Clinical Applications of Cardiovascular Drugs

267 Pages·1980·7.41 MB·English

by  Leonard S. Dreifus

CLINICAL APPLICATIONS OF CARDIOVASCULAR DRUGS
DEVELOPMENTS IN
CARDIOVASCULAR MEDICINE
VOLUME 5
1. C.T. Lancee, Echocardiology, 1979. ISBN 90-247-2209-8.
2. J. Baan, A.C. Arntzenius, LL. Yellin, Cardiac Dynamics. 1980. ISBN 90-247-
2212-8.
c.c.
3. H.J.Th. Thalen, Meere, Fundamentals ofC ardiac Pacing. 1979. ISBN 90-
247-2245-4.
4. H.E. Ku1bertus, H.J.J. Wellens, Sudden Death. 1980. ISBN 90-247-2290-X.
series ISBN 90-247-2336-1
CLINICAL APPLICATIONS
OF CARDIOVASCULAR
DRUGS
edited by
LEONARD S. DREIFUS
Jefferson Medical College
The Lankenau Hospital
Philadelphia. P A
and
ALBERT N. BREST
Jefferson Medical College
Philadelphia, P A
1980
MARTINUS NIJHOFF PUBLISHERS
I I
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Library of Congress Cataloging in Publication Data
Main entry under title:
Clinical applications of cardiovascular drugs
(Developments in cardiovascular medicine; v. 5)
Includes index.
I. Cardiovascular agents. 2. Cardiovascular system - Diseases - Chemotherapy. I. Dreifus,
Leonard S. II. Brest, Albert N. III. Series. [DNLM: I. Cardiovascular agents. WI DE997PE
v. 5/ QVI50 C641]
RM345.C57 615'.71 79-26152
ISBN-13: 978-90-247-2369-0 e-ISBN-13: 978-94-010-9178-7
DOl: 10.1007/978-94-010-9178-7
Copyright © 1980 by Martinus Nijhoff Publishers bv, The Hague.
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or
transmitted in any form or by any means, mechanical, photocopying, recording, or otherwise, without
the prior written permission of the publisher, Martinus Nijhoff Publishers bv, P.O. Box 566,2501 CN
The Hague, The Netherlands.
CONTENTS
Contributors VII
Preface . IX
1. Antiarrhythmic agents
LEONARD S. DREIFUS and JOEL MORGANROTH
2. Inotropic drugs: cardiac glycosides . 46
PAUL E. FENSTER and FRANK I. MARCUS
3. Treatment of cardiogenic shock . 69
ROBERT J. HENNING and MAX HARRY WElL
4. Antianginal drugs 95
ROBERT ZELIS, A. JAMES LIEDTKE, and STEPHEN F. FLAIM
5. Vasodilator drugs 136
WILLIAM W. PARMLEY and KANU CHATTERJEE
6. Diuretic drugs. ISS
ALBERT N. BREST and DAVID T. LOWENTHAL
7. Antihypertensive drugs. 168
DAVID T. LOWENTHAL and ALBERT N. BREST
8. Antithrombotic drugs 191
EDWARD GENTON
9. Hyperlipidemias (hyperlipoproteinemias) and atherosclerosis: patho-
physiology and control. 231
PETER T. Kuo
Index. 259
CONTRIBUTORS
BREST, Albert, N., M.D., James C. Wilson Professor of Medicine, Director, Division of Cardiology,
Jefferson Medical College, 1025 Walnut Street, Philadelphia, PA 19107, USA.
CHATTERJEE, Kanu, M.B., MRCP, Professor of Medicirie, University of California, School of
Medicine, San Francisco, CA 94143, USA.
DREIFUS, Leonard S., M.D., F.A.C.C., Professor of Medicine and Physiology, Jefferson Medical
College, Chief, Cardiovascular Division, The Lankenau Hospital, Lancaster and City Line
Avenues, Philadelphia, PA 19151, USA.
FENSTER, Paul E., M.D., Instructor in Medicine, Cardiology Section, University of Arizona, Health
Sciences Center, Tucson, AZ 85724, USA.
GENTON, Edward, M.D., Professor of Medicine, McMaster University, 1200 Main Street West,
Hamilton, Ontario L8S 4J9, Canada.
HENNING, Robert J., M.D., Associate Professor of Medicine, University of Southern California,
1300 N. Vermont Avenue, Los Angeles, CA 90027, USA.
Kuo, Peter T., M.D., Professor of Medicine, Chief, Division of Cardiovascular Diseases, Rutgers
Medical School, University Heights, Piscataway, NJ 08854, USA.
LOWENTHAL, David T., M.D., Professor of Medicine and Pharmacology, Director, Division of
Clinical Pharmacology, William Likoff Cardiovascular Institute, 230 N. Broad Street, Phila
delphia, P A 19102, USA.
MARCUS, Frank I., M.D., Professor of Medicine, Chief of Cardiology, Health Sciences Center,
University of Arizona, Tucson, AZ 85724, USA.
PARMLEY, William W., M.D., Professor of Medicine, Chief, Cardiovascular Division, Rm. 1186
Moffitt Hospital. University of California, San Francisco, CA 94143, USA.
WElL, Max Harry, M.D., Chairman and Clinical Professor, Division of Critical Care Medicine,
Director, Institute of Critical Care Medicine, University of Southern California, School of
Medicine, 1300 N. Vermont Avenue, Los Angeles, CA 90027, USA.
ZELlS, Robert F., M.D., Professor of Medicine and Physiology, Chief, Division of Cardiology, The
Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, PA 17033, USA.
LIEDTKE, A. James, M.D., Professor of Medicine, The Division of Cardiology, The Pennsylva
nia State University, College of Medicine, The Milton S. Hershey Medical Center, Hershey,
P A 17033, USA.
FLAIM, Stephen F., Ph.D., Assistant Professor of Medicine and Physiology, The Division of
Cardiology, The Pennsylvania State University, College of Medicine, The Milton S. Hershey
Medical Center, Hershey, PA 17033, USA.
MORGANROTH, Joel, M.D., Associate Professor of Medicine, Jefferson Medical College, Associate
Chief, Cardiovascular Division, The Lankenau Hospital, Lancaster and City Line Avenues,
Philadelphia, PA 19151, USA.
PREFACE
During the past decade enormous progress has been made in the development
of new cardiovascular drugs and in our understanding of the clinical pharma
cology and the pharmacokinetics of old drugs. In addition, newer applications
of older agents have emerged. For example, vasodilators such as nitroglycerin
are now being employed in the treatment of congestive heart failure, and anti
hypertensives such as bretylium are used in the management of ventricular
arrhythmias.
Individual chapters in this book focus on (1) the clinical pharmacology and
pharmacokinetics of the individual drugs, and (2) the clinical applications of
these drugs, with attention also to serum concentrations, pathophysiology, and
drug interactions where appropriate.
The contributors to this text have labored to provide the reader with a
meaningful, practical update on the clinical uses and usefulness of cardioactive
drugs. We are deeply grateful to each of them for their generous participation in
this endeavor.
LEONARD S. DREIFUS, M.D.
ALBERT N. BREST, M.D.
1. ANTIARRHYTHMIC AGENTS
LEONARD S. DREIFUS and JOEL MORGANROTH
Ideally, the management of cardiac arrhythmias must be predicated on (1)
complete elucidation of the genesis of the various rhythm disturbances, and (2)
a full understanding of the pharmacologic action of individual antiarrhythmic
agents. Only with this precise information does it become possible to administer
a particular agent or agents specifically effective against a given arrhythmia.
Unfortunately, neither of the above requirements have totally satisfied the
pharmacologic management of cardiac rhythm disorders and treatment still
remains empirical. Antiarrhythmic drug therapy has been further complicated
by the high incidence of severe and prohibitive side effects. Most agents act as
protoplasmic poisons and consequently the possibility of antiarrhythmic drugs
aggravating a preexisting electrophysiologic mechanism must always be con
sidered. Although great strides have been made in the understanding of the
pharmacokinetics of antiarrhythmic drugs, the clinician is often surprised by the
actions of a specific agent and may be unable to predict whether the drug will be
beneficial or precipitate more hazardous problems in the same patient or under
other circumstances. This is particularly true when one antiarrhythmic agent is
used in the wake of another, since the interactions of various antiarrhythmic
drugs still remain unclear (1). Several recent articles have brought into sharp
focus both the electrophysiology and pharmacology of antiarrhythmic agents
(2-7).lt is the purpose of this chapter to discuss some of the newer information on
antiarrhythmic drugs, including their possible modes of action and pharmaco
kinetics. Specifically, the drugs will be discussed in terms of their main indica
tions for usage, although considerable effort will be made to describe the bene
ficial and antagonistic effects of combined antiarrhythmic drug therapy.
I. LIDOCAINE
1.1. Pharmacokinetics
Lidocaine is the most frequently utilized antiarrhythmic agent in the manage
ment of ventricular arrhythmias associated with acute myocardial processes. It is
clinically important to understand that toxicity is clearly related to lidocaine
2 L.S. DREIFUS AND J. MORGANROTH
blood levels. Also, it should be stressed that decreased clearance and longer half
life oflidocaine should be taken into consideration when toxicity appears during
long-term infusions. Furthermore, toxic manifestations of lidocaine may persist
longer than would have been expected from the data obtained after shorter
infusions. It is clinically prudent, even in patients without cardiac or hepatic
disease, that the rate of infusion oflidocaine should be reduced to approximately
one half in order to compensate for the decrease in the rate of elimination of the
drug after the first 24 hours.
It is generally accepted that the disposition oflidocaine after rapid intravenous
bolus injection is best described by an open two-compartment pharmacokinetic
model with a fast distribution phase (half-life, 8 min) and a slower elimination
phase (half-life, 100 min). In most instances, lidocaine is given as a bolus, and
immediately followed by a continuous intravenous infusion. Frequently, the
duration of the infusion exceeds 24 hours and is predicated by the clinical setting.
On the other hand, five to seven hours are required to meet a steady plasma
concentration by constant intravenous infusion without antecedent loading dose
(8). Lidocaine is well absorbed when given intramuscularly, and blood levels can
be achieved within five minutes lasting for two hours. with a peak concentration
being reached at thirty minutes (9). However. the response to the prophylactic
use of intramuscular lidocaine is not entirely consistent, and has not been
associated with constant blood levels (10). Because plateau blood levels are
determined by the infusion rate and the clearance of the drug, a decrease in
clearance after long infusion would lead to blood levels higher than expected,
and thus to toxic effects. Furthermore, assuming that the volume of distribution
does not change. a decrease in the clearance would manifest itself by a longer
half-life upon discontinuation of a protracted infusion after the first signs of
toxicity. Hence, the toxic effects might not disappear as rapidly as suggested by
the short-term studies. Most studies of the pharmacokinetics oflidocaine suggest
that plasma concentration time curves after single intravenous injection has
shown a biexponential change with an initial rapid decline followed by slower
decay (II). When given orally, only 35~/o of administered lidocaine can be
detected in the systemic circulation because of hepatic extraction (II, 12, 13).
The rapid absorption of oral lidocaine can produce extremely high toxic levels.
but the short duration of action appears totally ineffective for optimal anti
arrhythmic effect.
It is generally agreed that lidocaine in therapeutic doses. either given as a single
intravenous bolus or constant intravenous infusion. does not appear to cause
significant depression of myocardial contractility or hemodynamic derange
ments. This is true even in patients with heart disease or acute myocardial
infarction. Mild inotropic and chronotropic actions may occur at low dose levels
due to central effect (II). Rahimtoola (14) and others have studied the effect of
lidocaine at therapeutic doses, either as an intravenous bolus or constant infu-
ANTIARRHYTHMIC AGENTS 3
sion, in patients with acute myocardial infarction. They found no depression of
heart rate or of systemic and pulmonary artery pressures. Also, central venous
pressure, left ventricular end-diastolic pressure, cardiac output, stroke volume,
left ventricular stroke or systemic vascular resistance, preejection period, left
ventricular ejection and the ratio of pree jection period to left ventricular ejection
time remain essentially unchanged.
1.2. Metabolism
The metabolic pathway for the degradation of metabolism is via the liver (13,
IS). In the steady state, approximately 70% of administered lidocaine is extracted
from the liver while only a small amount of unmetabolized lidocaine is excreted
in the urine (16, 17). The most significant factors influencing the disposition of
lidocaine include hepatic failure, lowered cardiac index, and congestive heart
failure. Clearance is apparently not significantly altered in patients with renal
failure although the clearance of lidocaine metabolites is probably delayed (11).
1.3. Electrophysiologic and antiarrhythmic effects
It appears that lidocaine produces a concentration-dependent decrease in Vmax
and depression of membrane responsiveness (18). Depression of conduction by
lidocaine could theoretically convert areas of unidirectional block into bidirec
tional block, thereby abolishing reentry. Consequently, lidocaine may exert a
different effect on healthy and diseased tissues. Maximum diastolic potential and
Vmax are reduced or further depressed by therapeutic concentrations of lido
caine. The action potential duration and the refractory period ofPurkinje fibers
are shortened by lidocaine (19). The degree of alteration is related to the location
of the particular Purkinje fiber; the most significant effects of lidocaine are seen
:it a site close to the insertion of the free running strands into the ventricular
myocardium (20, 21). Furthermore, lidocaine causes the greatest changes in
action potential duration and refractoriness in normal Purkinje fibers, in which
these parameters are initially longest (20).
Lidocaine suppresses spontaneous diastolic depolarization and automatic
impulse formation in Purkinje fibers at membrane potentials between -90 and
-60 mV due to a time and voltage-dependent decrease in outward potassium
current (iKz) (22, 23).
1.4. Antiarrhythmic effects
Lidocaine is extremely effective in controlling ventricular ectopic beats of any
cause, and facilitates electrical defibrillation following experimental coronary
artery ligation as well as in the immediate reperfusion period (11). Several