Chapter 12 Drugs for angina treatment PDF

Chapter 12: Drugs Used in the Treatment of Angina Pectoris Instructor: Hui Di Wang Objectives: Explain major factors that determine cardiac O2 supply & demand Describe three forms of angina & the treatment strategy for each Discuss the use of organic nitrates, beta- blockers and cal...

Chapter 12: Drugs Used in the Treatment of Angina Pectoris Instructor: Hui Di Wang Objectives: Explain major factors that determine cardiac O2 supply & demand Describe three forms of angina & the treatment strategy for each Discuss the use of organic nitrates, beta- blockers and calcium channel blockers in antianginal therapy (mechanisms, pharmacokinetics, adverse effects)  Objectives: Explain why the combination of a nitrate with a beta-blocker or a calcium channel blocker may be more effective than either alone. Objectives: Learn the following definitions Ischemia Stable angina (atherosclerotic) Unstable angina Variant angina (Vasospastic) Coronary vasodilator Vasodilator Nitrate tolerance, tachyphylaxis Preload and afterload Double product Intramyocardial fiber tension Basic and Clinical Pharmacology Bertram G. Katzung Ch 12  Ischemia It may be defined as the reduction of blood flow to a tissue below its metabolic needs. Common types of regional ischemia include angina pectoris (heart), intermittent claudication (muscle), and cerebrovascular insufficiency (brain). Angina Angina pectoris is a sensation of strangulation, squeezing, and crushing of the chest. The defect that cause anginal pain is inadequate coronary oxygen delivery relative to the myocardial oxygen requirement. Factors that determine cardiac O2 demand (1) A major determinant is myocardial fiber tension, i.e. the higher the tension, the greater the oxygen requirement. Factors that determine cardiac O2 demand (2) Preload – Is a function of blood volume and venous tone (capacitance side). – Venous tone is mainly controlled by sympathetic outflow. – Activities that increase sympathetic activity usually increase preload. Factors that determine cardiac O2 demand (3) Afterload – Is also called arterial BP – Arterial BP depends on peripheral vascular resistance. – Peripheral vascular resistance is determined by sympathetic activity at the arteriolar vessels. Factors that determine cardiac O2 demand (4) Heart Rate Cardiac contractility  Double Product Double product is the product of heart rate and systolic blood pressure. The double product correlates with myocardial oxygen demand/consumption. Double product Factors that determine cardiac O2 demand & supply Demand: myocardial fiber tension (preload; afterload); heart rate; Cardiac contractility… Supply – myocardial blood flow – regional flow distribution  Angina is the result of an imbalance between oxygen supply and oxygen demand  Stable Angina Common triggers 4“E's”: Exertion Emotional Stress Exposure to cold or hot/humid weather Eating a heavy meal -Pain: seconds, 5-10 minutes. -more frequently in the morning: diurnal increases in sympathetic tone (Podrid, 2012).  Unstable Angina Rupture of an atherosclerotic plaque, platelet aggregation, formation of a thrombus, -a sudden increase in the frequency, intensity or duration -occur at rest -a new onset of severe anginal episodes Vasospastic angina, Prinzmetal's Angina or variant angina) -caused by focal coronary artery vasospasm in either the presence or absence of atherosclerotic plaques. (Pinto et al, 2013).  Three types of angina stable (exertional, classic angina, atherosclerotic angina) - Demand ischemia Unstable (thrombus, pain at rest; usually heralds imminent myocardial infarction) -Supply ischemia variant (vasospastic) -Supply ischemia  Angina Chronic Unstable Printzmetal’s Stable Angina Angina Variant (exertional, (thrombus) Angina classic angina, (vasospastic) atherosclerotic) Demand Supply Supply Ischemia Ischemia Ischemia Stable Angina Fig. 46-1  Stable Angina Increase in O2 demand Treatment strategy??? – Decrease O2 demand? Problems achieving increases in coronary blood flow In ischemia, blood flow may be reduced by atherosclerosis of the large conducting vessels. In that event, local control mechanisms operating in the ischemic area will dilate the small resistance vessels. Problems achieving increases in coronary blood flow Problems achieving increases in coronary blood flow Because the resistance vessels in an ischemic area are already dilated, one might predict that vasodilator drugs would be of limited usefulness in treating the ischemia. Thus, treatment is more commonly aimed at reducing oxygen demand. I. Nitroglycerin: Cellular Actions II. Calcium channel blockers III. Beta-blockers Glutathione S-transferase Platelet aggregation Nitroglycerin: Mechanisms and pharmacological effects acts directly on vascular smooth muscle primary action on VEINS, especially at low dose (preload?) minimal action on arterioles Increase heart rate. Nitroglycerin: Pharmacokinetics Nitroglycerin: Pharmacokinetics Nitroglycerin is metabolized rapidly on “first pass” through the liver. Consequently, it is often administered sublingually or transdermally (either as an ointment or a patch). Although nitrates taken orally exhibit a longer duration of action, chronic use of these preparations is often associated with the development of tolerance.  Nitroglycerin: Tolerance The effectiveness of the nitrates in relaxing smooth muscle diminishes with continuous exposure of the tissue to the nitrates. This phenomenon is termed "tachyphylaxis" or "tolerance". This may be important with long-acting orally administered compounds, or with transdermal applications. The incidence of tolerance may be reduced by intermittent administration of the preparation (e.g. patch 12 hours on and 12 hours off). Nitroglycerine: Adverse Effects The most common adverse effects are due to excessive vasodilation. – Headache – Orthostatic hypotension – Reflex tachycardia: Beta-blocker Nitroglycerine: Contraindications – Known hypersensitivit – Hypotension or uncorrected hypovolemia – Increased intracranial pressure (head trauma – Inadequate cerebral circulation – Constrictive pericarditis or pericardial tamponade Nitroglycerine: Contraindications -Concurrent use of Sildenafil (Trade Names: Viagra, Revatio ®) -Sildenafil potentiates the hypotensive effects of nitrates -After patients have taken sildenafil, it is unknown when nitrates can be safely administered within the 24 hours  Summary of Nitroglycerine (1) Nitrates, through the liberation of nitric oxide, dilate both the resistance and capacitance vessels but the effect on the capacitance side is more dramatic. By dilating capacitance vessels (venodilatation), the nitrates will decrease venous return and the filling pressures in the heart (ie they decrease the preload), and thereby decrease myocardial wall tension and oxygen demand. Summary of Nitroglycerine (2) The nitrates are rapidly inactivated through first pass metabolism in the liver. Accordingly, nitroglycerin is often administered sublingually or transdermally via a patch. Some nitrates are administered orally in huge doses to achieve therapeutic plasma concentrations.  Summary of Nitroglycerine (3) Tolerance and cross tolerance among the nitrates is a major problem with chronic administration of the nitrates, particularly the orally administered ones. The incidence of tolerance may be reduced by intermittent administration of nitrates (e.g. patch can be worn 12 hours on and 12 hours off). II. Calcium Channel Blockers Calcium Channel Blockers Nifedipine:Blood vessels>heart Verapamil: Heart>blood vessels Diltiazem: Heart>blood vessels Use for prophylaxis in angina Prophylaxis: The prevention of disease t Calcium Channel Blockers Verapamil: Heart>blood vessels Diltiazem: Heart>blood vessels Nifedipine:Blood vessels>heart Nifedipine has much less depressant activity on the heart than does diltiazem and verapamil. Calcium channel blockers: Adverse Effects Adverse effects of the calcium channel blockers depend on the particular drug but may include the followings: --Headache, constipation, edema, nausea, flushing, and dizziness. – Heart failure, atrioventricular blockade, and sinus node depression, arrhythmias. Calcium channel blockers: Adverse Effects – Prompt release formulation of Nifedipine is associated with an increased risk of myocardial infarction. What effects of nifedipine might lead to this result? Calcium Channel Blockers Stable angina: decrease O2 demand Vasospasm angina: -decrease O2 demand -increase blood flow III. Beta Adrenergic Blockers Propranolol, Atenolol, Metoprolol Beta Adrenergic Blockers Hemodynamic Effects In the presence of high sympathetic activity, such as exercise, what would be the effect of a beta blocker on: Heart rate? Cardiac contractility? Peripheral resistance? Coronary artery resistance? Beta Adrenergic Blockers: Mechanism of action In the presence of high sympathetic activity, such as exercise, what would be the effect of a beta blocker on: Heart rate? Cardiac contractility? Peripheral resistance? Coronary artery resistance? block cardiac β1 receptors->decrease O2 demond  Beta Adrenergic Blockers ß-blockers are used in the treatment of stable angina because they reduce oxygen demand. However, they are contraindicated in variant angina because they may worsen a coronary spasm, possibly by leaving a-receptors unopposed. They have a negative inotropic effect that may be hazardous to patients with heart failure. Asthma and other bronchospastic patients?  Beta Adrenergic Blockers chronic prophylaxis The ß-blockers are administered orally, they have a longer duration of action than the nitrates, and they are less prone to the development of tolerance. For this reason they are suited to the chronic prophylaxis (prevent before hand) of angina. Summary of Beta Adrenergic Blockers ß-blockers are effective in the prophylactic treatment of stable angina because they reduce myocardial oxygen demand by decreasing heart rate and contractility. ß-blockers are contraindicated in variant angina. ß-blockers exert a much longer duration of action than sublingual nitroglycerin, and tolerance is less problematic with b-blockers. Thus the b-blockers are more suited for chronic prophylaxis of stable angina. ? T.46-1 MECHANISMS OF ANTIANGINAL ACTION Mechanism of Pain Relief Drug Class Stable Angina Variant Angina  O2 supply by  O2 demand by dilating Nitrates veins, which  preload relaxing coronary vasospasm Beta  O2 demand by  heart rate Not used blockers & contractility  O2 demand by dilating Ca++ arterioles, which  afterload  O2 supply by Channel (all CCBs); relaxing coronary Blockers  heart rate & contractility vasospasm (verapamil & diltiazem)  Angina Chronic Printzmetal’s Unstable Angina Stable Angina Variant Angina 1. Nitrates 1. Nitrates 1. Nitrates 2. Beta-blockers 2. Beta-blockers Beta-blockers 3. Anti-platelet drugs 3. Calcium-Channel (aspirin) and 2. Calcium-Channel anticoagulants (heparin) Blockers Blockers 4 Morphine: reduce pain Reduce oxygen demand!!