3. DRUGS

30

Comment: Topical and systemic β-blockers are poorly additive with respect to lowering IOP.

Comment: Although some β-blockers have intrinsic sympathomimetic activity (ISA) or α-blocking properties, their clinical properties are similar to those of other non-selective β-antagonists. However, ISA may reduce respiratory and cardiovascular side-effects related to β-blockade.

5.Timolol, and possibly all other β-blockers, have minimal IOP-lowering efficacy during sleep.

Comment: Non-selective topical β-blockers are contraindicated in patients with asthma, chronic obstructive pulmonary disease (emphysema and bronchitis) some cases of congestive heart failure, bradycardia, and heart block.

6.The IOP-lowering efficacy of betaxolol, a relatively selective β-1-blocker, is less than that of non-selective β-blockers.

Comment: Betaxolol is relatively safer than a non-selective β-blocker in patients with known reactive airway disease.

7.Carbonic anhydrase inhibitors (CAIs) are effective IOP-lowering agents. Comment: CAIs reduce IOP by suppressing aqueous humor production through inhibition of the isoenzyme carbonic anhydrase II.

Comment: CAIs are the only category of drugs available commercially in both topical and systemic formulations to lower IOP.

Comment: For systemic CAIs, major side effects include paresthesia, malaise, gastrointestinal disturbances, renal disorder, blood dyscrasia, and metabolic acidosis.

Comment: For topical CAIs, side effects include ocular burning, stinging, bitter taste, superficial punctuate keratopathy, blurred vision, tearing, headache, and transient myopia.

Comment: CAIs may increase ocular blood velocity; however, there is insufficient evidence for any clinical benefit of this effect for glaucoma patients. Comment: Topical CAIs and systemic CAIs are poorly additive with respect to lowering IOP.

8.Systemic CAIs are contraindicated with sulfonamide allergy, with depressed sodium and/or potassium blood levels, and in metabolic acidosis.

9.The non-selective adrenergic agonists, epinephrine and its pro-drug (dipivefrin) are effective IOP-lowering agents.

Comment: Adrenergic agonists reduce IOP by decreasing aqueous formation and increasing outflow.

Comment: Adrenergic agonists are contraindicated in infants and children because of systemic side effects.

Comment: IOP lowering efficacy of adrenergic agonists is less than that with timolol. This class is often additive to prostaglandin analogues but not to non-selective β-blockers.

Comment: Local side effects include hyperemia and blepharoconjunctivitis. Systemic circulatory effects include hypertension and tachyarrhythmias.

10.Selective alpha-2 adrenergic agonists reduce IOP by suppressing aqueous inflow and increasing outflow. They also may affect episcleral venous pressure.

Comment: Systemic side effects with selective alpha-2 adrenergic agonists include dry mouth, drowsiness and hypotension.

11.There is insufficient evidence for neuroprotection by selective alpha-2 adrenergic agonists in humans.

12.Bunazosin, a selective α1A antagonist, increases uveoscleral outflow. Comment: Although it is well-tolerated, the hypotensive effect of topical bunazosin is weaker than that of topical timolol.

13.Prostaglandin analogues (PGAs) are the most effective IOP-lowering agents of all topical glaucoma medications, and generally are first line therapy. Comment: PGAs lower IOP by increasing uveoscleral aqueous humor outflow, and may also have an effect on outflow facility.

Comment: Common side effects of prostaglandin analogue drops include conjunctival hyperemia, reversible increase of eyelash length, thickness and pigmentation, irreversible increase of iris pigmentation, and increase of eyelid skin pigmentation. Rare side effects include uveitis, reactivation of herpetic keratitis and cystoid macula edema.

Comment: PGAs are systemically safe, but are relatively contraindicated in pregnancy, as are all glaucoma medications.

14.Preservatives used for multi-dose topical ophthalmic medications can cause ocular surface changes.

Comment: Benzalkonium chloride (BAK), in particular, has been associated with ocular surface changes in chronic use. Alternative preservative systems are increasingly used in multi-dose bottles in an effort to decrease the potential for deleterious effects on ocular surface. However, direct comparisons between these agents are lacking.

Comment: Preservative free systems, in the form of unit dose packages, are a viable alternative to traditional multi-dose bottles. In theory, they may have fewer ocular surface effects, however, direct comparisons with preserved agents are lacking.

I Cholingergic Agents

Changwon Kee, Takeshi Yoshitomi, Neeru Gupta

Mechanisms of action

Cholinergic agents were the first class of drugs applied to the eye for the treatment of glaucoma.1 These drugs improve outflow facility through tension on the trabecular meshwork as a biomechanical consequence of ciliary muscle contraction, and ciliary muscle disinsertion from the sclera and meshwork areas abolished this effect.2

32

Contraction of the ciliary muscle is mediated by muscarinic-receptor activation. Direct acting parasympathomimetic agents, such as pilocarpine and carbachol, stimulate muscarinic receptors, while indirect acting agents, such as echothiophate iodide and physostygmine, promote muscarinic receptor activity by increasing acetylcholine availability. Five different subtypes of mAChRs have been identified and classified according to their different G protein coupling properties.3 The human ciliary body contains M1, M2 and M3 muscarinic receptor subtypes,4-8 and the latter seems abundant. M4 and M5 subtypes have not been studied in the ciliary body.9,10

Direct acting agents

Pilocarpine

Pilocarpine is derived from the plant Pilocarpus microphyllus, in which the drug occurs as the isomer isopilocarpine. Pilocarpines are prepared as solutions, gels, and membrane-controlled delivery systems (Ocusert). The solutions, which are most commonly used, are available in concentrations ranging from 0.25% to 10%. As the pilocarpine concentrations greater than 4% do not generally increase the ocular hypotensive effect, the 1% to 4% solutions are most commonly used.11,12

Pilocarpine is prescribed for use four times daily to lower IOP. It is recommended to start with the lowest concentration of pilocarpine, typically 1%, and increase the dose until the desired pressure-lowering effect is obtained. Pilocarpine binds to melanin in the iris and ciliary body, and iris color may influence IOP response. Eyes with darkly pigmented irides may require higher concentration of pilocarpine for maximum effect.13 Pilocarpine shows an additive hypotensive effect when used in conjunction with β-blocking agents, alpha-2 adrenergic agonists, carbonic anhydrase inhibitors, and prostaglandin analogues.14-19 Pilocarpine constricts the pupil and pulls the iris out of the angle and may therefore may be useful for the treatment of acute angle closure or widening of the angle in the plateau iris syndrome.20

Local side effects

Ocular side effects of cholinergic medications relate to muscarinic cholinergic receptors found in the iris, causing iris sphincter muscle contraction. In patients with cataract, pupillary constriction may worsen visual acuity and predispose to posterior synechiae, and in those with glaucoma, may aggravate visual field constriction. Anterior movement of the iris/ciliary body diaphragm may predispose to angle closure and transient worsening of myopia. In the young patient, ciliary body contraction can induce problematic fluctuating accommodative myopia and in many instances, brow ache or headache depending on individual tolerability.21 Headaches may disappear with continued application.21 Instillation of 2% pilocarpine causes an average accommodative myopia of 5.8 diopters in young patients. Increased permeability of the blood-aqueous barrier can result in severe inflammation when the drug is used postoperatively and in other inflam-

matory conditions.22,23 Other ocular side effects include conjunctival hyperemia, dermatitis around the eyelids, retinal detachment, and annular ciliochoroidal detachment.24-26Attempts to minimize these effects have been made by altering drug formulations or delivery systems.

Systemic side effects

Muscarinic receptors are also located in the gastrointestinal tract, sweat glands, cardio-pulmonary system, and urinary tract. Thus, rare systemic side effects after topical administration of cholinergic agents may include nausea, vomiting, diarrhea, sweating, bradycardia, bronchial spasm, pulmonary edema and urinary frequency.27-29

Indications

Pilocarpine can be used for treating both primary open-angle glaucoma and primary angle-closure glaucoma following laser iridotomy.

Contraindications

Pilocarpine decreases the IOP through increasing trabecular outflow facility, therefore, applying this agent to the angle-closure glaucoma with 360 degrees of PAS in the angle is ineffective. As pilocarpine causes breakdown of blood aqueous barrier, it should not be used in the secondary glaucoma associated with uveitis. If it is used in the neovascular glaucoma, the contraction of iris and ciliary muscles by pilocapine produces severe ocular pain without any effect on decreasing the IOP. Pilocarpine may be contraindicated in eyes predisposed to rhegmatogenous retinal detachment.

Aceclidine

Aceclidine is a parasympathomimetic drug acting directly on the motor endplate.30,31 It induces contraction of longitudinal ciliary muscle more than circular ciliary muscle, increasing outflow facility with less accommodation than pilo- carpine.21,30-33 Aceclidine hydrochloride used topically in a strength of 2 or 4% is available in Russia, France, Italy and in several other countries of Europe, but not in the USA and Asian countries.

Efficacy

Aceclidine is less effective in decreasing IOP than pilocarpine on a concentration basis (e.g., 4% aceclidine has the same ocular hypotensive effect as 2% pilocarpine).34 Aceclidine is thought to induce less ciliary muscle spasm and accommodation than pilocarpine. It is less toxic than pilocarpine.34 Aceclidine was found to produce slightly more powerful moisis than pilocarpine.35

34

Acetylcholine

Acetylcholine (often abbreviated ACh) is a neurotransmitter in the autonomic nervous system. Although not used for the medical treatment of open angle glaucoma, acetylcholine chloride (Miochol in the USA, Ovisot in Japan) is used intraocularly to induce rapid miosis during ocular surgery. Acetylcholine is supplied in a sterile vial contains dehydrated acetylcholine chloride. The diluent (usually sodium chloride) is mixed with the acetylcholine just before use because of the compound’s instability.

Injection of 0.5 to 2 ml of 0.1 to 1% concentration of acetylcholine intracamerally produces miosis within a few seconds, it acts directly at the muscarinic receptor in the iris and ciliary smooth muscle very fast. However, cholinesterase in the anterior chamber also quickly inactivates it by hydrolysis, which makes this drug’s acting time very short. It also has no effect as an eyedrop for medical treatment of glaucoma because of hydrolysis during penetration of the cornea. Administration of acetylcholine during cataract surgery not only induces miosis, but also reduces postoperative intraocular pressure elevations.36-38

Systemic and local side effects

Corneal edema, corneal clouding, and decompensation have been reported with the use of intraocular acetylcholine.39 Systemic effects such as hypotension, sweating, bradycardia, and flushing occasionally have been noted.

Carbachol

Carbachol which was first synthesized in 1932 has been used for treatment of glaucoma.40,41 Carbachol is different from pilocarpine in structure, but their actions are greatly similar. Carbachol is less permeable to cornea42 and more resistant to hydrolysis by the cholinesterases than pilocarpine and gives it a longer duration of action. Carbachol has most of the same local side effects as pilocarpine, but they are somewhat more severe. Carbachol often is less well tolerated than pilocarpine. Carbachol is primarily used as eyedrop, but it is also used during ophthalmic surgery. Intraocular carbachol requires about two to five minutes to achieve maximum miosis and maintains it longer than acetylcholine. Intraocular carbachol not only produces prolonged miosis, but also results in a significant reduction in postoperative intraocular pressure after cataract surgery.43

Local side effects

Corneal clouding, bullous keratopathy, and increased postoperative iritis have been associated with the use of intraocular carbachol.44 Intraocular carbachol can be toxic to the corneal endothelium and should be avoided in cases involving compromised endothelium.45

Indirect acting cholinergic agents

Indirect cholinergic agents inhibit acetylcholinesterase found in human ocular tissue.46 The mechanism of improved outflow facility is presumed similar to that discussed for pilocarpine. Physostigmine is a reversible inhibitor, and available as an ointment. Echothiophate Iodide is an irreversible cholinesterase inhibitor and has a prolonged duration of action.47 This advantage however is offset by adverse reactions such as systemic toxicity related to cholinesterase depletion with chronic therapy, including respiratory paralysis during general anesthesia with muscle relaxant use.48 Local adverse effects include cataracts with anterior and posterior subcapsular changes that appear to be dose-related,49 though the mechanism is unclear. Iris cysts may occur in children, and ocular inflammation and corneal toxicity are not uncommon in addition to effects common to cholinergic agents. For these reasons, indirect agents are usually reserved for patients who are pseudophakic or aphakic, if other options are not available.

References

1.Kaufman PL. Mechanisms of action of cholinergic drugs in the eye. In: Drance SM, Neufeld AN (Eds.), Glaucoma. Orlando: Grune and Stratton; 1984: pp. 395-427.

2.Kaufman PL, Barany EH. Loss of acute pilocarpine effect on outflow facility following surgical disinsertion and retrodisplacement of the ciliary muscle from the scleral spur in the cynomolgus monkey. Invest Ophthalmol 1976; 15: 793-807.

3.Caulfield MP, Birdsall NJ. International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev 1998; 50: 279-290.

4.Gupta N, McAllister R, Drance SM, Rootman J, Cynader MS. Muscarinic receptor M1 and M2 subtypes in the human eye: QNB, pirenzipine, oxotremorine, and AFDX-116 in vitro autoradiography. Br J Ophthalmol 1994; 78: 555-559.

5.Gupta N, Drance SM, McAllister R, Prasad S, Rootman J, Cynader MS. Localization of M3 muscarinic receptor subtype and mRNA in the human eye. Ophthalmic Res 1994; 26: 207-213.

6.Gil DW, Krauss HA, Bogardus AM, WoldeMussie E. Muscarinic receptor subtypes in human iris-ciliary body measured by immunoprecipitation. Invest Ophthalmol Vis Sci 1997; 38: 1434-1442.

7.Zhang X, Hernandez MR, Yang H, Erickson K. Expression of muscarinic receptor subtype mRNA in the human ciliary muscle. Invest Ophthalmol Vis Sci 1995; 36: 1645-1657.

8.Gabelt BT, Kaufman PL. Inhibition of outflow facility and accommodative and miotic responses to pilocarpine in rhesus monkeys by muscarinic receptor subtype antagonists. J Pharmacol Exp Ther 1992; 263: 1133-1139.

9.Caulfield MP. Muscarinic receptors--characterization, coupling and function. Pharmacol Ther 1993; 58: 319-379.

10.Hulme EC, Birdsall NJ, Buckley NJ. Muscarinic receptor subtypes. Annu Rev Pharmacol Toxicol 1990; 30: 633-673.

11.Drance SM, Nash PA. The dose response of human intraocular pressure to pilocarpine. Can J Ophthalmol 1971; 6: 9-13.

12.Drance SM, Bensted M, Schulzer M. Pilocarpine and intraocular pressure. Duration of effectiveness of 4 percent and 8 percent pilocarpine instillation. Arch Ophthalmol 1974; 91: 104-106.

36

13.Harris LS, Galin MA. Dose response analysis of pilocarpine-induced ocular hypotension. Arch Ophthalmol 1970; 84: 605-608.

14.Airaksinen PJ, Valkonen R, Stenborg T, et al. A double-masked study of timolol and pilocarpine combined. Am J Ophthalmol 1987; 104: 587-590.

15.Maclure GM, Vogel R, Sturm A, Binkowitz B. Effect on the 24-hour diurnal curve of intraocular pressure of a fixed ratio combination of timolol 0.5% and pilocarpine 2% in patients with COAG not controlled on timolol 0.5%. Br J Ophthalmol 1989; 73: 827-831.

16.Puustjarvi TJ, Repo LP. Timolol-pilocarpine fixed-ratio combinations in the treatment of chronic open angle glaucoma. A controlled multicenter study of 48 weeks. Scandinavian Timpilo Study Group. Arch Ophthalmol 1992; 110: 1725-1729.

17.Fernandez-Bahamonde JL, Alcaraz-Michelli V. The combined use of apraclonidine and pilocarpine during laser iridotomy in a Hispanic population. Ann Ophthalmol 1990; 22: 446-449.

18.Toris CB, Alm A, Camras CB. Latanoprost and cholinergic agonists in combination. Surv Ophthalmol 2002; 47 Suppl 1: S141-147.

19.Toris CB, Zhan GL, Zhao J, Camras CB, Yablonski ME. Potential mechanism for the additivity of pilocarpine and latanoprost. Am J Ophthalmol 2001; 131: 722-728.

20.Ganias F, Mapstone R. Miotics in closed-angle glaucoma. Br J Ophthalmol 1975; 59: 205206.

21.Francois J, Goes F. Ultrasonographic study of the effect of different miotics on the eye components. Ophthalmologica 1977; 175: 328-338.

22.Mori M, Araie M, Sakurai M, Oshika T. Effects of pilocarpine and tropicamide on bloodaqueous barrier permeability in man. Invest Ophthalmol Vis Sci 1992; 33: 416-423.

23.Zimmerman TJ, Wheeler TM. Miotics: side effects and ways to avoid them. Ophthalmology 1982; 89: 76-80.

24.Grant WM. Toxicology of the eye. Springfield: Charles C Thomas 1974.

25.Beasley H, Fraunfelder FT. Retinal detachments and topical ocular miotics. Ophthalmology 1979; 86: 95-98.

26.Kwon GR, Kee C. A case of bilateral malignant glaucoma with ciliochoroidal detachment. J Korean Ophthalmol Soc 1998; 39: 614.

27.Greco JJ, Kelman CD. Systemic pilocarpine toxicity in the treatment of angle closure glaucoma. Ann Ophthalmol 1973; 5: 57-59.

28.Curti PC, Renovanz HD. The effect of unintentional over doses of pilocarpine on pulmonary surfactant in mice. Klin Monastsbl Augenheilk 1981; 79: 113.

29.Littmann L, Kempler P, Rohla M, Fenyvesi T. Severe symptomatic atrioventricular block induced by pilocarpine eye drops. Arch Intern Med 1987; 147: 586-587.

30.Fechner PU, Teichmann KD, Weyrauch W. Accommodative effects of aceclidine in the treatment of glaucoma. Am J Ophthalmol 1975; 79: 104-106.

31.Drance SM, Fairclough M, Schulzer M. Dose response of human intraocular pressure to aceclidine. Arch Ophthalmol 1972; 88: 394-396.

32.Poyer JF, Gabelt BT, Kaufman PL. The effect of muscarinic agonists and selective receptor subtype antagonists on the contractile response of the isolated rhesus monkey ciliary muscle. Exp Eye Res 1994; 59: 729-736.

33.Hubbard WC, Kee C, Kaufman PL. Aceclidine effects on outflow facility after ciliary muscle disinsertion. Ophthalmologica 1996; 210: 303-307.

34.Romano JH. Double-blind cross-over comparison of aceclidine and pilocarpine in open-angle glaucoma. Br J Ophthalmol 1970; 54: 510-521.

35.Zhu L, Cui YY, Feng JM, Wu XJ, Chen HZ. Aceclidine and pilocarpine interact differently with muscarinic receptor in isolated rabbit iris muscle. Life Sci 2006; 78: 1617-1623.

36.McKinzie JW, Boggs MB Jr. Comparison of postoperative intraocular pressures after use of Miochol and Miostat. J Cataract Refract Surg 1989; 15: 185.

37.Wedrich A, Menapace R. IntraocuIar pressure following small incision cataract surgery and polyhema posterior chamber lens implantation: a comparison between acetylcholine and carbachol. J Cataract Refract Surg 18:500, 1992.