Handbook of Experimental Pharmacology Continuation of Handbuch der experimentellen Pharmakologie

Vol. 69

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· J. R. Vane' P. G. Waser

Pharmacology of the Eye Contributors

G.1. Chader . 1. Cunha-Vaz . P. H. Fischer· R. W Flower B. R. Friedland· I. Gery . M. 0. Hall· M.-H. Heinemann L. M. Jampol . T. R. Jones· P. L. Kaufman· 1. C. LeDouarec I. H. Leopold· V 1. Lotti· T. H. Maren . K. Masuda D. M. Maurice· S. Mishima· R. B. Nussenblatt . M. Pandolfi A. Patz . 1. R. Polansky· A. M. Potts· W H. Prusoff· T. W Reid 1. R. Robinson· M. Rosenberg· M. L. Sears· D. Seigel· H. Shichi J. Stjemschantz . C.A. Stone· R. N. Weinreb· T. Wiedman

Editor

M.L. Sears

Springer-Verlag Berlin Heidelberg New York Tokyo 1984

Professor Dr. MARVIN L. SEARS Department of Ophthalmology and Visual Science School of Medicine Yale University 333 Cedar Street New Haven, CT 06510jUSA

With 147 Figures

ISBN-13 :978-3-642-69224-6 e-ISBN-13 :978-3-642-69222-2 DOl: 10.1007/978-3-642-69222-2

This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically those of translation, reprinting, re·use of illustrations, broadcasting, reproduction by photocopying machine or similar means, and storage in data banks. Under § 54 of the German Copyright Law where copies are made for other than private use, a fee is payable to "Verwertungsgesellschaft Wort", Munich.

© by Springer-Verlag Berlin Heidelberg 1984

Softcover reprint of the hardcover 1st edition 1984

The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use.

Product liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature.

Typesetting, printing and bookbinding: Briihlsche Universitatsdruckerei, Giessen 2122/3130-543210

Preface

Roots of the theory and practice of ocular pharmacology may be traced to the ancient Mesopotamian code of Hammurabi and then to several papyri reflecting the clinical interests of the Egyptians. The evolution of its art and science was irregularly paced until the nineteenth century when Kohler, in 1884, proved the anesthetic effect of cocaine on the cornea, and when Fraser, Laquer, Schmiedeberg, Meyer, and others studied the pharmacology of the autonomic nervous system by way of observations of the pupil. Advances in the past few decades have been nothing short of explosive. How can the student, physician, or basic research scientist stay in touch with these electrifying studies? To help with the answer to this question, the authors set as their goal the development of increased understanding so that the student, research scientist, and ophthalmologist can cope with the latest discoveries. The authors want to narrow what appears to be an ever-increasing gap between basic science and ophthalmology. The basic aspects of pharmacology have been presented in light of the natural physiology. In this regard, while distinctions among endogenous mechanisms, drug effects, and the pathogenesis of disease are to be separately recognized, appreciation must be given to the concept that both the desirable and unwanted manifestations or functions caused by either disease or drugs must very often represent a quantitative change in normal metabolic pathways. "The most likely way, therefore, to get any insight into the nature of those parts of creation, which come within our observations, must in all reason, be to number, weigh and measure," as Stephen Hales, (1677-1761) wrote (Vegetable Staticks. Watson, New York 1969). The authors have, wherever possible, in this first effort at a text in ocular pharmacology, attempted to guide themselves by a quantitative approach.

The current text includes reports of articles up to the end of 1982. The authors have not considered treatment of the topic of therapeutics per se. In particular, the drug device and drug delivery areas have not been discussed. Numerous recent references deal with these subjects anyway. This book is not intended to cover clinical ocular pharmacology, but rather to provide a sound foundation on which the use of drugs in ocular therapy can be based. The authors will have considered their goal accomplished if an improved understanding has been provided for the reader and increased pleasure has been given to those particularly interested in pharmacology as applied to the eye.

New Haven MARVIN L. SEARS

List of Contributors

G. J. CHADER, Laboratory of Vision Research, National Eye Institute, National Institutes of Health, Bldg. 6, Rm. 222, Bethesda, MD 20205/USA

J. CUNHA-VAZ, Department of Ophthalmology, University of Coimbra, Coimbra, Portugal

P. H. FISCHER, Department of Oncology, University of Wisconsin, School of Medicine, Madison, WI 53792/USA

R. W. FLOWER, Applied Physics Laboratory, Johns Hopkins Road, Laurel, MD 20810/USA

B. R. FRIEDLAND, Department of Pharmacology and Therapeutics, University of Florida, College of Medicine, Gainesville, FL 32610/USA

I. GERY, Laboratory of Vision Research, National Eye Institute, National Institutes of Health, Bldg. 6, Rm. 232, Bethesda, MD 20205/USA

M. O. HALL, Jules Stein Eye Institute, UCLA Medical Center, Los Angeles, CA 90024/USA

M.-H. HEINEMANN, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021/USA

L. M. JAMPOL, Sickle Cell Eye Clinic, University of Illinois, Department of Ophthalmology, Medical Center, Hospital Eye and Ear Infirmary, 1855 W. Taylor Street, Chicago, IL 60612/USA

T. R. JONES, Department of Ophthalmology and Visual Science, Yale University, School of Medicine, 333 Cedar Street, New Haven, CT 06510/USA

P. L. KAUFMAN, Department of Ophthalmology, University of Wisconsin, Hospital Clinics,600 Highland Avenue, Madison, WI 53792/USA

J. C. LEDoUAREC, Searle Research and Development, Sophia Antipolis, B.P. 23, F -06562 Valbonne Cedex

VIII List of Contributors

I. H. LEOPOLD, Department of Ophthalmology, University of California, College of Medicine, Irvine, CA 92717 jUSA

V. J. LOTTI, Merck Sharp and Dohme Research Laboratories, West Point, PA 19486jUSA

T. H. MAREN, Department of Pharmacology and Therapeutics, University of Florida, College of Medicine, The J. Hillis Miller Health Center, Gainesville, FL 32610jUSA

K. MASUDA, Department of Ophthalmology, School of Medicine, University of Tokyo, 113 Hongo, 7-3-1 Bunkyo-ku, Tokyo, Japan

D. M. MAURICE, Division of Ophthalmology, Department of Surgery, Stanford University, School of Medicine, Stanford, CA 94305jUSA

S. MISHlMA, Department of Ophthalmology, School of Medicine, University of Tokyo, 113 Hongo, 7-3-1 Bunkyo-ku, Tokyo, Japan

R. B. NUSSENBLATT, Laboratory of Vision Research, National Eye Institute, National Institutes of Health, Bldg. 6, Room 232, Bethesda, MD 20205jUSA

M. PANDOLFI, Department of Ophthalmology, University of Lund, Malmo General Hospital, S-21401 Malmo; King Faisal University, Department of Ophthalmology, Khobar Teaching Hospital, P.O. Box 2208, AI-Khobar, Saudi Arabia

A. PATZ, Retinal Vascular Center, Wilmer Ophthalmological Institute, Johns Hopkins Hospital, 601 North Broadway, Baltimore, MD 21205jUSA

J. R. POLANSKY, Department of Ophthalmology, School of Medicine, University of California, Parnassus Avenue, San Francisco, CA 94143jUSA

A. M. POTTS, Department of Ophthalmology, School of Medicine, University of Louisville, Kentucky Lions Eye Institute, 301 E. Muhammad Ali Blvd., Louisville, KY 40202jUSA

W. H. PRUSOFF, Department of Pharmacology, Yale University, School of Medicine, 333 Cedar Street, New Haven, CT 06510jUSA

T. W. REm, Department of Ophthalmology and Visual Science, Yale University, School of Medicine, 333 Cedar Street, New Haven, CT 06510jUSA

J. R. ROBINSON, School of Pharmacy, University of Wisconsin, 425 N. Charter Street, Madison, WI 53706jUSA

M. ROSENBERG, Department of Ophthalmology, University of Illinois, Medical Center, Hospital Eye and Ear Infirmary, 1855 W. Taylor Street, Chicago, IL 60612jUSA

List of Contributors IX

M. L. SEARS, Department of Ophthalmology and Visual Science, School of Medicine, Yale University, 333 Cedar Street, New Haven, CT 06510jUSA

D. SEIGEL, Clinical Trials Section, Office of Biometry and Epidemiology, National Eye Institute, National Institutes of Health, Bldg. 31, Room 6A.16, Bethesda, MD 20205jUSA

H. SHIcm, Institute of Biological Sciences, Oakland University, Rochester, MI 48063jUSA

J. STJERNSCHANTZ, Department of Ophthalmology, School of Medicine, Yale University, 333 Cedar Street, New Haven, CT 06510jUSA

C. A. STONE, Merck Sharp and Dohme Research Laboratories, West Point, P A 19486jUSA

R. N. WEINREB, Department of Ophthalmology, Glaucoma Service, University of Texas Health Sciences Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75235jUSA

T. WIEDMAN, School of Pharmacy, University of Wisconsin, 425 N. Charter Street, Madison, WI 53706jUSA

Contents

CHAPTER 1

The History of Ophthalmic Therapeutics M.-H. HEINEMANN. With 7 Figures.

References . . . . . . . . . . . . .

CHAPTER 2

Ocular Pharmacokinetics D. M. MAURICE and S. MISHIMA. With 20 Figures

Abbreviations. . . A. Introduction. . . . . . . . .

I. Objectives. . . . . . . . II. Compartments and Barriers

III. Routes of Administration and Penetration . 1. Topical Administration. 2. Local Injection . . . . . . . . . . . 3. Systemic Administration . . . . . . .

IV. Animal Models and Human Experimentation 1. Animal Models . . 2. Human Experiments ........ .

B. ;Topical Administration . . . . . . . . . . . I. Factors Involved in Intraocular Penetration

1. The Tears and Contact with Ocular Surface . 2. Corneal Penetration . . 3. Conjunctiva and Sclera. . . . . . . . . . 4. Intraocular Structures . . . . . . . . . . 5. Metabolism of Drugs During Intraocular Penetration.

II. Compartmental Analysis .. 1. Compartmentation. . . . 2. Two-Compartment Model 3. Tear Patterns . . . . . . 4. Other Compartments. . . 5. Kinetics of Ocular Responses to Drugs. 6. Parameter Determination. . . .

III. Conclusions and Recommendations. . . .

16

19 20 20 22 22 23 24 25 25 25 26 26 26 26 31 36 37 39 41 41 43 49 52 53 59 66

XII

C. Local Injections I. Subconjunctival

1. Regurgitation . 2. Depot Dynamics 3. Aqueous Humor Concentration 4. Entry Pathways . 5. Vitreous Penetration . 6. Retrobulbar Injection

II. Intravitreal Injection 1. Diffusion in Vitreous. 2. Loss from the Vitreous Chamber 3. Drug Kinetics. 4. Application to Humans.

D. Systemic Administration I. Intraocular Drug Penetration

1. Structures Related to Entry from Blood 2. The Blood-Vitreous Barrier. 3. Chemical Factors in Drug Penetration 4. Drug Distribution in the Eye

II. Compartmental Analysis 1. Formulation of Aqueous Humor Dynamics 2. One-Compartment Approximation . 3. Changes in Aqueous Concentration 4. Kinetics of Intracameral Penetration 5. Penetration into the Vitreous 6. Penetration into the Cornea and Lens

III. Conclusions and Recommendations. E. Kinetics in Ocular Disease .

I. Inflammation and its Models II. Effects on Ocular Parameters

1. Permeability 2. Active Transport 3. Vasomotor Effects.

III. Effects on Drug Kinetics 1. Topical Application 2. Systemic Penetration . 3. Periocular Injection 4. Intravitreal Injection .

F. Conclusion References

CHAPTER 3 Biotransformation and Drug Metabolism. H. SHICIfl. With 25 Figures

A. Introduction. . . . . . . . . . . B. Hepatic Drug-Metabolizing Systems

Contents

67 67 67 68 68 70 71 71 72 72 72 75 77 77 77 78 79 80 82 84 84 86 88 89 91 93 95 96 96 97 97 98 99 99 99

100 101 101 101 102

117 118

Contents XIII

I. Microsomal Electron Transport Systems (Phase I Enzymes) 118 1. Cytochrome P-450. . . . . . . . . . . . . . . . . 119 2. NADPH· Cytochrome P~450 Reductase . . . . . . . 120 3. Cytochrome bs and NADH . Cytochrome bs Reductase. 121

II. Reactions Catalyzed by the Cytochrome P~450 System 121 l. Oxidative Reactions . . . . . . . . . 121 2. Reductive Reactions . . . . . . . . . 126

III. Conjugation Reactions (Phase II Reactions) 127 l. Glucuronidation. 128 2. Sulfation . . . . . . . . . . 129 3. Acetylation. . . . . . . . . 130 4. Conjugation with Amino Acids 131 5. Methylation . . . . . . . . 132 6. Conjugation with Glutathione . 133

IV. Induction of Drug~Metabolizing Enzymes 135 C. Ocular Drug Metabolism . . . . . . . . . 138

I. Aryl Hydrocarbon Hydroxylase Induction in the Eye 138 II. Tissue Distribution of Drug~Metabolizing Enzymes in the Eye 139

III. Drug Toxicity - An Experimental Approach. 141 D. Concluding Remarks 142 References . . . . . . . . . . . . . . . . . . . 143

CHAPTER 4

Cholinergics P.L. KAUFMAN, T. WIEDMAN, and J.R. ROBINSON. With 11 Figures

A. Chemistry Related to Biological Activity 149 I. Cholinergic Neurotransmission 149

II. Direct~Acting Agonists . 150 1. Muscarinic Agents . . . . 150 2. Nicotinic Agents . . . . . 153

III. Indirect~Acting Agonists: Anticholinesterases 154 l. Carbamates . . . . . . . . . . . . . 154 2. Organophosphorous Compounds . . . . 156

B. Ocular Anatomy/Physiology Relevant to Cholinergic Mechanisms: Acute Effects of Cholinergic Drugs . 156

I. Lacrimation· 156 II. Cornea. . . . . . . . . . . 157

III. Lens. . . . . . . . . . . . 158 IV. Pupillary Movement and Accommodation 159 V. Aqueous Humor Formation, Removal, and Composition;

Blood-Aqueous Barrier . . . . . . 161 l. Basic Anatomy and Physiology. . 161 2. Acute Effects of Cholinergic Drugs 163

XIV

VI. Retina ....................... . VII. Oculorotary and Respiratory Skeletal Muscles. . . . . . .

C. Longer-Term Effects of Cholinergic Drugs or Altered Cholinergic Neurotransmission . . . . . . . . . . . . . . . . . . . . .

I. Cholinergic Sensitivity in Ocular Smooth Muscles . . . . . I. Physiologically and Pharmacologically Induced Alterations 2. Disease-Induced Alterations . 3. Surgically Induced Alterations

II. Cholinergic Toxicity . . . . . . 1. Lens (Cataractogenesis) . . . 2. Iris/Ciliary Muscle/Trabecular Meshwork

References

CHAPTER 5a

Autonomic Nervous System: Adrenergic Agonists M. L. SEARS. With 21 Figures

A. Introduction. . . . . . . . . . . . . . . . . . B. Cellular Sites and Mechanism of Adrenergic Action. C. Modulation and Interaction of Receptor Types . D. Sensitivity. . . . . . . . . . . E. Stereoisomerism . . . . . . . . F. Storage, Release, and Degradation

I. Monoamine Oxidase . . . . II. Catechol-O-methyltransferase

G. Pharmacokinetics . . . . . . . I. Penetration . . . . . . . .

II. Distribution and Accumulation III. Duration . . . . . . . . . . IV. Action of Drugs on Intraocular Pressure

H. Tissue Functions. . . I. Lacrimal Gland .

II. Cornea and Lens. III. Iris. . . . . .

J. Blood Flow . . . . K. Intraocular Pressure L. Other Interactions .

I. Guanyl Cyclase II. Steroids and Adrenergics

III. Adrenergics and Prostaglandins IV. Adrenergics and Ocular Pigment

M. Retina References . . . . . . . . . . . . .

Contents

168 169

170 170 170 174 175 175 175 178 180

193 193 195 196 197 198 198 199 200 200 200 200 201 201 201 202 203 205 207 228 228 229 229 230 231 233

Contents

CHAPTER 5b

Autonomic Nervous System: Adrenergic Antagonists V.J. LoTTI, J.C. LEDoUAREC, and C.A. STONE

xv

A. Introduction. . . . . . . . 249 B. Beta-Adrenergic Antagonists. 249

I. Animal Pharmacology. . 249 1. Intraocular Pressure . 249 2. Aqueous Humor Dynamics 257 3. Interactions with Beta-Adrenergic Receptors in the Eye 258 4. Mechanisms of Action on Intraocular Pressure 262 5. Ocular Penetration and Distribution 264 6. Other Ocular Pharmacology 265

II. Clinical Pharmacology. . . . 267 1. Intraocular Pressure 267 2. Aqueous Humor Dynamics 268 3. Beta-Adrenergic Receptor Blockade in the Eye 268 4. Mechanisms of Action 269 5. Ocular Penetration . . 269

C. Alpha-Adrenergic Antagonists 270 I. Animal Pharmacology. . 270

1. Selective Alpha-Adrenergic Antagonists 270 2. Alpha- and Beta-Adrenergic Antagonists (Labetalol) . 271

II. Clinical Pharmacology . 272 References . . . . . . . . . . . . . . . . . . . . . . . . 272

CHAPTER 6

Carbonic Anhydrase: Pharmacology of Inhibitors and Treatment of Glaucoma B. R. FRIEDLAND and T. H. MAREN. With 10 Figures

A. History. . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 B. Pharmacology of the Clinically Used Carbonic Anhydrase Inhibitors. 281 C. Physiology of Ocular Carbonic Anhydrase Inhibition 288

I. Aqueous Humor Dynamics . 288 II. Aqueous Flow. . . . . . . . 289

III. Relation to Pressure . . . . . . 289 IV. Chemical Mechanisms of Flow. 290 V. Relation to Systemic Effects. .

VI. Pharmacology of the Inhibitors Related to Ocular Effect and Enzyme Inhibition . . . . . . . . . . .

D. Clinical Uses of Carbonic Anhydrase Inhibitors I. Glaucoma .............. .

II. Miscellaneous Uses and Effects . . . . . E. Urolithiasis with Carbonic Anhydrase Inhibitors F. Other Toxic Effects. G. Summary References . . . . . .

293

293 297 297 298 299 300 303 303

XVI Contents

CHAPTER 7

Autacoids and Neuropeptides. J. STJERNSCHANTZ. With 5 Figures

A. Introduction. 311 B. Prostaglandins, Prostacyclin, Thromboxane, and Lipoxygenase Products 312

I. General Background 312 II. Occurrence and Biosynthesis in the Eye 314

III. Elimination 315 IV. Effects in the Eye 316

1. Blood Flow . 316 2. Blood-Aqueous Barrier and Formation of Aqueous Humor 317 3. Intraocular Pressure 321 4. Outflow of Aqueous Humor 322 5. Iridial and Ciliary Smooth Muscles 322 6. Miscellaneous Effects 323

V. Interaction with the Autonomic and Sensory Nervous Systems in the Eye. 323

VI. Pathophysiological Considerations 325 1. Immediate Response to Injury of the Eye . 325 2. Inflammation of the Eye 327 3. Other Disorders in the Eye Possibly Involving Prostaglandins . 328

C. Histamine. 329 I. General Background 329

II. Occurrence and Effects in the Eye 330 III. Pathophysiological Considerations 331

D. 5-Hydroxytryptamine . 332 I. General Background 332

II. Occurrence and Effects in the Eye 332 E. Plasma ECinins . 334

I. General Background 334 II. Effects in the Eye 334

F. The Renin-Angiotensin System 336 I. General Background 336

II. Occurrence in the Eye 337 G. Substance P . 337

I. General Background 337 II. Distribution in the Eye 338

III. Effects in the Eye 339 1. Retina. 339 2. Iridial Smooth Muscles . 339 3. Ocular Circulation and Blood-Aqueous Barrier 340 4. Intraocular Pressure 341 5. Formation and Outflow of Aqueous Humor. 341

H. Enkephalins . 342 I. General Background 342

II. Occurrence and Effects in the Eye 342 J. Neurotensin . 342

Contents

K. Hypothalamic Peptides Regulating the Adenohypophysis I. Somatostatin . . . . . . . . . . . . .

II. Thyrotropin-Releasing Hormone. . . . . . . III. Luteinizing-Hormone-Releasing Hormone ...

L. Peptide Hormones Secreted by the Neurohypophysis I. General Background . . . . . . . . . .

II. Effects of Antidiuretic Hormone in the Eye III. Effects of Oxytocin in the Eye

M. Melanocyte-Stimulating Hormones I. Effects in the Eye . . . . .

N. Vasoactive Intestinal Polypeptide. I. General Background . . . .

II. Localization and Effects in the Eye . O. Glucagon . . . . . . . P. Gastrin/Cholecystokinin. Q. Summary References . . . . . . . .

CHAPTER 8

Vitamin A. G.J. CHADER. With 6 Figures

A. Introduction. . . . B. Retinoid Structure . . C. Retinoid Properties. . D. Retinoid Identification

I. Spectral Methods II. Fluorescence Methods

III. Colorimetric Methods IV. High-Pressure Liquid Chromatography

E. Retinoid Metabolism F. Retinoid Uptake. . . . G. Retinoid Action ....

I. The Visual Process . II. Glycoprotein Biosynthesis .

III. Hormone-like Action . References . . . . . . . . . . .

CHAPTER 9

Anti-Infective Agents. I. H. LEOPOLD

A. Introduction. . . . . . . . . B. Accurate Diagnosis and Drug Choice .

1. Mechanisms of Action II. Penetration and Absorption . .

1. Protein and Tissue Binding . 2. The Blood - Aqueous Barrier.

XVII

343 343 343 344 344 344 344 346 346 346 347 347 347 348 348 349 350

367 368 369 370 371 372 372 373 373 375 376 376 379 379 380

385 385 385 390 390 390

XVIII Contents

3. Physicochemical Influences. . . . 391 4. Aqueous and Uveoscleral Outflow 391

III. Limiting Factors 391 1. Age. . . . . 391 2. Renal Disease 392 3. Liver Disease. 392 4. Enzymes. . . 392 5. Pregnancy . . 392 6. Ocular Damage and Disease 392

IV. Routes of Administration. . . 393 1. Topically Applied Antibiotic Drops 398 2. Continuous Corneal Lavage with Antibiotic Solutions 399 3. Subconjunctival Injections of Antibiotics. . . . . . 401

V. Use of Antibiotics in Combination. . . . . . . . . . 402 1. Prevention of Emergence of Drug-Resistant Mutants 402 2. Treatment of Mixed Infections . . . . . . . . . 402 3. Initial Treatment of Vision-Threatening Infections. 402 4. Antibiotic Synergism and Antagonism. . . 403

VI. Adverse Drug Interactions . . . . . . . . . 406 C. Postoperative Intraocular Infections (Endophthalmitis) 409

I. Incidence. . . . . . 412 II. Results of Therapy . . . . . . . . . . . . 413

III. Contributory Factors . . . . . . . . . . . 413 1. Sources of Infection in the Surgical Environment 413 2. Ophthalmic Operative Area . . . . . . . . . 413 3. Influence of Host Tissue. . . . . . . . . . . 414 4. Organisms Responsible for Intraocular Infection 414

IV. Antibiotic Prophylaxis 415 V. Use of Steroids 416

VI. Vitrectomy . . . . . 416 D. Antibiotics . . . . . . . . 417

I. Penicillin Derivatives. 417 1. Ampicillin . 418 2. Amoxicillin 418 3. Carbenicillin 418 4. Ticarcillin . 419

II. Probenecid . . 420 III. Cepha1osporins 420 IV. Aminoglycosides 423

1. Streptomycin and Dihydrostreptomycin 423 2. Gentamicin 424 3. Tobramycin 424 4. Neomycin . 425 5. Kanamycin 426 6. Amikacin . 426 7. Spectinomycin 427 8. Others. . . . 427

Contents XIX

V. Erythromycin. 427 VI. Lincomycin. . 428

VII. Clindamycin . 429 VIII. Oleandomycin 429

IX. Carbomycin 429 X. Spiramycin . 430

XI. Novobiocin. 430 XII. Ristocetin . 430

XIII. Vancomycin 430 XIV. Bacitracin . 431 XV. Polymyxin B 431

XVI. Soframycin . 432 XVII. Colistin . . 432

XVIII. Sulfonamides 433 XIX. Trimethoprim-Sulfamethoxazole . 434 XX. Chloramphenicol . . . . . . 434

1. Penetration and Absorption 435 2. Toxicity and Side Effects. . 435

XXI. Tetracyclines . . . . . . . . 437 1. Penetration and Absorption 437 2. Fluorescence. . . . . . 438 3. Toxicity and Side Effects. 439

XXII. Pyrimethamine 439 1. Value . . . . . . . . 440 2. Toxicity . . . . . . . 440 3. Penetration and Dosage 441

XXIII. Drugs Used in the Treatment of Fungal Infections. 441 1. Griseofulvin, Nystatin, and Amphotericin B 441 2. 5-Fluorocytosine . . . . . . . . . . . . . . 443 3. Imidazoles. . . . . . . . . . . . . . . . . 443

XXIV. Diethylcarbamazine in the Treatment of Onchocerciasis. 444 References . . . . . . . . . . . . . . . . . . . . . . . . . 446

CHAPTER lOa

Anti-Inflammatory Agents: Steroids as Anti-Inflammatory Agents J. R. POLANSKY and R. N. WEINREB. With 18 Figures

A. Introduction. . . . . . B. Historical Development. . . . . . .

I. Cortisone . . . . . . . . . . . II. Use of Steroids in Ophthalmology

C. Steroid Therapy . . . . . . . . . I. Activity of Steroid Compounds

1. Potency ........ . 2. Absorption and Distribution 3. Metabolism. . . . . . . .

459 459 459 461 466 466 466 470 473

XX Contents

II. Routes of Administration 475 1. Topical. . 475 2. Periocular 480 3. Systemic . 482 4. Intravitreal 484

III. Therapeutic Approaches 485 1. Specific Clinical Problems and Controversies 485 2. Current Assessment 490

IV. Complications. 490 1. Glaucoma . . . . 491 2. Cataract . . . . . 500 3. Other Ocular Effects. 502 4. Systemic Complications 503

D. Cellular and Molecular Mechanisms 505 I. The Immune System . . . . . 505

1. Leukocyte Kinetics and Function 506 2. Vascular and Inflammatory Effects. 512 3. Ocular Immune Mechanisms 514

II. The Glucocorticoid Receptor . . . . 514 1. The Target Cell . . . . . . . . . 515 2. Cellular Sensitivity and Modulation of Steroid Responses. 517 3. Permissive Effects and Hormonal Interactions 520 4. Glucocorticoid Receptors in Ocular Tissues 521 5. Implications 523

References . . . . . . . . . . . . . . . . . . . 524

CHAPTER 10b

Anti-Inflammatory Agents: Nonsteroidal Anti-Inflammatory Drugs K. MASUDA. With 4 Figures

A. Introduction. . . . . . . . . . . . . . . . . . . . . . 539 B. Mechanism of Action of Nonsteroidal Anti-Inflammatory Drugs 539 C. Salicylates. . . . . . 542 D. Indomethacin . . . . . . 543 E. Pyrazolon Derivatives. . . 545 F. Propionic Acid Derivatives 546 G. Anthranilic Acid Derivatives. 548 References . . . . . . . . . . 548

CHAPTER 11

Chemotherapy of Ocular Viral Infections and Tumors P. H. FISCHER and W. H. PRUSOFF. With 6 Figures

A. Introduction. . . . . . . . . . . . . B. Clinically Available Antiviral Agents . .

I. 5-Iodo-2'-deoxyuridine (Idoxuridine)

553 554 554

Contents XXI

1. Synthesis. . . . . . . 554 2. Antiviral Activity . . . 555 3. Effects on Normal Cells 555 4. Mechanism of Action . 556

II. 9-p-D-Arabinofuranosyladenine (Adenine, Arabinoside, Vidarabine) 557 1. Synthesis. . . . . . . 557 2. Antiviral Activity . . . 558 3. Effects on Normal Cells 558 4. Mechanism of Action . 559

III. 5-Trifluoromethyl-2' -deoxyuridine (Trifluorothymidine, Viroptic, Trifluridine). . . . 559 1. Synthesis. . . . . . . 559 2. Antiviral Activity . . . 559 3. Effects on Normal Cells 560 4. Mechanism of Action . 560

C. Newer Agents Under Development. 561 I. 9-(2-Hydroxyethoxymethyl)guanine (Acyclovir, Acycloguanosine). 561

1. Synthesis. . . . . . . 561 2. Antiviral Activity . . . 561 3. Effects on Normal Cells 563 4. Mechanism of Action . 563

II. 5-Ethyl-2' -deoxyuridine (Aedurid) 564 1. Synthesis. . . . . . . 564 2. Antiviral Activity . . . 564 3. Effects on Normal Cells 565 4. Mechanism of Action . 565

III. E-5-(2-Bromovinyl)-2'-deoxyuridine . 565 IV. 1-(2-Deoxy-2-fluoro-p-D-arabinosyl)-5-iodo-cytosine . 566 V. 5-Iodo-5' -amino-2' ,5' -dideoxyuridine 566

1. Synthesis. . . . . . . 566 2. Antiviral Activity . . . 567 3. Effects on Normal Cells 567 4. Mechanism of Action . 567

VI. Phospho no acetate and Phosphonoformate (Foscarnet) 568 1. Synthesis. . . . . . . 568 2. Antiviral Activity . . . 569 3. Effects on Normal Cells 569 4. Mechanism of Action 570

References . . . . . . . . . . . 570

CHAPTER 12

Immunosuppressive Drugs I. GERY and R. B. NUSSENBLATT. With 8 Figures

A. Introduction. . . B. Alkylating Agents . . . . . . . . . . . .

585 587

XXII

I. Chemical Structure and Metabolism II. Mode of Action. . . . . . .

III. Effects on the Immune System C. Antimetabo1ic Drugs . .

I. Purine Analogs . . . . . . . 1. Mode of Action . . . . . 2. Effects on the Immune System

II. Pyrimidine Analogs . . . . . . 1. Mode of Action . . . . . . 2. Effects on the Immune System

III. Folic Acid Analogs . . . . . . 1. Mode of Action . . . . . . 2. Effects on the Immune System

D. Cyclosporin A. . . . . . . . . . I. Mode of Action. . . . . . .

II. Effects on the Immune System E. Antilymphocyte Sera .

I. Preparations . . . . . . . . II. Mode of Action. . . . . . .

III. Effects on the Immune System IV. Adverse Side Effects .....

F. Ionizing Irradiation. . . . . . . . G. Immunosuppressive Agents of Potential Future Use. H. Immunosuppressive Agents in Ocular Conditions .

I. Cyclophosphamide. II. Chlorambucil

III. Azathioprine . IV. Methotrexate . V. Cyclosporin A

VI. Antilymphocyte Sera . VII. Adverse Side Effects

References .

CHAPTER 13

Anticoagulants, Fibrinolytics, and Hemostatics M. PANDOLFI. With 3 Figures

A. Introduction: The Hemostatic Mechanism B. Anticoagulants. . . . . . . . . .

I. Direct Anticoagulants (Heparin) . . II. Indirect Anticoagulants . . . . . .

III. Contraindications: Precautions in Ophthalmology. C. Fibrino1ytics. . . . . . . . . . . . .

I. Commonly Used Fibrinolytic Agents 1. Streptokinase 2. Urokinase 3. Plasmin ..

Contents

588 589 589 590 590 591 591 592 593 593 593 593 594 594 595 596 597 597 597 598 598 599 599 599 600 600 600 601 601 601 601 602

611 614 614 615 616 617 617 617 617 618

Contents XXIII

II. Therapeutic Thrombolysis: Effect on Hemostasis 618 III. Fibrinolytics in Ophthalmology . . . . . . . 619

1. Occlusion of the Central Retinal Vein . . . 619 2. Hemorrhages in the Anterior Chamber and Vitreous Body 620

D. Hemostatics. . . . . . . . 621 I. Specific. . . . . . . . 622

1. Substitution Therapy. 622 2. Antifibrinolytics . 623

II. Nonspecific 625 References . . . . . . . . 625

CHAPTER 14

Oxygen. R. W. FLOWER, M. O. HALL, and A. PATZ

A. Introduction. . . . . . . . . B. Oxygen and the Adult Eye C. Oxygen and the Immature Eye.

I. Retrolental Fibroplasia . . II. Monitoring Oxygen Administration in the Nursery

D. Oxygen Interaction with Other Drugs .. . I. Anti-Inflammatory Agents ..... .

II. Antioxidants in Retrolental Fibroplasia 1. a-Tocopherol .... 2. Superoxide Dismutase . 3. Other Antioxidants .

E. Conclusions References . . . . . . . . .

CHAPTER 15

The Alipathic Alcohols. A. M. POTTS

627 627 630 630 632 633 633 633 633 634 636 636 636

A. General. . . . . . . . . . . . . . . . . . . . . . . . . . . . 639 B. Ocular Effects of Single Doses of Ethanol in Nonhabituated Individuals 640

I. Muscle Balance . . . . . . . 640 II. Extraocular Muscles in Action 640

III. Nystagmus . . . . 642 IV. Intraocular Muscles 643

1. The Iris . . . . 643 2. Accommodation 643

V. Electrophysiological Measurements 643 VI. Miscellaneous Measurements of Visual Function . 645

VII. Intraocular Pressure . . . . . . . . 646 C. The Special Case of Disulfiram (Antabuse) 646 D. Chronic Alcoholism and the Eye 646 E. Methanol 647 References . . . . . . . . . . . 649

XXIV

CHAPTER 16

Photosensitizing Substances. A. M. POTTS. With 1 Figure

A. Direct Action of Ultraviolet Light on Skin. I. Mechanism of Ultraviolet Action .

II. Direct Action of Light on the Eye. B. Photosensitization

I. Mechanism. . . . . . II. Ocular Effects . . . .

C. Photosensitizing Substances I. Exogenous Photo sensitizers .

II. Endogenous Photosensitizers D. Conclusions References .

CHAPTER 17

Trace Elements in the Eye. T. R. JONES and T. W. REID. With 1 Figure

A. Introduction. B. Iron . C. Zinc .. D. Copper. E. Selenium F. Vanadium. G. Chromium H. Conclusion References .

CHAPTER 18

Clinical Trials. D. SEIGEL

A. A Strategy of Research . . . . . B. Planning the Trial . . . . . . .

I. Defining the Research Goals . II. Sample Size . . .

III. The Ethical Basis C. Conducting the Trial .

I. Bias . . .... II. Data Monitoring.

III. Follow-up. . . . D. Analysis of the Results

I. Adherence II. Eyes Come in Twos

III. Variable Duration of Follow-up IV. Tests of Significance and Data Analysis.

E. A Greater Awareness . References . . . . . . . . . . . . . . . . .

Contents

655 655 656 657 658 659 660 660 662 665 665

667 670 672 674 676 678 679 680 681

687 688 688 689 689 690 690 691 691 692 692 693 694 695 696

. 697

Contents

CHAPTER 19a

Diagnostic Agents in Ophthalmology: Sodium Fluorescein and Other Dyes L.M. JAMPOL and J. CUNHA-VAZ. With 1 Figure

xxv

A. Sodium Fluorescein. . . . . . . . . . . . . . . . . 699 I. Introduction . . . . . . . . . . . . . . . . . 699

II. Defects of the Corneal and Conjunctival Epithelia. 700 III. Use for Applanation Tonometry . 701 IV. Fitting of Contact Lenses . . . . . . . . . . . 701 V. Assessment of the Lacrimal System . . . . . . . 702

VI. The Seidel Test - Documentation of Appearance of Aqueous Humor in the Cul-de-Sac . . . . . . . . . . . . . .. 703

VII. Measurement of the Rate of Aqueous Humor Formation.. 704 VIII. Measurement of Arm - Retina Circulation Times and Retinal

Transit Times . . . . . . . . . . . . 704 IX. Fundus and Iris Fluorescein Angiography 705 X. Assessment of the Blood-Ocular Barriers 707

1. Aqueous Fluorophotometry 708 2. Vitreous Fluorophotometry 708 3. Histopathology 709

B. Rose Bengal. . . . . . . . . . . 710 C. Indocyanine Green. . . . .. . . 710 D. Other Dyes for Retinal and Choroidal Angiography 711 E. Other Dyes for Vital Staining of the Conjunctiva and Cornea 711 References . . . . . . . . . . . . . . . . . . . . . . . . 712

CHAPTER 19b

Diagnostic Agents in Ophthalmology: Drugs and the Pupil M. ROSENBERG and L.M. JAMPOL

A. Introduction. . . . . . . . . . 715 B. The Sympathetic Nervous System 715

I. Epinephrine. . . . . 716 II. Cocaine. . . . . . . . . . 717

III. Hydroxyamphetamine 717 C. The Parasympathetic Nervous System. 718 D. Distinction Between Pharmacologic Blockade and Oculomotor Nerve

Palsy. . . . . . . . . . . . . . . . 719 E. Diagnosis of Accommodative Esotropia . 720 References . . . . . . . . . . . . . . . 720

SUbject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . 721