Eye
Glaucoma: Acetylcholine receptor agonists
BNF 11.6, 12.3.5, and 7.4.1
Agonists at muscarinic acetylcholine receptors
These drugs have the same effects as stimulation of the parasympathetic nervous system. A degree of specificity can be achieved by local administration (e.g. eye drops).
Pilocarpine causes contraction of the iris (small pupil); this opens the trabeculae, lowering intraocular pressure.
Muscarinic agonists increase bronchial and salivary secretions.
Parasympathomimetics increase detrusor muscle (bladder) contraction and can relieve acute urinary retention.
Muscarinic agonists mimic the effect of the vagus nerve on the heart, producing bradycardia.
Potential uses
• Treatment of glaucoma.
• Treatment of open-angle and closed-angle glaucoma.
• To induce pupillary constriction preoperatively for surgery for glaucoma.
• For xerostomia (dry mouth) following radiotherapy to the head and neck or due to Sjögren’s syndrome.
• Previously used to relieve postoperative acute urinary retention. This requires intravenous administration, which can be hazardous; it has been superseded by catheterization.
Contraindications and cautions
• Glaucoma due to inflammation (acute iritis, anterior uveitis).
• Avoid systemic treatment (tablets) in pregnancy and breastfeeding, asthma/COPD (increased secretions and bronchospasm), and cardiovascular disease (bradycardia and hypotension).
• Reduce the dose if these drugs are given systemically to patients with severe renal or hepatic insufficiency.
How to use
Glaucoma
(see 
Teaching point: Treatment of glaucoma, p. [link] for guidance)
• Available as eye drops, ocular inserts, and gel.
• The eye drops work for only 2 hours, so require administration 3 times daily.
• Patients with a darkly pigmented iris may require a higher dose.
Most common and most serious adverse effects
• Headache and browache are the most commonly reported adverse effects. They are most common in young patients who have recently started treatment.
• Transient blurred vision, local stinging, and painful ciliary spasm are relatively common.
• Systemic parasympathetic adverse effects (nausea, diarrhoea, sweating, pallor, and bronchoconstriction) are rare with local ocular treatment.
• Systemic exposure can be minimized by pressing on the medial canthus for 1 minute during administration.
• Retinal detachment has occurred during treatment with these drugs; ensure that the fundus has been examined before using them.
Major drug-drug interactions
• Because they are usually given topically, these drugs do not usually cause drug interactions.
Patient information
• Warn about the possibility of stinging, pain, and transiently blurred vision with eye drops.
• Warn patients that they may have difficulty in forming skilled visual tasks. This is especially true of driving at night.
• Preservatives used in eye drops can form deposits on soft (hydrophilic) contact lenses. After instilling the eye drops, wait for 15 minutes before putting in soft contact lenses.
Prescribing information: Acetylcholine receptor agonists
Glaucoma
• Pilocarpine eye drops (concentrations range from 0.5–4%—check which is required). Apply up to 4 times daily.
Glaucoma: Carbonic anhydrase inhibitors
BNF 11.6, 4.8, and 2.2.7
Inhibitors of the enzyme carbonic anhydrase
Inhibition of carbonic anhydrase results in reduced formation of aqueous humour.
Inhibition of carbonic anhydrase inhibits bicarbonate reabsorption. This causes a diuresis of alkaline urine and an initial kaliuresis. The resulting acidosis prevents further potassium loss after a week or two.
Inhibition of carbonic anhydrase causes resetting of the central pH set point.
Potential uses
• Treatment of glaucoma.
• Licensed for use in patients who are beta-blocker resistant or in whom a beta-blocker is contraindicated.
• Unlicensed use as prophylaxis against mountain sickness (acetazolamide).
• Occasionally used as a second-line treatment for atypical absent, atonic, and tonic seizures (specialized use).
• No longer used for their diuretic action.
• There is evidence of toxicity due to systemic acetazolamide during pregnancy. There is no evidence to determine whether these drugs given as eye drops are safe or not. Only use if essential.
Contraindications and cautions
• Acetazolamide is a sulfonamide derivative; do not use in people with a history of severe allergy to sulfonamides (see
Sulfonamides, p. [link], for more information).• Do not use acetazolamide for long-term treatment; it carries a high risk of metabolic adverse effects.
• These drugs are excreted via the kidney. Avoid them in severe renal impairment, as they accumulate.
• Do not use a carbonic anhydrase inhibitor for chronic congestive angle-closure glaucoma.
• Avoid these drugs in pregnancy; there is no evidence that they are safe. The greatest risk is likely to be associated with systemic administration.
How to use
Glaucoma
(see Teaching point: Treatment of glaucoma, p. [link] for guidance)
• These drugs reduce intraocular pressure in open-angle glaucoma and secondary glaucoma. They are also used perioperatively in closed-angle glaucoma.
• Beta-blockers or a prostaglandin analogue are first-line treatments (see
Beta-adrenoceptor antagonists and Prostaglandins, p. [link] and p. [link]).• If these drugs are used, dorzolamide (eye drops) is preferred.
• Carbonic anhydrase inhibitors can be given alone if a beta-blocker is contraindicated. More commonly, they are added in patients who have an inadequate response to a beta-blocker.
• Acetazolamide is available as tablets and an intravenous injection. Avoid intramuscular administration, as this is painful.
Prophylaxis against mountain sickness (unlicensed indication)
• Suggested dose is acetazolamide 125 mg twice daily.
• Suggested regimen is to start treatment 24 hours before ascending to altitude (>8000 feet, 2500 metres), and to continue treatment for at least 5 days once at altitude.
• Acetazolamide is not a treatment for established mountain sickness; if symptoms occur, the individual should descend.
• Seek expert local advice before prescribing acetazolamide for this indication.
Most common and most serious adverse effects
• Carbonic anhydrase inhibitors (especially acetazolamide) can cause severe hypokalaemia and acidosis. Hypokalaemia is most common in the first weeks of treatment; tolerance then occurs because of the acidosis and the plasma potassium concentration normalizes.
• The acidosis can be corrected by giving potassium bicarbonate as effervescent tablets.
• Paraesthesia, especially of the lips, is relatively common.
• Other common adverse effects include drowsiness and fatigue, headache, flushing, and gastrointestinal upset.
• Acetazolamide is a sulfonamide derivative. It can cause sulfonamide-like adverse effects (see
Sulfonamides, p. [link]).• Stevens–Johnson syndrome is a rare adverse effect.
Major drug-drug interactions
• The hypokalaemia caused by these drugs can potentiate the actions of digoxin, causing toxicity.
• Co-administration with aspirin can worsen the acidosis.
• The excretion of flecainide, mexiletine, and quinidine is reduced in alkaline urine. Reduce the dose.
• The excretion of lithium is enhanced by treatment with carbonic anhydrase inhibitors. Measure the serum lithium concentration 1–2 weeks after starting treatment. Note that the sample should be taken exactly 12 hours after the previous dose of lithium.
• Ensure that the patient has been instructed about the correct use of the eye drops and that they know which eye requires treatment, if only one is affected.
Monitoring
Safety
• The metabolic effects of carbonic anhydrase inhibitors are most marked during the first 2 weeks of treatment. The frequency with which you should measure the patient’s electrolytes will depend on the clinical problem and concomitant medications (see earlier notes).
• Measure the arterial pH if the patient becomes unwell and you suspect acidosis.
Patient information
• Glaucoma—make sure the patient knows which eye requires treatment if only one eye is affected, or to treat both, and for how long.
• Altitude sickness—ensure that the patient knows that this is a prophylactic treatment, not a treatment for established altitude sickness.
Prescribing information: Carbonic anhydrase inhibitors
Glaucoma
• Acetazolamide 0.25–1.0 g daily in divided doses, by mouth or intravenous infusion:
• Tablets contain 250 mg of acetazolamide.
• Brinzolamide eye drops (10 mg/mL). Apply twice daily; increased to 3 times daily if necessary.
• Dorzolamide eye drops (2%). Apply 3 times daily if used alone. Apply twice daily if used in combination with a beta-blocker (a combination formulation with timolol is available).
Teaching Point: Treatment of glaucoma
Simple glaucoma, also called open-angle glaucoma, although asymptomatic, can lead to severe visual field impairment and eventually blindness. The cause is obstruction in the trabecular network, resulting in raised intraocular pressure. In turn this causes a gradual reduction in the blood supply to the optic nerve head. Reducing intraocular pressure prevents the progression of glaucoma. Most clinicians begin with medical therapy, proceed to laser therapy if necessary, and finally perform surgery if control remains inadequate.
Drug treatments for open-angle glaucoma act by reducing aqueous humour production or by increasing aqueous humour outflow. They are given topically as eye drops, providing good efficacy with a low incidence of systemic adverse effects.
Drugs used for the chronic treatment of simple (open-angle) glaucoma
Mechanism of action | Drug class | Examples |
|---|---|---|
Reduced aqueous humour production | Beta-blockers | Betaxolol, carteolol, levobunolol, metipranolol, timolol |
Alpha-adrenoceptor agonists | Brimonidine, dipivefrine | |
Carbonic anhydrase inhibitors | Acetazolamide (oral), brinzolamide, dorzolamide | |
Increased aqueous humour outflow | Prostaglandin derivatives | Bimatoprost, latanoprost, travoprost |
Alpha-adrenoceptor agonists | Brimonidine, dipivefrine | |
Acetylcholine receptor agonists | Carbachol, pilocarpine |
See individual topics for more information.
The other drug treatments are usually added to first-line treatment for patients who have an inadequate response. They are not considered first-line treatments because of limited efficacy (carbonic anhydrase inhibitors) or a high incidence of local adverse effects (acetylcholine receptor antagonists, alpha-adrenoceptor agonists). The goal of therapy is usually to reduce the intraocular pressure to below 21 mmHg.
Acute closed-angle glaucoma results from complete blockage of flow of aqueous humour into the anterior chamber of the eye; it is a medical emergency (seek specialist advice). Osmotic agents (e.g. mannitol, glycerine, urea), which act by shrinking vitreous humour volume and are given systemically, are sometimes used for short periods for acute closed-angle glaucoma, or before incisional surgery.
Glaucoma: Drugs for macular degeneration
Potential uses
• These are very specialized drugs and may only be given under the direction of a specialist.
• NICE offers the following advice for the use of verteporfin:
• Photodynamic therapy is recommended for wet age-related macular degeneration with a confirmed diagnosis of classic (no occult) subfoveal choroidal neovascularization and best-corrected visual acuity of 6/60 or better.
• Photodynamic therapy is not recommended for wet age-related macular degeneration with predominantly classic but partly occult subfoveal choroidal neovascularization except in clinical studies.
• Ranibizumab is more clinically effective than pegaptanib in improving net visual acuity.
Contraindications and cautions
• There is little experience of the use of these drugs in pregnancy. Systemic exposure is low but the risk is unknown.
• Verteporfin is contraindicated in severe liver disease and porphyria.
How to use
• Pegaptanib and ranibizumab are given by intravitreal injection.
• They are given as a course of injections over 3 months. Patients are then followed monthly and additional treatments given as appropriate.
• Verteporfin is given by intravenous infusion. It is activated by local irradiation using non-thermal red light to produce cytotoxic derivatives.
• Following initial treatment patients are reviewed at 3 monthly intervals and additional treatments given if there is evidence of recurrence.
• Patients who experience a severe decrease of vision (equivalent to 4 lines or more) within 1 week after treatment should not be retreated, at least until their vision has completely recovered to pretreatment level and the potential benefits and risks of subsequent treatment have been carefully considered by the treating physician.
Most common and most serious adverse effects
• The most common adverse effects of ranibizumab and pegaptanib are consistent with the route of delivery and are generally rare:
• Endophthalmitis, intraocular inflammation, retinal detachment and tear, and iatrogenic traumatic cataract.
• Increases in intraocular pressure have been seen within 1 hour of injection.
• For verteporfin, abnormal (e.g. blurry or hazy) vision is common following treatment and is likely to resolve. More severe loss of vision occurs rarely, in which case treatment should be reconsidered.
• More serious effects are rare: retinal detachment, subretinal haemorrhage, vitreous haemorrhage.
• Patients who receive verteporfin will have significant photosensitivity to sunlight or bright indoor lighting for 48 hours after the infusion.
• Because verteporfin is given systemically it can cause systemic hypersensitivity reactions, but these are rare.
Major drug-drug interactions
• Because of their mechanism of action these drugs are unlikely to cause drug–drug interactions.
Monitoring
• Monitor intraocular pressure and for signs of ocular infection following injection of pegaptanib and ranibizumab.
Patient information
• Patients who receive verteporfin will be photosensitive for 48 hours after the infusion. During this time they should avoid direct sunlight or bright indoor light such as tanning salons, bright halogen lighting, or high-power lighting in surgery operating rooms or dental surgeries. If patients have to go outdoors they should use protective clothing and dark sunglasses. UV sunscreens are not effective in protecting against photosensitivity reactions.
• Ambient indoor light is safe.