Drug Treatment of Ischemic Heart Disease Munir Gharaibeh, MD, PhD,

Drug Treatment of Ischemic Heart Disease Munir Gharaibeh, MD, PhD, MHPE Faculty of Medicine, The University of Jordan November, 2014

Categories of Ischemic Heart Disease Fixed "Stable“, Effort Angina Variant Angina “Primary Angina” Unstable Angina Myocardial Infarction

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Secondary Angina Primary Angina Classical Angina of Effort Variant (Prinzmetal’s) Angina at Rest Typical Atypical 1768 1957 Small vessels Large vessels Single or multiple Single Atherosclerosis Vasospasm ST depression 03/07/23 ST elevation Munir Gharaibeh MD, PhD, MHPE 4

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Stunning?: Myocardial stunning is the reversible reduction of function of heart contraction after reperfusion not accounted for by tissue damage or reduced blood flow. 03/07/23 Munir Gharaibeh MD, PhD, MHPE 6

Control of smooth muscle contraction Contraction is triggered by influx of calcium through L-type transmembrane calcium channels. The calcium combines with calmodulin to form a complex that converts the enzyme myosin light-chain kinase to its active form (MLCK*). MLCK phosphorylates the myosin light chains, thereby initiating the interaction of myosin with actin. Beta2 agonists (and other substances that increase cAMP) may cause relaxation in smooth muscle by accelerating the inactivation of MLCK and by facilitating the expulsion of calcium from the cell. 03/07/23 Munir Gharaibeh MD, PhD, MHPE 7

Control of vascular smooth muscle contraction 03/07/23 Munir Gharaibeh MD, PhD, MHPE 8

Mechanism of IHD Due to an imbalance of the ratio: O2 Supply (Coronary Blood Flow) O2 Demand (Work of the Heart) 03/07/23 Munir Gharaibeh MD, PhD, MHPE 9

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Pharmacological modification of the major determinants of myocardial O2 supply 03/07/23 Munir Gharaibeh MD, PhD, MHPE 11

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Drug effects on vascular smooth muscle contraction. Calcium influx is inhibited by CCBs, leading to muscle relaxation. Organic nitrates release nitric oxide, which activates guanylyl cyclase and increases formation of cyclic guanosine monophosphate. cGMP causes smooth muscle relaxation by activating kinases that increase myosin phosphatase activity and decrease myosin phosphate levels. α 1-Adrenoceptor agonists activate phospholipase C (PLC), which increases formation of inositol triphosphate (IP 3) from phosphatidylinositol bisphosphate (PIP 2), leading to increased release of calcium from the sarcoplasmic reticulum. β 2-Adrenoceptor agonists increase formation of cyclic Munir Gharaibeh MD, PhD, MHPE adenosine monophosphate (cAMP), which activates kinases 13 that inhibit myosin light-chain kinase. 03/07/23

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Organic Nitrates Nitroglycerine Prototype, (GTN): used for more than 140 years. Nonspecific smooth muscle relaxant. Action not antagonized by any known antagonist. 03/07/23 Munir Gharaibeh MD, PhD, MHPE 15

Nitrates, nitrites, and other substances that increase the concentration of nitric oxide (NO) in vascular muscle 03/07/23 Munir Gharaibeh MD, PhD, MHPE 16

Nitroglycerine (GTN) Usually administered sublingually. Can be administered by various routes. Fast onset of action(1-3minutes, Peaks at 10 minutes). Short duration (15-30minutes). Reductase enzyme in liver will breakdown the drug. 03/07/23 Munir Gharaibeh MD, PhD, MHPE 17

Nitroglycerine (GTN) Causes general vasodilation: Arteriolar min) dilation: short lived (5-10 Decreases systemic blood pressure (afterload) and causes reflex tachycardia and increased contractility, ?might increase MVO2. Venous dilation: more intense, even with low doses, lasts for 30 minutes. Decreases venous return (preload) and decreases MVO2. 03/07/23 Munir Gharaibeh MD, PhD, MHPE 18

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Nitroglycerine (GTN) Side Effects: Headache. Hypotension and tachycardia. Increased intraocular and intracranial pressures. Methemoglobinemia. Tolerance: only for the arteriolar effects. Withdrawal: in workers in ammunition industry. 03/07/23 Munir Gharaibeh MD, PhD, MHPE 21

Nitrate and Nitrite Drugs Used in the Treatment of Angina. Drug Duration of Action Short-acting: Nitroglycerin, sublingual 10–30 minutes Isosorbide dinitrate, sublingual 10–60 minutes Amyl nitrite, inhalant 3–5 minutes Long-acting: Nitroglycerin, oral sustainedaction 6–8 hours Nitroglycerin, 2% ointment, transdermal 3–6 hours Nitroglycerin, slow-release, buccal 3–6 hours Nitroglycerin, slow-release patch, transdermal 8–10 hours Isosorbide dinitrate, sublingual 1.5–2 hours 03/07/23 Isosorbide dinitrate, oral Munir Gharaibeh MD, PhD, MHPE 4–6 hours 22

Beta Adrenergic Blockers Prevent actions of catecholamines, so more effective during exertion. Do not dilate coronary arteries. Do not increase collateral blood flow. Cause subjective and objective improvement: decreased number of anginal episodes, nitroglycerine consumption, enhanced exercise tolerance, and improved ECG. 03/07/23 Munir Gharaibeh MD, PhD, MHPE 23

Beta Adrenergic Blockers 03/07/23 Munir Gharaibeh MD, PhD, MHPE 24

Calcium Channel Blockers Particularly beneficial in vasospasm. Can affect platelets aggregation. May be dangerous in heart failure and in patients susceptible to hypotension. 03/07/23 Munir Gharaibeh MD, PhD, MHPE 25

Properties of Several Recognized Voltage-Activated Calcium Channels. Typ e Channel Name Where Found Properties of the Calcium Current Blocked By L CaV1.1– CaV1.3 Cardiac, skeletal, smooth muscle, neurons (CaV1.4 is found in retina), endocrine cells, bone Long, large, high threshold Verapamil, DHPs, Cd2 , -aga-IIIA T CaV3.1– CaV3.3 Heart, neurons Short, small, low threshold sFTX, flunarizine, Ni2 , mibefradil1 N CaV2.2 Neurons, sperm2 Short, high threshold Ziconotide,3 gabapentin,4 -CTXGVIA, aga-IIIA, Cd2 P/Q CaV2.1 Neurons Long, high threshold -CTXMVIIC, aga-IVA 2 Neurons, sperm Munir Gharaibeh MD, PhD, MHPE Pacemaking SNX-482,26 aga-IIIA R 03/07/23CaV2.3 -

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Calcium Channel Blockers Side Effects: Hypotension. Headache, dizziness. Flushing. Peripheral 03/07/23 edema. Munir Gharaibeh MD, PhD, MHPE 32

Effects of Nitrates Alone and with Beta Blockers or Calcium Channel Blockers in Angina Pectoris. Nitrates Alone Beta Blockers or Calcium Channel Blockers Combined Nitrates with Beta Blockers or Calcium Channel Blockers Heart rate Reflex1increase Decrease Decrease Arterial pressure Decrease Decrease Decrease End-diastolic volume Decrease Increase Non or decrease Contractility Reflex1increase Decrease Non 03/07/23 Ejection time PhD, MHPE Decrease Munir Gharaibeh MD, Increase Non 33

Dipyridamole Inhibits 03/07/23 the uptake of adenosine and inhibits adenosine deaminase enzyme. Thought to be a good coronary dilator. Increases the blood flow to the normal area i.e. “Coronary Steal Phenomenon”. Still used as an antiplatelet drug (in TIAs), but not better than aspirin. Munir Gharaibeh MD, PhD, MHPE 34

Others ACEI. Anticoagulants and/or Thrombolytic Therapy. Cholesterol Lowering Agents. Angioplasty Surgery. 03/07/23 Munir Gharaibeh MD, PhD, MHPE 35

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Newer Antianginal Drugs Metabolic modulators: Ranolazine. Direct bradycardic agents: Ivabradine. Potassium channel activators: Nicorandil. Rho-kinase inhibitors: Fasudil. Sulfonylureas: Glibenclamide. Thiazolidinediones. Vasopeptidase inhibitors. Nitric oxide donors: L- arginine. Capsaicin. Amiloride. 03/07/23 Munir Gharaibeh MD, PhD, MHPE 38