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DRUGS ACTING ON CARDIOVASCULAR SYSTEM

DRUGS ACTING ON CARDIOVASCULAR SYSTEM. Myocardial ischemia. Coronary artery disease. Hypertension. Hypertrophic cardiomyopathy. Valvular heart disease. 6.5 – 16.5 million patients with stable angina 1,2. ≥ $1.9 billion in direct costs 3.

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DRUGS ACTING ON CARDIOVASCULAR SYSTEM

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  1. DRUGS ACTING ON CARDIOVASCULAR SYSTEM

  2. Myocardial ischemia Coronary artery disease Hypertension Hypertrophic cardiomyopathy Valvular heart disease 6.5–16.5 million patients with stable angina1,2 ≥ $1.9 billion in direct costs3

  3. Ischemia is related to myocardial O2 supply and demand Heart rate Diastolic time Spasm Contractility Coronary blood flow Oxygen demand Oxygen supply Collaterals Wall tension Systolicpressure Volume Ischemia

  4. Classification of Ischemic Heart Disease Acute coronary syndromes Ischemic Heart Disease Chronic coronary artery disease (stable angina) -Unstable Angina -Myocardial infarction

  5. Development of ischemia Consequences of ischemia Ischemia Ranolazine Myocardial ischemia: Sites of action of anti-ischemic medication ↑ O2 Demand Heart rate Blood pressure Preload Contractility ↓ O2 Supply Ca2+ overload Electrical instability Myocardial dysfunction(↓systolic function/ ↑diastolic stiffness) Traditional anti-ischemic medications: β-blockers Nitrates Ca2+ blockers

  6. New mechanistic approaches to myocardial ischemia • Rho kinase inhibition (fasudil) • Metabolic modulation (trimetazidine) • Preconditioning (nicorandil) • Sinus node inhibition (ivabradine) • Late Na+ current inhibition (ranolazine)

  7. Rho Fasudil Rho kinase Rho kinase inhibition: Fasudil Rho kinase triggers vasoconstriction through accumulation of phosphorylated myosin Agonist Ca2+ Ca2+ Receptor PLC PIP2 VOC ROC IP3 SR Ca2+ Myosin Myosin phosphatase MLCK Ca2+ Myosin-P Calmodulin

  8. O2 requirement of glucose pathway is lower than FFA pathway During ischemia, oxidized FFA levels rise, blunting the glucose pathway Metabolic modulation (pFOX): Trimetazidine Myocytes Glucose Free Fatty Acid Acyl-CoA Pyruvate β-oxidation Trimetazidine Acetyl-CoA Energy for contraction pFOX = partial fatty acid oxidation FFA = free fatty acid

  9. Metabolic modulation (pFOX) and ranolazine • Clinical trials showed ranolazine SR 500–1000 mg bid (~2–6 µmol/L) reduced angina • Experimental studies demonstrated that ranolazine 100 µmol/L achieved only 12% pFOX inhibition • Ranolazine does not inhibit pFOX at clinically relevant doses • Inhibition of fatty acid oxidation does not appear to be a major antianginal mechanism for ranolazine

  10. Preconditioning: Nicorandil • Activation of ATP-sensitive K+ channels • Ischemic preconditioning • Dilation of coronary resistance arterioles O N HN NO2 O • Nitrate-associated effects • Vasodilation of coronary epicardial arteries IONA Study Group. Lancet. 2002;359:1269-75. Rahman N et al. AAPS J. 2004;6:e34.

  11. If current is an inward Na+/K+ current that activates pacemaker cells of the SA node Ivabradine Selectively blocks If in a current-dependent fashion Reduces slope of diastolic depolarization, slowing HR Sinus node inhibition: Ivabradine Control Ivabradine 0.3 µM 40 20 Time (seconds) 0 0.5 –20 –40 –60 Potential (mV)

  12. Ranolazine Late Na+ current inhibition: Ranolazine Myocardial ischemia Late INa Na+ Overload Ca2+ Overload Mechanical dysfunctionLV diastolic tensionContractility Electrical dysfunctionArrhythmias

  13. 0 SodiumCurrent Late Peak Myocardial ischemia causes enhanced late INa 0 Ischemia SodiumCurrent Late Na+ Peak Impaired Inactivation Na+ Adapted from Belardinelli L et al. Eur Heart J Suppl. 2006;(8 suppl A):A10-13. Belardinelli L et al. Eur Heart J Suppl. 2004;6(suppl I):I3-7.

  14. Na+/Ca2+ overload and ischemia Myocardial ischemia Intramural small vessel compression( O2 supply) O2 demand Late Na+ current Na+ overload Diastolic wall tension (stiffness) Ca2+ overload

  15. Ranolazine: Key concepts • Ischemia is associated with ↑ Na+ entry into cardiac cells –Na+ efflux in recovery by Na+/Ca2+ exchange results in ↑ cellular [Ca2+]i and eventual Ca2+ overload –Ca2+ overload may cause electrical and mechanical dysfunction • ↑ Late INa is an important contributor to the [Na+]i - dependent Ca2+ overload • Ranolazine reduces late INa Belardinelli L et al. Eur Heart J Suppl. 2006;8(suppl A):A10-13.Belardinelli L et al. Eur Heart J Suppl. 2004;(6 suppl I):I3-7.

  16. Clinical Syndrome Episodes of Chest Pain Deficit in Myocardial Oxygen Most often caused by atherosclerotic plaques Angina Pectoris

  17. Antianginal Agents • Nitrates • Beta blockers: previously discussed • Calcium channel blockers: previously discussed

  18. Decrease Myocardial Demand for Oxygen Increase Blood Supply to Myocardium Antianginal Agents

  19. Dilate all blood vessels, primarily venous circulation, but slight arterial vasodilatation Venodilation is a result of relaxation of smooth muscle surrounding veins Potent dilating effect directly on coronary arteries!!!!!! Nitrates: Mechanism of Action

  20. Nitrates:Therapeutic Uses • Relax Smooth Muscle • Produce Vasodilatation • Decrease Preload • Decrease Workload • Decrease Afterload

  21. 4) Antianginal Drugs • Organic Nitrates • Used to treat or prevent angina • Mechanism: • Nitrates are converted to NO in vascular smooth muscle • NO activates guanylate cyclase • Increase formation of cGMP so that the intracellular calcium levels decrease • Vasodilation

  22. 4) Antianginal Drugs(Cont’d) • Relieves anginal pain by relaxing smooth muscles in the blood vessels (vasodilation) by several mechanisms • Dilate veins • Dilate coronary arteries • Dilate arterioles • Most widely used nitrate is nitroglycerin (Glyceryl trinitrate) • Since it is highly lipid soluble, it can be administered by sublingual and transdermal route, as well as oral and intravenous routes • Most widely used nitrate is nitroglycerin (Glyceryl trinitrate) • Since it is highly lipid soluble, it can be administered by sublingual and transdermal route, as well as oral and intravenous routes

  23. 4) Antianginal Drugs (Cont’d) • Nitrate preparations and dosage

  24. 4) Antianginal Drugs (Cont’d)

  25. 4) Antianginal Drugs (Cont’d)

  26. 4) Antianginal Drugs (Cont’d) • Tolerance • Tolerance to nitrate induced vasodilation can develop rapidly • This may be due to depletion of sulfhydryl (S-H) groups in the vascular smooth muscle. These groups are needed to convert nitrate to NO

  27. 4) Antianginal Drugs (Cont’d) • Adverse Effects • Headache • Orthostatic hypotension • Symptoms include light headedness and dizziness • Reflex tachycardia

  28. Older antianginal drugs: Pathophysiologic effects O2 Supply O2 Demand Coronary blood flow Heart rate Arterial pressure Venous return Myocardial contractility Drug class β-blockers DHP CCBs Non-DHP CCBs Long-acting nitrates * / Boden WE et al. Clin Cardiol. 2001;24:73-9.Gibbons RJ et al. ACC/AHA 2002 guidelines. www.acc.org/clinical/guidelines/stable/stable.pdf Kerins DM et al. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. CCB = calcium channel blocker DHP = dihydropyridine *Except amlodipine

  29. Older antianginal drugs: Clinical conditions that may limit use *Treated with PDE5 inhibitors †Nondihydropyridine CCBs Gibbons RJ et al. ACC/AHA 2002 guidelines. www.acc.org/clinical/guidelines/stable/stable.pdf

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