapeutic aim in variant angina is to prevent coronary vasospasm by nitrate or CCBs Introduction Types of angina 3. Unstable angina syndrome • • • or acute coronary Characterized by pain with increased frequency that occurs with less and less exertion, culminating in pain at rest Cause: abrupt reduction in blood flow, as might result from coronary thrombosis or rupture of an atherosclerotic plaque, with consequent platelet adhesion and aggregation Requires hospital admission and more aggressive therapy to prevent death and progression to MI Antianginal drugs 1) 2) 3) 4) Nitrates Calcium channel blockers (CCBs) Beta-blocking drugs Novel/newer antianginal drugs Nitrates • Agents: nitroglycerine, isosorbide mononitrate, and isosorbide dinitrate • Nitates are available as oral tablets, transdermal patches, sublingual tablets, and intravenous infusion • Nitrates exert their effect by intracellular conversion to nitric oxide (NO) Mechanism of Action of Nitrates Nitrates become denitrated by glutathione S-transferase Nitric Oxide Guanylate Cyclase* GTP cGMP Activates cGMP-dependent protein kinase Activation of PKG results in phosphorylation of several proteins that reduce intracellular calcium causing smooth muscle relaxation Nitrates • Nitroglyerine: – – – – – Rapid onset of action (2-5 mins) Maximal effect observed at 3 to 10 minutes Short half-life (1-3 mins) Significant first-pass metabolism (F < 10-20%) Commonly administered either sublingually or via a transdermal patch Nitrates • Isosorbide mononitrate (oral tablets): It does not undergo significant first-pass metabolism and so has excellent bioavailability after oral administration • Oral isosorbide dinitrate undergoes denitration to two mononitrates, both of which possess antianginal activity with longer half-lives (3-6 hours) and are presumed to contribute to the therapeutic efficacy of the drug Nitrates Cardiovascular effect • Low concentrations of nitroglycerin preferentially dilate the veins more than the arterioles (gradient response) • This result in marked relaxation of veins with increased venous capacitance, decreased venous return to the heart, and reduces the work of the heart (decreases myocardial oxygen consumption) Nitrates Cardiovascular effect • Higher doses of organic nitrates cause further venous pooling and may decrease arteriolar resistance as well, thereby decreasing systolic and diastolic blood pressure and cardiac output and causing pallor, weakness, dizziness, and activation of compensatory sympathetic reflexes • Nitroglycerin dilates the coronary vasculature, providing an increased blood supply to the heart muscle, but concentric atheromas can prevent significant dilation Nitrates Clinical uses • • • • Nitrates are used to treat acute anginal attacks (sublingual nitroglycerin) and as a prophylaxis against recurrent attacks There are effective in stable, variant, and unstable angina pectoris All nitrates are effective, but they differ in their onset of action and rate of elimination Nitrates are frequently given in combination with βblockers and CCBs Nitrates Adverse effects • Extensions of therapeutic vasodilation: orthostatic hypotension, tachycardia, and throbbing headache (3060% of patients) • Sildenafil potentiates the action of the nitrates. To preclude the dangerous hypotension and inadequate perfusion of critical organs that may occur, this combination is contraindicated Nitrates Tolerance • Repeated and frequent exposure to organic nitrates is accompanied by the development of tissue tolerance: the blood vessels become desensitized to the vasodilating action of nitrates • The magnitude of tolerance is a function of dosage and frequency of use • Tolerance may result from: 1) True vascular tolerance 2) Pseudotolerance Nitrates Tolerance • Tolerance can be avoided by: 1) Daily “nitrate-free interval” to restore sensitivity to the drug. This interval is typically 10 to 12 hours, usually at night, because demand on the heart is decreased at that time 2) Nitroglycerin patches are worn for 12 hours then removed for 12 hours Calcium channel blockers Mechanism of action • Ca2+ channel antagonists, also called Ca blockers, inhibit Ca2+ channel function • All the Ca2+ channel blockers bind to the α1 subunit of the L-type Ca2+ channel, which is the main poreforming unit of the channel • CCBs bind more effectively to open channels and inactivated channels 2+ entry Calcium channel blockers Mechanism of action • Binding of the drug reduces the frequency of opening in response to depolarization • This result is a marked decrease in transmembrane calcium current, which in turn results in smooth muscle with a long-lasting relaxation and in cardiac muscle with a reduction in contractility throughout the heart and decreases in sinus node pacemaker rate and AV node conduction velocity Calcium channel blockers Organ system effects 1. Smooth muscle • In the vascular system, arterioles appear to be more sensitive than veins • All the Ca2+ channel blockers decrease coronary vascular resistance and increase coronary blood flow • The dihydropyridines (e.g. nifedipine) are more potent vasodilators and have a greater ratio of vascular smooth muscle effects relative to cardiac effects than do diltiazem and verapamil Calcium channel blockers Organ system effects 2. Cardiac muscle • In the SA and AV nodes, depolarization largely depends on the movement of Ca2+ through the slow channel. Therefore, low-response, or calcium-dependent, action potentials—may be reduced or blocked by all of the calcium channel blockers Calcium channel blockers Clinical uses of CCBs • CCBs are effective in both effort angina (reduction in myocardial oxygen consumption) and vasopastic angina (relaxation of coronary arteries) • The choice of a particular calcium channel-blocking agent should be made with knowledge of its specific potential adverse effects as well as its pharmacologic properties Calcium channel blockers Clinical uses of CCBs • Important differences between the available CCBs arise from the differences in their relative smooth muscle versus cardiac effects • The dihydropyridines are more potent vasodilators in vivo and in vitro than verapamil, which is more potent than diltiazem Calcium channel blockers Clinical uses of CCBs • Therefore dihydropyridine be used more safely than verapamil or diltiazem in the presence of AV conduction abnormalities and depressed cardiac function • Sustained-release forms of the Ca2+ channel blockers are used clinically to reduce the number of daily doses needed to maintain therapeutic drug levels • In the case of nifedipine, sustained-release forms of the drug appear to mitigate the reflex tachycardia sometimes seen following oral administration Calcium channel blockers Clinical uses of CCBs • Verapamil and diltiazem reduce cardiac contractility & oxygen requirement in a dose-dependent fashion • In patients with a history of atrial tachycardia, flutter, & fibrillation, verapamil and diltiazem provide a distinct advantage b/c of their antiarrhythmic effect Calcium channel blockers Adverse effects • Excessive inhibition of calcium influx can cause serious cardiac depression, including cardiac arrest, bradycardia, atrioventricular block, and heart failure • Minor toxicities include flushing, dizziness, nausea, constipation, and peripheral edema • Constipation is particularly common with verapamil • Patients receiving β-blocking drugs are more sensitive to the cardio-depressant effects of CCBs Beta-blockers • They decrease the oxygen demands of the myocardium by blocking β1 receptors, and they reduce the work of the heart by decreasing heart rate, contractility, cardiac output, and blood pressure • The demand for oxygen by the myocardium is reduced both during exertion and at rest • β-blockers are the DOC to treat exercise-induced angina, but are ineffective and should not be used against vasospastic angina Novel antianginal drugs Nicorandil • It displays a dual mechanism of action: a) It opens up ATP-sensitive K+ channels, thereby causing dilatation of peripheral and coronary resistant arterioles b) It acts as nitric oxide donor that dilates coronary arteries and systemic venous capacitance vessels • Common adverse effects include headache (especially on initiation of treatment), flushing, dizziness, decreased BP and/or increase in heart rate, and GIT side effects Novel antianginal drugs Metabolic modulation (pFOX): Trimetazidine • Trimetazidine is metabolic modulator that does not reduce oxygen demand or increase blood supply • It act by shifting myocardial metabolism to substrates that require less oxygen per unit of ATP produced • • ADRs: GIT disturbance, dizziness, and headache.5 Trimetazidine use can result in movement disorders such as parkinsonian symptoms (tremor, akinesia, hypertonia), gait instability, and restless legs Metabolic modulation (pFOX): Trimetazidine Myocytes FFA Glucose Acyl-CoA Pyruvate β-oxidation • O2 requirement of glucose pathway is lower than FFA pathway • During ischemia, oxidized FFA levels rise, blunting the glucose pathway Trimetazidine Acetyl-CoA Energy for contraction MacInnes A et al. Circ Res. 2003;93:e26-32. pFOX = partial fatty acid oxidation Lopaschuk GD et al. Circ Res. 2003;93:e33-7. FFA = free fatty acid Stanley WC. J Cardiovasc Pharmacol Ther. 2004;9(suppl 1):S31-45. Newer antianginal drugs Sodium channel blocker: Ranolazine • It reduces contractility resulting from the blockade of a late sodium current (late INa) in myocaridla cells that facilitates calcium entry via the sodium-calcium exchanger • The decrease in intracellular sodium causes and increase in calcium expulsion via the Na-Ca+2 exchanger • ADRs tend to be mild to moderate in severity and often develop within the first two weeks of treatment • The most common ADRs are constipation, nausea, and weakness Ranolazine: Mechanism of action Ischemia ↑ Late INa Ranolazine inhibits the late inward Na current Na+ overload Ca2+ overload Diastolic relaxation failure (increased diastolic tension) Extravascular compression Newer antianginal drugs Sinus node inhibition: Ivabradine • Ivabradine blocks I(f) channel in the pacemaker cells of the sinoatrial (SA) node • This slows the heart rate without affecting myocardial contractile function or peripheral vascular resistance • Adverse effects include visual “flashing lights” known as phosphenes in up to 16% of patients, which are usually only mild to moderate in intensity and transient Sinus node inhibition: Ivabradine Control Ivabradine 0.3 µM 40 20 0 –20 –40 –60 Potential (mV) SA = sinoatrial 0.5 Time (seconds) • If current is an inward Na+/K+ current that activates pacemaker cells of the SA node • Ivabradine – Selectively blocks If in a current-dependent fashion – Reduces slope of diastolic depolarization, slowing HR DiFrancesco D. Curr Med Res Opin. 2005;21:1115-22.
