Mechanism Of Action

Cholinergic drugs mimic the effects of acetylcholine (ACh), which is a transmitter at postganglionic parasympathetic junctions, as well as at other autonomic, somatic, and central synapses. ACh is synthesized by the enzyme choline acetyltransferase and produces its effects by binding to cholinergic receptors at the effector site.1

ACh, released from vesicles in nerve terminals, is then hydrolyzed within a few milliseconds by acetylcholinesterase (AChE). This rapid destruction of ACh frees the cholinergic receptors in preparation for the next stimulation. Cholinergic drugs act either directly by stimulating cholinergic receptors or indirectly by inhibiting the enzyme cholinesterase, thereby protecting endogenous ACh.1

The modified Goldmann equation can be used to describe the hydraulics of aqueous humor dynamics as follows:

where

F = aqueous humor flow Ctrab = facility of outflow from the anterior chamber via the trabecular meshwork (TM) and Schlemm's canal IOP = intraocular pressure Pe = episcleral venous pressure (the pressure against which fluid leaving the anterior chamber via the trabecular-canalicular route must drain) U = uveoscleral outflow

If we rearrange the equation to isolate IOP, it is apparent that for a modality (e.g., a drug) to lower IOP, it must either decrease F or Pe, or increase Ctrab or U.

Cholinergic drugs have been used in glaucoma therapy for more than a century.3 They have a minimal effect on aqueous humor formation and episcleral venous pressure.1 Rather, their effect on IOP is the result of various actions on aqueous humor outflow, which have been thought consequent to agonist-induced, musca-rinic receptor-mediated contraction of the ciliary muscle.

Ciliary muscle contraction can affect aqueous outflow in two ways. Because there is no epithelial or endothelial barrier separating the spaces between the trabecular lamellae from those between the ciliary muscle bundles, in the absence of cholin-ergic stimulation, aqueous humor is free to flow down a pressure gradient from the former to the latter, and then into the suprachoroidal space, through the sclera, and into the orbit (figure 5.1).1 This posterior, unconventional, or uveoscleral route can account for nearly one-third of aqueous drainage in normal young monkeys4 but less in older primates.5 Ciliary muscle contraction obliterates the intermuscular spaces (figure 5.2),6,7 obstructing uveoscleral outflow.8

The other way in which ciliary muscle contraction can affect IOP is by increasing conventional outflow facility. There is an intimate anatomic relationship between the anterior tendons of the ciliary muscle bundles and the scleral spur, peripheral cornea, TM, and inner wall of Schlemm's canal.9,10 One function of some of these tendons is to anchor the muscle to the spur and the cornea. Other tendons splay out and intermingle with the elastic network within the TM (figure 5.3), ultimately inserting onto specialized regions on the surface of the inner wall endothelial cells via connecting fibrils. Muscle contraction results in an unfolding of the meshwork and widening of the canal, facilitating aqueous outflow from the anterior chamber through the mesh into the canal lumen and thence into the venous collector channels and the general venous circulation.1,11 Facilitation of outflow via the conventional route more than compensates for the obstruction of the uveoscleral route; thus, the net effect of ciliary muscle contraction is to decrease IOP.12

Cholinomimetic drug effects on IOP have been presumed to be due to these biomechanical consequences of ciliary muscle contraction, with little or no effect due to iris sphincter constriction13 (except in angle closure, e.g., pupillary block and plateau iris, where sphincter contraction pulls the iris root away from the TM). Total removal of the iris from the monkey eye does not alter the facility response to pilocarpine, indicating that neither miosis nor even the presence of the iris is necessary for the response.14 The pilocarpine effect on outflow facility is abolished if the anterior tendons of the ciliary muscle are severed (figure 5.4),15

Figure 5.1. Primate anterior ocular segment. Arrows indicate aqueous flow pathways. Aqueous is formed by the ciliary processes, enters the posterior chamber, flows through the pupil into the anterior chamber, and exits at the chamber angle via trabecular and uveoscleral routes. Redrawn with permission from figure 4 (p. 160) of Kaufman PL, Wiedman, T, Robinson JR. Cholinergics. In: Sears ML, ed. Pharmacology of the Eye. New York: Springer-Verlag; 1984:149-191. Handbook of Experimental Pharmacology; Vol 69. Copyright 1984 Springer-Verlag GmbH & Co KG.

Figure 5.1. Primate anterior ocular segment. Arrows indicate aqueous flow pathways. Aqueous is formed by the ciliary processes, enters the posterior chamber, flows through the pupil into the anterior chamber, and exits at the chamber angle via trabecular and uveoscleral routes. Redrawn with permission from figure 4 (p. 160) of Kaufman PL, Wiedman, T, Robinson JR. Cholinergics. In: Sears ML, ed. Pharmacology of the Eye. New York: Springer-Verlag; 1984:149-191. Handbook of Experimental Pharmacology; Vol 69. Copyright 1984 Springer-Verlag GmbH & Co KG.

indicating the necessity of the muscle-meshwork attachment and the absence of a facility-relevant effect directly on the cells of the TM or of Schlemm's canal.

Pilocarpine is only a partial agonist16'17 and is atypical in other ways. Uncertainty remains as to whether there is also some effect of cholinergic agonists on the TM itself. The cholinomimetic agonist aceclidine increases outflow facility in monkey eyes after ciliary muscle disinsertion' although the disinsertion may not have been complete.18 Cultured TM cells produce second messengers in response to physiologic concentrations of carbachol.19 Perfused organ cultured human eyes devoid of the ciliary muscle exhibit an increase in outflow facility in response to very low doses of cholinergic agonist, but not to higher doses.20 However, this effect of low doses of pilocarpine on outflow facility could not be reproduced in intact monkey eyes in vivo.21 The TM itself may have a contractile biology, possibly mediated via a muscarinic mechanism and with relevance to aqueous outflow.22-24 Muscarinic receptors, primarily of the M3 subtype, have been identified in cultured human TM cells.19 Excised bovine TM strips exhibit contractile responses to the muscarinic agonist carbachol, aceclidine, and pilocarpine.25 However, in vivo contractility of the TM, possibly mediated by muscarinic mechanisms, may be overshadowed by the

Figure 5.2. Effect of pilocarpine and atropine on intramuscular spaces within the ciliary muscle of vervet monkey. (A) Intracameral heavy pilocarpine solution induced crowding of muscle bundles within the anterior part of the longitudinal muscle. Arrows indicate zone of localized contraction. (B) Intramuscular pilocarpine followed by intracameral heavy atropine solution (atropine was allowed to act for 3 minutes) induced loose arrangement of anterior longitudinal muscle bundles. Arrows indicate boundary between zone of localized relaxation and other contracted parts of the muscle. (C) Same protocol as in B, but atropine was allowed to act for 10 minutes. Zone of loosely arranged muscle bundles reaches far toward posterior region. Only the posterior extremity of muscle appears intensely contracted. Arrows indicate boundary between contracted and relaxed muscle portions (Heidenhain's Azan stain, ( x 35). Reprinted with permission from Barâny EH, Rohen JW. Localized contraction and relaxation within the ciliary muscle of the vervet monkey (Cercopithecus ethiops). In: Rohen JW, ed. The Structure of the Eye: Second Symposium. Stuttgart: Schattauer Verlag; 1965:287-311.

Figure 5.2. Effect of pilocarpine and atropine on intramuscular spaces within the ciliary muscle of vervet monkey. (A) Intracameral heavy pilocarpine solution induced crowding of muscle bundles within the anterior part of the longitudinal muscle. Arrows indicate zone of localized contraction. (B) Intramuscular pilocarpine followed by intracameral heavy atropine solution (atropine was allowed to act for 3 minutes) induced loose arrangement of anterior longitudinal muscle bundles. Arrows indicate boundary between zone of localized relaxation and other contracted parts of the muscle. (C) Same protocol as in B, but atropine was allowed to act for 10 minutes. Zone of loosely arranged muscle bundles reaches far toward posterior region. Only the posterior extremity of muscle appears intensely contracted. Arrows indicate boundary between contracted and relaxed muscle portions (Heidenhain's Azan stain, ( x 35). Reprinted with permission from Barâny EH, Rohen JW. Localized contraction and relaxation within the ciliary muscle of the vervet monkey (Cercopithecus ethiops). In: Rohen JW, ed. The Structure of the Eye: Second Symposium. Stuttgart: Schattauer Verlag; 1965:287-311.

dynamic contractility involved in maintaining cellular junctions and adhesions of TM cells with their extracellular environment.26

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