PHYSIOLOGICAL AND PHARMACOLOGICAL INFLUENCES UPON INTRAOCULAR PRESSURE
Authors: W.MORTON GRANT
Journal: Pharmacological Reviews (1955)

The physiology and pathology of the intraocular pressure have now been explored to the stage of development of good working hypotheses. General hydrodynamic principles governing the intraocular pressure have been formulated and experimentally tested. Good evidence indicates that the aqueous humor is formed by a secretion-diffusion mechanism. Energy from metabolism in the ciliary processes accomplishes transport from the blood and concentration within the eye of hydroxyl, bicarbonate and ascorbate ions, thereby furnishing the osmotic driving force for movement of water into the eye. Sufficient potential osmotic energy is available to produce an intraocular pressure of more than 100 mm. Hg, but in normal eyes the pressure is limited by continual escape of aqueous humor through special channels. The rate of escape of aqueous humor is governed by the resistance to flow which is encountered in these channels, and by the difference between pressure in the eye and the pressure of the blood in veins into which the escape channels drain. In normal eyes, the various parameters governing the intraocular pressure are such that a steady state with equal rates of inflow and outflow of aqueous humor obtains at pressures in the neighborhood of 15 mm. Hg. In glaucomatous eyes, an abnormally great resistance is encountered in the outflow channels and the intraocular pressure is elevated although the rate of inflow is not increased. Various causes for obstruction to outflow in glaucoma appear to characterize different forms of the disease. The most obvious obstruction is presented by the iris in eyes which have abnormally narrow spaces between the outflow channels and the dome of the iris. However, in the most prevalent form of glaucoma this space is ample and the iris is in no way implicated. In this case neither the anatomical site nor the cause for the abnormal resistance to outflow has been identified.

Attempts to correlate the influence of drugs on the intraocular pressure with the present concepts of physiology and pathology have succeeded to the extent of having achieved some distinctions between influence on rate of inflow of aqueous humor and influence on resistance to outflow. However, in few instances have the mechanisms by which drugs exert these influences been satisfactorily elucidated. In the case of mechanical opening, or closing, of an abnormally narrow space between iris and outflow channels, the mechanism of control of the obstruction by miotic or mydriatic drugs is evident, but in practically all other instances the manner of control of outflow or inflow remains obscure.

Development of the pharmacology of the intraocular pressure approximately parallels the development of its physiology and pathology. Progress in these three fields is to a considerable extent dependent on solution of the same problems. For instance, for elucidation of the mode of action of autonomic drugs in open-angle glaucoma, there is need of fundamental information on the site and nature of the resistance to outflow and on the basis for its increase in glaucoma. Furthermore, the relationship of outflow of aqueous humor to the condition of the meshwork of the tissue in the angle of the anterior chamber and to the pressure and flow of blood in the anastomosing outflow channels must be elucidated, in the interests of physiology and pathology, as well as pharmacology. More detailed knowledge of the secretory process for formation of aqueous humor would be valuable in relation to the pharmacology of control of intraocular pressure.

The approach to further investigation must be governed somewhat by the availability of suitable eyes, as well as by the objectives. For fundamental studies of mechanism of formation and control of aqueous humor, various animal eyes are convenient and probably well suited. Similarly, animal eyes may be useful for investigation of the dynamics of outflow and of the relationship to venous pressure, as well as for estimates of variability of the intraocular blood volume. However, the anatomical and possibly physiological differences between animal eyes and human eyes, and the lack of a suitable counterpart of human glaucoma in animals, necessitates that studies which are to relate to human disease be carried out, as far as feasible, on human eyes. Clinical investigations, of course, offer valuable opportunity, especially for studies of hydrodynamics and testing of drugs, but the experimental possibilities are naturally limited to non-injurious procedures. Studies post-mortem on eyes left for scientific purposes by altruistic individuals can furnish much additional information concerning outflow of aqueous humor. Most valuable, at the present time, should be the study, post-mortem or post-enucleation, of glaucomatous eyes. This would be particularly valuable if these eyes were thoroughly studied clinically beforehand. Unfortunately, although many individuals who have glaucoma die daily, it is extremely rare that the eyes are donated for the scientific study of their disease. 

Methods of study currently available have not yet been fully exploited, but there is need for methods with greater sensitivity and wider clinical applicability for determining rate of secretion, rate of outflow, and resistance to outflow of aqueous humor and for the measurement of intrascleral, as well as extrascleral vascular pressures.