Drug Interactions

A combination of outflow-enhancing with inflow-suppressing compounds can be used to decrease IOP further than with maximal doses of either compound alone. Combining different classes within the outflow-enhancing or inflow-suppressing groups may also lead to a greater IOP reduction than with either alone. However, the IOP response to a combination of drugs is usually less than the sum of the individual effects.

The IOP reduction caused by cholinergics may be partially additive to that of the uveoscleral outflow-enhancing prostaglandin (PG) derivative latanoprost. This finding has caused some confusion in the ophthalmologic community, given pilo-carpine's ability to contract the ciliary muscle and thereby reduce uveoscleral outflow and the ability of high pilocarpine doses to inhibit the IOP-lowering effect of PGF2a in monkeys. Ciliary muscle contraction is probably not maximal at the concentrations of miotics used clinically; therefore, some PG most likely can still penetrate the spaces between ciliary muscle bundles to initiate changes that enhance uveoscleral outflow.56 Latanoprost is indeed less additive to stronger miotic therapies, where spaces between ciliary muscle bundles presumably would be more completely obliterated.57 One study noted that latanoprost and eserine were partially additive, but that neither the eserine dosing regimen nor clinically employed pilocarpine dosing contracts the ciliary muscle in the living human maximally for very long, if at all.58 Furthermore, even massive doses of cholinomimetics do not completely eliminate uveoscleral outflow in monkeys,59 and PGF2a can partly relax even a maximally cholinergically precontracted ciliary muscle.60 Thus, some PG can be expected to reach the relevant parts of the ciliary muscle even if the only access is via the anterior chamber, and even more so if a transconjunctival-transscleral penetration pathway is operative. The net result, assuming no other factors, is partial but not complete attenuation and partial but not complete additivity of cholinomimetics to PG-induced ocular hypotension.

Conversely, because PGF2a relaxes the cholinomimetically precontracted ciliary muscle,60 latanoprost and PGF2a may actually enhance the IOP-lowering effect of cholinomimetics by inhibiting their obstruction of uveoscleral outflow, in addition to enhancing uveoscleral outflow themselves. However, PG-induced relaxation of the ciliary muscle might also reduce cholinomimetic enhancement of facility via the TM route, which depends upon contraction of the muscle.2 Furthermore, a small PG enhancement of facility via the TM cannot be entirely excluded in humans.61 The apparent effect of the eicosanoids on cholinomimetic-induced IOP lowering will be the net resultant of these processes.

Pilocarpine may also be used to control IOP in combination with beta-adrenergic antagonists, carbonic anhydrase inhibitors, alpha-2- or beta-2-adrenergic agonists, or hyperosmotic agents. Concurrent local use of anticholinergic drugs will interfere with the action of pilocarpine; appropriate doses of systemic anticholinergics usually will not, because of insufficient ocular drug levels. Use of ophthalmic physostigmine prior to echothiophate may partially attenuate the magnitude and duration of the effects of the latter, because the short-acting physostigmine binds to and protects the cholinesterase enzyme until the echothiophate has diffused.33

Concurrent use of echothiophate with ester-derived local mucosal or parenteral anesthetics may inhibit the metabolism of these anesthetics, leading to prolonged anesthetic effect and increased risk of toxicity.

Exposure of patients using echothiophate to carbamate (e.g., aldicarb, methomyl, carbofuran) or organophosphate-type insecticides or pesticides (e.g., malathion, parathion, fenitrothion, mevinphos) may increase the possibility of systemic effects because the insecticide or pesticide is absorbed through the respiratory tract or skin.

Inhibition of cholinesterase activity by echothiophate reduces or slows cocaine metabolism, thereby increasing and/or prolonging cocaine's effects and increasing the risk of toxicity.

5.6 RESULTS OF CLINICAL TRIALS

Major clinical trials of cholinomimetics have not been undertaken, because the compounds were already in use before the methodology for clinical trials was standardized. However, numerous smaller studies have documented their safety, efficacy, and mode of action.

5.7 DIRECT, SHORT-ACTING DRUGS

Muscarine, pilocarpine, aceclidine (3-acetoxyquinuclidine), arecoline, and acetyl-beta-methylcholine (methacholine) are examples of direct-acting muscarinic drugs;

they directly stimulate muscarinic receptors to initiate a response.1'3'27'33'62'63 Carbachol (carbamylcholine) is both a direct-acting muscarinic agonist and a direct-acting nicotinic agonist' in addition to having indirect agonist activities (i.e.' it increases drug activity by inhibiting the degradative enzyme cholinesterase). Aceclidine is also slightly cholinesterase resistant and has weak anticholinesterase activity.

5.7.1 Pilocarpine

Chemical

V-'SH, HCj

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