Systemic

Cholinergic drugs can produce a variety of systemic side effects, including nausea, vomiting, diarrhea, abdominal cramping, saliva­ tion, sweating, bradycardia, hypotension, bronchospasm, muscle weakness, and central nervous system stimulation (Box 27-2). Anticholinesterase drugs can produce systemic reactions even when administered as directed, whereas the direct-acting miotics are more likely to produce these symptoms when instilled every few minutes during the treatment of acute angle-closure glaucoma.111 Because of the risk of systemic side effects from rapid, multiple dose administration of pilocarpine drops, this form of treatment for acute angle-closure glaucoma should be avoided. It is better to treat first with other pressure-lowering agents to get the IOP into a range that will allow no more than four drops of pilocarpine 2% to produce the desired miosis.

Farm workers exposed to both anticholinesterase medication and organophosphorus insecticides and pesticides are at great risk of developing these reactions.112 The side effects are caused by systemic distribution of the drug after absorption through the conjunctiva and the mucosa of the oropharynx and nasopharynx. Severe systemic reactions to anticholinesterase eyedrops are reported in patients following conjunctivodacryocystorhinostomies ( Jones’ procedures).113

The potential systemic side effects of these drugs must be understood not only by ophthalmologists but also by family physicians, internists, and general surgeons. Failure to recognize the systemic effects of anticholinesterase medication applied topically to the eye can result in unnecessary laboratory and X-ray studies, unwarranted medical treatment, and even dangerous exploratory surgery. Ophthalmologists should inquire about the presence of side effects and warn patients and patients’ other physicians about the potential toxicity of these agents.

Systemic side effects may be reduced by punctal occlusion. A patient who develops a severe and potentially life-threatening systemic reaction to anticholinesterase medication should be treated with 2 mg of atropine, injected subcutaneously or intra­ venously, and 25 mg/kg of pralidoxime (Protopam), infused intravenously over 2 hours. Pralidoxime releases cholinesterase from the phosphoryl group of the cholinesterase inhibitor.114,115

Systemic absorption of anticholinesterase medication inhibits plasma pseudocholinesterase. This enzyme is necessary for the

metabolism of succinylcholine and the metabolism of local anesthetics with ester linkages (e.g., procaine and tetracaine).116,117 Thus

patients receiving cholinesterase inhibitors are at risk of developing

Box 27-2  Systemic side effects of topical cholinergic drugs

Bronchial spasm, asthma, pulmonary edema Nausea, vomiting, abdominal pain

Weakness, fatigue, muscle spasm – may mimic myasthenia gravis109,110 Paresthesia

Prolonged respiratory paralysis after general anesthesia including succinylcholine

Toxic reactions to local anesthetics containing an ester linkage group Sweating, salivation, lacrimation

Hypotension, bradycardia Nightmares, depression, delusions

Exacerbation of myasthenia gravis and interference with its drug treatment

Note: all systemic side effects are more common and more severe with the anticholinesterase drugs.

protracted apnea after succinylcholine or toxic reactions to some local anesthetics. The anesthesiologist and the patient must be warned of these dangers.

Suggestions for use

Miotics have become third-level drugs since the advent of-adrenergic agonists, -blockers, prostaglandin analogs, and topical carbonic anhydrase inhibitors – all of which have fewer visual side effects.When prescribing a miotic, it is wise to start with a low concentration of a direct cholinergic agent (e.g., 1% pilocarpine). The concentration should then be increased as needed, preferably using a therapeutic trial in one eye. Alternatively one should consider pilocarpine gel as the miotic of first choice because of the convenience of administration and the relative lack of daytime side effects; this is especially true in young patients or in those with lens opacities. All direct cholinergic drugs (except pilocarpine gel and Ocusert) are prescribed for use every 6–8 hours.

Administration of standard miotics on a twice-daily basis produces adequate IOP control in less than 60% of patients.45 Higher concentrations of miotics often have a longer duration of effect than lower concentrations.The increased duration of action, however, is offset by increased symptoms and side effects.The duration of action of both pilocarpine and carbachol can be prolonged, the concentration lowered and the frequency of administration reduced by the simple act of nasolacrimal occlusion.118

Patients should be instructed about the purpose of the drug, the time schedule for administration, and the proper technique for instillation, including nasolacrimal occlusion. They should be warned about the common side effects, including headache, fluctuating vision, and dim vision at night.The headache and fluctuating vision often become less severe with time and frequently disappear after a few days.

Examination

Before initiating miotic treatment, a careful examination of the peripheral retina should be performed whenever possible. If substantial vitreoretinal abnormalities are found, it may be safer to choose a non-miotic ocular hypotensive agent. If no safer medical or surgical options are available, laser or cryotherapy to any retinal pathology that might presage a retinal detachment should be considered before commencing a cholinergic treatment.

Because miotic agents can produce paradoxical pupillary block by moving the lens–iris diaphragm forward, patients should be

re-examined by gonioscopy after miotic therapy has commenced to determine whether the angle has narrowed.5,119 Drug-induced

angle closure is more common with the anticholinesterase agents and is more likely in patients with anatomically narrow angles or spherophakia.Visual field studies should be performed after pupillary dilation; otherwise, miosis may reduce sensitivity and produce artifactual depression of the visual field. If this is not discovered for a period of time, progressive glaucomatous damage may be suspected. Alternatively (although perhaps not as academically correct), all visual fields can be performed with a miotic pupil as long as the pupil is the same size each time.

The pupil should be dilated at least twice a year to prevent formation of posterior synechiae, to allow visualization of the optic disc and peripheral retina, and to determine the true field of vision.