Stoelting's Anesthesia and Co-Existing Disease

683 Pages·2012·29.728 MB·English

by  R. L. Hines, K. Marschall

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STOELTING'S ANESTHESIA AND CO-EXISTING DISEASE ISBN: 978-1-4557-0082-0
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Library of Congress Cataloging-in-Publication Data
Stoelting's anesthesia and co-existing disease. — 6th ed. / [edited by] Roberta L. Hines, Katherine E. Marschall.
p. ; cm.
Anesthesia and co-existing disease
Includes bibliographical references and index.
ISBN 978-1-4557-0082-0 (hardcover : alk. paper)
I. Stoelting, Robert K. II. Hines, Roberta L. III. Marschall, Katherine E. IV. Title: Anesthesia and co-existing
disease.
[DNLM: 1. Anesthesia—adverse effects. 2. Anesthesia—methods. 3. Anesthetics—adverse effects. 4. Intraop-
erative Complications. WO 245]
617.9'6041—dc23 2012005770
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C O N T R I B U T O R S
Shamsuddin Akhtar, MD Laura L. Hammel, MD
Associate Professor of Anesthesiology Assistant Professor of Anesthesiology and Critical Care
Director, Medical Student Education University of Wisconsin Hospital and Clinics
Yale University School of Medicine Madison, Wisconsin
New Haven, Connecticut
Michael Hannaman, MD
Brooke E. Albright, MD Assistant Professor, Department of Anesthesiology
Captain, U. S. Air Force University of Wisconsin School of Medicine
Staff Anesthesiologist and Public Health
Landstuhl Regional Medical Center Madison, Wisconsin
Landstuhl/Kirchberg, Germany
Antonio Hernandez Conte, MD, MBA
Sharif Al-Ruzzeh, MD, PhD Assistant Professor of Anesthesiology
Resident in Anesthesiology Co-Director, Perioperative Transesophageal
Yale-New Haven Hospital Echocardiography
New Haven, Connecticut Cedars-Sinai Medical Center
Partner, General Anesthesia Specialists Partnership, Inc.
Ferne R. Braveman, MD Los Angeles, California
Professor of Anesthesiology
Vice-Chair of Clinical Affairs Adriana Herrera, MD
Chief, Division of Obstetrics Anesthesia Assistant Professor
Department of Anesthesiology Associate Program Director
Yale University School of Medicine Department of Anesthesiology
New Haven, Connecticut Yale University School of Medicine
New Haven, Connecticut
Michelle W. Diu, MD, FAAP
Assistant Professor of Anesthesiology Zoltan G. Hevesi, MD, MBA
Yale University School of Medicine Professor of Anesthesiology and Surgery
New Haven, Connecticut University of Wisconsin
University of Wisconsin Hospital and Clinics
Samantha A. Franco, MD Madison, Wisconsin
Assistant Professor of Anesthesiology
Yale University School of Medicine Roberta L. Hines, MD
New Haven, Connecticut Nicholas M. Greene Professor and Chairman
Department of Anesthesiology
Loreta Grecu, MD Yale University School of Medicine
Assistant Professor of Anesthesiology Chief of Anesthesiology
Yale University School of Medicine Yale-New Haven Hospital
New Haven, Connecticut New Haven, Connecticut
Alá Sami Haddadin, MD, FCCP Natalie F. Holt, MD, MPH
Assistant Professor, Division of Cardiothoracic Anesthesia Assistant Professor, Department of Anesthesiology
and Adult Critical Care Medicine Yale University School of Medicine
Medical Director, Cardiothoracic Intensive Care Unit New Haven, Connecticut;
Department of Anesthesiology Attending Physician, West Haven Veterans Affairs
Yale University School of Medicine Medical Center
New Haven, Connecticut West Haven, Connecticut
vii
viii Contributors
Viji Kurup, MD Wanda M. Popescu, MD
Associate Professor, Department of Anesthesiology Associate Professor of Anesthesiology
Yale University School of Medicine Director, Thoracic Anesthesia Section
New Haven, Connecticut Yale University School of Medicine
New Haven, Connecticut
William L. Lanier, Jr., MD
Professor of Anesthesiology Ramachandran Ramani
College of Medicine Associate Professor of Anesthesiology
Mayo Clinic Yale University School of Medicine
Rochester, Minnesota New Haven, Connecticut
Thomas J. Mancuso, MD, FAAP Robert B. Schonberger, MD, MA
Associate Professor of Anesthesia Fellow, Sections of Cardiac and Thoracic Anesthesia
Harvard Medical School Department of Anesthesiology
Senior Associate in Anesthesia Yale University School of Medicine
Director of Medical Education New Haven, Connecticut
Children's Hospital Boston
Boston, Massachusetts Denis Snegovskikh, MD
Assistant Professor of Anesthesiology
Katherine E. Marschall, MD Yale University School of Medicine
Department of Anesthesiology New Haven, Connecticut
Yale University School of Medicine
Attending Anesthesiologist Hossam Tantawy, MD
Yale-New Haven Hospital Assistant Professor of Anesthesiology
New Haven, Connecticut Yale University School of Medicine
New Haven, Connecticut
Veronica A. Matei, MD
Assistant Professor of Anesthesiology Russell T. Wall, III, MD
Yale University School of Medicine Vice-Chair and Program Director
New Haven, Connecticut Department of Anesthesiology
Georgetown University Hospital
Raj K. Modak, MD Professor of Anesthesiology and Pharmacology
Assistant Professor of Cardiac and Thoracic Anesthesia Senior Associate Dean
Director, Cardiac Anesthesia Fellowship Program Georgetown University School of Medicine
Department of Anesthesiology Washington, DC
Yale University School of Medicine
New Haven, Connecticut Kelley Teed Watson, MD
Clinical Assistant Professor
Tori Myslajek, MD Yale University School of Medicine
Assistant Professor of Anesthesiology New Haven, Connecticut;
Yale University School of Medicine Cardiothoracic Anesthesiologist
New Haven, Connecticut Department of Anesthesiology
Self Regional Healthcare
Adriana Dana Oprea, MD Greenwood, South Carolina
Assistant Professor of Anesthesiology
Yale University School of Medicine
New Haven, Connecticut
Jeffrey J. Pasternak, MD
Assistant Professor of Anesthesiology
College of Medicine
Mayo Clinic
Rochester, Minnesota
P R E F A C E
In 1983 the first edition of Anesthesia and Co-Existing Dis- edition, all aspects of the pathophysiology and treatment of
ease was published with the stated goal “to provide a concise significant co-existing disease have been updated as needed.
description of the pathophysiology of disease states and their All major medical society guidelines and recommendations
medical management that is relevant to the care of the patient for the management of medical disorders that are important
in the perioperative period.” The result was a very useful, basic to the practicing anesthesiologist have been summarized. More
reference text and review guide that continued through three figures and treatment algorithms have been included, and ref-
more editions and became one of those exceptional works that erences have been made to the frontiers of medicine, that is, to
is a “must have” in every anesthesiologist's personal library. those remarkable new medical and surgical treatments that will
The fifth edition of Anesthesia and Co-Existing Disease influence the practice of anesthesiology over the next several
marked a turning point in the history of the book. Drs. years.
Robert K. Stoelting and Stephen F. Dierdorf passed the edito- We hope that our readers will continue to find this book
rial “baton” to us, and we were very pleased with the response to be “relevant to the care of the patient in the perioperative
of the anesthesiology community to the publication of the fifth period.”
edition in 2008. Roberta L. Hines, MD
The continued explosion of new medical information has Katherine E. Marschall, MD
made another edition of this classic text necessary. In the sixth
v
1
C H A P T E R
Ischemic Heart Disease
SHAMSUDDIN AKHTAR n
Stable Myocardial Ischemia (Angina Pectoris) Cardiac Transplantation
Diagnosis Management of Anesthesia
Treatment Postoperative Complications
Acute Coronary Syndrome Anesthetic Considerations in Heart Transplant Recipients
ST Elevation Myocardial Infarction Key Points
Unstable Angina/Non–ST Elevation Myocardial Infarction
Complications of Acute Myocardial Infarction
Cardiac Dysrhythmias
Pericarditis
The prevalence of vascular disease and ischemic heart disease
Mitral Regurgitation
in the United States increases significantly with age (Figure
Ventricular Septal Rupture
1-1). By some estimates 30% of patients who undergo sur-
Congestive Heart Failure and Cardiogenic Shock
gery annually in the United States have ischemic heart dis-
Myocardial Rupture
ease. Angina pectoris, acute MI, and sudden death are often
Right Ventricular Infarction
the first manifestations of ischemic heart disease, and cardiac
Stroke
dysrhythmias are probably the major cause of sudden death
Perioperative Implications of Percutaneous Coronary
in these patients. The two most important risk factors for the
Intervention
development of atherosclerosis involving the coronary arter-
Percutaneous Coronary Intervention and Thrombosis
ies are male gender and increasing age (Table 1-1). Additional
Surgery and Risk of Stent Thrombosis
risk factors include hypercholesterolemia, systemic hyperten-
Risk of Bleeding with Antiplatelet Agents
sion, cigarette smoking, diabetes mellitus, obesity, a seden-
Bleeding versus Stent Thrombosis in the Perioperative
tary lifestyle, and a family history of premature development
Period
of ischemic heart disease. Psychologic factors such as type A
Management of Patients with Stents
personality and stress have also been implicated. Patients with
Perioperative Myocardial Infarction
ischemic heart disease can have chronic stable angina or acute
Pathophysiology
coronary syndrome at presentation. The latter includes ST ele-
Diagnosis
vation myocardial infarction (STEMI) and unstable angina/
Preoperative Assessment of Patients with Known or
Suspected Ischemic Heart Disease non–ST elevation myocardial infarction (UA/NSTEMI).
History
Physical Examination STABLE MYOCARDIAL ISCHEMIA
Specialized Preoperative Testing (ANGINA PECTORIS)
Management of Anesthesia in Patients with Known
or Suspected Ischemic Heart Disease Undergoing The coronary artery circulation normally supplies suffi-
Noncardiac Surgery cient blood flow to meet the demands of the myocardium
Risk Stratification in response to widely varying workloads. An imbalance
Management after Risk Stratification between coronary blood flow (supply) and myocardial oxy-
Intraoperative Management gen consumption (demand) can precipitate ischemia, which
Postoperative Management frequently manifests as angina pectoris. Stable angina typi-
cally develops in the setting of partial occlusion or significant
1
2 STOELTING'S ANESTHESIA AND CO-EXISTING DISEASE
40
TABLE 1-2 n Common causes of acute chest pain
35.5
Men Women
35
System Condition
30
Cardiac Angina
n (%) 25 22.8 20.8 RAceustte o mr uyoncsatardbilael ainnfgairncation
o
ati 20 Pericarditis
ul
op 15 13.9 Vascular Aortic dissection
P Pulmonary embolism
10 Pulmonary hypertension
6.0 6.0 Pulmonary Pleuritis and/or pneumonia
5 Tracheobronchitis
0.8 0.6 Spontaneous pneumothorax
0
Gastrointestinal Esophageal reflux
20-30 40-59 60-79 80(cid:31)
Peptic ulcer
Age (yr)
Gallbladder disease
FIGURE 1-1 Prevalence of coronary heart disease by age and Pancreatitis
gender in the United States (2005 to 2008). (Data from the Musculoskeletal Costochondritis
National Center for Health Statistics and National Heart, Lung, and Cervical disc disease
Blood Institute.) Trauma or strain
Infectious Herpes zoster
Psychologic Panic disorder
TABLE 1-1 n Risk factors for development of ischemic
heart disease
be perceived as epigastric discomfort resembling indigestion.
Male gender Some patients describe angina as shortness of breath, mistak-
Increasing age ing a sense of chest constriction as dyspnea. The need to take
Hypercholesterolemia
a deep breath, rather than to breathe rapidly, often identifies
Hypertension
shortness of breath as an anginal equivalent. Angina pectoris
Cigarette smoking
Diabetes mellitus usually lasts several minutes and is crescendo-decrescendo in
Obesity nature. A sharp pain that lasts only a few seconds or a dull ache
Sedentary lifestyle that lasts for hours is rarely caused by myocardial ischemia.
Genetic factors/family history
Physical exertion, emotional tension, and cold weather may
induce angina. Rest and/or nitroglycerin relieve it. Chronic
stable angina refers to chest pain or discomfort that does not
(>70%) chronic narrowing of a segment of coronary artery. change appreciably in frequency or severity over 2 months or
When the imbalance becomes extreme, congestive heart fail- longer. Unstable angina, by contrast, is defined as angina at
ure, electrical instability with cardiac dysrhythmias, and MI rest, angina of new onset, or an increase in the severity or fre-
may result. Angina pectoris reflects intracardiac release of quency of previously stable angina without an increase in lev-
adenosine, bradykinin, and other substances during ischemia. els of cardiac biomarkers. Sharp retrosternal pain exacerbated
These substances stimulate cardiac nociceptive and mecha- by deep breathing, coughing, or change in body position sug-
nosensitive receptors, whose afferent neurons converge with gests pericarditis. There are many causes of noncardiac chest
the upper five thoracic sympathetic ganglia and somatic nerve pain (Table 1-2). Noncardiac chest pain is often exacerbated
fibers in the spinal cord, and ultimately produce thalamic and by chest wall movement and is associated with tenderness
cortical stimulation that results in the typical chest pain of over the involved area, which is often a costochondral junc-
angina pectoris. These substances also slow atrioventricular tion. Esophageal spasm can produce severe substernal pres-
nodal conduction and decrease cardiac contractility, which sure that may be confused with angina pectoris and may also
improves the balance between myocardial oxygen demand be relieved by administration of nitroglycerin.
and supply. Atherosclerosis is the most common cause of
impaired coronary blood flow resulting in angina pectoris. ELECTROCARDIOGRAPHY
During myocardial ischemia, the standard 12-lead electrocar-
diogram (ECG) demonstrates ST-segment depression (char-
Diagnosis
acteristic of subendocardial ischemia) that coincides in time
Angina pectoris is typically described as retrosternal chest with anginal chest pain. This may be accompanied by tran-
discomfort, pain, pressure, or heaviness. The chest discomfort sient symmetrical T-wave inversion. Patients with chronically
often radiates to the neck, left shoulder, left arm, or jaw and inverted T waves resulting from previous MI may mani-
occasionally to the back or down both arms. Angina may also fest a return of the T waves to the normal upright position
Chapter 1 ISCHEMIC HEART DISEASE 3
(pseudonormalization of the T wave) during myocardial isch-
TABLE 1-3 n Sensitivity and specificity of stress
emia. These ECG changes are seen in 50% of patients. Variant
testing*
angina, that is, angina that results from coronary vasospasm
rather than occlusive coronary artery disease, is diagnosed by Modality Sensitivity Specificity†
ST elevation during an episode of angina pectoris.
Exercise ECG is useful for detecting signs of myocardial Exercise electrocardiography 0.68 0.77
ischemia and establishing their relationship to chest pain. Exercise SPECT 0.88 0.72
The test also provides information about exercise capacity. Adenosine SPECT 0.90 0.82
The appearance of a new murmur of mitral regurgitation or Exercise echocardiography 0.85 0.81
a decrease in blood pressure during exercise adds to the diag- Dobutamine echocardiography 0.81 0.79
nostic value of the test. Exercise testing is not always feasible, Data from Gibbons RJ, Abrams J, Chatterjee K, et al. ACC/AHA 2002
either because of the inability of a patient to exercise or the guideline update for the management of patients with chronic stable
angina: a report of the American College of Cardiology/American Heart
presence of conditions that interfere with interpretation of
Association Task Force on Practice Guidelines. Circulation. 2003;107:
the exercise ECG (paced rhythm, left ventricular hypertrophy, 149–158. (Committee to Update the 1999 Guidelines for the Management
digitalis administration, or preexcitation syndrome). Con- of Patients with Chronic Stable Angina).
SPECT, Single-photon emission computed tomography.
traindications to exercise stress testing include severe aortic
*Without correction for referral bias.
stenosis, severe hypertension, acute myocarditis, uncontrolled †Weighted average pooled across individual trials.
heart failure, and infective endocarditis.
The exercise ECG is most likely to indicate myocardial isch-
emia when there is at least 1 mm of horizontal or down- sloping Many patients who are at increased risk of coronary events
ST-segment depression during or within 4 minutes after exer- cannot exercise because of peripheral vascular or musculo-
cise. The greater the degree of ST-segment depression, the skeletal disease, deconditioning, dyspnea on exertion due to
greater is the likelihood of significant coronary artery disease. pulmonary disease, or prior stroke. Noninvasive imaging tests
When the ST-segment abnormality is associated with angina for the detection of ischemic heart disease are usually recom-
pectoris and occurs during the early stages of exercise and mended when exercise ECG is not possible or interpretation
persists for several minutes after exercise, significant coronary of ST-segment changes would be difficult. Administration of
artery disease is very likely. Exercise ECG is less accurate but atropine, infusion of dobutamine, or institution of artificial
more cost effective than imaging tests for detecting ischemic cardiac pacing produces a rapid heart rate to create cardiac
heart disease. A negative stress test result does not exclude the stress. Alternatively, cardiac stress can be produced by admin-
presence of coronary artery disease, but it makes the likelihood istering a coronary vasodilator such as adenosine or dipyri-
of three-vessel or left main coronary disease extremely low. damole. These drugs dilate normal coronary arteries but evoke
Exercise ECG is less sensitive and specific in detecting ischemic minimal or no change in the diameter of atherosclerotic coro-
heart disease than nuclear cardiology techniques (Table 1-3). nary arteries. After cardiac stress is induced by these inter-
ventions, radionuclide tracer scanning is performed to assess
NUCLEAR CARDIOLOGY TECHNIQUES myocardial perfusion.
Nuclear stress imaging is useful for assessing coronary perfu-
sion. It has greater sensitivity than exercise testing for detec- ECHOCARDIOGRAPHY
tion of ischemic heart disease. It can define vascular regions Echocardiographic wall motion analysis can be performed
in which stress-induced coronary blood flow is limited and immediately after stressing the heart either pharmacologi-
can estimate left ventricular systolic size and function. Trac- cally or with exercise. New ventricular wall motion abnor-
ers such as thallium and technetium can be detected over the malities induced by stress correspond to sites of myocardial
myocardium by single-photon emission computed tomog- ischemia, thereby localizing obstructive coronary lesions.
raphy (SPECT) techniques. A significant coronary obstruc- In contrast, exercise ECG can indicate only the presence
tive lesion causes less blood flow and thus less tracer activity. of ischemic heart disease and does not reliably predict the
Exercise perfusion imaging with simultaneous ECG testing location of the obstructive coronary lesion. One can also
is superior to exercise ECG alone (see Table 1-3). Exercise visualize global wall motion under baseline conditions and
increases the difference in tracer activity between normal and under cardiac stress. Valvular function can be assessed as
underperfused regions, because coronary blood flow increases well. Limitations imposed by poor visualization have been
markedly with exercise except in those regions distal to a coro- improved by newer contrast-assisted technologies that have
nary artery obstruction. Imaging is carried out in two phases: improved the accuracy of stress echocardiography.
the first is immediately after cessation of exercise to detect
regional ischemia, and the second is 4 hours later to detect STRESS CARDIAC MAGNETIC RESONANCE IMAGING
reversible ischemia. Areas of persistently absent uptake signify Pharmacologic stress imaging with cardiac magnetic reso-
an old MI. The size of the perfusion abnormality is the most nance imaging compares favorably with other methods and is
important indicator of the significance of the coronary artery being used clinically in some centers, especially when other
disease detected. modalities cannot be used effectively.
4 STOELTING'S ANESTHESIA AND CO-EXISTING DISEASE
ELECTRON BEAM COMPUTED TOMOGRAPHY chronic stale angina is to achieve complete or almost complete
Calcium deposition occurs in atherosclerotic vessels. Coro- elimination of anginal chest pain and a return to normal activ-
nary artery calcification can be detected by electron beam ities with minimal side effects.
computed tomography. Although the sensitivity of electron
beam computed tomography is high, it is not a very specific TREATMENT OF ASSOCIATED DISEASES
test and yields many false-positive results. Its routine use is Conditions that increase oxygen demand or decrease oxygen
not recommended. delivery may contribute to an exacerbation of previously stable
angina or worsen existing angina. These conditions include
CORONARY ANGIOGRAPHY fever, infection, anemia, tachycardia, thyrotoxicosis, heart fail-
Coronary angiography provides the best information about ure, and cocaine use. Treatment of these conditions is critical
the condition of the coronary arteries. It is indicated in to the management of stable ischemic heart disease.
patients with known or possible angina pectoris who have
survived sudden cardiac death, those who continue to have REDUCTION OF RISK FACTORS AND LIFESTYLE
angina pectoris despite maximal medical therapy, and those MODIFICATION
who are being considered for coronary revascularization, as The progression of atherosclerosis may be slowed by cessation
well as for the definitive diagnosis of coronary disease for of smoking; maintenance of an ideal body weight by consump-
occupational reasons (e.g., in airline pilots). Coronary angi- tion of a low-fat, low-cholesterol diet; regular aerobic exercise;
ography is also useful for establishing the diagnosis of nonath- and treatment of hypertension. Lowering the low-density
erosclerotic coronary artery disease such as coronary artery lipoprotein (LDL) cholesterol level by diet and/or drugs such
spasm, Kawasaki's disease, radiation-induced vasculopathy, as statins is associated with a substantial decrease in the risk
and primary coronary artery dissection. Among patients with of death due to cardiac events. Drug treatment is appropriate
chronic stable angina 25% will have significant single-, dou- when the LDL cholesterol level exceeds 130 mg/dL. The goal of
ble-, or triple-vessel coronary artery disease, 5% to 10% will treatment is a decrease in LDL to less than 100 mg/dL. Patients
have left main coronary artery disease, and 15% will have no with ischemic heart disease may benefit from even lower LDL
flow-limiting obstructions. levels (<70 mg/dL), which can be achieved by a combination
The important prognostic determinants in patients with of diet and statin therapy. Hypertension increases the risk
coronary artery disease are the anatomic extent of the athero- of coronary events as a result of direct vascular injury, left
sclerotic disease, the state of left ventricular function (ejection ventricular hypertrophy, and increased myocardial oxygen
fraction), and the stability of the coronary plaque. Left main demand. Lowering the blood pressure from hypertensive lev-
coronary artery disease is the most dangerous anatomic lesion els to normal levels decreases the risk of MI, congestive heart
and is associated with an unfavorable prognosis when man- failure, and stroke. In combination with lifestyle modifica-
aged with medical therapy alone. Greater than 50% stenosis tions, β-blockers, and calcium channel blockers are especially
of the left main coronary artery is associated with a mortality useful in managing hypertension in patients with angina pec-
rate of 15% per year. toris. If left ventricular dysfunction accompanies hyperten-
Unfortunately, coronary angiography cannot predict which sion, an angiotensin-converting enzyme (ACE) inhibitor or an
plaques are most likely to rupture and initiate acute coronary angiotensin receptor blocker (ARB) is recommended.
syndromes. Vulnerable plaques, that is, those most likely to
rupture and form an occlusive thrombus, have a thin fibrous MEDICAL TREATMENT OF MYOCARDIAL ISCHEMIA
cap and a large lipid core containing a large number of mac- Antiplatelet drugs, nitrates, β-blockers, calcium channel
rophages. The presence of vulnerable plaque predicts a greater blockers, and ACE inhibitors are used in the medical treat-
risk of MI regardless of the degree of coronary artery stenosis. ment of angina pectoris.
Indeed, acute MI most often results from rupture of a plaque Three classes of antiplatelet drugs are widely used in the
that had produced less than 50% stenosis of a coronary artery. management of ischemic heart disease: aspirin, thienopyri-
Currently, there is no satisfactory test to measure the stability dines (clopidogrel and prasugrel), and platelet glycoprotein
of plaques. IIb/IIIa inhibitors (eptifibatide, tirofiban, and abciximab).
A fourth class of antiplatelet drug, which affects platelet cyclic
adenosine monophosphate (dipyridamole), is not widely used.
Treatment
A new class of short-acting, reversible platelet inhibitors (can-
Comprehensive management of ischemic heart disease has grelor and ticagrelor) is currently under development.
five aspects: (1) identification and treatment of diseases that Aspirin inhibits the enzyme cyclooxygenase-1 (COX-1);
can precipitate or worsen ischemia, (2) reduction of risk fac- this results in inhibition of thromboxane A , which plays
2
tors for coronary artery disease, (3) lifestyle modification, an important role in platelet aggregation. This inhibition of
(4) pharmacologic management of angina, and (5) revascular- COX-1 is irreversible, lasts for the duration of platelet life span
ization by coronary artery bypass grafting (CABG) or percuta- (around 7 days), and can be produced by low dosages of aspi-
neous coronary intervention (PCI) with or without placement rin. Low-dose aspirin therapy (75 to 325 mg/day) decreases the
of intracoronary stents. The goal of treatment of patients with risk of cardiac events in patients with stable or unstable angina
Chapter 1 ISCHEMIC HEART DISEASE 5
pectoris and is recommended for all patients with is chemic has a faster onset of action, and demonstrates less interindi-
heart disease. Clopidogrel inhibits the adenosine diphosphate vidual variability in platelet responses compared with clopi-
(ADP) receptor P2Y and inhibits platelet aggregation in dogrel. It also is more potent than clopidogrel, and a higher
12
response to ADP release from activated platelets (Figure 1-2). risk of bleeding has been associated with its use. Platelet glyco-
Clopidogrel-induced inhibition of ADP receptors is irrevers- protein IIb/IIIa receptor antagonists (abciximab, eptifibatide,
ible and also lasts for the duration of the platelet's life span. tirofiban) inhibit platelet adhesion, activation, and aggrega-
Seven days after cessation of this drug 80% of platelets will tion. Short-term administration of antiplatelet drugs is par-
have recovered normal aggregation function. Clopidogrel is a ticularly useful after placement of an intracoronary stent.
prodrug that is metabolized into an active compound in the Organic nitrates decrease the frequency, duration, and
liver. Due to genetic differences in the enzymes that metabo- severity of angina pectoris and increase the amount of exercise
lize clopidogrel to the active drug, significant variability in its required to produce ST-segment depression. The antianginal
activity has been observed. By some estimates, 10% to 20% effects of nitrates are greater when used in combination with
of patients taking aspirin and clopidogrel demonstrate hypo- β-blockers or calcium channel blockers. Nitrates dilate coro-
responsiveness (resistance) or hyperresponsiveness. Further- nary arteries and collateral blood vessels and thereby improve
more, some drugs, such as proton pump inhibitors, can affect coronary blood flow. Nitrates also decrease peripheral vas-
the enzyme that metabolizes clopidogrel to its active com- cular resistance, which reduces left ventricular afterload and
pound and thereby can reduce the effectiveness of clopidogrel. myocardial oxygen consumption. The venodilating effect
Clopidogrel can be used in patients who have a contraindica- of nitrates decreases venous return and hence left ventricu-
tion to or are intolerant of aspirin. Prasugrel also inhibits the lar preload and myocardial oxygen consumption. They also
ADP P2Y receptor irreversibly. However, the pharmacoki- have potential antithrombotic effects. Nitrates are contrain-
12
netics of prasugrel are more predictable. It is rapidly absorbed, dicated in the presence of hypertrophic cardiomyopathy or
Collagen
ADP
ATP Ticlopidine
Clopidogrel
TxA2 Prasugrel
GP V1
TP(cid:30) P2X1
TRA CYP450
TP(cid:29) P2Y metabolism
1
PAR1 Ca2(cid:31)
Adenyl
cyclase
Ticagrelor
PAR4 P2Y
12 Cangrelor
cAMP
Thrombin
Activation
COX-1 ASA
TxA GP IIb/IIIa
2
inhibitor
GP IIb/IIIa
Dense granule
secretion Stable
ATP, ADP, Fibrinogen
aggregation
Ca2(cid:31)
(cid:29)-granule GP IIb/IIIa
Shape GP IIb/IIIa
secretion
change
Coagulation factors,
Amplification proinflammatory
mediators Transient
aggregation
FIGURE 1-2 Platelet activation mechanisms and sites of blockade of antiplatelet therapies. ↑, Increased; ↓, decreased; ADP, adenosine
diphosphate; ASA, acetylsalicylic acid; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; COX-1, cyclooxygenase-1;
CYP450, cytochrome P450; GP, glycoprotein; GPVI, [glycoprotein VI]; P2X , P2Y , purinergic receptors; PAR, protease-activated receptor; TP,
1 1
thromboxane receptor; TRA, [thrombin recepter agonist]; TxA , thromboxane A . (From Cannon CP, Braunwald E. Unstable angina and non-ST
2 2
elevation myocardial infarction. In: Bonow RO, Mann DL, Zipes DP, et al, eds. Braunwald's Heart Disease. Philadelphia, PA: Saunders; 2012.)