2012 Mydriatics and Cycloplegics for attendees.pptx

MYDRIATICS, CYCLOPLEGICS, ANDMYDRIOLYTICSAlison Clode, DVM, DACVONorth Carolina State UniversityCollege of Veterinary MedicineRaleigh, North Carolina

OVERVIEW• MYDRIATICS• Sympathomimetics – NOT cycloplegics• Epinephrine• Phenylephrine• Homatropine• Cocaine• MYDRIOLYTICS• Dapiprazole• Parasympatholytics – cycloplegics• Tropicamide• Atropine• Homatropoine• Cyclopentolate• scopalamine

SYMPATHETIC INNERVATION OF THE IRIS• Iris dilator muscle• α receptors (primarily α 1 )• NE = neurotransmitter• Stimulation à contraction of irisdilator à dilation

SYMPATHOMIMETICS• Adrenergic agonists (α- and β-agonists)• Direct-acting: mimic NE• Phenylephrine• Epinephrine• Indirect-acting:• Hydroxyamphetamine (stimulatesrelease of NE from nerve terminal)• Cocaine (prevents reuptake of NE)• No cycloplegia• Generally used in combo

PHENYLEPHRINE IN OPHTHALMOLOGY• Direct-acting α 1 -agonist• 2.5% or 10% solution• Beyond 5%, higher concentration does notincrease degree or duration of mydriasis• Lower efficacy in eyes with darkly pigmentedirides *• Efficacy increased with use of topicalanesthetic• Loses stability if exposed to light, heat, or air (notnecessarily indicated by change in color of solution)• Uses:• Preoperative mydriasis (topical or intracameral)• Breakdown posterior synechiae• Ocular surface vasoconstriction• Diagnosis of Horner’s* Lam PTH, et al., Clin Experiment Ophthalmol 2003

PHENYLEPHRINE• Side effects• Discomfort upon instillation• Exfoliation of iridal pigment• Keratitis• Rebound miosis and conjunctivalcongestion• Systemic hypertension,tachycardia, reflex bradycardia• Pulmonary edema *• Contraindications **• Cardiac disease, hypertension, insulindependentdiabetes, arterioslcerosis(10% formulation)• Only one drop of 10% per eye per hour• Concurrent use of MAO inhibitors,tricyclic antidepressants, others…• Concurrent use in atropinized patients(tachycardia and hypertension)• Prolonged or sustained release routesnot recommended• Only use 2.5% in infants and elderlypatients* Venkatakrishnan J, et al., Eur J Ophthalmol 2011** Portello JK. Clin Ocular Pharm 5 th Edition, 2008

PHENYLEPHRINE (10%) IN ANIMALSDogs Cats Horses CowsOverall efficacy Fair Ineffective alone Ineffective alone Ineffective aloneTime to maximalmydriasisLonger than othermydriatics aloneNo change in time tomaximal mydriasis ofother drugs when incomboShortens time tomaximal mydriasis ofatropine 1% when incomboIncreases time tomaximal mydriasis ofatropine 1% when incomboDuration ofmydriasisShorter than othermydriatics alone(except 1%tropicamide)Increases duration ofmydriasis of otherdrugs when in comboDecreases durationof mydriasis ofatropine 1% when incomboNo change induration of mydriasisof atropine 1% whenin comboSide effectsSig increase BPSig decrease HR* Herring IP. Vet Ophthalmol 4 th ed, 2007

EPINEPHRINE• Direct-acting α- and β- receptor agonist• Poor intraocular penetration after topicaladministration• May augment mydriasis relative to α-agonistmonotherapy *• Uses:• Intraoperative mydriasis and hemostasis• 1:10,000 (intracameral bolus)• 1:1,000,000 (irrigation fluids)• Must be preservative- and bisulfate-free* Janbaz CC, et al., Acta Ophthlamol 2011

EPINEPHRINE IN ANIMALSDogsCatsOverall efficacy 0.1% ineffective Ineffective alone (2%)Time to maximal dilation1% and 2% produce maximal dilationin approximately two times longerthan 0.5% tropicamide2% “maximal” dilation is less maximalthan other agentsDuration of dilation6 to 9 hours (shorter thantropicamide)* Herring IP. Vet Ophthalmol 4 th ed, 2007

HYDROXYAMPHETAMINE• Indirect-acting adrenergic agonist• Releases NE from adrenergic nerve terminals• May also directly stimulate α- and β- adrenergicreceptors• May be more readily counteracted by miotics• Similar efficacy to phenylephrine• Not affected by iris color• Not affected by topical anesthetic• Increased efficacy in combination• Uses:• Mydriatic in humans• Lesion localization in Horner’s syndrome• Side effects:• Minimal risk of IOP elevation• Increase blood pressure• Tachyphylaxis

COCAINE• Indirect-acting adrenergic agonist• Prevents reuptake of NE at synapticjunction• Anesthetic activity• Uses:• (Mydriasis)• (Local anesthesia)• (Vasoconstriction)• Confirmation of Horner’s diagnosis• Side effects:• CNS stimulation (systemic absorption israpid with ocular administration)• Significant corneal epithelial damage

HORNER’S SYNDROME• Horner’s syndrome = unopposed parasympathetic tone• Miosis• Ptosis• Enophthalmos• Elevated third eyelid• Cutaneous hyperthermia (especially in ruminants)• Dry ipsilateral nostril (especially in ruminants)• Decreased sweating (except in horses)• Increased sweating (only in horses)

HORNER’S SYNDROME• First order (central) lesion =hypothalamus to T1-3• Second order (preganglionic) lesion =spinal cord to sympathetic trunk tocranial cervical ganglion• Third order (postganglionic) lesion =cranial cervical ganglion to eye

HORNER’S SYNDROMEEFFERENT SYMPATHETIC LESIONLOCALIZATIONDegree of Dilation4% cocaine Inhibition of NE reuptakeby postganglionic neuronMechanism of action Central Lesion PreganglionicLesionPostganglionicLesionimpaired absent absent1%hydroxyamphetamineStimulation of NE releasefrom postglanglionicneuronnormal mydriasis normal mydriasis incomplete/absent1% phenylephrine Direct stimulation ofreceptors on effector cellabsent absent mydriasisCentral Pre-G Post-G EC

PARASYMPATHETIC INNERVATION OF THE EYE• Muscarinic receptors• Multiple subtypes• Iris• Ciliary body• Some nicotinic receptors??• Inhibition à mydriasis + cycloplegia•• Parasympatholytic agents• Atropine• Scopolamine• Homatropine• Cyclopentolate• Tropicamidewww.vrp.com

PARASYMPATHOLYTICS – DETAILS• AKA: anticholinergics, antimuscarinics• Competitively bind muscarinic receptors in iris and CB• Mydriasis – diagnostic and therapeutic• Cycloplegia –• Treat myopia: relaxation of CB relaxes accommodation, reduces tension that leads to elongationof eye and resultant myopia• Treat amblyopia: visual blur in good eye forces ‘lazy’ eye to pick up the slack• Refraction:• Multiple muscarinic receptor subtypes in iris sphincter and CB in humans• 60-75% M3 (CB, iris sphincter)• 5-10% M2, M4 (CB, iris sphincter)• 7% M1 (CP, iris sphincter)• 5% M5 (iris sphincter)

ATROPINE• Nonselective muscarinic antagonist• Comparatively poor penetration• Stability is pH and temperature dependent• pKa 9.8, primarily ionized at physiologic pH• Most potent cycloplegic availableIridalbinding leads to depot• Rapid onset, prolonged duration• Uses:• Refraction• Treatment of• Uveitis• Myopia• Amblyopia

ATROPINE• Side effects• Local irritation• Increase IOP• Angle-closure glaucoma• Open-angle glaucoma (unpredictable)• Rapid systemic uptake:• Systemic peripheral effects predominate over central effects• Decreased salivation, facial flushing, decreased sweating, urinary retention, excitement,…• Worse in young and elderly patients (convulsions)• Two drops of 1% contain 1 mg of atropine

ATROPINE IN ANIMALSTime to maximalmydriasisDogs Cats Horses Cows1 hourMore rapid with 4%(versus 1%)1 hourMore rapid with 4%(versus 1%)10 hoursMore rapid with 3%(versus 1%)< 1 hourSlower with 3%(versus 1%)Duration of maximalmydriasisEffect on IOPEffect on STT Significant reduction *4 – 5 days 2.5 – 6 days 5.5 – 14 days *** 1 – 7 daysSignificant increase(4 mmHg) **None ****Decreased IOP *****Other Salivation Salivation Significantlydecreased GI motility******* Hollingsworth S, et al., J Am Vet Med Assoc 1992** Stadtbaumer K, et al., Vet Ophthalmol 2006*** Davis J, et al., Vet Ophthalmol 2003**** Mughannam A, et al., Vet Ophthalmol 1999***** Herring I, et al., Vet Ophthalmol 2000****** Williams M, et al., Vet Ophthalmol 2000

HOMATROPINE• Nonselective muscarinic antagonist• Partially synthetic, partially naturally-derived• 1/10 potency of atropine• pKa 9.9, primarily ionized at physiologic pH, therefore poorly diffusable• Relatively weak but prolonged mydriatic and cycloplegic effect• Uses:• Treatment of anterior uveitis• Side effects:• As for atropine

SCOPOLAMINE (HYOSCINE)• Nonselective muscarinic antagonist• Comparable to atropine• Highly potent• Shorter duration of action• Greater incidence of idiosyncratic reactions• Uses:• Cycloplegic refraction• Anterior uveitis• Side effects:• CNS toxicity (acute psychosis)

SCOPOLAMINE IN ANIMALSTime to maximalmydriasisDuration of maximalmydriasisDogs Horses Cows< 1 hour 4 hours 2 hours4 – 5 days 4.5 days 6 daysOther Comparable to atropine 4% More rapid but shorterduration than atropineComparable to 3% atropineSlower but longer durationthan 1% atropine* Hering IP. Vet Ophthallmol 4 th ed, 2007

CYCLOPENTOLATE• Nonselective muscarinic antagonist• pKa 8.4, primarily ionized at physiologic pH, therefore poorly diffusable• Effects greatly influenced by iridal pigmentation• Effects comparable to atropine but shorter• Uses:• Cycloplegic refraction (agent of choice in most)• Anterior uveitis• Intraoperative mydriasis• Side effects:• Irritation• Corneal epithelial toxicity• IOP elevation• Greater CNS effects than atropine• Drowsiness, ataxia, slurred speech• Worse in young, neurologically impaired

CYCLOPENTOLATE IN ANIMALSDogs Cats Horses CowsTime to maximalmydriasisDuration of maximalmydriasisOther< 1 hour < 1 hour 12 hours 12 hours2.5 days 3 – 4.5 days 4 – 5 days 2 – 4 daysOnset comparable toatropineDuration shorter thanatropine1% cyclopentolatecomparable to 1%atropine1% and 2%cyclopentolatecomparable to 1%atropineOnset significantlylonger than othermydriaticsIntermediate durationHerring IP. Vet Ophthalmol 4 th ed, 2007

TROPICAMIDE• Nonselective muscarinic antagonist, possibly more selective for M4• pKa 5.27, 2.3% ionized at physiologic pH, therefore best intraocular penetration of mydriatic-cycloplegics• Rapid onset, short duration• Cycloplegic action is concentration-dependent (mydriatic effect is not)• Mydriatic effects less influenced by iris pigmentation• Duration prolonged by prior application of topical anesthetic• Uses:• Diagnostic mydriasis• Combination with hydroxyamphetamine ideal in humans for minimal effect on accommodation• Side effects:• Discomfort• IOP increase• Low risk for systemic side effects because even though absorbed, low affinity for systemic M receptors

TROPICAMIDE IN ANIMALSDogs Cats Horses CowsTime to maximalmydriasis< 1 hour(1%)< 1 hour(0.5% or 1%)1 hour(0.5% or 1%)3 hours(0.5% or 1%)Duration of maximalmydriasisEffect on IOP

MYDRIOLYTICS• Goal = safe and effective reversal of mydriatics• Option = cholinergic agonist (i.e., pilocarpine) to reverse adrenergic agonist (i.e.,phenylephrine)• Drawback = cholinergic agonist increases risk of accommodative CB spasm, angleclosureglaucoma, and pupillary block• Drawback = stimulation of dilator and constrictor simultaneously leads to shallow ACand risk of pupillary block (in humans)

DAPIPRAZOLE• Reverses mydriasis by blocking iris dilator α receptors• Produces miosis and decreases IOP• Concentration-dependent miosis, within 10 minutes, duration up to 6 hours *• More rapid in eyes with lighter-colored irises• IOP reduced up to 6 hours• Partially reverses cycloplegia• Use:• Reversal of phenylephrine-, homatropine-, or tropicamide-induced mydriasis• 2 drops, then 2 drops 5 minutes later, although 1 drop may be sufficient ** Hogan TS, et al., J Ocul Pharm Ther 1997

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