NIDA Research Monograph Series #108: Cardiovascular Toxicity of Cocaine: Underlying Mechanisms

248 Pages·1991·2.5 MB·English

by  Thadani, Pushpa (editor)

National Institute on Drug Abuse
RESEARCH
MONOGRAPH SERIES
Cardiovasculas
Toxicity of
Cocaine:
Underlying
Mechanisms
1 0 8
U.S. Department of Health and Human Services • Public Health Service • National Institutes of Health
Cardiovascular Toxicity
of Cocaine: Underlying
Mechanisms
Editor:
Pushpa Thadani, Ph.D.
Division of Preclinical Research
National Institute on Drug Abuse
Research Monograph 108
1991
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Alcohol, Drug Abuse, and Mental Health Administration
National Institute on Drug Abuse
5600 Fishers Lane
Rockville, MD 20857
For sale by the Superintendent of Documents, U.S. Government Printing Office
Washington, D.C. 20402
ACKNOWLEDGMENT
This monograph is based on the papers and discussion from a technical
review on “Cardiovascular Toxicity of Cocaine: Underlying Mechanisms,” held
on August 9-10, 1989, in Bethesda, MD. The review meeting was sponsored
by the National institute on Drug Abuse,
COPYRIGHT STATUS
The National Institute on Drug Abuse has obtained permission from the
copyright holders to reproduce certain previously published material as noted in
the text. Further reproduction of this copyrighted material is permitted only as
part of a reprinting of the entire publication or chapter. For any other use, the
copyright holder’s permission is required. All other material in this volume
except quoted passages from copyrighted sources is in the public domain and
may be used or reproduced without permission from the Institute or the authors.
Citation of the source is appreciated.
Opinions expressed in this volume are those of the authors and do not
necessarily reflect the opinions or official policy of the National Institute on Drug
Abuse or any other part of the U.S. Department of Health and Human Services.
The U.S. Government does not endorse or favor any specific commercial
product or company. Trade, proprietary, or company names appearing in this
publication are used only because they are considered essential in the context
of the studies reported herein.
NIDA Research Monographs are indexed in the Index Medicus. They are
selectively included in the coverage of American Statistics Index, Biosciences
Information Service, Chemical Abstracts, Current Contents, Psychological
Abstracts, and Psychopharmacology Abstracts.
DHHS publication number (ADM)91-1767
Printed 1991
ii
Contents
Page
Preface vii
Overview 1
Pushpa V. Thadani
Maternal-Fetal Cardiovascular System: A Target of Cocaine 7
James R. Woods, Jr., and Mark A. Plessinger
Pharmacokinetics and Time-Action Profile of Cocaine in Dogs 28
R. Douglas Wilkerson, Peter N. Temesy-Armos,
and Theodore D. Fraker, Jr.
Acute Tolerance to the Chronotropic Effect of Cocaine in Humans 41
John J. Ambre, Timothy J. Connelly, Tsuen-lh Ruo,
and Thomas K. Henthorn
Mechanisms of Cardiac and Vascular Responses to Cocaine 55
Mark M. Knuepfer, Carrie A. Branch, and
Vernon W. Fischer
Cardiovascular Effects of Cocaine in Squirrel Monkeys 74
Srihari R. Tella, Charles W. Schindler,
and Steven R. Goldberg
iii
Role of the Sympathetic Nervous System in the
Cardiovascular Effects of Cocaine 92
Richard A. Gillis, Lisa C. Bachenheimer,
Kenneth L. Dretchen, Hashim K. Erzouki,
Yvonne M. Hernandez, Rakesh K. Jain,
Muskesh K. Jain, Fred E. Kuhn,
Jack Quest, and Gary L. Schaer
Cocaine-Induced Myocardial Depression 110
Theodore D. Fraker, Jr., Peter N. Temesy-Armos,
and R. Douglas Wilkerson
Prevalence of Myocardial lschemia in Cocaine Addicts 116
Koonlawee Nademanee
Cocaine-Induced Myocardial Infarction:
Clinical Observations and Pathogenetic Considerations 121
Jeffrey M. lsner and Saurabh K. Chokshi
Cardiac Electrophysiological Effects of Cocaine
in Animal Models 131
Peter N. Temesy-Armos, Theodore D. Fraker, Jr.,
and R. Douglas Wilkerson
Effects of Cocaine on Intracellular Calcium Handling
in Cardiac and Vascular Smooth Muscle 139
Cynthia L. Perreault, Kathleen G. Morgan, and
James P. Morgan
Cocaine-Induced Changes in the Biochemistry
and Morphology of Rabbit Aorta 154
Ronald O. Langner and Collette L. Bement
Effects of Cocaine on the Physiology of
Exercise 167
Robert K. Conlee, David W. Barnett, K. Patrick Kelly,
and Dong Ho Han
iv
Effect of Acute Cocaine Administration on
Cardiac and Respiratory Patterning in the
Freely Moving Cat 181
Ronald M. Harper, Rebecca K. Harper,
Robert R. Terreberry, Christopher A. Richard,
and Robert B. Trelease
Direct and Indirect Morphological Markers of
Cocaine Toxicity in the Human Heart 202
Margaret E. Billinghem
Cocaine-Associated Cardiovascular Disease:
Clinical and Pathological Aspects 220
Renu Virmani
List of NIDA Research Monographs 230
v

Preface
On August 9-10, 1989, the National Institute on Drug Abuse held a technical
review meeting titled “Cardiovascular Toxicity of Cocaine: Underlying
Mechanisms” to review the state of knowledge and to identify areas of future
research. Biomedical scientists discussed the potential site(s) of cocaine’s
cardiovascular actions and the possible mechanisms underlying these cardiac
events in immature and mature cardiovascular systems in various animal
models and in human tissues. A report summarizing the major findings and the
future areas of research identified at the meeting was published (Thadani et al.
1990), and included the following summary findings: (1) More than one
mechanism is involved with the deleterious effects of cocaine on myocardium;
(2) pharmacokinetic investigations indicate that in animals and in humans the
elimination of cocaine occurs in a nonlinear fashion, which could cause an
unexpected rise in blood cocaine levels in cocaine addicts during a binge
period; and (3) a subgroup of the population may be more vulnerable to the
cardiotoxic effects of cocaine. Areas of research identified in this field included
more investigations at the cellular and subcellular levels, on the central nervous
system and respiratory system contributions In these cardiac responses, and on
the genetic aspect of cocaine myocardial effects. This monograph consists of
the papers presented at the technical review.
REFERENCE
Thadani, P.V., et al. Cardiovascular toxicity of cocaine: Underlying
mechanisms. J Appl Cardiol 5:317-320, 1990.
vii

Overview
Pushpa V. Thadanl
Use of cocaine during pregnancy has been associated with increased incidence
of miscarriage, rupture of maternal Intracranial aneurysm, abruptio placentae,
and delivery of small-for-gestational-age babies. These pregnancy-related
complications are thought to result from increasing circulating blood
catecholamine levels and vasoconstriction of the regional vascular beds due to
cocaine-induced inhibition of catecholamine reuptake at adrenergic nerve
terminals.
Dr. James Woods, Jr., and Mark Plessinger describe the impact of these
changes on fetal and maternal cardiovascular systems following administration
of cocaine to pregnant ewes. Maternal administration of cocaine produced
dose-dependent increases in maternal heart rate (HR) and blood pressure (BP).
In the fetus, elevations in HR and BP were accompanied by reductions in
arterial PO,. Direct administration of cocaine to the fetus caused no change in
fetal arterial PO, but produced an increase in BP and HR. These findings
indicated that cocaine-induced changes in the fetal cardiovascular system are
the result of the drug’s direct and Indirect effects. Direct effects are caused via
maternal-fetal transfer, whereas indirect actions result from fetal hypoxemia
induced by vasoconstrlction of uterine vasculature. Pharmacological studies
showed that cocaine-evoked vasoconstriction of uterine vasculature involved
stimulation of alpha-adrenergic receptors as well as some other mechanism.
Analysis of cocaine levels in maternal and fetal blood indicated that cocaine
crosses the placenta rapidly and disappears into two vascular compartments
without equilibration.
Because severe cardiopulmonary and neurologic complications also were seen
in pregnant ewes following high doses of cocaine, Dr. Woods and Plessinger
examined the role of pregnancy-related hormones in cocaine-induced
cardiovascular responses. Administration of progesterone to nonpregnant ewes
resulted in cocaine-induced cardiovascular responses similar to those seen in
pregnant animals, suggesting that this hormone may contribute to the amplified
cocaine responses.
1