Antiischemic Drugs

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Anti-ischemic Drugs

• JENIFER E. LEE
• UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE

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Coronary Artery Disease(CAD) A Growing Epidemic

• In 2001, CAD accounted for 1 in 5 deaths in
  North America.
• It is now the leading cause of death worldwide.
• Economic costs of CAD is estimated at 133
  billion/yr.

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Prevalence Of Coronary Artery Disease By Age And
Sex
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Coronary IschemiaSupply and Demand Economics
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Coronary Ischemia Supply and Demand Economics
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The Grip of Angina
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Supply-Demand Mismatch
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Determinants of Myocardial Oxygen Supply
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Determinants of Myocardial Oxygen Supply
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Coronary Flow Reserve
Adapted from Maseri A, Ischemic Heart Disease,
Churchill Livingstone, 1995
11
Nitric Oxide
Opie LH Heart Physiology Lippincot Williams
Wilkins, 2004
12
Vascular Smooth Muscle Calcium Channels
Adapted from Opie LH, Heart Physiology, from
Cell to Circulation. Lippincott Williams
Wilkins, 2004
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Myocardial Oxygen Demand
Heart Rate
Wall Stress
Contractility
Adapted from Runge et al, Netters Cardiology
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MVO2 a HR X SBP
Myocardial Oxygen Demand
MVO2 a HR X SBP
Heart Rate
Adapted from Runge et al, Netters Cardiology
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Myocardial Oxygen Demand
CO HR X SV
Heart Rate
Contractility
Adapted from Runge et al, Netters Cardiology
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Myocardial Contraction
LH, Heart Physiology, Williams Lippincott and
Williams 2004
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Myocyte Excitation-Contraction Coupling
Opie, Heart Physiology, from Cell to Circulation,
2004
18
Adapted from Opie LH, Heart Physiology, Williams
Lippincott and Williams 2004
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Wall Stress(s)

• LaPlaces Law
• Wall Stress P x R
• 2h

Radius
Pressure
Wall Thickness
Adapted from Runge et al, Netters Cardiology
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Supply-Demand Mismatch

• Oxygen Supply
• h O2 carrying capacity
• h FiO2
• h Hct
• Coronary blood flow
• Vasodilate
• Maintain normal BP

• Oxygen Demand
• Heart rate
• i HR
• Contractility
• iCa ion influx
• Wall stress
• ipreload
• iafterload

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Anti-ischemic Drugs

• Isosorbide mononitrate 120 mg po bid
• Atenolol 175 mg po qd
• Diltiazem CD 180 mg po bid
• Lisinopril 4 mg po qd
• Atorvastatin 20 mg po qhs
• ASA 81 mg po qd
• Clopidegrel 75 mg po qd

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Anti-ischemic Drugs

• Isosorbide Mononitrate 120 mg twice/day
• Atenolol 175 mg/day
• Diltiazem CD 180 mg twice/day
• Lisinopril 4 mg/day
• Atorvastatin 20 mg/day
• ASA 81 mg/day
• Clopidegrel 75 mg/day

• Nitrate
• Beta-blocker
• Calcium-channel blocker
• ACE-inhibitor
• HMG-CoA reductase inhibitor
• Prostaglandin inhibitor
• Thienopyridene

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Nitrates
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Nitric Oxide
Opie LH Heart Physiology Lippincot Williams
Wilkins, 2004
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Short Acting Nitroglycerin

• Sublingual, mucosal, and transdermal permits
  rapid drug effect.
• Duration of effect is brief due to rapid hepatic
  metabolism.
• Typically used on an as needed basis.
• Can be used prophylactically.

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Long Acting Nitrates

• Isosorbide mononitrate
• Active metabolite of isosorbide dinitrate
• No first pass hepatic metabolism
• Duration of action 6-8 hrs.

• Isosorbide dinitrate
• Rapid hepatic metabolism
• 2 active metabolites
• Duration of action approximately 6 hrs.

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Net Effect of Nitrates on Supply and Demand
Adapted from Shub C et al, Mayo Clinic Proc
60539, 1985
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Nitrate Tolerance

• Occurs with chronic administration of long acting
  nitrates.
• Efficacy of drug diminishes with chronic exposure
  (tachyphylaxis).
• Tolerance readily reverses with nitrate free
  interval.

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Adverse Effects

• Headache and flushing
• Hypotension
• Hypoxemia
• Contraindicated with sildenafil
• Methemoglobinemia

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Anti-ischemic Drugs

• Isosorbide Mononitrate 120 mg twice/day
• Atenolol 175 mg/day
• Diltiazem CD 180 mg twice/day
• Lisinopril 4 mg/day
• Atorvastatin 20 mg/day
• ASA 81 mg/day
• Clopidegrel 75 mg/day

• Nitrate
• Beta-adrenoreceptor blocker
• Calcium-channel blocker
• ACE-inhibitor
• HMG-CoA reductase inhibitor
• Prostaglandin inhibitor
• Thienopyridene

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Adrenergic Receptors

• Beta1
• SA node, AV node, His-Purkinje system
• Myocardium
• Juxtaglomerular apparatus
• Adipocytes
• Beta2
• Peripheral and coronary vasculature
• Bronchi
• Peripheral Muscle
• Uterine Muscle
• Alpha
• Peripheral circulation

Beta-1
Beta-2
Alpha
Adapted from Runge et al, Netters Cardiology
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Beta Blocker Characteristics

• Cardioselectivity
• Intrinsic sympathomimetic activity(ISA)
• Alpha-adrenoreceptor blocking activity

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Characteristics of Beta-adrenoreceptor Blocking
Agents
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Effect of Beta-adrenoreceptor Blockade on Supply
and Demand
Adapted from Shub C et al, Mayo Clinic Proc
60539, 1985
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Adverse Effects of Beta Blockers

• CNS effects
• Conduction abnormalities
• CHF
• Peripheral vascular disease
• Exacerbation of insulin associated hypoglycemia

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Anti-ischemic Drugs

• Isosorbide Mononitrate 120 mg twice/day
• Atenolol 175 mg/day
• Diltiazem CD 180 mg twice/day
• Lisinopril 4 mg/day
• Atorvastatin 20 mg/day
• ASA 81 mg/day
• Clopidegrel 75 mg/day

• Nitrate
• Beta-blocker
• Calcium-channel blocker
• ACE-inhibitor
• HMG-CoA reductase inhibitor
• Prostaglandin inhibitor
• Thienopyridene

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Role of Calcium Channels in Myocardial Contraction
Opie LH, Heart Physiology, Williams Lippincott
and Williams 2004
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Role of Calcium Channel in Vascular Smooth Muscle
Function
Opie LH, Heart Physiology, Williams Lippincott
and Williams 2004
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Pacemaker Cell Action Potential
Lilly l, Pathophysiology of Heart Disease,
Lippincott, Williams Wilkins
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Calcium Channel Antagonists
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Calcium Channel Antagonists
SR, CD, XL are long acting preparations
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Effect of Calcium Channel Blockers on Supply and
Demand
Adapted from Shub C et al, Mayo Clinic Proc
60539, 1985
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Adverse Effects

• Hypotension
• Exacerbation of CHF
• Conduction abnormalities
• Edema
• Gastrointestinal
• Gingival hyperplasia
• Increase in cardiovascular mortality?

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Treatment of Ischemic Heart Disease
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of Prescriptions for beta-blocker and calcium
channel blockers/yr 207,000,000

• Pounds of Snack Food Consumed/Yr 27,
  000,000

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