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Recent advances in ischemic heart diseases
- 1. { RECENT ADVANCES IN ISCHEMICHEART DISEASES By Dr. Sachin R. Choudhari JR 2, Dept. of Pharmacology SVNGMC , Yavatmal
- 2. INTRODUCTION WHATIS ANGINA PECTORIS ??? AVAILABLE TREATMENT OTHER ANTIANGINAL DRUGS NEED FOR NEW AGENTS RECENTS ADVANCES SUMMARY OUTLINE…..
- 3. An imbalancebetween the supply of oxygen and the myocardial demand resulting in myocardial ischaemia Most common cause of cardiovascular morbidity and mortality Peak incidence of symptomatic IHD is age 50-60 (men) and 60-70 (women) M>F MC cause of death worldwide by 2020 Consist of Angina and Myocardial Infarction INTRODUCTION
- 4. Angina : Stable Angina Unstable Angina Variant Angina / Vasospastic Angina Myocardial infarction : STEMI NSTEMI
- 5. Principal symptomsof patient with ischemic heart disease Manifested by sudden, severe, pressing substernal pain that often radiates to the left shoulder and along the flexor surface of the left arm Usually precipitated by exercise, excitement or a heavy meal
- 6. Type of Angina Pectoris typicalStable Angina ↓ coronary flow ,Occurs on physical Exertion (five minutes or less) Unstable angina Epicardial coronary spasm & formation of non-occlusive thrombi Can Occurs at rest Heart attack (emergency) Variant , vasospastic or prinzmetal angina .. Reversible coronaryspasm .. Occurs at rest 2%
- 7.
- 8.
- 9. ACUTE ANGINA: Rest Sublingual Nitroglycerine CHRONIC ANGINA : Long acting nitrates Beta blockers CCBs K+ channel opener pFOX inhibitors CURRENT TREATMRNT STRATEGY
- 11. 1. Nitrates : a.Short acting : Glyceryl trinitrate b. Long acting : Isosorbide dinitrate Isosorbide mononitrate Erythrityl tetranitrate Pentaerythritol tetranitrate 2. Beta blockers : propranolol Metoprolol Atenolol Antianginal drug :
- 12. 3. Calcium channelblockers : a. Phenyl alkylamine : Verapamil Gallopamil b. Benzothiazepines : Diltiazem c. Dihydropyridines : Nifedipine Felodipine Amlodipine Nitrendipine Nimodipine Lacidipine Lercanidipine Benidipine 4. Potassium channel opener : Nicorandil
- 13. Others : 1.Dipyridamole 2. Trimetazidine 3. Ranolazine 4. Ivabradine 5. Oxyphendrine
- 14. Organic nitrates& nitrites are simple nitric & nitrous esters of glycerol. Cause a rapid decrease in myocardial oxygen demand Effective for all types of angina. Activation of guanylate cyclase increases cGMP activating a cGMP kinase leading to dephosphorylation of myosin light chains decreasing contractile force. Nitrates :
- 15. Reduced venous return (Dueto dilatation of the veins) Decrease left ventricular volume Decrease preload Decrease workload Decrease oxygen consumption 1st mechanism of action
- 16. Reduction on peripheralresistance (Secondary to dilatation of aorta) Decrease blood pressure Decrease after load Decrease workload Decrease oxygen consumption 2nd mechanism of action :
- 17. Coronary artery dilatation Decreasecoronary bed resistance (Relieved coronary vasospasm) Increase coronary blood flow Increase oxygen supply 3rd mechanism of action :
- 19. Throbbing headache Flushing of the face Dizziness Postural Hypotension Tolerance Dependence Methemoglobinemia Adverse effects :
- 20. Decrease oxygendemands of the myocardium by lowering the HR and contractility (decrease CO) Reduce PVR by direct vasodilatations of both arterial & venous vessels Reduce the frequency and severity of anginal episodes (when used in combination with nitrates) Improve survival in post MI patients and decrease the risk of subsequent cardiac events & complications Beta blockers :
- 21. Decrease heart rate& Contractility Increase duration of diastole Decrease workload Increase coronary blood flow Decrease O2 consumption Increase oxygen supply MOA:
- 22. Decompensated congestiveheart failure Asthma Complete heart block Contraindications :
- 24. Inhibit theentrance of Ca+2 into cardiac and smooth muscle cells of the coronary and systemic arterial beds Produce some vasodilation (↓ PVR) and (-) inotropes By acting on AV node thus serving to control cardiac rhythm They are useful in Prinzmetal angina in conjunction with nitrates Calcium channel blockers :
- 25. Works mainlyon the arteriolar vasculature decreasing after load it has minimal effect of conduction or HR. Metabolized in the liver and excreted in both the urine & the feces Causes less flushing, headache, hypotension and peripheral edema Induces less reflex sympathetic stimulation DHP other than Nifedipine:
- 26. Main effecton cardiac conduction decreasing HR and thereby O2 demand It has much more (-) inotropic effect than other Ca+2 channel blockers It is a weak vasodilator Because of its focused myocardial effects it is not used as an antianginal unless there is a tachyarrhythmia It interferes with digoxin levels causing elevated plasma levels Verapamil :
- 27. This agentfunction similarly to Verapamil however it is more effective against Prinzmetal angina Dilates coronaries It has less effect on HR It has similar metabolism and side effects as Verapamil Diltiazem :
- 28. Nausea andvomiting Dizziness Flushing of the face Tachycardia : Due to hypotension Adverse effect :
- 29. Cardiogenic shock Recent myocardial infarction Heart failure Atria-ventricular block Contraindications :
- 30. 1 . Nitratesand B-blockers : The additive efficacy is primarily a result of one drug blocking the adverse effect of the other agent on net myocardial oxygen consumption B-blockers : Blocks the reflex tachycardia associated with nitrates Nitrates : Attenuate the increase in the left ventricular end diastolic volume associated with B-lockers by increasing venous capacitance Combination therapy :
- 31. Useful inthe treatment of exertional angina that is not controlled adequately with nitrates and B-blockers B-blockers : Attenuate reflex tachycardia produce by nifedipine These two drugs produce decrease blood pressure Calcium channel blockers +beta blockers :
- 32. Useful insevere vasospastic or exertional angina (particularly in patient with exertional angina with congestive heart failure and sick sinus syndrome) Nitrates reduce preload and after load Ca channels reduces the after load Net effect is on reduction of oxygen demand Calcium channel blocker + nitrates :
- 33. Useful inpatients with exertional angina not controlled by the administration of two types of anti-anginal agent Nifidipine – decrease after load Nitrates – decrease preload B-blockers – decrease heart rate & myocardial contractility Triple drugs: Nitrates + calcium channel blockers + beta blocker
- 35. Nicorandil ,Pinacidil : Minoxidil and Diazoxide : older Drugs used in hypertension MOA: Activation of ATP sensitive K+ channel – hyperpolarization of vascular smooth muscle – relaxation of Smooth muscle Also acts as NO donor and increases cGMP : Arterio-venous relaxation Dilatation of all types of coronary vessels Potassium Channel Openers :
- 36. Benefits inangina (equipotent to nitrates, beta blockers and Ca++ channel blockers) Reduced angina frequency Increased exercise tolerance Ischaemic preconditioning for Myocardial stunning , arrhythmia and infarct size (Mitochondrial K+ATP channel opening) ADRs: Flushing, palpitation, nausea, vomiting, aphthous ulcer
- 37. Dipyridamole : Powerful coronary dilator dilates resistance vessels and abolishes autoregulation , but has no effect on larger conducting coronary vessels pharmacological success but therapeutic failure : coronary steal phenomenon By potentiating PGI2 and increasing cAMP in platelets, it enhances antiaggregatory influences Not useful as an antianginal drug Employed for prophylaxis of coronary and cerebral thrombosis in post- MI and post stroke patients Other antianginal drugs :
- 38. Labelled aspFOX (fatty acid oxidation pathway) inhibitor Inhibiting mitochondrial long chain 3-ketoacyl-CoAthiolase (LC3-KAT) Reduces fatty acid metabolism and increases glucose metabolism in myocardium Since oxidation of fatty acid requires more O2, shift back of substrate to glucose would reduce O2 demand Limiting intracellular acidosis and Na+, Ca2+ accumulation during ischaemia Protecting against Oxygen free radical induced membrane damage. Trimetazidine
- 39. No effecton HR and BP , both at rest as well as during exercise Absorbed orally, partly metabolized and largely excreted unchanged in urine t ½ : 6 hr. Widely used in France, Spain, some other European countries and India, but not in the UK or USA Mostly an add on medication to conventional therapy Side effects : gastric burning, dizziness, fatigue and muscle cramps
- 40. Acts byinhibiting a late Na+ current (late INa) in the myocardium which indirectly facilitates Ca2+ entry through Na+/Ca2+ exchanger Decrease calcium level decreases contractility (cardioprotective effect) Sparing of fatty acid oxidation No effect on HR and BP, but prolongs exercise duration in angina patient Side effects : dizziness, weakness, constipation, postural hypotension, headache and dyspepsia Ranolazine :
- 41. Several trial: Aim : To see efficacy in decreasing frequency of anginal attacks and in prolonging exercise duration 1. MARISA : (2004) 2. CARISA : (2004) 3. ERICA : (2005) 4. MERLIN TIMI 36 : (2007) It is metabolized in liver by CYP3A4 and excreted in urine
- 42. ‘Pure’ heartrate lowering antianginal drug (alternative to β blockers.) Significant action : Blockade of cardiac pacemaker (sino-atrial) cell ‘f’ channels, which are ‘funny’ cation channels Resulting inward current (If) determines the slope of phase 4 depolarization results in heart rate reduction without any other electrophysiological or negative inotropic effect HR reduction decreases cardiac O2 demand and prolongation of diastole tends to improve myocardial perfusion (O2 supply) Ivabradine :
- 43. 40% bioavailabledue to first pass metabolism; degraded by CYP3A4 and excreted in urine Side effects : Excess bradycardia , visual disturbance Indicated in chronic stable angina in patients with sinus rhythm who are intolerant to β blockers Contraindications : HR < 60/min , AF
- 44. claimed toimprove myocardial metabolism so that heart can sustain hypoxia better Its efficacy and status in coronary artery disease is not defined Can diminish or alter taste sensation. Oxyphedrine :
- 45. 1. Non selectivity 2.Affect hemodynamic parameters 3. Do not protect heart from stress induced adrenergic effects 4. Beneficial effect is short-lived 5. Tolerance Need for new drugs ???
- 46.
- 47. It’s aCCB and similar to verapamil It reduces AV conduction Can be used as adjuvant for prophylaxis of angina Did not find much favor for clinical use Side effect : Dyguesia Ladoflazine :
- 48. A Rho-kinaseinhibitor Rho kinase, an intracellular signaling molecule involved in the vascular smooth muscle contractile response to agonists such as acetylcholine, angiotensin II, endothelin, norepinephrine, platelet-derived growth factor, and serotonin In phase 2 dose-finding trials : in Japanese patients : increased maximum exercise time and time to the onset of > 1 mm ST-segment depression compared with baseline Well tolerated Minimal effects on blood pressure or heart rate at rest or during exercise FASUDIL :
- 49. A newclass of CAs, which selectively blocks T-type of Ca2+ channels Trial shows : statistically significant but clinically modest improveinent in total ETT duration Decreases all hemodynamic parameters Associated with a significantly larger reduction in the number of weekly anginal attacks Combination of mibefradil 50 mg and long-acting nitrates was well tolerated Mibefradil : (phase 2)
- 50. A newgeneration of CCBs A more vascular selective action than currently available agents A potent vasodilator in peripheral, coronary, and cerebral arterial beds and has substantially less myocardial depressant effect than nifedipine Acute administration : resulted in a larger increase in coronary blood flow and myocardial oxygen supply In acute studies, it appears to increase the myocardial oxygen supply to demand ratio Nicardipine :
- 51. First dehydropyridineavailable in both oral and intravenous dosage forms No or minimal effect on hemodynamic parameters Minimal negative inotropic or dromotropic effects even in patients with existing left ventricular dysfunction May be useful for the treatment of angina in patients with coexisting left ventricular dysfunction or borderline heart failure
- 52. Inhibitory effecton SA node leads to decrease HR It has negative chronotropic effect but little effect on AV node Causes less reflex tachycardia Slow onset of action and for longer duration Isradipine :
- 53. New DHPCCB with rapid onset of action but ultra short action It has selectivity for arterial smooth muscle as compared to vein or myocardium Useful for controlling severe HT Need to be evaluated more antianginal drugs Clevidipine :
- 54. It’s aCCB that blocks L and N type of calcium channels It dilates both arterioels and venules and thus reduces capillary pressure & reduces reflex tachycardia Used for HT Also reduces platelet activation Side effect : peripheral oedema Cilnidipine :
- 55. New secondgeneration dihydropyridine calcium antagonist Causes very similar hemodynamic changes at rest and during exercise Marked decrease in systemic vascular resistance, which was accompanied by an increase in cardiac index and stroke volume Major MOA is lowering of systemic vascular resistance Improves systolic cardiac function in patients with chronic stable angina Data also suggest an improvement in coronary blood flow during exercise Elgodipine : (phase 1)
- 56. New sydnoniminecompound in clinical development As a prodrug, it is transformed into a nitric oxide releasing metabolite in vivo In human study :Compared with placebo, blood pressure, heart rate during exercise, and cardiac output during exercise showed no significant change pirsidomine is an effective anti ischemic and antianginal agent Safety and efficacy need to be evaluated in large population Pirsidomine: (phase 2)
- 57. IHDs :Most common cause of cardiovascular morbidity and mortality Nitrates, CCB and Beta blockers are widely used agents for the Rx of Angina Currently available drugs are associated with many adverse effects In past 20 years , treatment strategies are not much changed since non availability of new drugs We need newer effective drugs which are specific in action with less adverse effects Summary :
- 58. Fkishman etal. Additional Antianginal and Anti-Ischemic Efficacy of Mibefradil in Patients Concomitantly Treated with Long-Acting Nitrates for Chronic Stable Angina Pectoris. Clin.Cardiol. 2000;Vol 21:483-490 Kuhn A , Carlsson J, Miketic S, Tebbe U. Hemodynamic and anti ischemic effects of intravenous elgodipine, a new dihydropyridine calcium channel blocker, in patients with chronic stable angina. Cardiovasc Drugs Ther. 1995 Aug;9(4):595-600. C. pepine. Nicardipine, A New Calcium Channel Blocker: Role for Vascular Selectivity. Clin. Cardiol. 12, 240-246 (1998) References :
- 59. Basics andclinical pharmacology-13th edition;BG Katzung & AJ Trevor Pharmacology for MBBS – 1st edition ; S K shrivastav Principals of pharmacology - 2nd edition ; HL sharma & KK sharma Essential of medical pharmacology- 7th edition; KD Tripathi