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  • 1. Antianginal drugs CVS Pharmacology Dr. Hiwa K. Saaed College of Pharmacy, University of Sulaimani28-Jun-14
  • 2. 28-Jun-14 Partial occlusion of coronary blood vessels by atherosclerotic plaque occurs in ~75% of adults in developed countries. Symptoms may not manifest until late in the history of the disease, but coronary atherosclerosis can lead to: Angina Angina (ischaemic chest pain): Myocardial infarction (heart attack): caused by the complete occlusion of the coronary artery and associated death of tissue Is a characteristic sudden, severe, pressing-like substernal chest pain radiating to the neck, jaw, back, and arms.
  • 3. What is Angina? ANGINA is pain or discomfort in the chest caused by inadequate blood flow through the coronary blood vessels, is a consequence of myocardial O2 demand exceeding supply. Is the principle symptom of ischemic heart disease (IHD); This is sometimes called myocardial ischaemia
  • 4. Angina pectoris  a spasm of the vascular smooth muscle  obstruction of blood vessels caused by atherosclerotic lesions These transient episodes (15 seconds to 15 minutes) of myocardial ischemia DO NOT cause cellular death, such as occurs in myocardial infarction (MI). 28-Jun-14 Angina is often brought on by exertion or excitement (when the O2 demands of the heart increase) from:
  • 5. Angina vs Heart attack 28-Jun-14
  • 6. Types of Angina  Chronic stable angina also called classic, typical, or effort angina  Unstable angina also called preinfarction or crescendo angina  Vasospastic angina also called Prinzmetal’s or variant angina 28-Jun-14
  • 7. Stable angina: the most common (90%) is chest pain caused by a temporary inadequacy of blood flow to the myocardium • Usually lasts 1-15 minutes, and is provoked by exercise, stress, extreme cold or heat, heavy meals, alcohol, or smoking. Rx: is promptly relieved by rest or nitroglycerin (a vasodilator). • The underlying cause is usually occlusion of the coronary arteries by atheroma - the narrowing of blood vessels by deposits of fatty or fibrous material
  • 8. B. Unstable angina  lies between stable angina and MI.  The pathology is similar to that involved in MI: a platelet- fibrin thrombus associated with a raptured atherosclerotic plaque, but without complete occlusion of the blood vessel. 1. chest pains occur with increased frequency 2. precipitated by progressively less effort. 3. The symptoms are NOT relieved by rest or nitroglycerin. 4. requires hospital admission and more aggressive therapy to prevent death and progression to MI. 28-Jun-14
  • 9. C. Prinzmetal's or variant or vasospastic angina  caused by spontaneous coronary artery spasm either at work or at rest ...  the angina attacks are unrelated to physical activity, HR, or BP.  generally responds promptly to coronary vasodilators, such as nitroglycerin and calcium-channel blockers.  but β-blockers are contraindicated??? 28-Jun-14
  • 10. Purpose of drug treatment  Relieve symptoms  Minimize the frequency, duration and intensity of attacks.  Improve the patient’s functional capacity with as few side effects as possible  Stop and regression of the disease process  Prevent or delay the worst possible outcome, MI & death 28-Jun-14
  • 11.  To reduce the cardiac workload and metabolic demand  To increase the perfusion of the heart muscle  To prevent myocardial infarction Organic nitrates, Ca2+ antagonists, β-adrenoreceptor antagonists Lipid lowering drugs, particularly statins, can be given if elevated plasma cholesterol levels are detected Antiplatelet drugs, especially low-dose (75mg) aspirin to reduce the possibility of thrombosis. Fibrinolytic drugs (e.g. heparin) are used in unstable angina Therapeutic goals
  • 12. Therapeutic strategies There are two treatment options: 1. Increase blood flow to ischemic heart muscle and/or 2. Decrease myocardial oxygen demand 28-Jun-14
  • 13. 28-Jun-14
  • 14. Determinant of myocardial O2 demand  Preload- diastolic filling pressure  Afterload-peripheral vascular resistance  Heart rate  Wall tension  Ejection time 28-Jun-14
  • 15. Angina-precipitating factors: exercise, emotional stress, sex ↑sympathetic activity ↑HR, Contraction force, wall tension, TPR ↑ work of the heart ↑ myocardial O2 demand ≠ myocardial O2 supply Ischemia 28-Jun-14
  • 16. Organic nitrates: 28-Jun-14 Nitroglyserin, Isosorbid dinitrat, Isosorbid mononitrate  ↓Preload  ↓ Afterload  Relieving vasospasm  Redistribution blood flow
  • 17. Glyceryl trinitrate, isosorbide mononitrate ANP Myosin Myosin P + Actin Smooth muscle cell CONTRACTION GC GTP cGMP ATP cAMP PDE inactivation SR ATP dependent Ca2+ pump Ca2+ store MLCK Myosin phosphatase Calmodulin PLC PL NO RelaxationContraction Endothelium Endothelin Depolarisation Adenosine or PGI2 Angiotensin Hyperpolarisation K+ AC GC GTP cGMP PKG PKA Ca2+ calmodulin  [Ca2+]i Ca2+ IP3 Na+ Ca2+
  • 18. Common nitrate preparations Plaque Collateral dilated Effect of nitrates Blood flow to ischaemic area of myocardium increased Glyceryl trinitrate can be taken by sublingual tablet or spray The effects start within minutes and last ~30 min Transdermal patches and i.v. preparations are also available Isosorbide mononitrate is a longer acting preparation which is given orally (half-life 4hrs), and slow release preparations are available. Side effects: nitrates can cause headache because of the pronounced vasodilation, and postural hypotension because of the drop in blood pressure
  • 19. B blockers :  Atenolol, metoprolol, propranolol, bisoprolol  ↓ HR,  ↓contractility,  ↓systolic wall tension,  ↑perfusion time 28-Jun-14
  • 20. CCBs: a,mlodipine, diltiazem, felodipine, nicardipine, nifedipine, verapamil All  ↓ afterload,  coronary vasodilation Verapamil & deltiazem:  ↓HR,  ↓contractility→↓O2 demand 28-Jun-14
  • 21. Organic nitrates & nitrites  are simple nitric and nitrous acid esters of glycerol.  They differ in their volatility. For example, 1. isosorbide dinitrate and isosorbide mononitrate are solids at room temperature, 2. nitroglycerin is only moderately volatile, and amyl nitrite is extremely volatile.  They are effective in all types of angina pectoris. 28-Jun-14
  • 22. Nitrates: Effects on CVS at therapeutic doses :has 2 major effects  a) Dilation of the large veins resulting in pooling of blood in the veins which diminish the preload and reduces the work of the heart  b) Dilates the coronary vasculature providing increased blood supply to the heart muscle  The total effect is a decrease in myocardial oxygen consumption because of decreased cardiac work 28-Jun-14
  • 23. A. Mechanism of action  relax vascular smooth muscle by their intracellular conversion to nitrite ions, to nitric oxide,  activates guanylate cyclase (GC) and increases the cGMP.  dephosphorylation of the myosin light chain, vascular smooth muscle relaxation. 28-Jun-14
  • 24. 28-Jun-14
  • 25. Pharmacokinetics of Nitroglycerin  Prototype: nitrate  significant first-pass effect metabolism of nitroglycerin occurs in the liver with PO forms  Therefore, it is common to take the drug either sublingually or via a transdermal patch,  The time to onset of action varies from 1 minute for nitroglycerin to more than 1 hour for isosorbide mononitrate. 28-Jun-14
  • 26. Pharmacokinetics  Isosorbide mononitrate owes its improved bioavailability and long duration of action to its stability against hepatic breakdown.  Oral isosorbide dinitrate undergoes denitration to two mononitrates, both of which possess antianginal activity. 28-Jun-14
  • 27. 28-Jun-14
  • 28. Nitrate Side Effects  long acting preparations cause headache in about 30% - 60% of patients  high doses can cause postural hypotension, flushing & tachycardia 28-Jun-14
  • 29. NITRATES TOLERANCE  Tolerance develops rapidly. The blood vessels become desensitized to vasodilation.  providing a daily “nitrate-free interval” to restore sensitivity to the drug.  This interval is typically 10 to 12 hours, usually at night, because demand on the heart is decreased at that time.  Nitroglycerin patches are worn for 12 hours then removed for 12 hours.  However, variant angina worsens early in the morning, perhaps due to circadian catecholamine surges.  Therefore, the nitrate-free interval in these patients should occur in the late afternoon. 28-Jun-14
  • 30. Antianginal Agents: Beta Blockers  atenolol, metoprolol, propranolol, nadolol  Are used only for prophylactic therapy of angina; they are of no value in an acute attack  Effective in preventing exercise-induced angina  But are ineffective against the vasospastic form 28-Jun-14
  • 31. Mechanism of Action  Suppress the activation of the heart by blocking B1 receptors I. Decrease the HR, resulting in: 1. decreased myocardial oxygen demand. 2. increased oxygen delivery to the heart. II. Decrease myocardial contractility, helping to conserve energy or decrease demand III. Reduce the work of the heart by decreasing COP and causing a slight decrease in BP 28-Jun-14
  • 32. Beta Blockers  Cardioselective β-blockers, such as metoprolol or atenolol, are preferred.  Thus, Propranolol is not preferred  Agents with intrinsic sympathomimetic activity (for example, pindolol) are less effective and should be avoided in angina.  The dose should be gradually tapered off over 5 to 10 days to avoid rebound angina or hypertension.  Side Effects:? 28-Jun-14
  • 33. Reasons for Using Nitrates and β-Blockers in Combination in Angina  β-Blockers prevent reflex tachycardia and contractility produced by nitrate-induced hypotension.  Nitrates prevent any coronary vasospasm produced by β-Blockers.  Nitrates prevent increases in left ventricular filling pressure or preload resulting from the negative inotropic effects produced by β-Blockers . 28-Jun-14
  • 34. Calcium Channel Blockers (CCBs) ex : verapamil, deltiazem, nifidipine  Calcium is essential for muscular contraction.  The CCBs protect the tissue by inhibiting the entrance of Ca+2 into cardiac and smooth muscle cells of the coronary and systemic arterial beds.  All CCBs are therefore arteriodilators that cause a decrease in vascular resistance. 28-Jun-14
  • 35. calcium-channel blockers 1. Verapamil mainly affects the myocardium, 2. whereas nifedipine exerts a greater effect on smooth muscle in the peripheral vasculature. 3. Diltiazem is intermediate in its actions. They lower blood pressure may worsen heart failure due to their -ve inotropic effect. 28-Jun-14
  • 36. calcium-channel blockers: Mechanism of Action  Cause peripheral arterial vasodilation  Reduce myocardial contractility (-ve inotropic action)  Result: decreased myocardial oxygen demand 28-Jun-14
  • 37. Mechanism of Action 28-Jun-14
  • 38. Calcium Channel Blockers  A- Nifedipine  a dihydropyridine derivative.  functions mainly as an arteriolar vasodilator.  This drug has minimal effect on cardiac conduction or heart rate.  Used in variant angina caused by spontaneous coronary spasm 28-Jun-14
  • 39. A- Nifedipine  Other members of this class, amlodipine, nicardipine, and felodipine,  have similar cardiovascular characteristics except for amlodipine, which does not affect heart rate or cardiac output. 28-Jun-14
  • 40. B- Verpamil  The diphenylalkylamine  slows cardiac atrioventricular (AV) conduction directly,  and decreases HR, contractility, BP, and oxygen demand.  causes greater -ve inotropic effects than nifedipine, but it is a weaker vasodilator. 28-Jun-14
  • 41. Verapamil  is extensively metabolized by the liver.  is contraindicated in patients with preexisting depressed cardiac function or AV conduction abnormalities.  Drug Interaction: verapamil increases digoxin levels.  It also causes constipation. 28-Jun-14
  • 42. C-Deltiazem  Its cardiovascular effects similar to verpamil  Reduce the HR but lesser than verpamil  Reduce BP  Relieve coronary artery spasm so used in variant angina  Can be used in angina in patients with concomitant diseases 28-Jun-14
  • 43. Therapeutic Uses of deltiazem I. First-line agents for treatment of: 1. angina, 2. hypertension, 3. supraventricular tachycardia II. Short-term management of atrial fibrillation and flutter 28-Jun-14
  • 44. Side Effects Very acceptable side effect and safety profile, May cause:  hypotension,  palpitations,  tachycardia or bradycardia,  constipation,  nausea,  dyspnea 28-Jun-14
  • 45. 28-Jun-14
  • 46. NEWER ANTIANGINAL DRUGS  Metabolic modulators, eg, ranolazine, trimetazidine  Direct bradycardic agents, eg, ivabradine  Potassium channel activators, eg, nicorandil 28-Jun-14
  • 47. Thank you 28-Jun-14

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