Handbook of Basic and Clinical Ocular Pharmacology and Therapeutics

Handbook of Basic and Clinical Ocular Pharmacology and Therapeutics provides a review of the basic anatomy, physiology, biochemistry and pathology of the eye with a focus drug therapy, drug delivery and use of therapeutic medical miniature devices. An understanding of the pharmacological actions of drugs acting on the eye requires the student and health care practitioner to learn additional principles in basic and clinical sciences that are unique to this organ. As a sensory organ, the eye is relatively inaccessible to the systemic circulation due to the blood-vitreous, blood-aqueous and blood-retinal barriers. Consequently, the administration of drugs for therapeutic effects in the eye necessitates an understanding of physico-chemical properties of the molecules and pharmacokinetic principles involved in the access to its site of action via topical, intracameral and intravitreal administration. This book includes information on the general principles of pharmacokinetics and pharmacodynamics of drugs as it pertains to the eye and in combating ocular disorders and diseases. Using a disease-themed approach, the book discusses basic and clinical pharmacological principles involved in the therapy of these diseases including the ocular side effect of systemically-administered drugs, drugs used in ophthalmic surgery and miscellaneous agents, the therapeutic utility of biologics, drug conjugates, combination products, gene and cellular therapy are also covered. Handbook of Basic and Clinical Ocular Pharmacology and Therapeutics is useful as a primary and secondary source of reference for up-to-date information about the pharmacological mechanisms of action, pharmacokinetics, side effects, drug-drug interactions and therapeutic indications of drugs for pharmacologists, pharmaceutical scientists, students in the health care disciplines (nursing, pharmacy, optometry, medical), and practitioners in optometry and ophthalmology. Front Cover Handbook of Basic and Clinical Ocular Pharmacology and Therapeutics Copyright Page Dedication Contents List of contributors Preface Acknowledgments 1 The eye as a target for drugs and other treatment modalities Subchapter 1.1 Anatomy and pathology Introduction Anatomy and overview of eye diseases Anatomy Brief overview of eye diseases with clinico-pathologic correlation Ocular surface and selected corneal diseases Inflammation Refractive diseases Glaucoma Retinal diseases Neovascularization References Subchapter 1.2 Ocular biochemistry Aqueous humor Production of aqueous humor Composition of aqueous humor Vitreous humor Retina Structure and function of neural pathway of the retina Phototransduction Oxidative stress in the retina References Subchapter 1.3 Physiology Anterior segment of the eye Posterior segment of the eye References Subchapter 1.4 Receptors, ion channels, and signal transduction pathways as targets for drug intervention to mitigate ocula... Introduction Phospholipase-C-coupled receptors, janus kinase pathway, transcription, and immunogenic factors in mediating conjunctivitis Role of multiple of receptor-signaling pathways involved in causing and treating glaucoma Receptor-tyrosine-kinase signaling pathways causing age-related macular degeneration Concluding remarks References 2 Ocular autonomic physiology and pharmacology Introduction Structure of the ocular autonomic nervous system Function of the ocular autonomic nervous system Autonomic control of pupil diameter Mechanisms of autonomic contractions of pupillary muscles Mydriatic and miotic agents Autonomic regulation of ocular accommodation Autonomic regulation of ocular blood flow Autonomic regulation of intraocular pressure Summary References 3 Ocular drug discovery and development Subchapter 3.1 Drug discovery in ophthalmology: creating new chemical entities in new classes of drugs Introduction/overview Type 3B ophthalmic drug discovery— prostaglandin analogs and ROCK inhibitors Modern ophthalmic drug discovery—rho kinase inhibitors Related investigations of ROCK inhibitors Other companies’ ROCK inhibitor efforts Conclusion References Further reading Subchapter 3.2 Screening strategies for drug discovery-focus on ocular hypertension Introduction In vitro assays for screening potential ocular hypotensive compounds Ex vivo ocular models for drug characterization Animal models of OHT disease and in vivo studies Conclusions References Further reading Subchapter 3.3 Therapeutic modality aspects in safety and efficacy of ocular drugs Pharmacokinetics of ocular drugs Bioavailability of topical drugs Bioavailability of periocular drugs Permeability Clearance Bioavailability of intraocular drugs Permeability Clearance Drug residence and sustained delivery Pharmacodynamics of ocular drugs Safety of ocular drugs Aggregation Impurities Antidrug antibodies Overview Conclusion References Subchapter 3.4 Investigational new drug-enabling studies for ocular and other therapeutics Introduction Investigational new drug study applications Studies and data to permit investigational new drug application filing Pharmaceutical agent quality Primary pharmacology of the active product ingredient Secondary pharmacology/safety pharmacology Pharmacokinetic studies Toxicological evaluation studies Genotoxicity studies Conclusions References Subchapter 3.5 Preclinical ocular regulatory science—investigational new drug-enabling studies References Subchapter 3.6 Ocular clinical regulatory sciences References 4 Drug formulation, delivery, and ocular pharmacokinetics Subchapter 4.1 Ocular formulation and novel drug delivery systems Introduction Routes of ocular drug administration and associated barriers Key considerations in the development of ophthalmic formulations Physical properties of the drugs Role of excipients Sterility Ophthalmic formulations Conventional ocular dosage forms Eye drops Ointments Emulsions Suspensions Punctal plug Novel controlled release ophthalmic formulations Nanosuspensions Nanoparticles Nanomicelles Hydrogels Composite hydrogel systems Microneedles Intravitreal implants References Subchapter 4.2 Ocular pharmacokinetics Introduction Anatomy/physiology Topical ocular administration Transcorneal absorption Absorption kinetics Conjunctival/scleral absorption Topical ocular distribution Distribution within the anterior segment Distribution to the posterior segment Elimination following topical ocular administration Ocular pharmacokinetic models—front of the eye delivery Intravitreal administration Intravitreal drug distribution and elimination Vitreal pharmacokinetic models Other routes of administration Systemic administration Ocular metabolism Hydrolytic enzymes Cytochrome P450 enzymes Phase II metabolism Other metabolizing enzymes Transporters Conclusion References 5 Pharmaco-devices therapy for glaucoma Subchapter 5.1 The importance of distal outflow resistance in the regulation of intraocular pressure Introduction Intraocular pressure regulation Aqueous humor outflow Proximal–distal outflow communication Distal outflow regulation Anatomy Collector channels Aqueous veins Intrascleral venous plexus Episcleral veins Resident macrophages Distal innervation IOP homeostasis Evidence for distal resistance Distal vessel regulation Collector channel morphology Aqueous humor flow patterns Clinical relevance of the distal portion of the outflow pathway Structural and functional outflow imaging Outflow imaging and glaucoma therapeutics Minimally invasive glaucoma surgeries Pharmacological interventions Summary and future directions References Subchapter 5.2 Various forms of glaucoma and their treatments Introduction Primary open-angle glaucoma and its treatment Normotensive glaucoma and its treatment Primary closed-angle glaucoma and its treatment Pharmaceutical treatment options for glaucomas Laser treatments to reduce intraocular pressure Surgical procedures to lower intraocular pressure Minimally invasive glaucoma surgeries-based devices for lowering intraocular pressure Neuroprotection for glaucoma treatment Conclusions References Further reading Subchapter 5.3 Glaucoma pharmacology Definition Types and pathophysiology Epidemiology Presentation Diagnosis Treatment Pharmacokinetics Prostaglandins Beta-adrenergic blockers Carbonic anhydrase inhibitors Sympathomimetics Parasympathomimetics Rho-associated protein kinase inhibitor Hyperosmotic agents Combination medications Preservative agents Lasers and surgeries References Subchapter 5.4 Minimally invasive glaucoma surgical devices References Subchapter 5.5 Gene therapy for ocular hypertension and glaucoma treatment Introduction Application of gene therapy to lower intraocular pressure Gene therapy for neuroprotection in glaucoma Conclusions References Subchapter 5.6 Retina–brain axis and neuroprotection Retina–brain axis Neuroprotection Memantine Brimonidine Citicoline Coenzyme Q10 Ginkgo biloba Neurotrophins Future directions References 6 Pharmacotherapy of retinal diseases Subchapter 6.1 Pharmacotherapy of retinal diseases Basic science Overview of the retina Therapeutic strategies for treatment of retinal diseases Intravitreal route Periocular routes Implants Other routes Pharmacology of agents used in the therapy of retinal diseases Vascular endothelial growth factors inhibitors Corticosteroids Ganciclovir Verteporfin Voretigene References Subchapter 6.2 Age-related macular degeneration and its treatment options Epidemiology Clinical characteristics Diagnosis Etiology and pathogenesis of age-related macular degeneration Treatments Bevacizumab Ranibizumab Aflibercept Brolucizumab Faricimab Concluding remarks References Subchapter 6.3 Pharmacotherapy of diabetic retinopathy Introduction Systemic therapy Control of blood glucose Control of dyslipidemia Control of hypertension Control of systemic inflammation/oxidative stress Local therapy Antiangiogenesis therapy Efficacy of intravitreal antivascular endothelial cell growth factor therapy for proliferative diabetic retinopathy with an... Efficacy of intravitreal antivascular endothelial cell growth factor therapy for diabetic macular edema Complications of intravitreal vascular endothelial cell growth factor Antiinflammatory strategies Neuroprotection for diabetic macular edema Pharmacotherapy as an adjunct to surgery Combination pharmacotherapy Clinical pathways Future directions References Subchapter 6.4 Inherited retinal dystrophies Inherited retinal dystrophies Retinitis pigmentosa Leber congenital amaurosis Usher syndrome X-linked retinoschisis Achromatopsia Choroideremia Stargardt Optogenetics References 7 Pharmacotherapy of inflammatory eye diseases Subchapter 7.1 Pharmacotherapy of inflammatory eye diseases Introduction Blepharitis Anatomical structures involved in blepharitis Drugs Pharmacokinetics Pharmacodynamics Side effects and Interactions Keratitis Anatomical structures involved in keratitis Drugs Pharmacodynamics Pharmacokinetics Side effects and interactions Uveitis Anatomical structures involved in uveitis Drugs Pharmacokinetics Pharmacodynamics Side effects and interactions References Subchapter 7.2 Noninfectious anterior, posterior, and panuveitis and their treatments Epidemiology Etiology and pathogenesis Clinical characteristics and diagnosis Anterior uveitis Posterior segment uveitis (intermediate, posterior, and panuveits) Treatments Topical corticosteroids Cycloplegics Nonsteroidal anti-inflammatory drugs Periocular corticosteroids Intravitreal corticosteroids Systemic corticosteroids Systemic immunosuppressive agents Biologic agents Concluding remarks References 8 Etiology and pharmacotherapy of ocular surface allergic diseases Introduction and overview Epidemiology and etiology of human conjunctivitis Short history of drug discovery for seasonal allergic conjunctivitis and perennial allergic conjunctivitis Screening strategies for ocular antiallergic compounds Pharmacotherapeutics for seasonal allergic conjunctivitis and perennial allergic conjunctivitis treatment Current pharmacotherapy for seasonal allergic conjunctivitis and perennial allergic conjunctivitis Other types of allergic conjunctivitis and their treatments Conclusion References 9 Pharmacotherapy of dry eye disease and ocular pain Dry eye disease and ocular pain, their manifestations and impact on the daily life of patients Animal and cell-based models for dry eye disease Sjögren syndrome model Desiccation stress model Meibomian gland dysfunction model Miscellaneous model Clinical aspects of dry eye disease Anti-inflammatory treatments Ocular pain (dry eye symptoms and injuries) Conclusion References 10 Pharmacotherapies for myopia and ocular refractive errors Subchapter 10.1 The pharmocotherapy of myopia—animal studies and clinical trials Introduction Animal studies of pharmacological agents Muscarinic acetylcholine receptors and antagonists Transcription factor ZENK Dopamine Role of D1 and D2-receptors Nitric oxide Adenosine receptor Gamma-aminobutyric acid Clinical studies of pharmacological agents Muscarinic receptor antagonists Atropine Tropicamide Cyclopentolate Pirenzepine Beta-adrenergic receptor antagonists Timolol Labetalol Adenosine receptor antagonist Summary References Subchapter 10.2 Cataracts and presbyopia Lens structure and functions Presbyopia and cataract: age-related degeneration of lens function Presbyopia Cataract Dysfunctional lens syndrome: an intermediate stage of lens aging A closer look at the aging lens Pharmacological treatment approaches Crystallin conformation correctors in presbyopia and cataract Miotics for transient correction of presbyopia Preclinical models of presbyopia and cataracts Hereditary cataract models Wild type model animals with naturally occurring cataracts Induced models of cataract Animal models of presbyopia Imaging modalities, assessments, and endpoints for presbyopia and cataracts Summary and Outlook References 11 Pharmacotherapy of ocular infectious diseases Introduction Bacterial and viral infections and their treatments Ocular fungal diseases and treatments Conclusion References 12 Ocular side effects of drugs administered systemically for treatment of nonocular diseases Introduction Drugs acting on the cardiovascular system Drugs acting on the central nervous system Antiinflammatory drugs Nonsteroidal antiinflammatory drugs Corticosteroids Antiviral and antimicrobial drugs Antiviral Drugs Antimicrobial drugs Anticancer drugs Drugs used for skin diseases Summary References 13 Current and emerging techniques/technologies in ocular research and drug/device development Subchapter 13.1 Genome-wide association studies to unravel genetics of ocular diseases Introduction Specific examples of GWAS for different forms of glaucoma GWAS for myopia Conclusions References Further reading Subchapter 13.2 Single-cell genetics approach in ophthalmology Cells in the eye Cell characterization by single-cell mRNA expression profiling Next-generation sequencing Single-cell isolation technology Bioinformatical analysis methods Retinal cell subtype identification Cell numbers and read numbers Single-cell analysis of retinal diseases Future development of mRNA expression profiling technology References Subchapter 13.3 Muller glia-derived exosomes and their microRNA cargo–potential for glaucoma therapies Introduction Neurotrophins and their protective roles in maintaining retinal ganglion cell survival Contribution of oxidative stress to glaucomatous damage—considerations for antioxidant therapies Experimental and clinical approaches for glaucoma neuroprotection based on the application of neurotrophic factors Stem cell transplantation as a neuroprotective approach to treat glaucoma Extracellular vesicles Potential of extracellular vesicles derived from Müller glia for the development of neuroprotective strategies in glaucoma Micro-RNAs and their potential for neuroprotective glaucoma therapies Conclusions and future trends References Subchapter 13.4 Genetics and other techniques to create novel animal models for ocular research Introduction Corneal and conjunctival diseases—animal models Ocular hypertension/glaucoma and animal models Cataracts and animal models Age-related macular degeneration and animal models Diabetic retinopathy and animal models Conclusions References Further reading Subchapter 13.5 Imaging of apoptosing retinal cells for early diagnosis Rationale to detection of apoptosing retinal cell technology The detection of apoptosing retinal cell technique Applications References Subchapter 13.6 Optogenetic approaches to gene therapy for vision restoration in retinal degenerative diseases Introduction The retina Inherited retinal degenerations Macular degeneration Vision restoration technologies Gene replacement Stem cells Electrodes Optogenetics Opsins Mechanism of phototransduction Applications of optogenetics for vision restoration Mammalian versus microbial opsins Kinetics Preclinical studies of native and engineered opsins Deactivation and recovery Gene delivery methods Viral delivery Routes of administration Viral serotypes and tropism Engineered adeno-associated virus capsids Laser gene delivery Electroporation Nonopsin optogenetic strategies Optogenetic retinal prostheses Upconversion nanoparticles Chemical photoactivable switches Photoisomerizable switches Photovoltaic switches Optogenetic clinical trials Concluding remarks and future directions Engineering complexity into restored retinal circuitry Developing better retina degeneration model Nonviral delivery of opsin-genes to targeted retinal cells and regions(s) of interest References Subchapter 13.7 Multispecific biologics in opthalmology Strategies in developing bispecific or multispecific biologics Design and development of bispecific biologics Development through preclinical and clinical phases Conclusion References Subchapter 13.8 CRISPR–Cas9: current and future utilities in ocular diseases Introduction to genome editing Tools for genome editing: ZFNs, TALENs, and CRISPR Overview of the CRISPR/Cas9 system Types of CRISPR–Cas enzymes DNA repair: nonhomologous end-joining versus homology-directed repair CRISPR–Cas9: current utility in ocular research Glaucoma Ocular angiogenesis Leber congenital amaurosis CRISPR–Cas9: clinical trials Conclusions References Subchapter 13.9 DNA methylation: its role in retinal health and diseases DNA methylation DNA methylation writers DNA methylation erasers DNA methylation readers Roles of DNA methylation in retina development DNA methylation and eye diseases DNA methylation and uveitis DNA methylation and age-related macular degeneration DNA methylation and diabetic retinopathy DNA methylation and glaucoma Conclusions References Index Back Cover