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Transcript
Ocular Pharmacology Erica Tolar DVM, DACVO Drug Delivery Topical-most common route for ophthalmic medications o Solution-the drug is completely dissolved in a solvent o Suspension-particles of a drug in a saturated aqueous vehicle Topical steroids-prednisone acetate; must shake well prior to use o The palpebral fissure holds approximately 25-30uL of fluid o The average eye drop contains 25-70uL of fluid o The eye can only hold one drop at a time! o Must wait 5 minutes between eye medications o Administering one drop right after another drug will reduce the availability of the first drug o Topical medications read the aqueous, iris, ciliary body, penetration past the lens is minimal o Melanin binding can influence the pharmacologic effect of drugs Atropine o Ointments or gels improve precorneal retention of the drug o Ointments can be administered at the same time, however you must give solutions prior to ointments o No delay in wound healing if you use ointments vs. solutions o Avoid ointments in corneal perforations or an impending corneal perforation o Soft contact lenses or collagen shields are another way to deliver medications Subconjunctival o Therapeutic drug levels for 8-12 hours after an injection with a water soluble medication and up to 2-3 weeks with a drug in suspension o Don’t inject through the sclera! Retrobulbar o Most often used for regional anesthesia o Potential complications: globe perforation, optic nerve injury, orbital hemorrhage, central anesthesia o Used in horses to perform standing procedures Intracameral o Used during intraocular surgery Intravitreal injection o Vitreous is resistant to medication penetration due to lack of blood supply o Complications: retinal detachment, lens trauma, hemorrhage Systemic penetration o Some medications can be stopped by the blood ocular barrier unless there is ocular inflammation, infection or trauma to promote penetration o Eyelids need to be treated with systemic therapy Anti-infectious Agents Indiscriminate use encourages the development of drug resistant bacteria Bacteriostatic or bactericidal Cephaloporins-cefazolin, first generation, gram positive cocci Aminoglycosides-gentamicin, tobramycin, neomycin o Gram positive and negative o Synergistic with cephalosporins o Available in an ointment preparation o Neomycin can cause irritation and some animals can have an allergic reaction o Gentamicin can delay epithelial healing Tetracycline-doxycycline o Mycoplasma and chlamydia o Decreases matrix metalloproteinases Chloramphenicol o Readily diffuses into the anterior chamber o Good for stromal abscesses o Aplastic anemia is a side effect in people so recommend glove use when applying Polypeptide antibiotics-polymyxin B, bacitracin, gramicidin, vancomycin o No penetration into the anterior segment Fluoroquinolones-ofloxacin, ciprofloxacin, moxifloxacin, gatifloxacin, levofloxacin o Gram positive and negative o Ciprofloxacin is available as an ointment o Minimal toxicity o Ofloxacin has higher corneal penetration and can exceed MIC better than ciprofloxacin o Retinal toxicity with oral baytril in cats Lincosamides and Macrolides-clindamycin, erythromycin, azithromycin o Toxoplasma, chlamydia, mycoplasma o Azithromycin has more gram negative spectrum-bartonella species Sulfonamides o Toxic to the lacrimal gland o 4% of dogs on TMS develop dry eye o Measure STT before starting medication and have the owner monitor STT every couple days in at least 1 eye Anti-viral o All are virostatic and don’t eliminate latent infection o Pyrimidine nucleoside analogues Idoxuridine, trifluridine o Purine nucleoside analogues Acyclovir, vidarabine, cidofovir, famcyclovir Cidofovir is BID dosing o L-Lysine Exchange arginine for lysine which decreases viral replication 500mg PO q12h o Interferon Unsure about stability out of a subzero freezer Glucocorticoids Block cyclooxygenase and lipooxygenase pathways Decrease cellular exudation Inhibit fibroblastic/collagen formation Slow epithelial migration Decrease post-inflammatory neovascularization Stabilize inflamed capillary permeability Dexamethasone sodium phosphate o 5-7 times more anti-inflammatory effect than prednisone acetate o Very poor corneal penetration o Not indicated for uveitis o Used for keratitis, conjunctivitis Don’t use steroids in the face of ulcerative keratitis May potentiate infectious keratitis and result in malacia Oral steroids have good intraocular penetration Hydrocortisone is an incredibly weak anti-inflammatory Nonsteriodal Anti-inflammatories Flurbiprofen, diclofenac, suprofen, ketorolac Diclofenac is better at stabilizing the blood ocular barrier Can worsen infectious keratitis especially herpetic keratitis in cats Rimadyl, meloxicam, previcoxx are good for ocular inflammation Calcineurin inhibitors Tacrolimus, cyclosporine, pimecrolimus Doesn’t penetrate into the aqueous Penetrates well into the lacrimal gland increasing lacrimation Good for inflammatory diseases of the cornea Medications can take up to 2 months to work Cytotoxic agents Azathioprine Activated in the liver Uveitis, scleritis, VKH, optic neuritis, GME Monitor CBC, liver values Megesterol Acetate Eosinophilic keratitis in cats Side effects: polyphagia, polydipsia, pyometra, diabetes, behavior changes Anti-glaucoma medications Reduce aqueous humor secretion Increase aqueous humor outflow o Direct-acting parasympathomimetics Pilocarpine-very acidic Causes miosis Minimal pressure lowering ability Carbachol-used after intraocular surgery to decrease post operative pressure spikes Avoid in secondary glaucoma o Indirect-acting parasympathomimetics Demecarium bromide Used for miosis to manage lens subluxations Optic nerve sparing effect Systemic toxicity can result (vomiting, diarrhea) Avoid in secondary glaucoma o Nonspecific adrenergic agonist Epinephrine and dipivefrin Decrease aqueous formation by decreasing blood flow and increase outflow Minimal pressure lowering ability alone o Alpha 2-Adrenergic Agonists Apraclonidine-decreases aqueous production but toxic o Beta blockers Nonspecific beta blocker-timolol, carteolol, levobunolol Decrease aqueous production Maximum reduction in 2-4 hours Decreases heart rate, can exacerbate asthma in cats o Carbonic Anhydrase Inhibitors Decreases aqueous production, 98% of carbonic anhydrase must be inhibited to achieve full IOP reduction Aqueous production is suppressed by 40-60% Dorzolamide, brinzolamide, methazolamide Systemic administration is comparable to topical administration BID-TID Using oral and topical together don’t have an additive effect Methazolamide causes systemic acidosis and $$$ Dorzolamide is acidic and can cause blepharitis o Prostaglandin Analogues Travaprost, latanoprost, unoprostone, bimatoprost Prodrug is enzymatically hydrolyzed during its passage through the corneal epithelilum and the active form is released in the anterior chamber Cats have different receptors and are not able to metabolize these drugs like dogs or humans Increases uveoscleral outflow as well as decrease aqueous production Latanoprost can decrease IOP in glaucomatous dogs 50% Dosing 1-2 times daily Used in primary glaucoma o Osmostic Agents IV or oral administration Distributed in the extracellular fluids causing an increase in their osmolality which causes a gradient from the aqueous and vitreous humor into the plasma NOT to be used in uveitis cases Mannitol, glycerin o Neuroprotectants Calcium channel blockers, nitric oxide inhibitors, free radical scavengers Demecarium bromide Mydriatics/Cycloplegics Cholinergic antagonists-paralyze the pupillary sphincter Sympathomimetics-stimulate the iris dilator muscle, no cycloplegia Not indicated in glaucoma Decreases STT Salivation, especially in cats Tropicamide o Minimal cycloplegia o Dilation in 30 minutes o Short acting Atropine o Potent mydriatic and cycloplegia o Maximum dilation in 30-60 minutes o Melanin binding Phenylephrine o Sympathomimetic o Use in combination with atropine to dilate the pupil o Vasoconstriction o Dilute formulation used in identifying location of lesion in Horner’s syndrome Epinephrine o Sympathomimetic o Used intracamerally during intraocular surgery Local anesthetics Impede sodium ion entrance to the axon interior preventing nerve depolarization Repeated application is toxic to the corneal epithelium and should NEVER be used as a therapeutic agent for pain Proparacaine o Needs to be refrigerated o Single application lasts 45 minutes, maximum effect lasts 15 minutes in dogs, 25 minutes in cats Tetracaine o Shorter duration of anesthesia compared to proparacaine o More irritating Lidocaine o Rapid onset, lasts 45 minutes to 1 hour o Used in local blocks Bupivacaine o 4 times more potent than lidocaine o Lasts 5-10 hours with the 0.5% solution o Use in combination with lidocaine Topical Disinfectants Dilute betadine solution 1:10 to 1:50 Tissue Adhesives Cyanoacrylate Antibacterial properties Reported to stop melting Surface must be dry when applying, use 30g needle to apply Produces heat when curing, can rupture a descemetocele Anticollagenase Agents Matrix metalloproteinases and serine proteinases maintain normal corneal health, dysregulation of these will result in corneal stromal degradation These agents decrease matrix metalloproteinase activity Acetylcysteine EDTA-binds zinc and calcium Tetracyclines-chelates cations needed for enzyme activity preventing degradation Serum o Antiproteolytic activity o Epithelialtrophic properties that promote corneal healing o Good for 1 week in the fridge o Must have aseptic preparation Galardin, Ilomostate-synthetic MMP inhibitors Hyaluronate Aquify-over the counter Remend/Equitrix-similar product, has not been compared to other HA products The Future Nanoparticle technology o Increases surface area dramatically which increases tissue exposure and absorption Iontophoresis o Propels charged compounds into ocular tissues o Uses a small electrical current to drive the drug into the tissue o Fungal keratitis, uveitis, retinoblastoma Drug eluting contact lenses o Deliver times up to 4 weeks rather than just hours Eye misters and microdroplets o Improve compliance-mean dogs! Implants o Controlled sustained drug release o Biodegradable and nonbiodegradable o Episcleral implants, intrascleral, suprachoroidal and intravitreal implants o Biodegradable inserts for the lower conjunctival sac Intraocular lenses o Make the lens a drug reservoir or “coat” the lens in a drug such as an antiinflammatory or antibiotic