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5.7.1.1 Formulations. The official drug name for pilocarpine is (3S-cis)-3-ethyldi-hydro-4-[(1-methyl-1H-imidazol-5-yl)methyl]-2(3H)-furanone] Brand names are listed in table 5.1. Pilocarpine hydrochloride solutions usually contain methylcellulose or a similar polymer and range in concentrations from 0.5% to 6%. Pilocarpine nitrate solutions range from 0.5% to 4%. The usual vehicles for pilocarpine are hydroxypropyl methylcellulose and polyvinyl alcohol. Benzalkonium chloride and sodium EDTA are added to prevent microbial growth. When maintained in a buffered' slightly acid solution' pilocarpine is indefinitely stable' retaining full activity at 6 months. Its effectiveness is maintained across a broad temperature range.

Pilocarpine is also formulated in a high-viscosity gel. In one study of adults with elevated IOP' a single dose of pilocarpine 4% gel applied at bedtime was approximately equal in effect to pilocarpine 2% or 4% eye drops applied four times daily; although the effect waned somewhat near the end of the 24-hour period.

Pilocarpine polymer is an aqueous emulsion consisting of a polymeric material to which pilocarpine base is chemically bound. The drug is released over a period of hours as the polymer is hydrolyzed.

Pilocarpine has also been combined in solution with other glaucoma therapeutics such as betaxolol' epinephrine' and physostigmine (table 5.1).

While pilocarpine is an inexpensive and effective IOP-lowering agent' it is not as commonly used today as in previous years because of its local adverse effects and multiple daily dosage requirements.

5.7.1.2 Pharmacokinetics, concentration-effect relationship, and metabolism. Pilo-carpine penetrates the cornea well and produces a low incidence of allergic reactions. Animal studies indicate that the cornea absorbs pilocarpine rapidly and then releases it slowly to the aqueous humor. However' degradation and complexing in the cornea result in only a small percentage (<3%) reaching the anterior chamber.

The onset of miosis with a 1% solution is 10 to 30 minutes. The maximum reduction in IOP occurs within 75 minutes with a solution, depending on its strength. The duration of action for miosis is about 4 to 8 hours following administration with a solution. The reduction in IOP lasts for 4 to 14 hours with a solution, varying with the strength used. In light-eyed individuals, 2% solution is at the top of the dose-response curve for lowering IOP. In brown-eyed white individuals, 4% solution may be required for maximum effect, while extremely dark-eyed individuals (African, Hispanic, and Asian Americans) may require a 6% solution. These differences relate to binding of the drug by pigment within the eye, making it unavailable to the relevant muscarinic receptors. In light-eyed individuals, the higher concentrations have been used to extend the duration of action, thereby reducing the frequency of administration to twice daily.

Pilocarpine is inactivated by tissues of the anterior segment of the eye, partly by reversible binding of the drug to tissues, but also by appreciable enzymatic hydrolysis to the primary metabolite, pilocarpic acid. Human serum contains a heat-labile component capable of inactivating pilocarpine. Incubation of 500 mg of pilocarpine with 0.5 mL human serum at 37°C for 1 hour will inactivate 40% of the pilocarpine. The amount of pilocarpine-hydrolyzing enzyme is not changed by prolonged pilocarpine use by glaucoma patients.

Cholinergic sensitivity varies inversely with local ACh concentration,45,48 the negative feedback putatively mediated by down- and up-regulation of musca-rinic receptors without change in rate of receptor degradation.48,49 Resistance to the IOP-lowering effect of miotics may occur after prolonged use. Responsiveness may be restored by substituting another miotic, timolol, epinephrine, or a carbonic anhydrase inhibitor for a for a short period of time, then resuming treatment with the original drug,33 although this seems inconsistent with our present understanding of the receptors and mechanisms controlling cholinergic responsiveness.

5.7.2 Carbachol. Carbachol is the carbamyl ester of choline and was synthesized in the early 1930s. It is no longer commonly used in current medical practice.

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