004 Stable Ischemic Heart Disease_Pharmacology.pdf

Stable Ischemic Heart Disease (SIHD) Hany A. Omar, Ph.D Professor of Pharmacology and Toxicology Head of the Pharmacy Practice and Pharmacotherapeutics Department College of Pharmacy, UoS Of...

Stable Ischemic Heart Disease (SIHD) Hany A. Omar, Ph.D Professor of Pharmacology and Toxicology Head of the Pharmacy Practice and Pharmacotherapeutics Department College of Pharmacy, UoS Office: M23-140 email: [email protected]  Learning Objectives At the end of this lecture students should be able to: 1. Understand rationale for drug therapy in ischemic heart diseases 2. Know classes of drugs used to treat myocardial infarction 3. Mode of action of nitrates 4. Be familiar with the pharmacokinetics of nitrates and how these parameters affect the formulations and delivery methods of nitrates 5. Know clinical uses and common side effects of nitrates 6. Understand the concept of nitrate tolerance 7. Know the different types of fibrinolytics and their mechanisms of action. ANGINA PECTORIS  Angina Pectoris It is ischemic myocardial pain results from imbalance between the oxygen supply (coronary flow) and the oxygen demand of the viable myocardium. Oxygen delivery may be inadequate because of coronary vasoconstriction, decreased perfusion pressure, arterial hypoxia, decreased oxygen carrying capacity of the blood or decreased flow of blood due to high viscosity. Main symptoms of angina include: The main common symptoms of angina include severe chest pain due to ischemia of the heart muscle, Angina may feel like pressure or squeezing in chest. The pain also extends to shoulders, arms, neck, jaw or back. Angina pain may even feel like indigestion.  Types of Angina 1-Stable (effort) angina: It is the most common (typical) type of angina. It occurs if the heart is working harder than usual. Pain increases with effort and is relieved by rest. The most common cause is atherosclerosis. Stable angina has a regular pattern. 2-Unstable angina: Doesn't follow a pattern. Chest pains occur with increased frequency and precipitated by progressively less effort. Pain may not be relieved by rest or nitroglycerin. Unstable angina is very dangerous and requires hospitalization and may cause infarction. 3-Variant (Prinzmetal's) angina: Variant angina is rare. It occurs mainly due to coronary vasospasm. It usually occurs while at rest, and the pain can be severe. Variant angina usually happens between midnight and early morning. Medicine can relieve this type of angina.  Differences between Angina pectoris and myocardial infarction Angina pectoris A reversible process and there is no permanent damage to the muscle. Myocardial infarction Ischemic necrosis due to total occlusion of coronary artery by a thrombus complicating atheromatous lesion. The changes in muscle are irreversible. Angina Vs Infraction  Treatment of angina pectoris Treatment lines include agents that either: Increase oxygen supply (vasodilators) or Decrease oxygen demand (agents that decrease myocardial work).  Treatment of angina pectoris 1-Vasodilators,Organic nitrates e.g. Isosorbide dinitrate & Glyceryltrinitrate (Nitroglycerin). These drugs release nitric oxide which is responsible for the vasodilatation similar to that produced by endothelial derived relaxing factor (EDRF). Mechanism of action: The nitrate receptors in vascular smooth muscles contain -SH (sulfhydryl) groups, reduce the nitrate into nitrite and then nitric oxide (NO). NO activates guanylate cyclase  cGMP  relaxation of blood vessels by  Ca2+ influx &  Ca2+ sequestration in sarcoplasmic reticulum. Nitrates cause dilation of coronary arteries  increase oxygen supply. 1-Nitrates & Nitrites  1-Nitrates & Nitrites Cardiovascular Effects Vasodilatation in: 1) Veins  Preload,  Ventricular filling pressure  Cardiac work & O2 demand 2) Arteries  Afterload &  Cardiac work 3) Coronaries  O2 supply to ischemic area & relieve spasm Antiplatelet Aggregation Effect – NO stimulates an increase in cGMP in platelets resulting in a decrease in platelet aggregation.  1-Nitrates & Nitrites Pharmacokinetics All therapeutically active agents in the nitrate group have identical mechanisms of action and similar toxicities. Therefore, pharmacokinetic factors govern the choice of agent and mode of therapy when using the nitrates. Short-acting o Sublingual (Nitroglycerin, Isosorbide dinitrate) o Inhalation (Amyl nitrite) Long-acting o Nitroglycerin (oral sustained-release nitrite, transdermal patchs) o Isosorbide dinitrate (oral)  1-Nitrates & Nitrites Pharmacokinetics Glyceryltrinitrate – Bioavailability via the oral route is limited by hepatic organic nitrate reductase which inactivates the drug, resulting in bioavailability of 180 systolic or 110 diastolic) 5. Recent surgery  retards the healing of the wound. Relative contraindications 1. Warfarin therapy 2. Active peptic ulcer  bleeding 3. Diabetic retinopathy and a history of hypertension. 4. Ischemic stroke (?)  bleeding Complications of fibrinolytic agents Advanced age and hypertensive patients have increased risk 1. Bleeding (most common) so give aminocaproic acid to stop the bleeding. 2. Intra-cranial hemorrhage (the most serious) 0.5-0.7%. 3. It liberates the platelets and thrombin from the clot so it may make another clot in other sites. To avoid this effect we give Aspirin with it 4. Allergy to Streptokinase and anistreplase (Antigenic) Interactions Aspirin and heparin increase both the activity and risk of bleeding of fibrinolytics.  Fibrinolytic Agents Streptokinase Protein produced by streptococci. It forms a complex with plasminogen converting it to plasmin. Complications and adverse effects Allergic reactions in