Radiocontrast Agents

618 Pages·1984·15 MB·English

by  M. Sovak (auth.)

Handbook of
Experimental Pharmacology
Continuation of Handbuch der experimentellen Pharmakologie
Vol. 73
Editorial Board
G. V. R. Born, London' A. Farah, Rensselaer, New York
H. Herken, Berlin' A. D. Welch, Bethesda, Maryland
Advisory Board
S. Ebashi· E. G. Erdos' V. Erspamer· U. S. von Euler' W S. Feldberg
G. B. Koelle' M. Rocha e Silva' 1. R. Vane' P. G. Waser
Radio contrast
Agents
Contributors
T. Almen . l L. Barnhart· P. B. Dean' S. EI-Antably . H. W Fischer
K. Golman . C.B. Higgins' G.B. Hoey· E.C. Lasser' G.P. Murphy
lA. Nelson' D.B. Plewes . K.R. Smith· M. Sovak . M.R. Violante
Editor
M.Sovak
Springer-Verlag
Berlin Heidelberg New York Tokyo 1984
Professor Dr. MILOS SOVAK
University of California in San Diego
School of Medicine
Department of Radiology, S-009
La Jolla, CA 92093/USA
and
Biophysica Foundation
3333 Torrey Pines Ct.
La Jolla, CA 92037/USA
With 189 Figures
Library of Congress Cataloging in Publication Data. Main entry under title: Radiocontrast agents. (Handbook of
experimental pharmacology; vol. 73) Includes bibliographies and index. I. Diagnosis, Radiography. 2. Contrast media.
I. Almen, T. (Torsten) II. Sovak, Milos. III. Series: Handbook of experimental pharmacology; v. 73. [DNLM:
I. Contrast Media. WI HA51L v. 73/WN 160 R1285] QP905.H3 vol. 73 [RC78] 615'.ls [616.07'572] 84-5448
ISBN-\3: 978-3-642-69517-9 e-ISBN-\3: 978-3-642-69515-5
DOl: 10.1007/978-3-642-69515-5
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© by Springer-Verlag Berlin Heidelberg 1984
Softcover reprint ofthe hardcover 1st edition 1984
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2122/3 \30-543210
List of Contributors
T. ALMEN, Department of Radiology, Malmo General Hospital, 21401 Malmo,
Sweden
J. L. BARNHART, University of California in San Diego, School of Medicine,
Department of Radiology, H-755, San Diego, CA 92103jUSA
P. B. DEAN, University of Turku, School of Medicine, Department of Radiology,
20520 Turku 52, Finland
S. EL-ANTABLY, Research Department, Medical Products Group, Mallinckrodt,
Inc., P.O. Box 5439, St. Louis, MO 63147jUSA
H. W. FISCHER, University of Rochester, School of Medicine, Department of
Radiology, Rochester, NY 14642jUSA
K. GOLMAN, University of Lund, Department of Experimental Research, Malmo
General Hospital, 21401 Malmo, Sweden
C. B. HIGGINS, University of California in San Francisco, School of Medicine,
Department of Radiology, San Francisco, CA 94143jUSA
G. B. HOEY, Research Department, Medical Products Group, Mallinckrodt, Inc.,
P.O. Box 5439, st. Louis, MO 63147jUSA
E. C. LASSER, University of California in San Diego, School of Medicine,
Department of Radiology, S-004, La Jolla, CA 92093jUSA
G. P. MURPHY, Research Department, Medical Products Group, Mallinckrodt,
Inc., P.O. Box 5439, St. Louis, MO 63147jUSA
J. A. NELSON, University of Utah, College of Medicine, Department of Radiology,
lA71 Medical Center, Salt Lake City, UT 84132jUSA
D. B. PLEWES, Radiology Department, University of Rochester, Medical Center,
Box 648, Rochester, NY 14642jUSA
K. R. SMITH, Research Department, Medical Products Group, Mallinckrodt,
Inc., P.O. Box 5439, St. Louis, MO 63147 jUSA
VI List of Contributors
M. SOVAK, University of California in San Diego, School of Medicine, Depart
ment of Radiology, S-009, La Jolla, CA 92093/USA and Biophysica
Foundation, 3333 N. Torrey Pines Ct., La Jolla, CA 92037/USA
M. R. VIOLANTE, University of Rochester, School of Medicine, Department of
Radiology, Rochester, NY 14642/USA
Preface
Contrast media are drugs by default. Had there been no default, there would be no
need for a related pharmacology, and thus no need for this book. Radiographic
contrast media (CM) are substances whose primary purpose is to enhance
diagnostic information of medical imaging systems. The position of CM in
pharmacology is unique. First, there is the unusual requirement of biological
inertness. An ideal CM should be completely biologically inert, i.e., stable, not
pharmacologically active, and efficiently and innocuously excretable. Because
they fail to meet these requirements, CM must be considered drugs.
The second unusual aspect of CM is that they are used in large quantities, their
annual production being measured in tens of tons. It is not in spite of, but because
of, the increased use of new radiographic systems, computed tomography, digital
radiography, etc., that consumption is on the rise. And, it is not likely that the
other emerging imaging modalities - NMR, ultrasonography, etc. - will displace
radiographic CM soon; it is quite probable that these remarkable compounds will
continue to play an active role in diagnostic imaging in the foreseeable future.
Following some 20 years of relative stagnation, the early seventies saw a major
improvement with the first nonionic CM, metrizamide. Recently, a second
generation of nonionic CM, compounds of low toxicity and high stability, was
introduced. It seems only logical to assume that future developmental efforts will
be directed toward design of compounds of equally good properties, but of lower
cost. Expenditures for medical care are rising excessively, and their containment is
rapidly becoming an important issue in most countries. Since the currently used
ionic CM are almost acceptable for most general applications, the new generation
of improved CM will not only have to be qualitatively superior to justify their
introduction, but will also have to be economically feasible. By reviewing past
experience in the design of improved CM, defining the state of the art, and
presenting the basic methodology of CM research, the aim of this book is to
inspire further progress in the important field of radiopharmacology and medical
imaging.
I should like to express my thanks to Minerva Kunzel and William
Shufflebotham, who helped me edit the manuscripts, and to Carol King and
Mary Seeberger, who patiently typed and retyped the ever-changing text. Further,
I wish to thank Sterling-Winthrop and Mallinckrodt Companies for their support,
and the Editorial Board of the Handbook and the Publisher for the care that made
this book possible.
La Jolla M. SOVAK
Contents
Introduction: State of the Art and Design Principles of Contrast Media.
M. SOVAK. With 9 Figures.
References. 19
CHAPTER 1
Chemistry of X-Ray Contrast Media. G. B. HOEY and K. R. SMITH
in collaboration with S. EL-ANTABLY and G. P. MURPHY. With 38 Figures
A. Introduction and Scope . . . . 23
B. Biological Requirements . . . . 23
I. Physicochemical Properties 24
1. Water Solubility 24
2. Viscosity. . . . 25
3. Osmolality. . . 25
II. Chemical Stability 26
III. Biological Safety 28
C. Ionic Contrast Media . 31
I. Synthesis. . . . 31
II. Evolution of Structural Types . 32
1. Improving the Functional Groups . 34
2. Reduction of Hypertonicity. . . . 51
D. Nonionic Contrast Media . . . . . . . . 54
I. Solubility Aspects of Nonionic Media 76
II. Viscosity Considerations 77
III. Osmolality . . 78
IV. Stability . . . . . . . 79
1. Deiodination . . . . 80
2. Instability of the Polyhydroxylalkyl Group 80
3. Hydrolysis of the Coupler Group 83
V. Synthesis of Nonionic Compounds. 85
1. Synthetic Approaches . . . . . 85
2. Manufacturing Costs . . . . . 92
VI. Stereochemical Aspects of Contrast Media 95
1. Isomers Resulting from Restricted Rotation 96
VII. High-Pressure Liquid Chromatography. . 99
VIII. Water-Insoluble Nonionic Contrast Media 101
1. Oily Contrast Media. . . . . . . . . 102
x Contents
2. Benzoate Esters. . . . 103
3. Perfluoroalkyl Halides . 106
E. Oral Cholecystographic Agents 107
References. . . . . . . . . . . . 114
CHAPTER 2
Urographic Contrast Media and Methods of Investigative Uroradiology
K. GOLMAN and T. ALMEN. With 35 Figures
A. Introduction . . . . . 127
B. Historical Remarks . . . . . . . . . 128
C. Attenuation of X-Rays . . . . . . . 132
I. Contrast Medium Concentration in Different Regions of the
Urinary Tract; Factors Influencing the Nephrogram and Pyelogram 133
1. Effects of Plasma Iodine Concentration 135
2. Effects of Urine Iodine Concentration. 138
II. Urinary Tract Volume Changes. 146
1. Urine Flow . . . . . . . . . 146
2. Theoretical Effects of Changes . 146
3. Experimental Effects of Changes 148
D. Pharmacodynamics . . . . . 149
I. Intravenous Lethal Dose. . . . . 149
II. Causes of Death . . . . . . . . 151
1. Lung Edema and Red Blood Cell Changes. 151
2. Nephrotoxicity. . . . . . 153
III. Other Adverse Reactions. . . . . 158
IV. Advantages of Ratio-3 Media. . . 158
E. Methods of Investigative Uroradiology . 158
I. Introduction . . . . 158
1. Choice of Species. . 159
2. Anesthesia. . . . . 159
3. Surgical Procedures. 160
II. Assays for Contrast Media . 160
III. Methods for the Measurement of the Depth of the X-Ray
Attenuating Layer. 163
1. Planimetry. . . . . . . . . . . . . . . 163
2. Urine Flow . . . . . . . . . . . . . . 164
IV. Methods for Studying Excretion Mechanisms. 166
1. Clearance of Contrast Media. . . . . . . 166
2. Tubular Micropuncture and Microperfusion 170
3. Cell Culture . . . . . . . . . . . . . . 171
V. Methods for Studying Renal Pharmacodynamics 171
1. Urine Osmolality. . . . . . 171
2. Ability to Concentrate Urine. 171
3. Urine Flow . . . . 172
4. Vascular Changes. . 172
5. Glomerular Damage 175
Contents XI
6. Tubular Damage 176
References. . . . . . . . 180
CHAPTER 3
Contrast Media in the Cardiovascular System. C. B. HIGGINS.
With 10 Figures
A. Introduction . . . . . . . . . . . . . . . . . . . 193
B. Classification of Cardiovascular Actions of Contrast Media. 193
C. Importance of Experimental Conditions . . . . . . . . . 195
I. Influence of the Experimental Model Used for Studying
Cardiovascular Effects of Contrast Media . . . . 195
II. Influence of the Site of Injection of Contrast Media 196
D. Specific Effects . . . . . . . . . . . 199
I. Electrophysiologic Cardiac Effects. 199
1. Impulse Generation. 200
2. Impulse Conduction . . . . 202
3. Arrhythmias. . . . . . . . 204
4. Electrocardiographic Changes 208
II. Hemodynamic Cardiac Effects . 210
1. Hemodynamic Changes During Contrast Ventriculography. 210
2. Use of Contrast Media as a Stress Test in Coronary Artery
Disease . . . . . . . . . . . . . . . . 212
III. Direct Myocardial Effects . . . . . . . . . . . 213
1. Isolated Heart and Isolated Cardiac Tissue. . . 213
2. Intracoronary Administration in the Intact Heart 216
3. Effects on Ischemic Myocardium and Failing Myocardium. 224
4. Mechanism of Action of Direct Cardiac Effects. . . .. 224
5. Clinical Evaluation of Contrast Media Used for Coronary
Arteriography . . . . . . . . . . . . . . 227
IV. Reflex or Neurally Mediated Circulatory Effects. 228
1. Vascular Effects . . . . . . . . . . . 231
2. General Circulation and Limb Circulation 231
3. Renal Circulation. . . 233
4. Splanchnic Circulation 236
5. Carotid Circulation. . 237
6. Coronary Circulation . 238
7. Microcirculation and Vascular Endothelium 240
E. Summary 243
References. . 243
CHAPTER 4
Basic Methods of Investigative Cardiovascular Radiology
M. SOVAK and C. B. HIGGINS. With 7 Figures
A. Introduction . . . . . . . . . . . . . . . . . . 253
B. Contrast Media. . . . . . . . . . . . . . . . . 253
I. Pharmacological Evaluation of Radiographic Contrast Media. . 254
XII Contents
C. Experimental Cardioradiographic Visualization 259
D. Choice of Experimental Animals 260
I. Infrahuman Primates 260
II. Cats. . 261
III. Calves . 261
IV. Rabbits 261
V. Pigs. . 262
1. Catheterization: Implantation of Chronic Catheters 263
2. Acute Catheterization. . . . . . . . . . . . . 263
VI. Dogs . . . . . . . . . . . . . . . . . . . . . 263
E. The Laboratory for Cardiovascular Contrast Media Research . 267
F. Cardiovascular Catheterization . . . . . . . . . . 272
G. Animal Models of Cardiovascular Pathological States 276
References. . . . . . . . . . . . . . . . . . . . . 287
CHAPTER 5
Contrast Media for Imaging of the Central Nervous System. M. SOVAK
A. Introduction . . . . . . . . . . . . . . . . 295
B. Angiographic Contrast Media in Neuroradiology 296
I. Current Ionic Contrast Media 297
1. Cranial Angiography . . . . . . . . . 297
2. Spinal Cord Angiography . . . . . . . 301
II. Newer Nonionic Monomers and Monovalent Dimer in
Neurovascular Use. . . 302
C. Intrathecal Contrast Media. . . . . . . . . . . . 304
I. Intrathecal Visualization . . . . . . . . . . . 306
II. New Developments in Intrathecal Contrast Media 320
References. . . . . . . . . . . . . . . . . . . . . 326
CHAPTER 6
Basic Methods of Investigative Neuroradiology
M. SOVAK. With 1 Figure
A. Introduction . . . 341
B. Anesthesia . . . . . 341
I. Premedication . 342
II. Injectable Anesthetics 342
III. Volatile Anesthetics . 344
C. Neurovascular Experimental Methods 344
D. Experimental Methods for the Subarachnoid Space 349
1. Choice of Anima1. . . . . . . . . . . . 349
2. Methods of Access to the Subarachnoid Space 350
E. Toxicity Screening of Experimental Compounds. 355
1. Aversion Conditioning . . . 355
2. Electrophysiological Methods 356
References. . . . . . . . . . . . . . 361