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 Richard Alan Lewis, M.D., M.S. Nov 2013 2 Ophthalmic Pharmacology 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) Richard Alan Lewis, M.D., M.S. Nov 2013 3 Ophthalmic Pharmacology 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. Richard Alan Lewis, M.D., M.S. Nov 2013 4 Ophthalmic Pharmacology 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 Richard Alan Lewis, M.D., M.S. Nov 2013 5 Ophthalmic Pharmacology 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. Richard Alan Lewis, M.D., M.S. Nov 2013 6 Ophthalmic Pharmacology 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 Richard Alan Lewis, M.D., M.S. Nov 2013 7 Ophthalmic Pharmacology 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