Drugs used in the treatment of Angina Pectoris

Introduction Angina pectoris refers to sudden, severe, pressing chest pain radiating to the neck, jaw, back, and arms caused by cardiac ischemia Occurs due to an imbalance in the myocardial oxygen supply-demand relationship caused by: An increase in myocardial oxygen demand (determined by heart rate, ventricular contractility, and ventricular wall tension) A decrease in myocardial oxygen supply (primarily determined by coronary blood flow) Both

Regional myocardial blood flow Heart Rate Coronary blood flow Contractility Oxygen demand Oxygen supply = Regional myocardial blood flow Preload > Afterload ischemia

Introduction Types of angina 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

Introduction Types of angina 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

Introduction Types of angina Unstable angina or acute coronary syndrome It lies between stable angina on the one hand and myocardial infarction on the other Characterized by pain with increased frequency that occurs with less and less exertion, culminating in pain at rest

Introduction Types of angina Unstable angina or acute coronary syndrome 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

Therapeutic objectives The major therapeutic are aimed at: Terminating or preventing an acute attack Increasing the patient’s exercise capacity Can be achieved by: Reducing overall myocardial oxygen demand Increasing oxygen supply to ischemic areas

Therapeutic objectives Reducing myocardial O2 demand can be achieved by decreasing heart rate/ myocardial contractility, reducing preload/cardiac filling, reducing afterload/ arterial pressure, & by shifting myocardial metabolism to substrates that require less oxygen per unit of adenosine triphosphate (ATP) produced Increasing O2 supply can be achieved by dilating the coronary vasculature

Therapeutic objectives Drugs used in typical angina function principally by reducing myocardial O2 demand by decreasing heart rate, myocardial contractility, and/or ventricular wall stress The principal therapeutic aim in variant angina is to prevent coronary vasospasm by nitrate or calcium channel-blocking vasodilators

Therapeutic objectives In unstable angina, vigorous measures are taken to achieve both—increase oxygen delivery and decrease oxygen demand strategies include the use of antiplatelet agents and heparin to reduce intracoronary thrombosis, often accompanied by efforts to restore flow by mechanical means, including percutaneous coronary interventions using coronary stents, or (less commonly) emergency coronary bypass surgery

Antianginal drugs Nitrates Calcium channel blockers (CCBs) Beta-blocking drugs

I. 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) NO activates guanylate cyclase and increases the cells' cyclic guanosine monophosphate (cGMP), which leads smooth muscle relaxation by dephosphorylation of myosin light chain phosphate

I. 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

I. Nitrates Isosorbide mononitrate owes its improved bioavailability and long duration of action to its stability against hepatic breakdown Oral isosorbide dinitrate undergoes denitration to two mononitrates, both of which possess antianginal activity

Time to peak effect and duration of action for some common organic nitrate preparations Onset of action Duration of action Key: Nitroglycerin Isosorbide dinitrate 5 min 1hr Sublingual tablet or spray Oral, sustained- release Transdermal 2 min 25 min Sublingual Oral, slow-release 30 min 8 hrs 35 min 4-8 hrs Isosorbide mononitrate 30 min 8-14 hrs Oral, extended- release 30 min 12 hrs

I. Nitrates & nitrites Cardiovascular effect Nitrovasodilators promote vascular smooth muscle relaxation 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) Nitroglycerin dilates the coronary vasculature, providing an increased blood supply to the heart muscle, but concentric atheromas can prevent significant dilation

I. Nitrates Action on platelets Nitric oxide released from nitroglycerin stimulates guanylyl cyclase in platelets as in smooth muscle The increase in cGMP that results is responsible for a decrease in platelet aggregation Unfortunately, recent prospective trials have established no survival benefit when nitroglycerin is used in acute myocardial infarction

I. Nitrates Other effects Nitrite ion reacts with hemoglobin (which contains ferrous iron) to produce methemoglobin (which contains ferric iron) Because methemoglobin has a very low affinity for oxygen, large doses of nitrites can result in pseudocyanosis, tissue hypoxia, and death The plasma level of nitrite resulting from even large doses of organic and inorganic nitrates is too low to cause significant methemoglobinemia in adults

I. Nitrates Other effects In nursing infants, the intestinal flora is capable of converting significant amounts of inorganic nitrate, eg, from well water, to nitrite ion Thus, inadvertent exposure to large amounts of nitrite ion can occur and may produce serious toxicity

I. Nitrates Clinical uses Nitrates are used to treat acute anginal attacks 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 Sublingual nitroglycerin is the DOC for prompt relieve of ongoing attack of precipitated by exercise or emotional stress Nitrates are frequently given in combination with β-blockers and CCBs

I. Nitrates Clinical use of nitrates Sublingual nitroglycerin: is the most frequently used agent for the immediate treatment of angina b/c of its rapid onset of action (1–3 minutes). Because its duration of action is short (not exceeding 20–30 minutes), it is not suitable for maintenance therapy IV nitroglycerine: has a rapid onset of action of intravenous nitroglycerin (minutes), but its hemodynamic effects are quickly reversed when the infusion is stopped. Clinical application of intravenous nitroglycerin is therefore restricted to the treatment of severe, recurrent rest angina Slowly absorbed preparations of nitroglycerin: such as buccal form, oral preparations, and several transdermal forms have been shown to provide blood concentrations for long periods but, this leads to the development of tolerance

I. Nitrates Treatment of cyanide poisoning Methemoglobin iron has a very high affinity for CN–; thus, administration of sodium nitrite (NaNO2) soon after cyanide exposure regenerates active cytochrome The cyanmethemoglobin produced can be further detoxified by the intravenous administration of sodium thiosulfate (Na2S2O3); this results in formation of thiocyanate ion (SCN–), a less toxic ion that is readily excreted

I. Nitrates Adverse effects Extensions of therapeutic vasodilation: orthostatic hypotension, tachycardia, and throbbing headache (30-60% 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 Methemoglobinemia at high blood concentration

I. 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

I. Nitrates Tolerance Tolerance may result from: True vascular tolerance: reduced capacity of the vascular smooth muscle to convert nitroglycerin to NO resulting from depletion of tissue thiol compounds Pseudotolerance: as a result of activation of mechanisms extraneous to the vessel wall. Initially, significant sympathetic discharge occurs and after one or more days of therapy with long-acting nitrates, retention of salt and water may reverse the favorable hemodynamic changes normally caused by nitroglycerin

Nitroglycerin patches are worn for 12 hours then removed for 12 hours I. Nitrates Tolerance Tolerance can be avoided by: 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 Nitroglycerin patches are worn for 12 hours then removed for 12 hours

Other nitro vasodilators Nicorandil is a nicotinamide nitrate ester that has vasodilating properties in normal coronary arteries but more complex effects in patients with angina It displays a dual mechanism of action: It opens up ATP-sensitive K+ channels, thereby causing dilatation of peripheral and coronary resistant arterioles It contains an NO2-moiety, which dilates systemic veins and epicardial coronary arteries

II. Calcium channel blockers Mechanism of action Ca2+ channel antagonists, also called Ca 2+ entry blockers, inhibit Ca2+ channel function Voltage-sensitive Ca2+ channels (L-type or slow channels) mediate the entry of extracellular Ca2+ into smooth muscle and cardiac myocytes and sinoatrial (SA) and atrioventricular (AV) nodal cells in response to electrical depolarization Voltage-sensitive channels consists of α1, α2, γ, and δ subunits

II. Calcium channel blockers Mechanism of action All the Ca2+ channel blockers bind to the α1 subunit of the L-type Ca2+ channel, which is the main pore-forming unit of the channel CCBs bind more effectively to open channels and inactivated channels

II. 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

II. Calcium channel blockers Vascular smooth muscle appears to be the most sensitive, but similar relaxation can be shown for bronchiolar, GIT, and uterine smooth muscle In the vascular system, arterioles appear to be more sensitive than veins. Therefore, orthostatic hypotension is not a common adverse effect Important differences between the available CCBs arise from the differences in their relative smooth muscle versus cardiac effects

II. Calcium channel blockers Diphenylalkylamines (e.g.Verapamil): is the least selective of any CCBs and has significant effects on both cardiac and vascular smooth muscle cells Benzothiazepines (e.g. diltiazem): it affects both cardiac and vascular smooth muscle cells; however, it has a less pronounced negative inotropic effect on the heart compared to that of verapamil Dihydropyridines: nifedipine, amlodipine, felodipine, isradipine ,nicardipine , and nisoldipine. They have a much greater affinity for vascular calcium channels than for calcium channels in the heart

II. Calcium channel blockers Organ system effects Smooth muscle All the Ca2+ channel blockers approved for clinical use 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 The dihydropyridines may cause reflex tachycardia if peripheral vasodilation is marked

II. Calcium channel blockers Organ system effects 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 Verapamil and diltiazem reduce cardiac contractility & oxygen requirement in a dose-dependent fashion

II. Calcium channel blockers Organ system effects Other effects Verapamil has been shown to inhibit insulin release in humans, but the dosages required are greater than those used in management of angina CCBs may interfere with platelet aggregation in vitro and prevent or attenuate the development of atheromatous lesions in animals. Clinical studies have not established their role in human blood clotting and atherosclerosis

II. Calcium channel blockers Organ system effects Verapamil & other CCBs have been shown to block the P-glycoprotein responsible for the transport of many foreign drugs out of cancer (and other) cells .Verapamil has been shown to partially reverse the resistance of cancer cells to many chemotherapeutic drugs in vitro

II. 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

II. Calcium channel blockers Clinical uses of CCBs Dihydroperidines (e.g. nifedipine) have a much greater affinity for vascular calcium channels than for calcium channels in the heart. Therefore can be used more safely than verapamil or diltiazem in the presence of AV conduction abnormalities and depressed cardiac function Verapamil and diltiazem produce less hypotension than dihydropyridines which can cause further deleterious lowering of pressure in patients with relatively low blood pressure

II. Calcium channel blockers Clinical uses of CCBs In patients with a history of atrial tachycardia, flutter, & fibrillation, verapamil and diltiazem provide a distinct advantage b/c of their antiarrhythmic effect Nimodipine & nicardipine, dihydropyridines, have a high affinity for cerebral blood vessels and appears to reduce morbidity after a subarachnoid hemorrhage Nicardipine is used by intravenous and intracerebral arterial infusion to prevent cerebral vasospasm associated with stroke

II. 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 calcium channel blockers

III. Beta-blockers The β-adrenergic–blocking agents 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 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 O2 requirement of glucose pathway is lower than FFA pathway During ischemia, oxidized FFA levels rise, blunting the glucose pathway Myocytes FFA Glucose Acyl-CoA Pyruvate β-oxidation Trimetazidine Metabolic modulation (pFOX): Trimetazidine Acetyl-CoA The free fatty acid oxidation hypothesis arose out of advances in understanding of myocardial metabolic pathways. Myocardial cells derive their energy via fatty acid and glucose metabolism. During ischemia the fatty acid pathway predominates. However, this pathway requires more oxygen than the glucose pathway.1 Theoretically, inhibition of fatty acid oxidation should promote a shift towards the more oxygen-efficient glucose pathway. Lopaschuk et al and Stanley have reported experimental data showing that the antianginal trimetazidine is an inhibitor of partial fatty acid oxidation (pFOX). However, MacInnes et al did not observe any inhibition with trimetazidine in other experimental models. Thus, inhibition of fatty acid oxidation as a major antianginal mechanism for trimetazidine remains to be definitively established. Energy for contraction MacInnes A et al. Circ Res. 2003;93:e26-32. Lopaschuk GD et al. Circ Res. 2003;93:e33-7. Stanley WC. J Cardiovasc Pharmacol Ther. 2004;9(suppl 1):S31-45. pFOX = partial fatty acid oxidation FFA = free fatty acid Chaitman BR, Skettino SL, Parker JO, Hanley P, Meluzin J, Kuch J, et al, for the MARISA Investigators. Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol. 2004;43:1375-1382.

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

2 Ca++ 3 Na+ Na+ 2 Ca++ 3 Na+ Na+ Late Sodium Channel Cardiac ischemia Reactive O2 species Ischemic metabolites 2 Ca++ 3 Na+ Na+ Calcium influx is increased in ischemia because of the membrane depolarization that hypoxia produces. In turn, this promotes the activity of several adenosine triphosphate–consuming enzymes, thereby depleting energy stores and worsening the ischemia

Ranolazine: Mechanism of action Ischemia Ranolazine inhibits the late inward Na current ↑ Late INa Na+ overload Ca2+ overload Ischemia is associated with disruptions in cellular sodium and calcium homeostasis. An enhanced late sodium current is likely to contribute to the sodium overload observed in ischemia. Late phase sodium channels have been shown to remain open longer in ischemic conditions. Sodium overload may result from decreased efflux and increased influx during ischemia, with greater intracellular accumulation of sodium as the duration of ischemia increases. This is followed by an increase in intracellular Calcium through the Na/Ca exchanger on the myocyte wall. Ju YK, Saint DA, Gage PW. Hypoxia increases persistent sodium current in rat ventricular myocytes. J Physiol. 1996;497 ( Pt 2):337-347. Murphy E, Perlman M, London RE, Steenbergen C. Amiloride delays the ischemia-induced rise in cytosolic free calcium. Circ Res. 1991;68:1250-1258. Jansen MA, van Emous JG, Nederhoff MG, van Echteld CJ. Assessment of myocardial viability by intracellular 23Na magnetic resonance imaging. Circulation. 2004;110:3457-3464. Diastolic relaxation failure (increased diastolic tension) Extravascular compression

Newer antianginal drugs Sinus node inhibition: Ivabradine Ivabradine blocks I(f) sodium channel in the pacemaker cells of the sinoatrial (SA) node This slows the heart rate without affecting myocardial contractile function or peripheral vascular resistance (bronchial and GIT smooth muscles) 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