DRUGS FOR ISCHEMIC HEART DISEASE Dr. Jyoti M. Benni Asst. Prof Dept. of Pharmacology USM-KLE, IMP, Belgaum LEARNING OUTCOMES Describe pathophysiology of IHD. Describe drug groups for angina and MI based on mechanism of action & adverse effects as therapeutics in angina and myocardial infarction. Surgical interventions – PCI, CABG INTRODUCTION Angina pectoris- Is a pain syndrome due to induction of an adverse oxygen supply/demand situation in a portion of myocardium. The primary cause of angina is imbalance in blood supply, due to: a decrease in myocardial oxygen delivery an increase in myocardial oxygen demand or both The types of angina (1)Stable angina (2)Unstable angina (3)Variant angina TYPES OF ANGINA Fixed atheromatous stenosis Exertional /Typical or classic angina underlying atherosclerosis giving rise to ischemia increased oxygen demand Anginal episodes can be precipitated by exercise, cold, stress, emotions or eating Unstable angina also known as: Preinfarction angina/Crescendo angina/ Angina at rest o Vasospastic / Variant/ Prinzmetal's angina Caused by transient vasospasm of the coronary vessels Chest pain may develop at rest / sleep. CORONARY ARTERY PATHOLOGY. Increased workload on the heart Decreased oxygen supply to the heart Antianginal drugs ↑ Blood flow & ↓ oxygen demand ANTIANGINAL DRUGS: CLASSIFICATION 1. NITRATES: Short acting: Nitroglycerine, Isosorbide dinitrate (sublingual) Long acting: Isosorbide dinitrate (oral), Isosorbide mononitrate, Erythritol tetranitrate 2. β BLOCKERS: Metoprolol, Atenolol. 3. CALCIUM CHANNEL BLOCKERS: Nifedipine, Amlodipine, Nimodipine, Verapamil , Diltiazem. 4. POTASSIUM CHANNEL OPENERS: Nicorandil 5. OTHERS: Dipyridamole, Trimetazidine, Ranolazine, Ivabradine Mechanism of Action of Nitrates Nitrates are vasodilators ACTIONS OF NITRATES Peripheral vasodilation: Venodilation ↓ venous return ↓ preload myocardial workload ↓ ↓ oxygen demand ↓ ↓ Arterial dilation ↓ PVR ↓ afterload Redistribution of coronary blood flow: Decreased preload improves subendocardial perfusion Pharmacokinetic Properties of Organic Nitrates GTN / NITROGLYCERINE ISOSORBIDE DINITRATE Similar properties to GTN. Volatile liquid, T1/2 40min tabs stored in Last dose not to be taken later than 6pm. tightly closed glass bottles. ISOSORBIDE MONONITRATE High first pass ERYTHRITYL & PENTAERYTHRITOL TETRANITRATE metabolism • Longer acting, used for prophylaxis • Last dose to be taken in afternoon and SR tab once a day in morning. ADVERSE EFFECTS OF NITRO VASODILATORS The major acute adverse effects are due to excessive vasodilation Orthostatic hypotension Palpitations Severe throbbing headache Dizziness, sweating Flushing Syncope Drug Interactions: Sildenafil (PDE-5 inhibitor) used for erectile dysfunction can potentiate the actions of nitrovasodilators severe hypotension {because they inhibit the breakdown of cGMP (they should not be taken within 24 hours of taking a nitrovasodilator) } TOLERANCE WITH NITROVASODILATORS Continuous or frequent exposure can lead to the development of complete tolerance Nitrate-free periods of at least 8 hrs (e.g.- overnight) are recommended to avoid or reduce tachyphylaxis Monday morning disease/sickness- in GTN, explosives factory workers. Sudden withdrawal has resulted in myocardial infarction, due to vasospasm. WITHDRAWAL OF NITRATES SHOULD BE GRADUAL. USES: 1. Angina pectoris Acute pain (stable) Tab. NTG 0.5mg SL, repeat 3 doses every 5min, prophylaxis- long acting nitrates. Acute prophylaxis- SL NTG 15min before exertional activities Unstable angina: Inj. NTG 5-10 µg/min IV infusion Variant angina – relieve vasospasm 2. Acute Myocardial Infarction (STEMI) - NTG slow IV infusion, (monitor for HR & BP) 3. CHF / CCF- ↓ preload 4. Others : Biliary colic, Esophageal spasm, Cyanide poisoning BETA-ADRENERGIC BLOCKERS Cardioselective agents preferred Beneficial effects 1. Negative Chronotropic action: prevent arrhythmias 2. Negative Inotropic ( work load) : Improve myocardial perfusion (more time spent in diastole) 3. Reduce myocardial O2 demand & benefit by reduce risk of impending MI/sudden cardiac death. 4. Favorable redistribution of blood flow in the ischemic subendocardial region 18 Atenolol, Metoprolol Caution: should be taken on regular basis. No abrupt withdrawal after chronic use, may ppt MI β blocker withdrawal syndrome AVOID BETA BLOCKERS IF: PR interval (ECG) >0.24 s 2° or 3° atrioventricular block Heart rate <60 beats/min Blood pressure <90 mmHg Shock Left ventricular failure with congestive heart failure Severe reactive airway disease CALCIUM CHANNEL BLOCKERS CLASSIFICATION: i) Dihydropyridines: Nifedipine, Felodipine, Amlodipine, Nitrendipine, Nimodipine, Lacidipine, Clevidipine, Clinidipine ii) Phenyl alkylamines: Verapamil. iii) Benzothiazepine: Diltiazem. CALCIUM CHANNELS: TYPES Location Cardiac & smooth 1) Voltage sensitive Ca++ Channels: muscle, SAN, AVN L (long lasting) type Regulate- excitation contraction T( transient) type coupling; conduction velocity N (neuronal) type. 2) Receptor operated Ca++ Channels 3) Leak Channels or stretch operated channels + ++ 4) Na - Ca Exchange channel CCB’S CALCIUM CHANNEL BLOCKERS Nefidepine, verapamil, Diltiazem Cardiac effects Vascular effects NIFEDIPINE: Rapid onset, short duration Decreases PVR, BP falls Reflex Tachycardia (Reflex sympathetic stimulation of heart). ADR: palpitations, flushing, ankle edema, hypotension, headache, drowsiness, voiding difficulty in elderly males, hampers DM. Dose: 5, l0 mg tab; 10, 20, 30 mg SR tab Felodipine, Lacidipine: : long t1/2 Amlodipine: slow oral abs, peak after 6-9hrs, BA higher, t1/2 is longer 35-45hrs. Nitrendipine: releases NO from endothelium & inhibit cAMP PDE. It retards atherosclerosis. Nimodipine: short acting, penetrates BBB, selectively relaxes cerebral vasculature. Approved in trt of SAH, Congenital Intracranial aneurysms. CA++ CHANNEL BLOCKERS: DRUG INTERACTIONS Avoid -blockers in combination with verapamil, diltiazem Bradycardia, AV block Avoid Verapamil & Diltiazem- increase in plasma digoxin levels AV block can also occur USES OF CCB’S: 1) Chronic stable angina- prophylaxis, variant angina- DOC, verapamil, amlodipine - relieve spasm 2) Hypertension- long acting DHP’s gp..EX: Tab Amlodipine 3) Cardiac arrhythmias- Verapamil & Diltiazem are highly effective in PSVT and supraventricular tachyarrhythmias. 4) Hypertropic cardiomyopathy- Verapamil/ Diltiazem 5) Others: Premature labor (Nifedipine), Migraine (verapamil), Nocturnal leg cramps, (verapamil), Raynaud’s disease( DHP’s). OTHER ANTIANGINAL DRUGS: DIPYRIDAMOLE Powerful coronary dilator, Inhibits platelet aggregation increases blood flow by preventing uptake and degradation of adenosine USES: prophylaxis of coronary & cerebral thrombosis Dilates resistance vessels but no effect on large conducting coronary vessels ‘ Coronary steal phenomena’ TRIMETAZIDINE (* PFOX INHIBITOR/ METABOLIC MODULATORS) IMPROVE CELLULAR TOLERANCE TO ISCHAEMIA. MOA: Inhibits Mitochondrial LC3-KAT enzyme in fatty acid oxidation = ↓ FA metabolism increases glucose metabolism in myocardium. Prevents superoxide induced cytotoxicity to myocardial cells (cardioprotective) PK: absorbed orally, t1/2 6hrs SE: gastric burning, dizziness, fatigue & muscle cramps Uses: • Add on drug in Angina and Post MI patients along with conventional drugs *pFOX: partial Fatty acid OXidation pathway DRUG THERAPY IN ACUTE MI (STEMI): Includes 1. Diagnosis of MI- Symptoms/signs Serial ECG changes Cardiac enzyme markers 2. Immediate Medical Management ( emergency care) Treatment of complications of MI 3. Post MI drug therapy (prophylaxis) 4. Post MI life style management IMMEDIATE MEDICAL MANAGEMENT 1) Analgesia – Morphine or pethidine + antiemetic - IV • reduce sympathetic activity↓↓↓ myocardial O2 consumption, vascular resistance, BP, infarct size & arrhythmias Allay anxiety 2) Sublingual GTN 0.5mg (prevent an impending MI) 3) Tab Aspirin 300mg/ Tab Clopidogrel 300mg stat dose 4) High flow Oxygen by nasal prongs Streptokinase, Anistreplase, THROMBOLYTIC DRUGS – Alteplase, Reteplase Tenecteplase, urokinase Greatest benefit if given within first 1-2hrs MOA (Golden period is initial 60 min) Limit infarct size & mortality If primary PCI available: preferred EARLY MEDICAL MANAGEMENT 6) Prevention and treatment of arrhythmias prophylactic IV infusion of β blockers (unless contraindicated) – Metoprolol 5-15mg IV/ 50-100mg PO “reduce arrhythmias and infarct size” & mortality If Tachyarrhythmias- lidocaine, procainamide Bradyarrhythmias & heart block- atropine, electric pacing. 7) Maintenance of blood volume & Correction of acidosis– do not volume overload POST MI DRUG THERAPY (FOR PREVENTION OF FUTURE ATTACKS) Chronic prophylaxis drugs – life long Antiplatelet drugs • Aspirin 75-150mg/day ±Clopidogrel 75mg/day • Prevent arrhythmias & reinfarction β blockers 1 • Tab Metoprolol 50mg BID ACE Inhibitors/ • Prevention of cardiac remodeling and Angiotensin Receptor subsequent CHF, improve survival. Blockers • Tab. Ramipril 2.5mg BD, Tab.Valsartan 40-160mg BD • Hypolipidaemic & anti-inflammatory activity Statins cardioprotective • ex Tab Simvastatin 20-80mg/day POST MI LIFESTYLE MODIFICATION SURGICAL INTERVENTIONS (REVASCULARIZATION) PTCA (Percutaneous transluminal coronary angioplasty)- Balloon angioplasty Process of dilating coronary artery stenosis by an inflatable balloon introduced into arterial circulation via femoral / brachial/ radial artery. Coronary angiography showing a severe proximal