Ординатура / Офтальмология / Английские материалы / Basic Sciences in Ophthalmology_Velayutham_2009

23 Parasympathomimetics,

Mydriatics and

Mydriolytics

PARASYMPATHOMIMETICS

Cholinergic agonist can be classified according to their mechanism of action as direct acting (activate cholinergic receptors at neuroeffector junctions— sphincter pupillae and ciliary body) and indirect acting (inhibiting cholinesterase inhibitors).

1.Direct acting — acetyl choline, methacholine, pilocarpine, carbachol.

2.Indirect acting

i)Reversible — Neostigmine, physostigmine, edrophonium, demecarium.

ii)Irreversible — Echothiophate.

Pilocarpine

It is a natural alkaloid plant Pilocarpus microphyllus. It is a direct acting cholinergic agonist with a dominant action at both peripheral and central muscarinic sites. The response of intraocular smooth muscle to pilocarpine is pupillary constriction, spasm of accommodation and decrease in intra ocular pressure.

Direct stimulation of longitudinal muscle of ciliary body which, in turn, causes the scleral spur to widen the intertrabecular spaces and increase the outflow thereby decreasing IOP. Pilocarpine appears to decrease IOP to the same degree (15% approximately) in both healthy and glaucomatous eyes (including the ocular hypertension patients). Darkly pigmented eyes demonstrate relative resistance to action of pilocarpine. It causes pupillary constriction and varying degree of accommodation. Long-term therapy alters the iris muscle activity and may cause permanent miosis resulting from loss of iris radial muscle tone and fibrosis of sphincter muscle.

Its onset of action is within 15 minutes and reaches maximum in 30 - 60 minutes.

Preparation: Topical 0.25% - 10% (Pilocarpine HCl, Pilocarpine nitrate). Applied 4 times a day. There is some additive action seen with PG analogues.

Ocusert: It is a type of sustained release system (membrane bound drug delivery system) which deliver at rates of 20 or 40 µg/ hr. Maximum effect is achieved in 2 hours after insertion of device and lasts for 7 days. Miosis with Ocusert is always less intense than solution. It provides less frequent, less intense, fewer fluctuations of vision. Disadvantage: difficulty with retention

Parasympathomimetics, Mydriatics and Mydriolytics 265

and unnoticed loss of device from the eye, rupture of the membrane resulting in excessive delivery and high cost.

Gel form - 4% Gel.- ½ inch ribbon applied once daily at bed time.

In acute angle closure with high pressure, the ischemic sphincter is unresponsive to pilocarpine. Topical beta blocker, apraclonidine or systemic agents are indicated initially to bring the pressure below 50 mmHg before pilocarpine is administered. The reduction in vitreous volume by a systemic hyperosmotic agent prevents forward movement of the lens caused by pilocarpine. Pilocarpine is also useful during laser iridotomy to facilitate stretching of iris.

Side Effects

Ocular

i)Accommodative spasm 2-3 hours after instillation especially in young patients.

ii)Miosis.

iii)Hastens development of cataract.

iv)Follicular conjunctivitis.

v)Pupillary block and secondary angle closure (forward displacement of irislens diaphragm).

vi)Allergic blepharoconjunctivitis.

vii)Band keratopathy.

viii)Conjunctival injection.

ix)Lid myokymia.

x)Retinal detachment ( anterior displacement of lensiris diaphragm, leading to vitreoretinal traction or tractional tears with or without posterior vitreous detachment). Pre-existing retinal lesion/ break should be prophylactically treated before prolonged therapy.

Systemic

i)Headache.

ii)Browache.

iii)Marked salivation.

iv)Profuse perspiration.

v)Nausea / vomiting.

vi)Bronchospasm / Pulmonary / edema.

vii)Systemic hypotension / bradycardia

viii)Muscle weakness.

ix)Abdominal pain / Diarrhea.

x)Respiratory paralysis.

Contraindications

-Presence of cataract ( especially nuclear sclerosis / posterior subcapsular cataract).

-Less than 40 years (accommodative spasm).

266Basic Sciences in Ophthalmology

-Neovascular glaucoma/ Uveitic glaucoma (breakdown of blood aqueous barrier).

-H/O retinal detachment.

-Asthma.

-Acute angle closure —further shallow anterior chamber-promotes peripheral anterior synchiae and angle closure.

Carbachol

It is a direct acting cholinergic agonist (both muscarinic and nicotinic). It is completely resistant to hydrolysis by cholinesterase.

Clinical use

It is available as chloride salt for topical application (0.75%, 1.5%, 2.25%, 3.0 %), and requires less frequent application( once in every 8 hours). It is available for intracameral use as 0.01% sterile balanced salt solution in 1.5 ml glass disposable vial and 0.5 ml is used by gentle irrigation.

Side effects

Systemic toxicity is uncommon. Ocular toxicity — miosis, transient conjunctival and ciliary injection and ciliary spasm. Allergic reactions are rare.

Echothiophate

It belongs to organophosphorus group and acts by inhibiting the cholinesterase enzyme. Onset of action is within 10 - 30 minutes and accompanying decrease of IOP is maximal after 24 hours and lasts for days or weeks. Ocular hypotensive effect has been attributed to an increase in facility of aqueous outflow similar to that produced by pilocarpine and carbachol.

Clinical use

Available as iodide salt in 0.03, 0.06, 0.125,and 0.25 %. It has a very short shelf life - so prepared fresh and supplied as a powder to be reconstituted with diluent containing buffer and preservative. After reconstitution, refrigerated solution is useful upto 6 months ( room temperature- 1 month).

Side effects

Ocular - cataract (characterized by anterior subcapsular opacities), greater risk of retinal detachment, reversible iris cyst.

Systemic - diarrhea, vomiting, respiratory paralysis, intestinal cramp, CNS symptoms, cardiac arrest, hypotension.

Nasolacrimal duct occlusion is mandatory after instillation in patients who are exposed to OPC fertilizers / insecticides to minimize side effects.

(OPC - Organo Phosphorous Compounds)

Contraindications

i)Phakic glaucoma.

ii)Patient with peripheral retinal disease.

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iii)Discontinue drug several weeks before elective surgical procedures in which succinyl choline is used.

iv)Should be discontinued 4 - 6 weeks before intra ocular surgery to minimize inflammatory effects and to diminish conjunctival and episcleral bleeding.

v)Avoid in uveitic glaucoma because of vasodilatation / aggravation of uveitis.

vi)Patients exposed to carbamates or OPC should be warned of additive effects and preventive measures such as wearing respiratory masks and frequent washing and clothing should be recommended.

MYDRIATICS

Phenylephrine

It is a synthetic sympathomimetic amine which is structurally similar to adrenaline which acts primarily on alpha 1 receptors with no effect on beta receptors.After topical application it contracts the iris dilator muscle and smooth muscle of conjunctival arterioles resulting in pupillary dilatation and blanching of conjunctiva. It acts on Muller's muscle of upper lid resulting in widening of palpebral fissure; it also reduces IOP in normal eyes and in eyes with open angle glaucoma.

It is available as 2.5 % and 10 % phenylephrine hydrochloride solution which is available as clear and colourless solution which is subject to oxidation on exposure to air, light or heat. In order to prolong its half life, sodium bisulphate an antioxidant, is added to the vehicle.

Clinical uses

Phenylephrine 2.5 % / 10 % on instillation results in maximum dilatation in 45 - 60 minutes and recovery occurs in 6-7 hours. Its cycloplegic action is less than that of Tropicamide. Corneal penetration of phenylephrine is increased by topical anaesthetics and loss of corneal integrity. Phenylephrine and tropicamide are mixed together for routine pupillary dilatation. Only 2.5 % solution is used in infants and elderly.

Other than mydriasis phenylephrine has several other uses like

1.Breaking posterior synechiae.

2.Used along with echothiophate to prevent formation of miotic cyst.

3.Used in Ptosis due to Horner's syndrome.

4.It may improve vision in cataract by mydriasis.

5.Used as diagnostic test in Horner's syndrome. Here 1% phenylephrine dilates the pupil with post ganglionic sympathetic denervation whereas, it may cause minimal or no dilatation in normal eyes. In central / preganglionic lesion pupil does not respond as there is no denervation hypersensitivity.

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Dapiprazole

Topical instillation produces miosis and reduces IOP. It blocks alpha receptors in the iris dilator muscle. It is available in the concentration of 0.12% to 1.5%. Miosis is concentration dependent and effect lasts for 6 hours. IOP can be reduced for upto 6 hours.

Clinical use

It is a safe miotic for reversing phenylephrine induced mydriaisis. 2 drops followed 5 minutes later by 2 drops causes nearly complete reversal of phenylephrine induced dilatation. Miosis begins 10 minutes after instillation and since it is due to alpha receptor blockage there is no shifting of iris-lens diaphragm and no subsequent shallowing of anterior chamber. As with Thymoxamine, iris color can affect the rate of pupillary constriction. It is slower with brown iris than green / blue iris.

It is also used for reversal of iatrogenically induced mydriasis produced by adrenergic agents or anticholinergic agents.

It is used as a weak miotic agent to reduce peripheral distortion after refractive surgery. Another theoretical use is in the treatment of pigment dispersion glaucoma, because alpha blocking effect causes miosis and iridoplegia. There is reduced shedding of pigment from the posterior iris causing less obstruction of aqueous outflow.

Drugs in the concentration of 0.25% - 0.5% are effective in angle closure glaucoma.

Side effects

1.It causes transient burning and conjunctival hyperaemia.

2.Corneal-edema, superficial punctate keratitis, chemosis, lid erythema, dry eyethese are due to effects of dilatation of conjunctival blood vessels.

3.Ptosis occurs due to alpha receptor blockade in Muller’s muscle.

Contraindications

Acute anterior uveitis, hypersensitivity to any drug component.

24

Cycloplegics

CYCLOPLEGICS

Atropine

It is a naturally occurring alkaloid isolated from plant Belladonna (Atropha Belladonna). It is an non-selective muscarinic antagonist. The pH of atropine is 9.8, so at physiological pH it is primarily ionized and the ionized state makes corneal penetration difficult. It is the most potent mydriatic and cycloplegic, commercially available as a sulphate derivative as 1% ointment and solution. Maximum mydriasis is achieved after 30 - 40 minutes and the drug effect lasts for 7 - 10 days and paralysis of accommodation (cycloplegia) is maximum after 60 - 180 minutes. The effect lasts for 7 - 12 days. In heavily pigmented eyes, atropine exhibits a relatively slow onset and prolonged duration of cycloplegic effect.

Clinical use

1.Refraction - especially in young actively accommodating children with suspected latent hyperopia or accommodative esotropia.

2.Uveitis

a)Relieves pain by relaxing ciliary muscle spasm.

b)Dilates pupil - prevents posterior synchiae.

c)Decreases the excessive permeability of inflammed vessels and thereby reduce cells and protein in the anterior chamber( flare).

3.Myopia - It has been suggested that topical ocular use of atropine may prevent or slow progression of myopia. By placing ciliary muscle at rest, accommodation is relaxed and the tension that produces elongation of eye may be reduced.

4.Amblyopia - as an alternative to direct occlusion in the treatment of amblyopia, referred to as 'penalization' for mild to moderate amblyopia.

Side effects

Ocular

-Direct irritation from drug preparation.

-Allergic contact dermatitis / allergic papillary conjunctivitis / allergic keratitis.

-Risk of angle closure glaucoma.

-Elevated IOP in open angle glaucoma patients (mechanism of pressure rise is not completely understood. Pressure elevation appears not to the degree of mydriasis attained but rather to a decrease in facility of aqueous outflow.

-Systemically administered atropine may also cause mydriasis and increase IOP in patients with open angle glaucoma.

Systemic side effects

-Dose dependent.

-Dry mouth, facial flushing, decreased sweating.

-CNS - convulsions, cognitive impairment, delirium.

-Patients with Down's syndrome have an cardio accelerated response to IV administration of atropine, mechanism of increased sensitivity to the

vagolytic action of atropine is not clear.

Treatment of atropine overdose - prevent dehydration and hyperpyrexia. Physostigmine is given in severe toxicity.

Contraindications

-Hypersensitivity.

-Tendency towards IOP elevation.

-Angle closure / open angle glaucoma.

-Child with Down's syndromehyperactive pupillary response to topical atropine.

Can be given in breast feeding women, but caution is to be exercised.

Homatropine

It is approximately 1/10 as potent as atropine. It is partially synthetic and partially from Solanaecea plants and commercially available as 2% and 5 % hydrobromide salt. Mydriatic effect is reached after 40 - 60 minutes of application and the effect lasts for 1 - 3 days. Paralysis of accommodation is reached after 30 - 60 minutes of application and the effect lasts for 1- 6 days. The amount of cycloplegia produced by Homatropine is less than that produced by comparable doses of atropine and cyclopentolate. Duration of cycloplegia obtained with Homatropine is longer than cyclopentolate.

Hyosine/Scopolamine

It is a non-selective antagonist derived from Hyoscyances niger and scopolia carniolia plant. It is commercially available as 0. 25% hydrobromide salt. The effect of mydriasis is maximally reached after 20-30 minutes and lasts for 3- 7 days, the effect of cycloplegia is reached maximum after 3060 minutes and last for 3- 7 days. There is higher incidence of idiosyncratic reactions to scopolamine than to other anti cholinergic agents, so it is not preferred as first choice. Use is reserved for patients who exhibit sensitivity to atropine.