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CsH15N202CI

5.7.2.1 Formulations. The official drug name for carbachol (carbamylcholine chloride) is ethanaminium, 2-[(aminocarbonyl)oxy]-N,N,N-trimethyl-, chloride. Brand names are listed in table 5.1.

Carbachol occurs as white or faintly yellow hygroscopic crystals or crystalline powder, is freely soluble in water, and is sparingly soluble in alcohol. The drug is odorless or has a slight amine-like odor. Commercially available ophthalmic solutions contain benzalkonium chloride as a preservative and wetting agent. The commercially available ophthalmic solution of 0.75% to 3% carbachol has a pH of 5 to 7. The commercially available intraocular injection of 100 mg/mL has a pH of 5 to 7.5. Carbachol intraocular injection should be stored at 15°C to 30°C and protected from freezing and excessive heat. The commercially available carbachol intraocular injection is stable for 18 months after the date of manufacture.

5.7.2.2 Pharmacokinetics, concentration-effect relationship, and metabolism. Carbachol is not destroyed by cholinesterase; therefore, its action is not enhanced by anticholinesterase drugs. Carbachol is stable in solution. It is not lipid soluble at any pH; hence, it penetrates the intact corneal epithelium poorly.

To be clinically useful, carbachol must be dispensed in combination with a wetting agent, such as benzalkonium chloride 0.03%, which increases corneal penetration.

A 1.5% solution of carbachol used three times daily has been reported to be more effective than a 2% solution of pilocarpine given four times daily in the control of IOP in primary open-angle glaucoma.

When administered as a solution, the onset of miosis is within 10 to 20 minutes and lasts 4 to 8 hours. The maximum reduction in IOP occurs within 4 hours and lasts about 8 hours.

When used intracamerally, carbachol (Miostat 0.01%) is an intensely powerful miotic. It is 100 times more effective and longer lasting than ACh similarly instilled intracamerally (which is rapidly hydrolyzed by endogenous cholinesterase) and 200 times more effective than pilocarpine. Maximal miosis is achieved within 5 minutes and lasts about 24 hours.

5.8 INDIRECT, LONG-ACTING DRUGS

Some of these indirect, long-acting drugs are still available in the United States but are more commonly used for the treatment of glaucomas in aphakia or pseudophakia across much of Europe and Latin America. This group of drugs (physostigmine, demecarium, echothiophate, isoflurophate) blocks AChE, thus preventing metabolic inactivation of ACh released from parasympathetic nerve endings.1,27,33,62,63 None of these drugs has any affinity for muscarinic ACh receptors; instead, they act by either carbamylating or phosphorylating AChE. For the carbamyl enzyme, the halflife is hours; for the phosphoryl enzyme, it is days. Thus, these drugs are suicide substrates of AChE, and some of their effects can last for days or weeks.

5.8.1 Echothiophate. Cholinesterase inhibitors other than echothiophate that have been or are still available for clinical ocular use include eserine, isofluorophate, and demecarium. However, echothiophate is most commonly employed by far and is discussed as the paradigm for this drug class.

5.8.1.1 Formulations. The official drug name for echothiophate (echothio-phate iodide) is ethanaminium, 2-[(diethoxyphosphinyl)-thio]-N,N,N-trimethyl-, iodide, or (2-mercaptoethyl)trimethylammonium iodide S-ester with O,O-diethylphosphorothioate]. It is sold under the brand name Phospholine Iodide, available in the following concentrations: 0.03%, 0.06%, 0.125%, and 0.25%.

Indefinitely stable when dry, echothiophate must be kept in a tightly sealed container because the powdered form is hygroscopic. Assays of refrigerated aqueous solutions show a drop to 90% of the original potency within 4 weeks. At room temperature, this drop is to 83% of the original potency within 4 weeks and to 76% in 8 weeks. Benzalkonium is incompatible, so chlorobutanol is used instead as a preservative.

5.8.1.2 Pharmacokinetics, concentration-effect relationship, and metabolism. Dose-response analysis of echothiophate with respect to IOP64 and outflow facility indicates that, often, little additional pharmacologic response is obtained by increasing the drug concentration to more than 0.06%.65 Occasionally, concentrations as high as 0.125% or, very occasionally, 0.25% are required, although the potential for ocular side effects increases substantially at these higher concentrations. A 0.03% concentration of echothiophate iodide has an effect similar to pilocarpine 1% to 2%, while 0.06% is approximately equivalent to pilocarpine 4%. Echothiophate has a duration of ocular hypotensive action significantly longer than pilocarpine, with a maximal effect in 4 to 6 hours and a substantial effect maintained after 24 hours. Miosis begins within 1 hour and is maximal within 2 hours. Miosis and IOP reduction can, in some cases, last for several weeks, but usually lasts at least 24 to 48 hours. Thus, drug administration is often needed only once daily.

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