Lecture No 12 Treatment of Angina Pectoris.pdf

‫بسم الرحمن الرحيم‬ Pharmacological Treatment of Angina Pectoris By Imad Addeen M. Taj Addeen Faculty of Pharmacy Angina Pectoris Angina pectoris is a principal symptom of ischemic heart disease. Angina means pain, pectoris means chest. It is a severe...

‫بسم الرحمن الرحيم‬ Pharmacological Treatment of Angina Pectoris By Imad Addeen M. Taj Addeen Faculty of Pharmacy Angina Pectoris Angina pectoris is a principal symptom of ischemic heart disease. Angina means pain, pectoris means chest. It is a severe chest pain that occurs when coronary blood flow is inadequate to supply the oxygen required by the heart. The condition is characterized by sudden, severe substernal pain, which may radiate to left arm and neck or jaw. Anginal pain occurs secondary to atherosclerosis of the coronary arteries. Drugs used in angina exploit two main strategies: reduction of oxygen demand and increase of oxygen delivery to the myocardium. Angina Pectoris Etiology of Angina The primary cause of angina is an imbalance between myocardial oxygen demand and oxygen supplied by coronary vessels. This imbalance may be due to: A decrease in myocardial oxygen delivery An increase in myocardial oxygen demand or both. Goal of therapy The goal of therapy with antianginal agents is to restore the balance between oxygen supply and demand in the ischemic region of the myocardium. Angina Pectoris Etiology of Angina Angina Pectoris Determinants of Cardiac Oxygen Demand and Supply: 1. Oxygen demand, it is determined by: Heart rate Contractility Afterload and Preload.  Drugs that reduce these factors will reduce oxygen demand.  2. Oxygen supply: It is determined by myocardial blood flow by dilation of coronary arteries. Types of Angina Pectoris 1. Stable Angina: Also called exertional angina, angina of effort or atherosclerotic angina. The underlying cause is usually atherosclerosis. Anginal episodes can be precipitated by exercise, cold, stress, emotion, or eating of heavy meal. When cardiac work increases (e.g., in exercise), the obstruction of flow and inadequate oxygen delivery results in the accumulation of metabolites, e.g., lactic acid, and ischemic changes that stimulate myocardial pain endings. Therefore, rest, by reducing cardiac work, usually leads to complete relief of the pain within 15 min. Atherosclerotic angina constitutes about 90% of angina cases. Types of Angina Pectoris Therapeutic rationale of stable angina: Decrease cardiac load (preload and afterload) and Increase myocardial blood flow (vasodilatation of coronary artery). 2. Vasospastic Angina: Also called variant angina, Prinzmetal's angina Caused by vasospasm of the coronary vessels. It is responsible for less than 10% of angina cases. Associated with underlying atheromas. Noradrenaline, serotonin (5-HT) and thromboxanes may be involved in the etiology of the spasm Chest pain may develop at rest. Therapeutic rationale: Decrease vasospasm of coronary vessels Stable Angina and Vasospastic Angina Types of Angina Pectoris 3. Unstable Angina: Also called preinfarction angina, crescendo angina or angina at rest. Caused by small platelet clots at the site of a ruptured atherosclerotic plaque. Associated with a change in the character, frequency, and episodes of angina at rest. Unstable angina requires vigorous therapy as it signals the occurrence of a myocardial infarction. Therapeutic rationale: Inhibit platelet aggregation and thrombus formation; decrease cardiac load and vasodilate coronary arteries. Pharmacology of Angina Three categories of pharmacological agents are use in treatment of angina: 1. Organic nitrates and nitrites They reduce preload Reduce afterload Vasodilate coronary arteries and Inhibit platelet aggregation. 2. Calcium channel blockers They reduce afterload Vasodilate coronary arteries May inhibit platelet aggregation Some also decrease heart rate and contractility. Pharmacology of Angina 3. Beta-adrenergic antagonists They decrease heart rate Decrease contractility Decrease afterload due to decrease in cardiac output May inhibit platelet aggregation. 4. Potassium channel openers: Nicorandil 5. Others: Antiplatelet agents (low-dose aspirin, clopidogrel, prasugrel) and Statins. Treatment of Angina 1.Organic nitrates Nitrates and nitrites are polyol esters of nitric acid and nitrous acid, and respectively relax vascular smooth muscle. Examples of nitrates are: Glyceryl trinitrate (GTN, nitroglycerin). Isosorbide dinitrate (ISDN, IsordilR). Isosorbide-5-mononitrate (5-ISMN). Amyl nitrate (volatile liquid administered by inhalation). All these agents lead to the formation of the reactive free radical, nitric oxide (NO). Organic nitrates Mechanism of Action Nitrates and nitrites are converted to nitric oxide (NO) NO activates a cytosolic form of guanylate cyclase Activated guanylate cyclase catalyzes the formation of cyclic GMP (cGMP) which activate a cGMP-dependent kinases, ultimately leading to dephosphorylation of myosin light chain and relaxation of the contractile apparatus, through: Activation of Ca2+-ATPases, which increases Ca2+ efflux. Inhibition of Ca2+ channels which decreases Ca2+ influx. Hyperpolarization of the sarcolemmal membrane by stimulation of Ca2+-activated K+ channels. Mechanism of Action of Nitrates Organic nitrates Pharmacological Effects  These drugs dilate all vessels but dilation of veins predominates over that of arterioles, resulting in a large reduction in preload.  Peripheral venodilatation decreases cardiac preload and myocardial wall tension; arterial dilation reduces afterload.  Both of these actions lower oxygen demand by decreasing the work of the heart.  Large epicardial coronary arteries are dilated.  Redistribution of coronary blood flow to ischemic regions is increased in nitrate-treated patients.  Collateral flow may be increased, improving perfusion of ischemic myocardium. Pharmacological Effects of Nitrartes Organic nitrates Pharmacological Effects Nitrates and nitrites ameliorate the symptoms of classic angina predominantly through the improvement of hemodynamics. Variant angina is relieved through the effects on coronary circulation. Platelet aggregation is reduced by nitrovasodilators, by stimulation of platelet guanylate cyclase. Nitrates and nitrites form nitrosothiol in smooth muscle by reaction with glutathione. On other smooth muscles: Smooth muscles of the bronchi, oesophagus, biliary tract, etc. are relaxed by nitrates. Organic nitrates Pharmacokinetics and selected drugs Hepatic first-pass metabolism is high with GTN and ISDN. These drugs have a large first-pass effect due to the presence of high- capacity organic nitrate reductase in the liver, which inactivates them. Sublingual administration is preferred for administration of GTN and ISDN to avoid this inactivation effect. Nitrates have a t1/2 of ≤ 10 minutes Nitroglycerin Nitroglycerin is preferably administered sublingually for rapid delivery and short duration. Sustained-delivery systems are available and are used to maintain blood levels. Aerosol, topical, IV, and oral preparations are also available. Organic nitrates Amyl nitrite is a volatile liquid that is inhaled. An unpleasant odour and extensive cutaneous vasodilation render it less desirable than nitroglycerin, and it is now rarely prescribed. Isosorbide dinitrate (ISDN) ISDN has active initial metabolites. Oral ISDN is converted to its active mononitrate metabolites (5-ISMN), its bioavailability is 20%. ISDN is administered orally or sublingually; it has better oral bioavailability and a longer half-life (up to 1 h) than nitroglycerin. Timed-release oral preparations are available with durations of action up to 12 hours. Isosorbide mononitrate has comparable actions with a longer plasma half-life Oral 5-ISMN is not subjected to first-pass metabolism, and its bioavailability is 100% Organic nitrates Routes of Administration of Nitrates: Amyl nitrate administered by inhalation The sublingual route of administration nitroglycerin is rapid (onset of action 1-3 min) and effective for the treatment of acute attacks of angina pectoris and avoid first bass metabolism. Intravenous route: may be useful in the treatment of severe recurrent unstable angina Slowly absorbed preparations: used to provide prolonged prophylaxis against angina attacks Transdermal administration (ointment or patch) of GTN Organic nitrates Therapeutic uses For acute attack of angina (sublingual nitroglycerin) and for prophylaxis of angina (isosorbide mononitrate orally). Sublingual nitroglycerin is most often used for severe, recurrent Prinzmetal’s angina. Continuous infusion or slowly absorbed preparations of nitroglycerin (including the transdermal patch) or derivatives with longer half-lives have been used for unstable angina and for CHF in the presence of Ml. Hypertensive emergency: Intravenous infusion of nitroglycerin is used Biliary colic: Sublingual nitroglycerin can be used to relieve biliary spasm and associated pain. Organic nitrates Therapeutic uses Unstable angina: It requires treatment with multiple drugs: Antiplatelet agents: Low-dose aspirin, clopidogrel or prasugrel are used. Anticoagulants: Low-molecular-weight heparin, unfractionated heparin or fondaparinux. Nitrates: Nitroglycerin (sublingual) is usually effective. Beta blockers: They (atenolol, metoprolol) are routinely administered in unstable angina unless contraindicated. Calcium channel blockers (CCBs): Amlodipine, nifedipine SR, diltiazem or verapamil are used. Statins: They have been shown to improve outcome in unstable angina. Organic nitrates Adverse effects Nitrates and nitrites produce vasodilation, which can lead to orthostatic hypotension, reflex tachycardia, throbbing headache (may be dose limiting), dizziness, blushing, and a burning sensation. Large doses produce methemoglobinemia and cyanosis. Drug interaction Nitrates are contraindicated with phosphodiesterase-5 inhibitors such as sildenafil and tadalafil, due to the potentiation of the vasodilatory effects of cGMP (Fig.). This may lead to increased risk of hypotensive effects and cardiovascular events. Organic nitrates Tolerance and Dependence to Nitrates Continuous or frequent exposure to organic nitrates may lead to the development of complete tolerance. The mechanism of tolerance may be: Diminished ability to convert nitrate to NO. Diminished release of NO because of depletion of endogenous sulphahydryl group. Alterations in guanylate cyclase activation. Treatment of tolerance: Nitrate-free periods of at least 8 hours (e.g., overnight) are suggested to avoid or reduce the development of tolerance. Organic nitrates Monday disease It is an industrial disease caused by chronic exposure to vasodilating concentrations of organic nitrates in the workplace It is characterized by: Headache Dizziness and Tachycardia on return to work after 2 days absence. “Monday disease,”is due to development of tolerance (during the work week) and loss of tolerance (over the weekend) for the vasodilating action and its associated tachycardia and resulting in headache (from cranial vasodilation), tachycardia, and dizziness (from orthostatic hypotension) every Monday. Beta-adrenoceptor Blockers  Examples of beta blockers are Propranolol, metoprolol, nadolol and timolol.  The beneficial effects of beta-blockers in exertional angina are mainly due to negative chronotropic and negative inotropic effects.  Beta-Blockers have slow onset of action and are useful in anginal prophylaxis.  Cardioselective beta-blockers are preferred.  Beta-Blockers with intrinsic sympathomimetic activity (e.g. pindolol) should be avoided as they may worsen angina.  Use of beta-blocker decreases mortality in patients with recent MI; hence, it should be started early and continued indefinitely.  Combined therapy with nitrates is often preferred in the treatment of angina pectoris because of the decreased adverse effects of both agents.??? Beta-adrenoceptor Blockers Mechanism of Action They block beta-1 adrenergic receptors in the cardiovascular system. They have a negative chronotropic and inotropic effect and reduce afterload which: Decreases myocardial oxygen consumption, especially during exercise. Improves myocardial perfusion due to lower heart rate. Beta-adrenoceptor Blockers Contraindications of Beta Blockers: In patients with overt heart failure. May produce AV block in patients receiving calcium channel blockers. In patients with asthma, bradycardia and peripheral vascular disease. In diabetic patients (they mask symptoms of hypoglycemia). Beta-blockers should not be withdrawn abruptly because this may precipitate dangerous arrhythmias or MI. Beta-blockers are contraindicated in variant angina which occurs due to coronary vasospasm.??? Coronary artery has α1- and β2-adrenergic receptors. Blockade of β2- receptors results in unopposed α1-mediated vasoconstriction and aggravation of variant angina. Calcium Channel Blockers (CCB) The calcium channel blockers which may be used in treatment of angina are Verapamil, Diltiazem, Dihydropyridines (nifedipine, nimodipine and nicardipine) and Bepridil. Mechanism of action CCB agents produce a blockade of L-type (slow) calcium channels, which are abundant in cardiac myocytes, arteriole smooth muscle cells, SA nodal tissue, and AV nodal tissue, which decreases contractile force and oxygen requirements. These agents cause coronary vasodilation and relief of spasm; they also dilate peripheral vasculature and decrease cardiac afterload. Bepridil blocks L-type channels, but also has significant sodium and potassium channel blocking activity in the heart. Calcium Channel Blockers (CCB) Pharmacological Effects of CCB All of the calcium channel blockers vasodilate coronary arterioles and reduce afterload, but each drug has different effects on heart rate and cardiac contractility. Verapamil, diltiazem, and bepridil have direct negative inotropic, chronotropic, and dromotropic effects. The dihydropyridines have negligible direct effects on heart rate or contractility. Therapeutic uses: These drugs are useful for both variant and chronic stable angina and are also used in instances where nitrates are ineffective or when β-adrenoceptor antagonists are contraindicated. Adverse effects: These drugs produce hypotension and edema as common adverse effect, and serum lipids are not increased. Selected Calcium Channel Blockers (CCB) Verapamil Verapamil produces slowed conduction through the AV node (predominant effect); this may be an unwanted effect in some situations (especially in the treatment of hypertension). Verapamil may produce AV block when used in combination with β- adrenoceptor antagonists. The toxic effects of verapamil include myocardial depression, heart failure, and edema. Diltiazem Diltiazem, a benzothiazepine, is intermediate in properties between verapamil and the dihydropyridines. Diltiazem is used to treat variant (Prinzmetal’s) angina, either naturally occurring or drug-induced and stable angina. Selected Calcium Channel Blockers (CCB) Dihydropyridines: Nifedipine, isradipine, nisoldipine, and nicardipine  These dihydropyridine calcium-channel blockers have predominant actions in the peripheral vasculature; they decrease afterload and to a lesser extent preload, and lower blood pressure.  These drugs have significantly less direct effect on the heart than verapamil. Pharmacokinetic properties CCB agents can be administered orally. When administered intravenously, they are effective within minutes. Selected Calcium Channel Blockers (CCB) Adverse Effects and Contraindications of CCB These adverse effects include depression of contractility (heart failure and bradycardia). AV block and cardiac arrest. An increased incidence of sudden death (due to cardiac arrhythmia), perhaps by increasing sympathetic tone (reported with Short-acting dihydropyridines). Calcium Channel Blockers are contraindicated in: Patients with overt heart failure. Patients with AV block In patients receiving beta-blockers. Potassium channel openers (potassium channel activator) Nicorandil Nicorandil is administered orally. It causes arteriolar and venodilatation, and also improves coronary blood flow. Tolerance does not develop to its actions. The side effects are headache, hypotension, palpitation, flushing, nausea, vomiting, ulcers in the mouth, etc. General Therapeutic of Angina Treatment of Stable Angina: Maintenance therapy of chronic stable angina includes long- acting nitrovasodilators, and calcium channel blockers. In hypertensive patients, monotherapy with calcium channel blockers or beta-blockers may be sufficient. In normotensive patients, monotherapy with long-acting nitrovasodilators may be adequate. For patients with persistent hypertension, sinus bradycardia, or AV node dysfunction, nifedipine or a longer-acting dihydropyridine is the drug of choice. General Therapeutic of Angina Treatment of Vasospastic Angina: Nitrates and the calcium channel blockers are much more effective than beta-adrenergic blocker therapy Surgical revascularization and angioplasty are not indicated for patients with variant angina. Coronary Artery Bypass Grafting Coronary bypass grafting is a surgical procedure in which the affected stenosed coronary artery or arteries is bypass in an attempt to reinstitute “normal coronary blood flow”. General Therapeutic of Angina Treatment of Unstable Angina: Verapamil has been found to be more effective than propranolol in controlling unstable angina. Adding nifedipine to beta-blocker and nitrate therapy can decrease the frequency of rest angina Aspirin has been shown to reduce the incidence of cardiac events in these patients. IV heparin or thrombolytic such as streptokinase may also be indicated in some patients. Pharmacotherapy of Acute Myocardial Infarction (MI) 1. Antiplatelet agent: Aspirin, 162 mg or 325 mg orally (chewed and swallowed), is administered at once to a patient with suspected or definite MI. If the patient is allergic to aspirin, clopidogrel 300 mg is administered. Antiplatelet agent should be continued once daily. 2. Analgesia: Intravenous morphine 10 mg for relief of pain. Antiemetics like promethazine 25–50 mg slow i.v. to prevent opioid-induced vomiting. 3. Nitrates: Intravenous nitroglycerin for recurrent or persistent pain and to treat LV failure. 4. Low flow oxygen therapy (2–4 L/minute) if there is decreased oxygen saturation. 5. Reperfusion therapy: Primary percutaneous coronary intervention (PCI) or thrombolytic therapy. Primary PCI, if facilities are available. Thrombolytic therapy: Streptokinase, alteplase, tenecteplase, reteplase or urokinase is used to restore coronary patency and reperfusion of infarcted area. Pharmacotherapy of Acute Myocardial Infarction (MI) 6. Anticoagulants: Low-molecular-weight heparin or unfractionated heparin is given to prevent reinfarction and thromboembolic complications. 7. Beta-Blockers should be administered during first 24 hours unless contraindicated. They prevent reinfarction, arrhythmias and reduce mortality. 8. ACE inhibitors (e.g. ramipril) or angiotensin receptor blockers (e.g. valsartan) are administered early to improve survival. 9. Statins (e.g. atorvastatin) should be started (secondary prevention) to reduce thrombotic events and reinfarction. 10. Acidosis is treated with intravenous sodium bicarbonate. General Treatment of Angina Pectoris