Comparison of action of cholinergic andanticholinesterase agents in glaucoma

Stephen M. Drance

The cholinergic agents have the advantages of systemic safety, fewer undesirable local sideeffects, and usefulness in angle-closure and narrow-angle glaucoma. The powerful cholinesteraseinhibitors, on the other hand, produce better diurnal reduction of intraocular pressure, requireless frequent administration, and can control many cases whose pressures cannot be otherwisebrought to heal. Neither group constitutes the ideal agent, and the search for this must there-fore continue. It must always be kept in mind that the agents used are powerful toxic drugsand for some people may be incapacitating. One must not be afraid to use them when indi-cated, but they should not be used indiscriminately.

EJL_J:

Ixperience with the treatment of theglaucomas with both cholinergic agentsand cholinesterase inhibitors dates back fornearly a century. Physostigmine, an anti-cholinesterase agent, was introduced as amedication in 1875; pilocarpine, which hasa direct effect, was first used in 1877.During the last 20 years, the new groupof powerful cholinesterase inhibitors hasmade its entry into the armamentarium ofglaucoma therapy. It is quite clear thatthe ideal drug has not yet been found.There are advantages and disadvantagesin the use of both groups of these agents.

We are not at a stage when we canmeaningfully compare the effects of thetwo groups of agents on the progression orprevention of the field changes, whichmust be our aim, but we can comparethem in terms of: (1) the mechanism ofaction, (2) the effect on ocular dynamics,and (3) the toxicity and side effects.

From the Department of Ophthalmology, Uni-versity of British Columbia, Vancouver, B. C ,Canada.

The cholinergic agents, exemplified bypilocarpine and carbachol, have directeffects on target cells. Their effects aresimilar to the muscarine action of naturallyreleased acetylcholine. They are not de-pendent on release of acetylcholine, andact on denervated tissues. The cholinester-ase inhibitors, such as physostigmine,mintacol, DFP, echothiophate iodide, anddemecarium bromide (and to some extentcarbachol) inhibit cholinesterases andpotentiate the action of acetylcholine re-leased at nerve endings. They appear tohave no effect on denervated tissues, andwill not produce an appreciable effect intissues where a local anesthetic has tem-porarily abolished nerve conduction.

Both groups of drugs lower intraocularpressures and decrease the resistance tooutflow as measured tonographically.1'5 Ineyes with open angles, this is independentof the myosis produced. It is presumed tobe caused by the effect of the ciliarymuscle on the outflow channels or on thevessels supplying and draining that seg-ment of the eye. Perfusion studies havesuggested that pilocarpine may also have

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Effects of cholinergic and antichoUnesterase agents 131

a direct histaminelike action on the endo-thelial cells of the trabeculum.0

The long-acting cholinesterase inhibitorshave a more marked action and longerduration of action on intraocular pressureand outflow facility, which means that: (1)these agents will influence intraocular pres-sure when the cholinergic agents alone orin combination with sympathomimeticagents have failed, and (2) they dampenthe diurnal swings of intraocular pressurein a more effective way than can beachieved with cholinergic agents.

In order to compare the effect of 4 percent pilocarpine with 0.06 per cent echo-thiophate iodide on the diurnal intraocularpressure variations, 20 eyes of 13 patientsin varying stages of ocular hypertensionand chronic simple glaucoma were studied.7

Pilocarpine was administered to the pa-tients in this group 4 times daily, at 8 A.M.,2 P.M., 6 P.M. and 10 P.M., whereas echo-thiophate iodide was administered at 7A.M. and 10 P.M. Diurnal tension curvesa month of echothiophate 0.06 per cent,were carried out on no therapy, after amonth of pilocarpine 4 per cent, and afterThe results show (Figs. 1 and 2) that pilo-carpine reduced intraocular pressure lesseffectively than echothiophate iodide, andthat 70 per cent of pilocarpine-treated eyesshowed peaks of intraocular pressure over24 mm. Hg, whereas only 20 per cent ofthe echothiophate-treated eyes showedsimilar peaks. Four of the 13 patients pre-ferred the echothiophate, whereas 6 pre-ferred pilocarpine and 3 expressed nopreference. This comparison dealt only withthe effects of these drugs on intraocularpressure. The practical application is that,when it has been decided in an individualthat meticulous pressure reduction is indi-cated, the cholinesterase inhibitor does thismore reliably than the cholinergic agent.This is important when no facilities areavailable for measurements of intraocularpressure around the clock. These resultsdo not mean that these powerful agentsshould be used as the first line of therapyin veiy early cases, when the decision to

treat has been made, but when criticalpressure control may be much less im-portant.

Single-dose responses of echothiophateiodide on intraocular pressure and outflowfacility were studied in 11 patients witheither ocular hypertension or advancedopen-angle glaucoma.s These patients hadintraocular pressures checked around theclock. Single doses of 0.03, 0.06, 0.125 and0.25 per cent echothiophate were instilledin one eye, and the other was used as acontrol. Drug effects were calculated bycomparing the logarithms of the pressurein the treated and the untreated eye atvarious times after the instillation of thedrug, and allowing for intraocular pressuredifferences at the same time of day in theuntreated state. There was a clear-cut doseresponse to echothiophate iodide with alatent period of some 13 to 21 hours. Themaximal effect occurred 27 hours after theinstillation of the drug, and there was asecond peak of action 24 hours later.Echothiophate iodide, 0.03 per cent, al-though its action was only barely signif-icant, followed the pattern of other con-

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132 Drance Inticstigatioc OphthalmologyApril 1966

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centrations and can be considered active.These findings do not necessarily reflectthe cumulative action of the various drugconcentrations when used repetitively; theyshow only a dose response to single in-stillations (Fig. 3).

A comparison of the two groups of drugswould not be complete without a discus-sion of the side effects, which can bedivided into local and systemic effects.

Side effects

Local.Accommodative spasm. This is produced

by both cholinergic agents and cholines-terase inhibitors. It is more marked withcholinesterase inhibitors, but it is moreeven with these agents. Some young pa-tients prefer weak solutions of long-actingcholinesterase inhibitors, which are lessincapacitating than the cholinergic agents,for this reason.

Headache.Browache.Visual difficulty due to myosis.Vascular dilatation.Iritis and posterior synechiae. These oc-

cur mainly with cholinesterase inhibitors.Cysts. These occur particularly with

cholinesterase inhibitors and are often re-ferred to as pupil margin cysts, but infact any part of the pigment epitheliummay be involved. Some of the bowing ofthe iris, particularly when it is localizedto one segment, may be caused by theformation of a cyst. Following iridectomy,one can see the cysts go all the way to theciliary body.

Pupillary block. This is an importantside effect which is much more markedwith the long-acting cholinesterase inhibi-tors. The cholinergic agents do, however,produce it as well. The cholinesterase in-hibitors are therefore contraindicated in

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Effects of cholinergic and anticholinesterase agents 133

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Fig. 3. The mean effect of single doses of varying concentrations of Phospholine iodide onintraocular pressure in eleven glaucomatous eyes. One eye was treated and the other used asa control. A rise in the log ratio (fall on the graph) indicates a fall in intraocular pressureproduced by the drug. The mean diumal curve pattern at the bottom of the figure was thatobtained during the 24 hours prior to instillation of the drug. The pattern has been empiricallyrepeated for illustrative purposes for 4 days.

very narrow angles which can be convertedfrom an open- to a closed-angle mecha-nism. It is not uncommon to find goodpressure-lowering effects when the drugsare first used which gradually, and some-times rather quickly, give way to poor con-trol again. Some of these apparent "resis-tances" to the drug are due to developmentof pupil block or forward displacement ofthe entire lens iris diaphragm which com-promises the outflow mechanism. A periph-eral iridectomy will relieve the situation inthose cases where pupil block was thecause of the phenomenon, and the drugfollowing such a procedure will again bevery effective in controlling pressure.

Retinal detachments. Both groups ofagents can be incriminated, although thecholinesterase inhibitors are much more

frequently responsible for this complica-tion. It must be remembered that manyglaucoma eyes have degenerative retinalareas and even tears, and that the mioticis usually only the precipitating causewhich induces the progressive retinal sepa-ration.

Tolerance or resistance. These occurmuch more frequently in the case of thecholinergic agents, although the cholines-terase inhibitors may enjoy a period ofpressure control and finally lose their effect.When a powerful cholinesterase inhibitorno longer controls intraocular pressure, aswitch to the cholinergic agents may againproduce reasonable control. The possibilityof pupil block as a cause of resistance hasbeen discussed.

Lens opacities. All ophthalmologists

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134 Drawee Investigative OphthalmologyApril 1966

using the powerful cholinesterase inhibi-tors have encountered patients who havedeveloped rapid visual deterioration due tomyosis in eyes already affected by lensopacities. When the drug was discontinued,some of these patients' visual acuity doesnot return to its previous level. Most ofthese cases have a posterior subcapsularopacity with some nuclear sclerosis. Recentreports from Sweden suggest that echo-thiophate iodide produces lens opacitiesvery frequently, and these are a combina-tion of specific anterior subcapsular whiteopacities in addition to senile nuclearsclerosis. There are many factors whichcould influence this situation. The coexist-ence of glaucoma and lens opacities is ofa very high order. The Scandinavian work-ers usually report a veiy high incidenceof pseudoexfoliation in their glaucomatouspatients, and these factors may have abearing on the results which they pre-sented. If a powerful cholinesterase in-hibitor is used with proper indication,when control with other agents is notpossible, and the alternative is a surgicalone, the incidence of gradually occurringlens opacities following fistulizing surgeryand even peripheral iridectomy is probablyvery much higher than the reported opaci-ties on echothiophate iodide. Experience ofthe past 9 years with this agent suggeststhat lens opacities undoubtedly can occureither produced by the drug, acceleratedby the drug, or merely coincidentally inpatients who are using the drug, but thetremendously high incidence of opacitiesreported must be proved to be due to thedrug in a study carefully designed to thisend.

Systemic. Systemic side effects can oc-cur with both groups of agents. Ocularpilocarpine or carbachol may produceasthmatic attacks in patients who sufferfrom this disease. Occasional nausea andcolicky abdominal pains are well known,and lacrimation, rhinorrhea, and salivationare quite common. Eserine has also pro-duced signs of systemic parasympatheticoverstimulation. The long-acting cholines-

terase inhibitors do, however, constitutea much more serious and potential danger.The majority of people on ocular medica-tion with these drugs show depression ofacetylcholinesterase in the red blood cellsand of serum pseudocholinesterase.9""Fortunately, the vast majority of thesepatients have no systemic side effects ofacetylcholine accumulation. The moreclosely one looks for mild side effects themore frequently they are found. The com-monest effects are gastrointestinal, andincreased secretions from lacrimal, sali-vary, and mucosal glands. More rarely,respiratory and cardiovascular effects areseen,1'-' 1:1 and occasional cases of neuro-logic disturbances1'1 have been reported.There is no doubt that patients on theseagents must be liable to acetylcholine ac-cumulation after vagal stimulation. Theyare also at risk to organophosphorous in-secticides or when treated for myasthenia.Pharmacogenetic13 studies may also showdifferences in the cholinesterase of thosepeople who show systemic symptoms fromocular instillation. The depression ofpseudocholinesterase may be responsiblefor prolonged apnea when succinylcholineis used to aid general anesthesia.

REFERENCES1. Krishna, N., and Leopold, I. H.: Echo-

thiophate iodide in treatment of glaucoma,Arch. Ophth. 62: 300, 1959.

2. Krishna, N., and Leopold, I. H.: Effect ofBC-48 on rabbit and human eye, Am. |.Ophth. 49: 270, 1960.

3. Becker, B., and Gage, T.: BC-48 and echo-thiophate iodide in chronic glaucoma, Arch.Ophth. 63: 102, 1960.

4. Drance, S. M., and Carr, F.: Effects of phos-pholine iodide on intraocular pressure inman, Am. J. Ophth. 49: 471, 1960.

5. Drance, S. M., and Carr, F.: Effects ofdemecarium bromide on intraocular pressurein man, Arch. Ophth. 62: 673, 1959.

6. Barany, E.: The mode of action of pilo-carpine on outflow resistance on the eye of aprimate, INVEST. OPHTH. 1: 712, 1962.

7. Pratt-] ohnson, j . A., Drance, S. M., andInnes, R.: Comparison between pilocarpineand echothiophate for chronic simple glau-coma, Arch. Ophth. 72: 485, 1964.

8. Stockdill, P., and Drance, S. M.: Dose re-

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Effects of cholinergic and anticholinesterase agents 135

spouses of human intraocular pressure to 12.various concentrations of echothiophateiodide, Tr. Ophth. Soc. United Kingdom. Inpress. 13.

9. Leopold, I. H., Krishna, N., and Lehman, R.A.: The effects of anticholinesterase agentson the blood cholinesterase of normal and 14.glaucoma subjects, Tr. Am. Ophth. Soc. 57:63, 1959.

10. Wahl, I. W., and Tyner, G. S.: Echothio-phate iodide, Am. J. Ophth. 60: 419, 1965. 15.

11. Humphreys, J. A., and Holmes, I. H.:Systemic effects produced by Phospholineiodide in treatment of glaucoma, Arch.Ophth. 69: 737, 1964.

Hiscox, P. E. A., and McCulloch, C : Cardiacarrest occurring in a patient on echothiophateiodide therapy, Am. j . Ophth. 60: 425, 1965.Drance, S. M.: Echothiophate iodide anddemecarium in the management of glaucoma,Am. J. Ophth. 50: 270, 1960.Klendshoj, N. C , and Olmstead, E. P.:Observation of dangerous side effects ofphospholine iodide in glaucoma therapy, Am.j . Ophth. 56: 247, 1963.Leopold, I. H.: Cholinergic and anti-cholinesterase agents in glaucoma therapy,Cilston Symposium, 1964. In press.

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