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