Drugs used in the Management of Ischemic Heart Disease Philip Marcus, MD MPH

Clinical Correlates of Coronary Ischemia Angina Pectoris Myocardial Infarction Congestive Heart Failure Cardiac arrhythmias Atrial ventricular

Medical Therapy of Ischemia: Increase blood supply Decrease vascular (arterial) tone Improve collateral blood flow Prevention of thrombosis Decrease Oxygen consumption Prevent Disease progression Reduction of LDL cholesterol ? Reduction of homocysteine levels

Supply and Demand: Blood supply Related to coronary blood flow Regulated by circulating mediators TXA2 5HT LTC4 PGI-2 (prostacyclin) Produced by intact endothelium Vasodilator Demand Determined by Oxygen required by myocardium to meet imposed work load All result in platelet aggregation and coronary artery spasm

 Adrenergic Blocking Agents: Non-selective agents Propranolol (Inderal®) Prototype agent Highly Lipid soluble Nadolol (Corgard®) Long half-life Timolol (Blocadren®) Primarily used in glaucoma Intraocular formulation (Timoptic®) Often combined with carbonic anhydrase inhibitor Pindolol (Visken®) Noted for ISA Sotalol (Betapace®) Indicated ONLY for ventricular arrhythmias

Myocardial Oxygen Demand: Determined by the amount of O 2 required by the myocardium to meet the workload imposed on it Excess demand may cause angina despite normal coronary arteries Aortic stenosis Major Determinants of Myocardial Oxygen Consumption (MVO 2 ): Wall Tension Systolic Intraventricular Pressure Ventricular Size Ventricular Wall Thickness Heart Rate Contractility (Inotropic state)

Classification of Angina Pectoris: Classic angina Angina generally associated with effort Drugs provide only symptomatic relief Drugs do not affect underlying pathology Organic Nitrates  adrenergic blockers Calcium channel blockers Variant, vasospastic angina Drugs act to decrease coronary artery spasm Do not act to reduce demand Act to increase supply  adrenergic blockers Calcium channel blockers

Drug Therapy: Organic Nitrates Calcium Channel Blockers  Adrenergic Blockers Aspirin Glycoprotein IIb/IIIa receptor antagonists Anticoagulation heparin

Organic Nitrates: Polyol esters of nitric and nitrous acids Used to relive pain of angina pectoris since the mid 19 th century 1857 amyl nitrite used 1879 nitroglycerin used Known to dilate blood vessels, including coronary arteries

Organic Nitrates: Initially thought to act via coronary vasodilatation All organic nitrates and nitrites will dilate arterial and venous smooth muscle Also will relax bronchial smooth muscle GI tract smooth muscle also relaxes Esophagus Biliary tract

Organic Nitrates: Mechanism of Action Nitrates act primarily on peripheral vasculature Venodilatation is predominant effect Arterial dilatation is lesser effect Effect will be to decrease venous return (preload) and therefore will Decrease left ventricular filling pressure and volume Arterial dilatation will cause decrease in SVR and therefore will Decrease left ventricular outflow impedance (afterload) Overall affect will be a reduction in myocardial Oxygen consumption

Effects of Nitrates in Angina: Decrease in MVO 2 secondary to: Decrease in LVEDP and LVEDV Decreases myocardial wall tension Myocardial wall tension= pressure x radius Decrease in SVR Improvement in subendocardial perfusion Secondary to decrease in LVEDP Relief of coronary artery spasm Vasodilatation of epicardial and coronary arteries Improved perfusion to ischemic myocardium Increased collateral flow with preferential redistribution Dilates eccentric stenoses

Effects of Nitrates in Angina: Reflex increase in heart rate Decreased diastolic perfusion time may result in decreased myocardial perfusion Reflex increase in contractility May result in Increase in MVO 2 Also, decrease in platelet aggregation and platelet adhesion

Nitrates and Nitrites used in the treatment of angina Short-Acting Nitroglycerin Sublingual Intravenous Amyl nitrite Inhalation Isosorbide dinitrate (ISDN) Sublingual

Nitrates and Nitrites used in the treatment of angina Long-Acting Nitroglycerin Oral, sustained action Transdermal Topical Ointment Patch Isosorbide dinitrate (ISDN) Oral Chewable Isosorbide mononitrate (ISMO®, Imdur®)

Mechanism of action: All nitrates and nitrites capable of releasing NO 2 - Thereafter, converted to NO in vascular smooth muscle NO = EDRF (endothelial derived relaxing factor) NO activates guanylate cyclase Increase in cGMP results

Mechanism of action: Increase in cGMP leads to dephosphorylation of myosin light chain kinase End result in vascular smooth muscle relaxation NO ultimately converted to SH-containing nitrosothiol which causes activation of guanylate cyclase Oxidation of nitrosothiol results in cysteine depletion which may be responsible for tolerance

 Adrenergic Blocking Agents: Non-selective agents Propranolol (Inderal®) Prototype agent Highly Lipid soluble Nadolol (Corgard®) Long half-life Timolol (Blocadren®) Primarily used in glaucoma Intraocular formulation (Timoptic®) Often combined with carbonic anhydrase inhibitor Pindolol (Visken®) Noted for ISA Sotalol (Betapace®) Indicated ONLY for ventricular arrhythmias

Metabolic fate of nitrates: Biotransformation via reductive hydrolysis Catalyzed by hepatic glutathione- organic nitrate reductase High capacity Lipid soluble organic nitrates convert to Water soluble, less potent, de-nitrated metabolites and inorganic nitrites

Pharmacokinetics: Poor oral bio-availability Typically <10-20% Sublingual route avoids first-pass effect t 1/2 ≈ 2-8 minutes ISDN metabolized to ISMN which is active form Excretion of glucuronide derivatives by the kidney

Indications for Nitrate Therapy: Angina pectoris Acute myocardial infarction Control of ischemic chest pain Reduction of Elevated BP Treatment of pulmonary edema Esophageal spasm Reduction of portal hypertension in cirrhosis Congestive heart failure

Adverse Effects of Nitrate Therapy: Acute adverse effects Generally extension of therapeutic vasodilatation Headache Common Tolerance occurs Throbbing Hypotension Postural (orthostatic) Dizziness, syncope Tachycardia Glaucoma Previously thought to be contraindication No real problem exists…can be used safely

Adverse Effects of Nitrate Therapy: Tolerance Develops both to adverse effects and therapeutic effects Nitrate-free period recommended May be related to diminished release of NO Role of cysteine depletion Partial reversal with –SH containing compounds Methemoglobinemia Useful in management of CN - poisoning

Combination Therapy:  adrenergic blockers will blunt elevated heart rate and contractility caused by nitrates Nitrates will blunt effect of  adrenergic blockers to elevated LVEDV Net result will be further reduction in MVO 2

 Adrenergic Blocking Agents: Multiple pharmacological effects Therapeutic effects primarily related to  receptor blockade Large number of agents available for clinical use

 Adrenergic Blocking Agents: Pharmacological Effects Cardiovascular System Negative chronotropic effects Decrease in spontaneous rate of depolarization of SA node Negative inotropic effects Reduction in Blood Pressure Decrease in spontaneous rate of depolarization of ectopic pacemakers (antiarrhythmic effect) Negative dromotropic effect Decrease A-V nodal conduction Decrease renin release from renal J-G cells

 Adrenergic Blocking Agents: Pharmacological Effects Central Nervous System Effect depends largely on lipid solubility Generally depressive effects Airways Increased airway resistance Secondary to bronchoconstriction No airway inflammation occurs

 Adrenergic Blocking Agents: Clinical Indications Hypertension Angina pectoris Myocardial infarction Hypertrophic subaortic stenosis Hypertrophic cardiomyopathy Cardiac arrhythmias Congestive Heart Failure Pheochromocytoma Migraine Essential tremor Glaucoma

 Adrenergic Blocking Agents: Clinical Indications-Unlabeled Uses Alcohol Withdrawal Syndrome Aggressive behavior Re-bleeding from esophageal varices Situational anxiety (stage fright) Thyrotoxicosis

 Adrenergic Blocking Agents: Classification Receptor subtype selectivity Non-selective Acts on both  receptor Selective  antagonists Action at  and  receptors Lipid solubility Lipophilic Enters CNS Non-lipophilic Intrinsic Sympathomimetic Activity (ISA) Membrane Stabilizing Effects

 Adrenergic Blocking Agents: All agents compared to propanolol which has an arbitrary potency of 1 Individual agents have specific indications Agents cannot be easily interchanged Agents also differ widely in terms of t 1/2

 Adrenergic Blocking Agents: Non-selective agents Propranolol (Inderal®) Prototype agent Highly Lipid soluble Nadolol (Corgard®) Long half-life Timolol (Blocadren®) Primarily used in glaucoma Intraocular formulation (Timoptic®) Often combined with carbonic anhydrase inhibitor Pindolol (Visken®) Noted for ISA Sotalol (Betapace®) Indicated ONLY for ventricular arrhythmias

 Adrenergic Blocking Agents: Selective  -1 antagonists Acebutolol (Sectral ®) ISA noted Atenolol (Tenormin ®) Least lipid solubility Metoprolol (Toprol XL®, Lopressor®) Most lipid solubility First agent shown to prevent second MI Esmolol (Brevibloc®) IV infusion Half-life measured in minutes Useful for arrhythmias

Beta-Blocking Agents used in Glaucoma Levobunolol (Betagan®) Betaxolol (Betoptic®) Metipranolol (OptiPranolol®) Carteolol (Ocupress®) Timolol maleate (Timoptic®) Levobetaxolol (Betaxon®)

Agents for Glaucoma Beta-blockers Cholinergic agonists Carbachol Pilocarpine Echothiophate Carbonic anhydrase inhibitors Prostaglandin agonists α-2 adrenergic agonist Sympathomimetics

 Adrenergic Blocking Agents:  and  receptor blockade Labetalol (Trandate ®)  and non-selective  blockade Indicated for use in hypertension Effective also in Pheochromocytoma Oral and IV formulations Carvedilol (Coreg ®) New agent, available only orally Racemic mixture  blocking effect with (S)- enantiomer  blocking activity in both (R) + and (S) - forms  and non-selective  blockade Indicated for hypertension and CHF

 Adrenergic Blocking Agents: Adverse Effects CNS Depression Lethargy Hallucinations Loss of libido Increase in airway resistance Bronchoconstriction Asthma symptoms Increase in serum K + Hypotension Bradycardia/Heart Block

 Adrenergic Blocking Agents: Adverse Effects Augments hypoglycemic action of insulin Decreases glycogenolysis and glucagon secretion May mask hypoglycemia Blocks sympathetic response to hypoglycemia Caution needed in insulin-dependent diabetics Lipid disturbances Decreases HDL cholesterol Increase in triglyceride levels Withdrawal symptoms Secondary to receptor supersensitivity Drug should not be discontinued abruptly Sudden withdrawal may precipitate angina

 Adrenergic Blocking Agents: Contraindications Asthma Absolute contraindication Severe Congestive Heart Failure Bradycardia Heart block Greater than 1 st degree Congenital or acquired long QT syndrome Applies only to Sotalol

Calcium Channel Blockers: Rationale for use Calcium involved in genesis of action potential in automatic and conducting cells of the heart Calcium links excitation to contraction in contractile cells of myocardium Also controls energy storage and use Movement of extracellular Calcium into cardiac and vascular smooth muscle cells controls contractile process Movement is through specific ion channels

Calcium Channel Blockers: Rationale for use Calcium channel blockers share the ability to inhibit movement of Ca ++ across the cell membrane Influences release of Ca ++ from sarcoplasmic reticulum in myocardial cells Several voltage-activated calcium channels exist L found in muscle and neurons T found in heart and in neurons N found in neurons

Calcium Channel Blockers: Chemistry Papaverine Vasodilator derived from opium poppy Found to have calcium channel blocking effects Verapamil First agent, diphenyl-alkylamine compound Result of attempt to synthesize more active analogs of papaverine Least selective agent Dihydro-pyridines Rapidly expanding class Nifedipine prototype agent Benzothiazepine compounds Diltiazem only agent Resembles cross between verapamil and Dihydro-pyridines

Calcium Channel Blockers: Dihydropyridine Class Acts predominantly on vascular smooth muscle Little, if any, direct cardiac effects Nifedipine (Procardia ®) Nicardipine (Cardene ®) Nisoldipine (Sular ®) Isradipine (DynaCirc ®) Felodipine (Plendil ®) Amlodipine (Norvasc ®)

Calcium Channel Blockers: Dihydropyridine Class Primarily used in the treatment of hypertension Little cardiac effects Some tachycardia occurs secondary to decrease in SVR Little effect on Cardiac Output

Calcium Channel Blockers: Verapamil Effects on both cardiac and vascular smooth muscle Also effects on conducting system Slows SA nodal firing Bradycardia results Slows AV nodal conduction Depresses myocardial contractility

Calcium Channel Blockers: Benzothiazepine class Diltiazem is prototype agent View as intermediate between verapamil and dihydro-pyridines Slows heart rate and AV nodal conduction, but less effect than verapamil Less pronounced negative inotropic effect than verapamil Useful also via IV infusion for control of atrial arrhythmias (rate control)

Calcium Channel Blockers: Clinical Applications Angina Classic Stable Unstable Variant (Prinzmetal’s) Supraventricular tachyarrhythmias Atrial fibrillation Atrial flutter Congestive Heart Failure Hypertension Raynaud’s syndrome Migraine headache

Calcium Channel Blockers: Adverse Effects Gastrointestinal Nausea Vomiting Constipation Central Nervous System Dizziness (excess vasodilatation) Vertigo Headache Cardiovascular Bradycardia Tachycardia Hypotension Edema

Calcium Channel Blockers: Contraindications Hypotension Heart block Greater than 1 st degree Sick-Sinus syndrome Severe CHF True for verapamil, not dihydro-pyridines Concomitant use of IV  -blockers True for IV verapamil