Ординатура / Офтальмология / Английские материалы / Glaucoma Medical Therapy Principles and Management_Netland_2008
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Contributors
Robert C. Allen, MD (deceased)
Department of Ophthalmology
Medical College of Virginia
Richmond, Virginia
R. Rand Allingham, MD
Department of Ophthalmology
Duke University Medical Center
Durham, North Carolina
Yaniv Barkana, MD
Department of Ophthalmology
Assaf Harofe Medical Centre
Beer Yaacov, Zerifin, Israel
Carl B. Camras, MD
Department of Ophthalmology
and Visual Sciences
University of Nebraska Medical
Center
Omaha, Nebraska
Pouya N. Dayani, MD
Department of Ophthalmology
and Visual Sciences
Washington University School
of Medicine
St. Louis, Missouri
Robert D. Fechtner, MD
Institute of Ophthalmology and
Visual Science
University of Medicine and Dentistry
of New Jersey
Newark, New Jersey
B’Ann True Gabelt, MS
Department of Ophthalmology
and Visual Sciences
University of Wisconsin
Madison, Wisconsin
Lisa S. Gamell, MD
Department of Ophthalmology
Beth Israel Medical Center
New York, New York
Thomas W. Hejkal, MD, PhD
Department of Ophthalmology
and Visual Sciences
University of Nebraska Medical Center
Omaha, Nebraska
Eve J. Higginbotham, MD
Department of Ophthalmology
Emory School of Medicine
Morehouse School of Medicine
Atlanta, Georgia
xxi
xxii Contributors
Nauman R. Imami, MD
Henry Ford Medical Center
Detroit, Michigan
Malik Y. Kahook, MD
UPMC Eye Center
University of Pittsburgh School
of Medicine
Pittsburgh, Pennsylvania
Elliott M. Kanner, MD, PhD
Hamilton Eye Institute
University of Tennessee Health
Science Center
Memphis, Tennessee
Michael A. Kass, MD
Department of Ophthalmology
and Visual Sciences
Washington University School
of Medicine
St. Louis, Missouri
Paul L. Kaufman, MD
Department of Ophthalmology
and Visual Sciences
University of Wisconsin
Madison, Wisconsin
Albert S. Khouri, MD
Institute of Ophthalmology and
Visual Science
University of Medicine and Dentistry
of New Jersey
Newark, New Jersey
Allan E. Kolker, MD
St. Louis, Missouri
Paul J. Lama, MD
Institute of Ophthalmology and
Visual Science
University of Medicine and Dentistry
of New Jersey
Newark, New Jersey
Simon K. Law, MD, PharmD
Jules Stein Eye Institute
University of California, Los Angeles
Los Angeles, California
David A. Lee, MD, MS, MBA
Jules Stein Eye Institute
University of California, Los Angeles
Los Angeles, California
Jeffrey M. Liebmann, MD
Manhattan Eye, Ear and
Throat Hospital
New York University Medical Center
New York, New York
Felipe A. Medeiros, MD
Hamilton Glaucoma Center
University of California, San Diego
La Jolla, California
Peter A. Netland, MD, PhD
Hamilton Eye Institute
University of Tennessee Health
Science Center
Memphis, Tennessee
Tony Realini, MD
West Virginia University Eye Institute
Morgantown, West Virginia
Robert Ritch, MD
New York Eye and Ear Infirmary
New York, New York
Howard I. Savage, MD
Wilmer Institute
Johns Hopkins University
Baltimore, Maryland
Joel S. Schuman, MD
UPMC Eye Center
University of Pittsburgh School
of Medicine
Pittsburgh, Pennsylvania
Robert N. Weinreb, MD
Hamilton Glaucoma Center
University of California, San Diego
La Jolla, California
Glaucoma Medical Therapy
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1
Ocular Pharmacology
SIMON K. LAW AND DAVID A. LEE
cular medications have an important role in the treatment of glaucoma. OMedications are usually considered the first line of treatment for glaucoma, and in most glaucoma patients medications alone can control their disease. Glaucoma medications lower intraocular pressure (IOP) by either reducing aqueous production or increasing aqueous outflow through either the conventional or the unconventional pathways. Frequently, multiple glaucoma medications are used in combination to adequately lower IOP. A clear understanding of the pharmaco-
kinetics of these medications is important to knowing several details:
1.Whether the drug itself or a metabolite is responsible for the therapeutic effect
2.The optimal route of drug administration
3.The optimal dosage regimen
4.The relationship between drug concentrations in tissues and their pharmacologic or toxicologic response
Pharmacokinetics is the study of the time-course changes of drug concentrations and their metabolites in tissues. It involves the determination of the rates of four processes: absorption, distribution, metabolism, and excretion.1 Biopharmaceutics is the study of the effects of drug formulation on the pharmacologic and therapeutic activity.2 It deals with the relationships between the drug response and the drug’s physical state, salt form, particle size, crystalline structure, surface area, dosage form, adjuvants, or preservatives present in the formulation. Pharmacokinetic and biopharmaceutic data are important for making informed judgments on drugs and their formulations—judgments that may allow the proper selection of an appropriate
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4Glaucoma Medical Therapy
drug, dosage regimen, and method of drug delivery to achieve a desired therapeutic outcome.
Drug–receptor interactions determine the intensity of a pharmacologic response. These interactions are governed by laws of mass action; therefore, the greater the concentration of free drug at the receptor site, the higher the statistical probability that the drug will bind to the receptor and have a greater pharmacologic effect.3 As the drug concentration declines around the receptor site, the drug response declines proportionately. Drug dose, dosage regimen, and route of administration can influence the concentration of drug in the target tissue; usually, the clinician has some control over these variables.
1.1 BIOAVAILABILITY IN OCULAR COMPARTMENTS
The pharmacokinetics of a drug can be mathematically modeled using a technique called compartmental analysis to develop descriptive and predictive information about a drug’s concentration at different times in different locations.4 A compartment is an anatomic or physiologic space within an organ that is separated by a barrier to drug transfer (figure 1.1). The drug is assumed to be homogeneously distributed within a compartment, and exchange of the drug between adjacent compartments occurs at a transfer rate determined by the prevailing biochemical and physiologic conditions. This transfer rate is the coefficient describing the change in drug concentration over time in reference to a specific compartment.
From the standpoint of the body as a whole, the eye is a component of the systemic compartment, which is composed of multiple subcompartments, such as tears, cornea, aqueous, iris, ciliary body, vitreous, sclera, retina, and lens. Often, the first pharmacokinetic information obtained for a drug is the corneal permeability coefficient, which is the corneal flux divided by the product of the initial drug concentration times the corneal surface area.5 Usually, this information can be obtained in vitro using Ussing-type chambers.6 The usual values obtained for a large number of compounds used in ophthalmology range from 0.44 10–6 to 78.8 10–6cm/sec.
Figure 1.1. Compartmental modeling.
Ocular Pharmacology |
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Values smaller than 10 10–6 cm/sec indicate poor penetration.7 Low corneal permeability may be compensated to some degree by higher potency or the introduction of functional groups into the chemical structure to alter the permeability coefficient.
Ocular bioavailability concerns the amount of drug absorbed compared to the amount of drug administered. Drug molecules pass between compartments by either diffusion or active transport processes. Diffusion of a drug follows its concentration gradient and is related inversely to molecular size and directly to the temperature. Active and passive drug transport depends on the chemical structure and molecular configuration of the drug and is affected by competition of other substances for the same transport system. Permeability coefficients for drugs are determined by measuring the drug concentration in compartments at various times.8 The cornea and anterior chamber have important roles in the distribution of drugs within the eye. Coefficients for the transfer of drugs are usually determined between the cornea and aqueous, the removal of drug from the anterior chamber to the blood, the loss of drug within the tears, and the entry of drug from the plasma into the anterior chamber. These transfer coefficients can be used to compare drugs and to gain a better understanding of the importance of each transfer process in the overall pharmacokinetic behavior of the drug.4
1.1.1Drug Transfer Rate and Concentration. The rates of the pharmacokinetic processes can be characterized as a function of the drug concentration. Many drug transfer processes follow first-order kinetics, in which the rate constant of transfer is
proportional to the drug concentration, and the drug half-life (t1/2) is a constant time regardless of the amount of drug administered.9 In a first-order kinetic process, the drug concentration decreases exponentially with time, and on the curvilinear plot of concentration versus time, the concentration asymptotically approaches some final value as time advances toward infinity. The plot of the log drug concentration versus time is linear, and the drug concentration decreases by one-half over each time interval corresponding to the half-life (figure 1.2). Commonly used ophthalmic drug formulations, such as solutions, gels, suspensions, and ointments, deliver drugs at rates that follow first-order kinetics.
A zero-order kinetic rate is not proportional to the drug concentration but is related to some functional capacity involved in the transfer of drug. Active drug transport systems change drug kinetics from first to zero order when the transfer capacity is fully saturated; a higher concentration of the drug will not increase the transfer rate. Normally, it is free drug that diffuses between compartments. Drugs bound to tissue proteins or melanin must be free from their binding sites before the
molecules can diffuse into adjacent compartments. Pharmacologic response correlates best with the concentration of free drug at the site of action.3 Zero-order kinetic delivery of a drug to the eye results if a constant concentration of the drug is maintained in the precorneal tear film, creating a steady-state concentration in the tissues, such as with the use of pilocarpine Ocuserts.
1.1.2Drug Absorption. Ocular absorption of a drug begins when a medication is instilled topically into the cul-de-sac. The drug solution then mixes with the tears to give some unknown dilution. The efficiency of ocular absorption depends on the
6Glaucoma Medical Therapy
Figure 1.2. Pharmacokinetics: semilogarithmic plot of concentration versus time.
adequate mixing of drug with the precorneal tear film and the residence time of drug in the precorneal area.4
A relatively stagnant precorneal tear film layer has a thickness of about 7–9mm and is composed of mucin, water, and oil.10 Eyelid blinking facilitates the mixing of the drug with the precorneal tear film. A gradient of drug concentration between the precorneal tear film and the cornea and bulbar conjunctival epithelia acts as a driving force for passive drug diffusion into the cornea and conjunctiva.7 The lag time is the time between the instillation of drug and its appearance in aqueous, which reflects the rate of drug diffusion across the cornea.
The amount of drug penetrating the eye is linearly related to its concentration in the tears, unless the drug interacts or binds with other molecules present in the cornea or the cornea becomes saturated because of limited drug solubility. The rate of drug concentration decline in the tears is proportional to the amount of drug remaining in the tears at the time and approximates first-order kinetics. This rate of
decline depends on the rate of dilution by fresh tears and the drainage rate of tears into the cul-de-sac.11,12
In normal humans, the basal rate of tear flow is approximately 1mL/min, and the physiologic turnover rate is approximately 10% to 15% per minute, which decreases with age. Basal tear flow is usually lower in patients with keratoconjunctivitis sicca and slightly higher in contact lens wearers.13 The half-life of the exponential decline of fluorescence in the precorneal tear film in normal humans, as measured by fluorophotometry, varies between 2 and 20 minutes. This variability also applies to other substances. The loss rate constant for fluorescein varies depending on the amount of tearing. Reflex tearing caused by stinging from instillation of an irritating drug produces a higher loss rate. Lid closure and local or general anesthesia can decrease the tear flow rate. Physical, psychological, and emotional factors can increase tearing.
Ocular Pharmacology |
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Blinking movements force part of the instilled volume through the puncta into the nasolacrimal duct. Each blink eliminates 2mL of fluid from the cul-de-sac.4 Aside from elimination by drainage through the nasolacrimal route, evaporation of tears, and deposition of drug on lid margins, drug may be bound to proteins in tears and metabolized by enzymes in tears and tissue.14 These processes tend to limit the amount of drug entering the eye. As a result of limited residence time in the precorneal area imposed by these factors, but mainly because of rapid drainage, only a small fraction of the dose (1% to 10%) reaches the internal structures. This fraction may be increased by prolonging the residence time at the absorptive surfaces and enhancing the penetration rate through the corneal epithelium, by making the molecule more lipophilic. Transcorneal movement can be increased by changing the barrier properties of the corneal epithelium, by applying an anesthetic, by preservatives in topical medications, or after damaging the epithelium. Conversion of epinephrine to its dipivalyl ester derivative increases its lipophilicity and serves as a prodrug to increase penetration through the epithelium.
The distribution of drugs within the eye depends on many factors. The eye is relatively isolated from the systemic circulation by the blood–retina, blood–vitreous, and blood–aqueous barriers. These barriers comprise the tight junctions between the capillary endothelial cells in the retina and iris, between the nonpigmented ciliary epithelial cells, and between the retinal pigment epithelial cells.15 These tight junctions exclude large molecules such as plasma proteins from entering the eye from the blood circulation, but allow many smaller molecules (molecular weight <500 daltons) and drugs to pass. The blood–aqueous barrier is evidenced by the low concentration of proteins in the aqueous and the failure of intravenously injected fluorescein to enter the aqueous unless the eye is inflamed. Many drugs in the blood circulation are unable to enter the eye because of these blood–ocular barriers.
The fraction of a topical drug that is absorbed by the eye can enter the systemic blood circulation by at least two pathways:
1.Along with the bulk flow of aqueous by way of the conventional outflow pathways of trabecular meshwork, Schlemm’s canal, aqueous collecting channels, and episcleral venous plexus
2.By being absorbed into the blood vessels of the uvea, choroid, and retina
A drug in the aqueous that leaves through the uveoscleral outflow pathway through the iris base and ciliary body may be reabsorbed into the choroidal vessels from the suprachoroidal space.
Drug loss from the precorneal area limits the time available for absorption into the eye. The time to peak drug levels in the eye is determined by the residence time in the precorneal area.16 Most drugs delivered topically to the eye exhibit similar apparent times to peak concentrations in aqueous as the drug drains out of the cul-de-sac within the first 5 minutes. The time it takes for most drugs to reach their peak concentrations in the aqueous is within a rather narrow range of 20–60 minutes.17 Within the cornea, drug may diffuse laterally to the limbus and enter the eye at the iris root. Drugs may also be absorbed from the cul-de-sac across the conjunctiva and enter the eye through the sclera. The sclera poses less of a barrier