Drugs used in the Management of Ischemic Heart Disease

Philip Marcus, MD

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

Myocardial Oxygen Demand: Determined by the amount of O2 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 (MVO2):

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 19th 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 MVO2 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 MVO2

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 NO2

-

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

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

t1/2 – 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 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

NO production from nitrate conversion

Combination Therapy:

adrenergic blockers will blunt heart rate and contractility caused by nitrates

Nitrates will blunt effect of adrenergic blockers to LVEDV

Net result will be further reduction in MVO2

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 t1/2

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

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 1st 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 Nimodipine used only for

subarachnoid hemorrhage

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 1st degree Sick-Sinus syndrome Severe CHF

True for verapamil, not dihydro-pyridines

Concomitant use of IV -blockers True for IV verapamil