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Myocardial Ischemia

Myocardial Ischemia. Manifests in Different Forms:. Stable Angina (atherosclerotic block of coronary artery) Unstable Angina (rupture of atherosclerotic plaque) Silent / Effort Ischemia (Often induced by exercise) Variant Angina (focal/diffuse coronary vasospasm)

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Myocardial Ischemia

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  1. Myocardial Ischemia

  2. Manifests in Different Forms: • Stable Angina(atherosclerotic block of coronary artery) • Unstable Angina(rupture of atherosclerotic plaque) • Silent / Effort Ischemia(Often induced by exercise) • Variant Angina(focal/diffuse coronary vasospasm) • Myocardial Infarction(Heart Attack, death of tissue)

  3. Pathophysiology:Etiology Atherosclerosis: Deposition of Fatty Substances esp. cholesterol or fatty acids in arteries Risks Factors include: Hypertension Hyperlipidemia Obesity Carbon Monoxide in Smoke Sedentary life-style

  4. Coronary Artery Spasm: Cause Unknown. May occur in patients with or without atherosclerosis Risks Factors include: Smoking Stress

  5. Pharmacological Intervention • Symptomatic(Angina) • Nitrates • Ca2+ Channel Blockers • β-Blockers • Prophylactic • Lipid Lowering Drugs • Anti-Coagulants • Fibrinolytic • Anti-platelet

  6. Determinants of Oxygen Demand Need to improve ratio Coronary blood flow / cardiac work or Cardiac O2 Supply / Cardiac O2 Requirement

  7. Coronary artery with partial blockage When a clogged artery keeps the heart from getting enough blood and oxygen, angina can occur

  8. Angina – Surgical Treatment(Coronary bypass, angioplasty, stents)

  9. Pharmacological Intervention:Drug Types • Drug Types Currently Used Reduce O2 Demand and/or Improve Coronary Flow Reduce BP Venous Return Force/Rate of Heart 1. Nitrates 2. Ca2+ Channel Blockers 3. β-Blockers Targeted towards reducing plaque formation 4. Lipid Lowering Drugs 5. Drugs Affecting Coagulation, Fibrinolysis & Platelet Aggregation Slower development of ischemia

  10. Prophylactic Intervention: Lipid Lowering Drugs 1. Statins Inhibit cholesterol synthesis 2. Resins Block cholesterol reabsorption 3. Niacin Decreased VLDL secretion 4. Fibrates Lipoprotein lipase synthesis Anti-thrombotic drugs

  11. Antianginal Agents

  12. Angina Pectoris • Angina pectoris is the chest pain or discomfort caused by inadequate coronary blood flow to the myocardium

  13. Goal of therapy To restore the balance between oxygen supply and demand in the ischemic region of the myocardium.

  14. High oxygen demand Low oxygen supply

  15. Anti anginal drugs

  16. Nitrates and nitrites Structure and mechanism Nitrates and nitrites are polyol esters of nitric acid HNO3 (nitrates) or nitrous acid HNO2 (nitrites) that relax vascular smooth muscle. Nitrates and nitrites activate guanylate cyclase and increase cyclic guanine nucleotides. This activates cGMP-dependent kinases that ultimately lead to dephosphorylation of myosin light chain.

  17. These drugs dilate all vessels: Peripheralvenodilationdecreases cardiacpreload and myocardial wall tension arterial dilation reduces afterload. Both of these actions lower oxygen demand by decreasing the work of the heart. Coronary vessels may also be dilated, and coronary blood flow to ischemic regions is increased.

  18. Nitrates and nitrites ameliorate the symptoms of classic angina predominantly through the improvement of hemodynamics. Variant angina is relieved through effects on coronary circulation. Nitrates and nitrites form nitrosothiol in smooth muscle by reaction with glutathione. Tolerance occurs upon glutathione depletion.

  19. Bioavailability and selected drugs These drugs have a large first-pass effect due to the presence of high-capacity organic nitrate reductase in the liver, which inactivates drugs. Nitrates have a t1/2 of less than 10 minutes.

  20. Nitroglycerin Nitroglycerin is preferably administered sublingually for rapid delivery and short duration. Sustained-delivery systems [Transderm-Nitro, Nitrodisc] are available and are used to maintain blood levels. Aerosol, topical, intravenous, and oral preparations are also available.

  21. Amyl nitrite is a volatile liquid that is inhaled. An unpleasant odor extensive cutaneous vasodilation render it less desirable than nitroglycerin.

  22. Isosorbide dinitrate Isosorbide dinitrate has active initial metabolites. This drug 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.

  23. Therapeutic uses Sublingual nitroglycerinis 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 MI.

  24. Adverse effects Nitrates and nitrites produce vasodilation, which can lead to: orthostatic hypotension reflex tachycardia throbbing headache (may be dose limiting) blushing a burning sensation. Continuous exposure may lead to tolerance. Large doses produce methemoglobinemia and cyanosis.

  25. β-Adrenoceptor antagonists β-Adrenoceptor antagonists decrease: heart rate blood pressure contractility resulting in decreased myocardial oxygen requirements. Combined therapy with nitrates is often preferred in the treatment of angina pectoris because of the decreased adverse effects of both agents. β-Adrenoceptor antagonists are contraindicated in the presence of bradycardia, AV block and asthma.

  26. Calcium channel-blocking agents Mechanism: Calcium channel-blocking agents produce a blockade of L-type (slow) calcium channels, which decreases contractile force and oxygen requirements. Agents cause coronary vasodilation and relief of spasm they also dilate peripheral vasculature and decrease cardiac afterload.

  27. Pharmacologic properties Calcium channel-blocking agents can be administered orally. When administered intravenously, they are effective within minutes. The therapeutic use of these drugs in angina is generally reserved for instances in which nitrates are ineffective or when β-adrenoceptor antagonists are contraindicated. Serum lipids are not increased. These drugs produce hypotension.

  28. Selected CCB drugs 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.

  29. The toxic effects of verapamil include myocardial depression, heart failure, and edema. Verapamil also has peripheral vasodilating effects that can reduce afterload and blood pressure. The peripheral effects of verapamil can produce headaches, reflex tachycardia, and fluid retention.

  30. Amlodipine, 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.

  31. 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.

  32. Bepridil Bepridil blocks both slow and fast sodium channels and both voltage-dependent and receptor-mediated calcium channels. Bepridil is used only when: other agents have failed or other agents have elicited intolerable adverse effects. Bepridil may cause ventricular arrhythmias.

  33. Dipyridamole Dipyridamole is a nonnitrate coronary vasodilator that interferes with uptake of the vasodilator adenosine. MOA: It inhibits thromboxane synthase, therefore lowering the levels of TXA2 and thus stops the effects of TXA2 (platelet aggregation, bronchoconstriction and vasoconstriction). It inhibits the cellular reuptake of adenosine into platelets, red blood cells and endothelial cells leading to increased extracellular concentrations of adenosine. It also inhibits the enzyme adenosine deaminase, which normally breaks down adenosine into inosine. This inhibition leads to further increased levels of extracellular adenosine. Dipyridamole also inhibits the phosphodiesterase enzymes that normally break down cAMP (increasing cellular cAMP levels and blocking the platelet response to ADP) and/or cGMP (resulting in added benefit when given together with NO or statins).

  34. Dipyridamole may be used for prophylaxis of angina pectoris, but the efficacy of this drug is not proved. • Dipyridamole produces adverse effects that include the worsening of angina, dizziness, and headache.

  35. K CHANNEL OPENERS : The most prominent action of K+ channel openers is Causes Smooth muscle relaxation of Vascular and Visceral tissues. Nicorandil Cromakalin

  36. Trimetazidine Used for angina pectoris. Trimetazidine is an anti-ischemic (anti-anginal) agent, that improves myocardial glucose utilization through inhibition of fatty acid metabolism By preserving the energy metabolism in cells exposed to hypoxia or ischemia, trimetazidine prevents a decrease in intracellular ATP levels, thereby ensuring the proper functioning of ionic pumps and transmembranous sodium-potassium flow whilst maintaining cellular homeostasis. It also inhibits oxidation of fatty acid in blood vessels.

  37. Drugs Affecting Plaque Formation

  38. Anti-thrombotic drugs There are three main classes of anti-thrombotic drugs Anti-coagulant drugs Fibrinolytic drugs Anti-platelet drugs

  39. Anticoagulant and antiplatelet drugs inhibits the coagulation process and administered to prevent the initial formation of thrombi/recurrence of thrombi. Fibrinolytic drugs act by dissolving existing thrombi or emboli and play an important role in the acute treatment of thrombosis.

  40. The principal indications of anti-thrombotic drugs are: The prevention and treatment of venous thromboembolism (VTE) The prevention of stroke in patients with atrial fibrillation The prevention and treatment of acute coronary syndrome (ACS)

  41. Anti-coagulants There are three principal classes of anticoagulants: Heparins Direct factor Xa inhibitors Vitamin K antagonists Direct thrombin inhibitors

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