Ophthalmic Pharmacology

Richard Alan Lewis M.D., M.S., PHARMACOLOGY FOPS PHARMACOKINETICS OF Professor, Departments of Ophthalmology, • The study of the absorption, OPHTHALMIC Medicine, Pediatrics, and Molecular distribution, metabolism, AGENTS and Human Genetics and excretion of a drug or and the National School of Tropical agent Introduction and Review Medicine Houston, Texas

PHARMACOKINETICS Factors Affecting Drug Penetration Factors Affecting Drug Penetration into Ocular Tissues • A drug can be delivered to ocular tissue: into Ocular Tissues – Locally: • Drug concentration and solubility: The higher the concentration the better the penetration, • Surfactants: The preservatives in ocular • Eye drop but limited by reflex tearing. preparations alter cell membrane in the cornea • Ointment and increase drug permeability, e.g., • Viscosity: Addition of methylcellulose and benzalkonium and thiomersal • Periocular injection polyvinyl alcohol increases drug penetration by • pH: The normal tear pH is 7.4; if the drug pH is • Intraocular injection increasing the contact time with the cornea and altering corneal epithelium. much different, it will cause reflex tearing. – Systemically: • Lipid solubility: Because of the lipid rich • Drug tonicity: When an alkaloid drug is put in • Orally environment of the epithelial cell membranes, relatively alkaloid medium, the proportion of the uncharged form will increase, thus more • IM the higher lipid solubility, the more the penetration. • IV penetration.

FLUORESCEIN FLUORESCEIN Chemistry Dosage

● C20H1205, brown crystal ● Adults: 500-750 mg IV ● M.W. 322.3 e.g., 3 cc 25% solution ● Peak absorption 485-500 nm. 5 cc 10% solution ● Peak emission 520-530 nm. ● Children: 1.5-2.5 mg/kg IV

Richard Alan Lewis, M.D., M.S. Nov 2013 1 Ophthalmic Pharmacology

Needle Diameter Ideal Flow through a small FLUORESCEIN tube varies with the 4th power Needle Outer Diameter Inner Diameter Side Effects of the radius (r4) Gauge mm mm Gauge r r4 ● Skin staining: 100% (6-12 hours) 18 1.270 0.838 20 0.3015 ~0.00826 ● Aqueous staining: 100% (8-24 hours) 20 0.908 0.603 ● Urine staining: 100% (24-36 hours) 21 0.819 0.514 21 0.257 ~0.00436 23 0.641 0.337 0.00826/0.00436 = 1.895 25 0.514 0.260

FLUORESCEIN ANGIOGRAPHY FLUORESCEIN ANGIOGRAPHY FLUORESCEIN Adverse Reactions Adverse Reactions Adverse Reactions Do not change with: ● Local Effects Reported with: - Extravascular - Informed consent - Intravenous ● Topical phenylephrine - NPO state - Intra-arterial ● Venipuncture - Premedication ● Systemic Effects ● Fundus photography - Mild - Dye concentration - Moderate - Severe

FLUORESCEIN FLUORESCEIN FLUORESCEIN Extravasation Extravasation Intravenous ● Intense local pain ● Think prevention ● Dull ache, ipsilateral extremity ● Warm, wet compress, - Duration: 20 - 45 minutes Chemical thrombophlebitis 30 minutes Q.I.D. - Management: self-limited Duration: 3-10 days ● Examine site at 24°, 48° reassurance Management: self-limited cold pack ● If avascular, refer to plastic ● Dermal necrosis surgeon

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FLUORESCEIN FLUORESCEIN ANGIOGRAPHY FLUORESCEIN ANGIOGRAPHY Intra-arterial Mild Adverse Reactions Mild Adverse Reactions

● Immediate INTENSE stain of ● Nausea and vomiting < 5% ● Transient distal extremity ● Extravasation ● Rapid and complete ● PAIN! ● Sneezing resolution - Duration: 1-24 hours ● Pruritus ● No treatment required - Management: Cold, Analgesia

FLUORESCEIN ANGIOGRAPHY FLUORESCEIN ANGIOGRAPHY FLUORESCEIN ANGIOGRAPHY Moderate Adverse Reactions Moderate Adverse Reactions Severe Adverse Reactions

● Urticaria (1.2%) ● Transient • Prolonged ● Syncope (0.3%) ● Medical therapy required • Intense therapy required ● ● Complete, if gradual, Thrombophlebitis resolution with no sequelae ● Local tissue necrosis • Threat to patient safety ● Nerve palsy • Variable recovery Overall: 1.6%

FLUORESCEIN ANGIOGRAPHY FLUORESCEIN FLUORESCEIN ANGIOGRAPHY Severe Adverse Reactions Toxicity Death ● Respiratory (1:3,800) - Laryngeal stridor, edema - Bronchospasm ● Phototoxicity to skin - Anaphylaxis ● Cardiovascular (1:5,300) (Premature, jaundiced infant, Death rate: 1:220,000 - Circulatory shock - Myocardial infarction, arrest UV therapy: J Peds: 1985; 107) ● Neurological (1:13,900) - Seizure (Overall: 1:1,900)

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FLUORESCEIN FLUORESCEIN FLUORESCEIN Precautions Precautions Prophylaxis: Nausea • Not approved for use in pregnancy • No evidence for teratogenicity, • Does NOT cross-react with embryocidicity iodinated contrast dyes Metoclopramide HCl • Not approved for use in children • Avoid patients with prior • Renal insufficiency prolongs serious reactions to fluorescein (Reglan) 20 mg IV elimination • Avoid historically risky patients • Diabetics should not confuse color 5 min before F/A with reactions for glucose

ADVERSE REACTIONS FLUORESCEIN ANGIOGRAPHY MANAGEMENT Management Screening

● Trained personnel ● Consent form, especially children ● Emergency equipment ● History of prior allergies, asthma - Airway (oral, AMBU) Not routinely conducted - A negative history is no - O2 (mask, prongs cylinder) guarantee of impunity - Parenteral fluids on pregnant subjects ● History of recent change in angina, (I.V. stand, fluids, sets) uncontrolled hypertension, - B/P cuff cardiac arrhythmia - Drugs

DRUGS for ANAPHYLACTOID FLUORESCEIN ANGIOGRAPHY Most serious reactions REACTIONS occur within minutes of Diphenhydramine (Benadryl) 25-50 mg p.o., i.m., i.v. injection. Severe Informed Consent Tripelennamine (Pyribenzamine) anaphylactoid reactions 25-50 mg p.o. may develop as late as Fexofenadine (Allegra) one hour after injection. 180 mg. p.o.

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INDOCYANINE GREEN INDOCYANINE GREEN Therefore, if there is Description Formulation any suspicion, the Tricarbocyanine dye with •Contains 5% Nal patient should wait peak spectral •pH 5.5 - 6.5 and be absorption at 800-810 nm, •Unstable in observed. emission at 830-840 nm, in blood. aqueous solution

INDOCYANINE GREEN INDOCYANINE GREEN INDOCYANINE GREEN Chemistry Indications Dosage

● Ophthalmic angiography • 0.5 mg/kg (<2 mg/kg) •C H N NaO S 43 47 2 6 2 ● Cardiac output • Adults: 40 mg in 2 ml •M.W. 774.96 ● Hepatic function, blood flow solvent with 5 cc N.S. flush

INDOCYANINE GREEN INDOCYANINE GREEN INDOCYANINE GREEN Pharmacology Contraindications Adverse Reactions • Anaphylaxis, urticaria ● Bound to plasma proteins ● Diluent contains Nal reported, without (albumin, 95%) ● Avoid allergy to iodides ● Hepatic secretion to bile allergy to iodides • 2 deaths reported

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Iodine/Iodide Allergy INDOCYANINE GREEN VERTEPORFIN Pregnancy • NO objective evidence • Trade Name: Visudyne demonstrates cross- • Safety in pregnancy, • Formula: C H N O nursing not established 41 42 4 8 reactivity between • Isomers of benzoporphorin allergy to shellfish and • No animal embryocidicity, teratogenicity studies • Molecular Weight: 718.8 iodine sensitivity!

J. Emerg. Med. 2010: 39 (5): 701-707

VERTEPORFIN VERTEPORFIN VERTEPORFIN Indication Metabolism Adverse Reactions

● Skeletal: back pain, 2-15% Light-activated drug for • Liver excretion into ● Skin: photosensitivity (5 days) photodynamic therapy of bile, feces ● GI: nausea various subretinal • Half-life 5-6 hours ● CV: syncope, hypotension, neovascularizations bradycardia

VERTEPORFIN VERTEPORFIN VERTEPORFIN Contraindications Other Cautions Precautions

• Photosensitization, • Pregnancy class C • Porphyria ~ 5 days • Liver dysfunction • Rats: anophthalmia • Avoid extravasation • Known hypersensitivity • Avoid nursing • Matched laser 689 nm.

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VERTEPORFIN PEGAPTANIB Cautions PEGAPTANIB Macugen • Trade name: Macugen ● Avoid other photosensitizers • Mechanism of Action: (thiazides, sulfas, antidiabetics • Formula:

● 83 sec. treatment, exactly 15 C294H342F13N107Na28O188P28 Selective antagonist of min. after 10 min. infusion [C2H4O]n, where n = ~900 Vascular Endothelial • Molecular Wt: ~50 kD Growth Factor (VEGF)

PEGAPTANIB PEGAPTANIB PEGAPTANIB Macugen Macugen Macugen • Mechanism: An aptamer, • Dose: 0.3 mg intravitreous • Indication: ‘Wet’ macular modified RNA oligonucleotide, degeneration that adopts the 3-dimensional • Frequency: Every 6 weeks conformation to bind to • Half-life: ~ 10 days • Contraindications: ocular infections; extracellular VEGF165 inhibiting • Metabolism: Degraded by its binding to VEGF receptors. nucleases known sensitivity

PEGAPTANIB PEGAPTANIB RANIBIZUMAB Macugen-Safety Macugen • Trade name: Lucentis • Pregnancy: Not studied • Supplied: in a prefilled, • Formula: recombinant • Nursing: Not studied single use, glass syringe, humanized IgG1 κ • Children: Not studied with 0.3 mg Macugen, monoclonal antibody • Safety or efficacy not packaged with 30 G x ½” fragment proven beyond 2 years BD needle • Molecular wt.: 48 kD

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RANIBIZUMAB RANIBIZUMAB Lucentis Lucentis • Indication: “Wet” • Dose: 0.5 mg intravitreous macular degeneration • Frequency: q month x 4, • Contraindications: then q 3 months sensitivity; active • Half-life: 7 – 12 days ocular infections

RANIBIZUMAB RANIBIZUMAB RANIBIZUMAB Lucentis Lucentis Lucentis • Mechanism of action: • Cautions: • Side Effects: Binds to all receptor Transient elevation of subconjunctival binding sites of VEGF-A, intraocular pressure; hemorrhage, pain, preventing interaction of endophthalmitis; v. floaters, elevated IOP, VEGF with its receptors. thromboembolic events (<4%) intraocular inflammation

BEVACIZUMAB BEVACIZUMAB BEVACIZUMAB Avastin Avastin • Trade name: Avastin • Formula: complete • Dose: 1.25 – 2.5 mg. • Metabolism: ? Nucleases humanized IgG intravitreous monoclonal antibody • Frequency: every 4 weeks • Excretion: ? • Molecular wt.: 149 kD • Half-life: 20 days (11-50 d)

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BEVACIZUMAB BEVACIZUMAB BEVACIZUMAB Avastin Avastin Avastin • Indications: OFF LABEL: • Side Effects: risk of • Mechanism of Action: “Wet” macular bleeding Binds competitively to degeneration; CNV, NVG, VEGF receptors blocking • Cost: among the most PDR, ROP, C/BRVO, VEGF’s activity expensive drugs in the diabetic macular edema world, widely marketed!

EYLEA: Aflibercept (EYLEA) Mechanism EYLEA Potential Risks • Failure to control CNV • Soluble Schedule “decoy- • Endophthalmitis receptor” of • Intravitreous injection • Retinal Detachment both VEGF-A and Placental • Q 4 weeks x 3; then • Transient elevation of IOP Growth Factor • Q 8 weeks for ~1 year • ?Thromboembolism? (PlGF)

Aflibercept (EYLEA) Routes of Administration: Routes of Administration: • Pregnancy Class C Topical Topical - Drops • Most ocular medications are • Nursing mothers? delivered topically - maximizes Factors affecting absorption: • Pediatric population? anterior segment concentrations • Drug concentration (limited by and minimizes systemic toxicity; tonicity) and solubility (aqueous • Mutagenesis? • Drug gradient from tear reservoir to solution vs. suspension) • Carcinogenesis? corneal and conjunctival epithelium • Viscosity (increased contact time) forces passive absorption.

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Routes of Administration: Routes of Administration: Routes of Administration: Topical - Drops Topical - Drops Topical - Drops • Lipid solubility: lipid-rich epithelial Surfactants: preservatives are • Reflex tearing: Ocular irritation and secondary tearing wash out cell membrane vs. water-rich surface-active agents that alter stroma of the drug reservoir in the tears cell membranes in the cornea • pH and ionic charge: Most eye and reduce contact time with and bacteria, increasing drug drops are weak bases, existing in cornea, especially when drops both charged and uncharged permeability and preventing are not isotonic, have non- forms, enhancing absorption. bacterial contamination. physiological pH, or contain irritants.

Routes of Administration: Routes of Administration: Routes of Administration: Topical - Drops Topical - Ungt. Topical - Ungt. • Tissue binding: proteins in the tears • Increases contact time of drug with ocular and on the ocular surface may surface; • Only drugs with high lipid bind drug making the drug • Mixture of petrolatum and mineral oil; solubility and some water unavailable or creating a slow • Water-soluble drugs are insolvent in the ointment and are present as solubility will get into release reservoir. This may affect microcrystals. both tears and corneal peak effect, duration of action, • The surface microcrystals dissolve in the and delayed local toxicity. tears; the rest are trapped until the epithelium. ointment melts.

Routes of Administration: Routes of Administration: Routes of Administration: Peri-ocular Injections Intra-ocular Injections Systemic • Subconjunctival, subTenon’s, • Allow instant drug delivery at • Extent of drug bound to plasma proteins peribulbar, and retrobulbar; therapeutic concentrations to also effects access of drug into eye - only • Allow drugs to bypass the target site; unbound form can pass blood-ocular barrier. conjunctival/corneal epithelial • Intracameral, e.g., antibiotics, barrier and reach therapeutic levels • Bolus administration exceeds the viscoelastics, miochol; capacity of a drug to bind to plasma in the posterior segment; • Intravitreous, e.g., proteins and so leads to higher • e.g., anesthetic agents, steroids triamcinolone, Avastin, Lucentis intraocular drug levels than with slow IV drip

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Routes of Administration: Sustained Release Devices MYDRIASIS Sustained Release • These devices deliver an adequate supply of medication at a steady-state level • Devices available for • e.g., – Ocusert delivering delivery of steroids, pilocarpine [G., μυδριασις] – Timoptic XE delivering gancyclovir within timolol – Ganciclovir sustained- Dilation of the pupil vitreous cavity release intraocular device – Collagen shields

Routes of Administration: Topical - Drops Dilating Agents • One drop = 50 µl • Dependent on iris • Volume of conjunctival cul-de-sac 7-10 µl pigmentation • To increase drop absorption: - wait 5-10 minutes between drops • Mechanism: Inhibition - compress lacrimal sac of iris constrictor and - keep lids closed for 5 minutes after ciliary muscles instillation

CYCLOPLEGIC AGENTS MYDRIASIS CYCLOPLEGIA • Atropine (0.5%, 1%) • Blockage of cholinergic [G. κυκλος = circle, • Homatropine (1%, 5%) stimulation to sphincter + πληγη = blow, stroke] • Scopolamine (Hyoscine) ms. of iris, ciliary body Paralysis of • Cyclopentolate (0.5, 1, 2%) • Stimulation of iris dilator accommodation • Tropicamide (0.5, 1%) ms. (ciliary ms.)

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Parasympatholytic Drugs CYCLOPENTOLATE HCl CYCLOPENTOLATE HCl Chemistry Mydriasis Cycloplegia Duration • Available as ATROPINE 30 min. 60 min. 10 – 14 days - Cyclogyl • Anticholinergic, HOMATROPINE 10 – 30 min. 30 – 90 min. 2 – 4 days - Ak-Pentolate, inter alia • Parasympatholytic • 0.5%, 1.0%, 2.0% coll. SCOPOLAMINE 40 min. 40 min. 2 – 6 days

CYCLO- 20 – 30 min. 15 – 45 min. 12 – 24 hrs PENTOLATE

CYCLOPENTOLATE HCl CYCLOPENTOLATE HCl CYCLOPENTOLATE HCl Action Toxicity Side Effects • Mydriasis • Facial flushing • Irritation with - Onset: 15 – 30 minutes • Wandering, irrelevant speech concentration - Duration: 24 hours • Disorientation, hallucinations • ↑ IOP in open angle • Cycloplegia • Psychosis glaucoma - Onset: 15 – 45 minutes • Ataxia, restlessness • Angle closure glaucoma - Duration: 24 hours • Grand mal seizures

CYCLOPENTOLATE HCl CYCLOPENTOLATE HCl TROPICAMIDE Allergy Guidelines Chemistry • Use lowest concentration • Irritation, injection • Avoid repetition • Lacrimation, • Anticholinergic, mucoid discharge • Avoid seizure-prone • Parasympatholytic infants, elderly • Atopic dermatitis • Use punctal occlusion

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TROPICAMIDE TROPICAMIDE TROPICAMIDE Action Side Effects • Mydriasis • Available as - Onset 15-30 min. ● Irritation on instillation - Mydriacyl - Duration 4-6 hours ● ↑ IOP in open angle glaucoma

- Tropicacyl, inter alia • Cycloplegia ● Angle closure glaucoma • 0.5%, 1.0% collyrium - Onset 20-30 min. ● Better mydriatic than cycloplegic - Duration 4-6 hours

TROPICAMIDE PHENYLEPHRINE PHENYLEPHRINE Toxicity • Chemistry: α1 adrenergic ● Available as stimulator, agonist • Rare, due to brief action - NeoSynephrine (radial iris fibers) • Cyanosis - Ak-Dilate • Action: • Muscle rigidity - Mydfrin - Mydriasis - Efricel, inter alia Onset: 10-20 min. • Vasomotor instability Duration: ~ 3° ● 2.5%, 10% collyria - Vasoconstriction

PHENYLEPHRINE PHENYLEPHRINE PHENYLEPHRINE Clinical Effects Side Effects • Other Actions: • Rapid onset - Reduced aqueous inflow • Virtual absence of • Irritation on instillation - Reduced resistance to cycloplegia • Angle closure glaucoma outflow • Accentuates effect of - Stimulation of dilator ms. mydriatic

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PHENYLEPHRINE PHENYLEPHRINE PHENYLEPHRINE Toxicity Toxicity Guidelines • Use punctal occlusion • 1 gtt. 10% coll. = 3.3-6.7 mg. • Sudden systemic hypertension • Do not use in patients on • Enhanced absorption in (babies) MAO inhibitors or tricyclic • Ventricular arrhythmias antidepressants inflamed eyes (e.g., Parnate, Tofranil, Elavil, • Myocardial infarction Sinequan).

PHENYLEPHRINE DAPIPRAZOLE Guidelines DAPIPRAZOLE Trade Name [Rev-Eyes] • Use cautiously in hypertension, cardiac disease, aneurysm • C N N HCl • Use 2.5% coll. in infants, Rev-Eyes® 19 27 5 elderly • M.W. 361.93 • Approximately gtt.1/eye/hour

DAPIPRAZOLE DAPIPRAZOLE DAPIPRAZOLE Description Pharmacology Now available through selected compounding • α-adrenergic smooth α-adrenergic pharmacies muscle blocker (e.g., Leitner’s Pharmacy and blocking agent • Induces miosis by Compounding Center, San Jose, CA dilator muscles

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DAPIPRAZOLE DAPIPRAZOLE DAPIPRAZOLE Pharmacology Indications Dosage • Reconstituted as • No action on ciliary ms. Iatrogenic mydriasis 0.5% collyrium • Minimal effect on by adrenergic • gtts ii O.U.; sphincter ms. (or parasympatholytic) agents repeat after 5 min.

DAPIPRAZOLE DAPIPRAZOLE DAPIPRAZOLE Pregnancy Pediatrics Contraindications • Safety in pregnancy, • Hypersensitivity nursing not established Safety and efficacy • Strong parasympatholytic • Not embryocidal, not established agents teratogenic in rats, • Use only once/week/pt. rabbits

TOPICAL ANESTHETICS TOPICAL ANESTHETICS PROPARACAINE • Proparacaine (Alcaine, ● Available as • Mechanism of Action: Ophthetic, Fluoracaine, inter alia) - Ophthaine - Reversible block, • Benoxinate (Fluress) - Aphthetic competitive inhibition of ACh • Tetracaine - Ak-taine - Decreased membrane • Cocaine - Alcaine permeability to Na+ flux (1% - 4% as anesthetic) ● 0.5%

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TOPICAL ANESTHETICS TOPICAL ANESTHETICS TOPICAL ANESTHETICS Side Effects Maximum Effective Concentrations • Onset: 5-30 sec. • Stinging on instillation Proparacaine 0.5% • Duration: • Suppression of reflex Tetracaine 1% - Varies with concentration, blinking Lidocaine 4% frequency of instillation • Increased corneal Cocaine 20% - Generally, 20-30 min. permeability to drugs Benoxinate 0.4%

TOPICAL ANESTHETICS TOPICAL ANESTHETICS PROPARACAINE Epithelial Toxicity Toxicity Onset: 5-20 sec. • Epithelial punctate keratopathy Minimal: Lidocaine (2-4%) (ave. ~13 sec.) • Retardation of epithelial healing Duration : 15-25 min. Maximal: Cocaine (4-20%) • Idiosyncrasy • Allergy: exfoliative dermatitis Irritation: minimal

PROPARACAINE PROPARACAINE Fluorescein – Topical Toxicity • Available as drops or Allergy strips ● Punctate epithelial keratopathy • Uses: stain corneal defects and abrasions, • Rare; ● Stromal edema (after 5-10 min.) applanation tonometry, detecting wound leak, ● Suppression of reflex blink; • No cross-reaction with NLD obstruction drying • Caution: tetracaine, benoxinate • Stains soft contact lens ● Suppression of epithelial • Fluorescein drops can be contaminated by regeneration Pseudomonas sp.

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ROSE BENGAL GLYCERIN, USP GLYCERIN • Stains devitalized epithelium Glycerol • Action: Osmotic agent • Uses: Severe dry eye, • Chemistry: Trihydric Alcohol herpetic keratitis - Hydroscopic (CH OHCHOCH OH) 2 2 - Deturgesces • Colorless viscous liquid corneal edema • Miscible with H2O, EtOH • Used in 50-75% conc. (aqueous) • Onset: 1-2 min.

GLYCERIN GLYCERIN GLYCERIN Side Effects Toxicity Advantages

• Burning pain on instillation • Inexpensive Rare, topically • Transient action (topical) • Use as gonioscopic lubricant

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