Antianginals

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  • It is proposed that Na + -related Ca 2+ overload mediates a vicious cycle of ischemia begetting more ischemia. Ca 2+ overload may result in increased left ventricular diastolic tension. As a result, myocardial O 2 consumption increases and intramural small vessels are compressed, causing increased O 2 demand and decreased O 2 supply, respectively. Positive feedback during ischemia increases the imbalance between myocardial oxygen supply and demand. Na + /Ca 2+ overload and ischemia
  • Antianginals

    1. 1. Angina Pectoris
    2. 2. Angina Pectoris <ul><li>Classic angina is characterized by substernal squeezing chest pain, occurring with stress and relieved with rest or nitroglycerin. </li></ul><ul><li>May radiate down the left arm </li></ul><ul><li>May be associated with nausea, vomiting, or diaphoresis. </li></ul>
    3. 3. Angina
    4. 4. Stable Angina Classification <ul><li>Exertional </li></ul><ul><li>Variant </li></ul><ul><li>Anginal Equivalent Syndrome </li></ul><ul><li>Prinzmetal’s Angina </li></ul><ul><li>Syndrome-X </li></ul><ul><li>Silent Ischemia </li></ul>
    5. 5. Angina: Exertional <ul><li>Coronary artery obstructions are not sufficient to result in resting myocardial ischemia. However, when myocardial demand increases, ischemia results. </li></ul>
    6. 6. Angina: Variant Angina <ul><li>Transient impairment of coronary blood supply by vasospasm or platelet aggregation </li></ul><ul><li>Majority of patients have an atherosclerotic plaque </li></ul><ul><li>Generalized arterial hypersensitivity </li></ul><ul><li>Long term prognosis very good </li></ul>
    7. 7. Angina: Prinzmetal’s Angina <ul><li>Spasm of a large coronary artery </li></ul><ul><li>Transmural ischemia </li></ul><ul><li>ST-Segment elevation at rest or with exercise </li></ul><ul><li>Not very common </li></ul>
    8. 8. Angina: Syndrome X <ul><li>Typical, exertional angina with positive exercise stress test </li></ul><ul><li>Anatomically normal coronary arteries </li></ul><ul><li>Reduced capacity of vasodilation in microvasculature </li></ul><ul><li>Long term prognosis very good </li></ul><ul><li>Calcium channel blockers and beta blockers effective </li></ul>
    9. 9. Angina: Silent Ischemia <ul><li>Very common </li></ul><ul><li>More episodes of silent than painful ischemia in the same patient </li></ul><ul><li>Difficult to diagnose </li></ul><ul><li>Holter monitor </li></ul><ul><li>Exercise testing </li></ul>
    10. 10. Angina: Treatment Goals <ul><li>Feel better </li></ul><ul><li>Live longer </li></ul>
    11. 11. Angina: Prognosis <ul><li>Left ventricular function </li></ul><ul><li>Number of coronary arteries with significant stenosis </li></ul><ul><li>Extent of jeoporized myocardium </li></ul>
    12. 12. Stable Angina <ul><li>Risk stratification </li></ul><ul><li>Noninvasive testing </li></ul><ul><li>Cardiac catheterization </li></ul>
    13. 13. Stable Angina Evaluation of LV Function <ul><li>Physical exam </li></ul><ul><li>CXR </li></ul><ul><li>Echocardiogram </li></ul>
    14. 14. Stable Angina Evaluation of Ischemia <ul><li>History </li></ul><ul><li>Baseline Electrocardiogram </li></ul><ul><li>Exercise Testing </li></ul>
    15. 15. CCSC Angina Classification <ul><li>Class I </li></ul><ul><li>Class II </li></ul><ul><li>Class III </li></ul><ul><li>Class IV </li></ul><ul><li>Angina only with extreme exertion </li></ul><ul><li>Angina with walking </li></ul><ul><li>1 to 2 blocks </li></ul><ul><li>Angina with walking </li></ul><ul><li>1 block </li></ul><ul><li>Angina with minimal activity </li></ul>
    16. 16. Angina: Exercise Testing High Risk Patients <ul><li>Significant ST-segment depression at low levels of exercise and/or heart rate<130 </li></ul><ul><li>Fall in systolic blood pressure </li></ul><ul><li>Diminished exercise capacity </li></ul><ul><li>Complex ventricular ectopy at low level of exercise </li></ul>
    17. 17. Stable Angina Guidelines for Nuclear EST <ul><li>Diagnosis/prognosis for CAD </li></ul><ul><li>Non-diagnostic EST </li></ul><ul><li>Abnormal resting ECG </li></ul><ul><li>Negative EST with continued chest pain </li></ul><ul><li>Intermediate probability of disease </li></ul>
    18. 18. Stable Angina Stress Echo <ul><li>Ischemia may cause wall motion abnormalities, no rise of fall in LVEF </li></ul><ul><li>Sensitivity/specificity same as nuclear testing </li></ul><ul><li>May be better in women </li></ul>
    19. 19. Exercise Testing Contraindications <ul><li>MI—impending or acute </li></ul><ul><li>Unstable angina </li></ul><ul><li>Acute myocarditis/pericarditis </li></ul><ul><li>Acute systemic illness </li></ul><ul><li>Severe aortic stenosis </li></ul><ul><li>Congestive heart failure </li></ul><ul><li>Severe hypertension </li></ul><ul><li>Uncontrolled cardiac arrhythmias </li></ul>
    20. 20. Stable Angina Non-Invasive Evaluation
    21. 21. Cardiac Catheterization Indications <ul><li>Suspicion of multi-vessel CAD </li></ul><ul><li>Determine if CABG/PTCA feasible </li></ul><ul><li>Rule out CAD in patients with persistent/disabling chest pain and equivocal/normal noninvasive testing </li></ul>
    22. 22. Risk Factor Modification <ul><li>Hypertension </li></ul><ul><li>Smoking </li></ul><ul><li>Dyslipidemia </li></ul><ul><li>Diabetes Mellitus </li></ul><ul><li>Obesity </li></ul><ul><li>Stress </li></ul><ul><li>Homocysteine </li></ul>
    23. 23. Stable Angina Treatment Options
    24. 24. Stable Angina Current Pharmacotherapy <ul><li>Beta-blockers </li></ul><ul><li>Calcium channel blockers </li></ul><ul><li>Nitrates </li></ul><ul><li>Nicorandil </li></ul><ul><li>Aspirin </li></ul><ul><li>Statins </li></ul><ul><li>ACE inhibitors </li></ul><ul><li>Metabolic modulators </li></ul>
    25. 25. Stable Angina Considerations when Choosing a Drug <ul><li>Effect on myocardium </li></ul><ul><li>Effect on cardiac conduction system </li></ul><ul><li>Effect on coronary/systemic arteries </li></ul><ul><li>Effect on venous capitance system </li></ul><ul><li>Circadian rhythm </li></ul>
    26. 26. Nicorandil : mode of action Nitrate-like action K + channel opener ATP Dilates epicardial Coronary arteries Venodilatation Dilates peripheral arterioles Dilates coronary Resistance vessels Decreased Preload Decreased afterload ↑ coronary blood flow ↓ Myocardial O 2 requirement ↓ Myocardial O 2 requirement ↑ coronary blood flow Nicorandil dual action
    27. 27. Major Actions <ul><li>Balanced Vasodilatation – dilates both peripheral arterioles and veins </li></ul><ul><li>Direct Cardioprotective Action – Ischemic preconditioning </li></ul><ul><li>Dilates coronary arteries - <100 microns in size </li></ul><ul><li>Prevents “no Reflow” phenomenon </li></ul>
    28. 28. Nikoran – Key concepts <ul><li>Dual anti anginal action </li></ul><ul><ul><li>- Nitrate like action </li></ul></ul><ul><ul><li>- Potassium channel opening </li></ul></ul><ul><li>Does not have any adverse haemodynamic effects </li></ul><ul><ul><li>- On heart rate </li></ul></ul><ul><ul><li>- Conduction of cardiac impulse </li></ul></ul><ul><ul><li>- Myocardial contractility </li></ul></ul><ul><li>Achieves Cardio protection by Ischemic preconditioning </li></ul><ul><li>Useful in recovery of myocardial stunning </li></ul><ul><li>Useful for no-Reflow during PTCA </li></ul><ul><li>No nitrate tolerance </li></ul>
    29. 29. Pharmacokinetics <ul><li>Well absorbed. No significant first-pass metabolism. </li></ul><ul><li>Bioavailability approx 75%,C max achieved in 30 to 60 mts. </li></ul><ul><li>Metabolism mainly by de-nitration with less than 20% of an administered dose being excreted in the urine. </li></ul><ul><li>Elimination half-life of about 1 hour. </li></ul><ul><li>No clinically relevant modifications in the pharmacokinetic profile have been seen in the elderly or in patients with liver disease or chronic renal failure. </li></ul>
    30. 30. IV Indications <ul><li>Management of angina associated with ACS </li></ul><ul><ul><li>Unstable Angina </li></ul></ul><ul><ul><li>NSTEMI </li></ul></ul><ul><ul><li>STEMI </li></ul></ul><ul><li>Management of No-Reflow / Slow flow associated with </li></ul><ul><ul><li>Thrombolysis </li></ul></ul><ul><ul><li>Angioplasty </li></ul></ul><ul><ul><li>CABG </li></ul></ul>Oral Indications <ul><li>Chronic Stable Angina </li></ul>
    31. 31. Nicorandil : Oral dose <ul><li>Convenient Bid dosage </li></ul><ul><li>Start with 5 mg twice daily </li></ul><ul><li>Upward titration : 10 – 20 mg twice daily </li></ul><ul><li>Maximum : 40 mg/ day </li></ul>
    32. 32. New class of Anti-anginals <ul><li>A new class of anti--anginal drugs exert primarily metabolic action. </li></ul><ul><li>Little or no effect on coronary or hemodynamic </li></ul><ul><li>- Does not affect BP, HR </li></ul><ul><li>Have considerable potential as primary and adjunctive therapy for angina, especially in patients refractory to standard therapies. </li></ul>
    33. 33. In Aerobic Condition (60-90%) Fatty Acid Myocytes Palmitate ATP Mitochondria TCA Cycle Acetyl Co A Palm-Co A Glucose Pyruvate Myocytes Pyruvate ATP Mitochondria TCA Cycle Acetyl Co A (10-40%)
    34. 34. In Ischemic Conditions Fatty acid oxidation out-competes glucose oxidation for the energy production Glucose Pyruvate Myocytes Glycogen Lactate H + Pyruvate ATP Mitochondria TCA Cycle Acetyl Co A ADP ATP Fatty Acid Myocytes Palmitate ATP Mitochondria TCA Cycle Acetyl Co A Palm-Co A
    35. 35. Ranolazine - MOA Adapted from Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13 . Na + /H + exchang er  Late Na + current  Diastolic wall tension (stiffness) <ul><li>Extravascular compression </li></ul>Na + overload Ca 2+ overload Myocardial ischemia Ranolazine ( Oxygen supply Demand)
    36. 36. Indications <ul><li>In patients of Chronic Stable Angina </li></ul><ul><li>Who do not adequately respond to optimal medical therapy </li></ul><ul><li>Who cannot undergo revascularization </li></ul><ul><li>Who experience angina inspite of revascularization </li></ul><ul><li>Ranolazine is indicated for the treatment of chronic angina and may be used alone or in combination with traditional therapies. </li></ul><ul><li>Dosage </li></ul><ul><li>Initial dose at 500 mg b.i.d. and can be increased to 1000 mg b.i.d., as needed,based on clinical symptoms. </li></ul><ul><li>The maximum recommended daily dose of Ranolazine is 1000 mg b.i.d . </li></ul>
    37. 37. 1. Cardiovasc Drugs Ther 1994: 8 741-747 2. JAMA 2004: 291: 309 – 316 3. J AM Coll Cardiol 2004: 43 : 1375 - 1382 Nicorandil Ranolazine Hybrid between organic nitrate and ATP - sensitive K + Channel Activator (Opener) Metabolic modulator Vasodilation is achieved by Nitrate like action and through the opening of potassium channels Inhibits the late Na+ current and thus reduces the Calcium overload Direct Cardioprotective Action like Ischemic preconditioning and also prevents No Reflow Phenomenon Does not exhibit any direct cardioprotective action Does not have any significant effect on exercise tolerance Improves exercise tolerance and reduces the frequency of angina attacks in patients with ischemic heart disease 1-3 Initial dosage- 5 mg/ day Maximum dosage- 40 mg/ day (O.D/ B.I.D) Initial dosage- 500 mg/ day Maximum Dosage- 1000 mg/ day (B.I.D)
    38. 38. * Eur Heart J. 2006 Jan;27(1):42-8 . Nicorandil can be coprescribed with antiarrhtyhmic agents like Amiodarone and Diltiazem Ranolazine cannot be coprescribed with antiarrhythmic agents because of induction of torsade points due to prolongation of QT interval Nicorandil IV is indicated in Acute Coronay Syndrome Ranolazine is not indicated in Acute Coronary Syndrome Nicorandil has no effect on diabetic patients Ranolazine significantly improved glycaemic control in diabetic patients.* Nicorandil Ranolazine
    39. 39. Thank You

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