Pharm E1: Ophtho

Ocular Drug Delivery: topical

Ocular Drug Delivery: topical

• Absorption: prompt, depending on formulation

• Special: convenient, economical, relatively safe

• Limitations/cautions: compliance, corneal/conjunctival toxicity, nasal mucosal toxicity, systemic side effects from nasolacrimal absorption

Ocular Drug Delivery: injections (subconjunctival, retrobulbar, sub-Tenon)

• Absorption: prompt or sustained, depending on formulation

• Special: anterior segment infxns, posterior uveitis, cystoid macularedema

• Limitations/precautions: local toxicity, tissue injury, globe perforation, optic nerve trauma, ocular muscle trauma, etc

Ocular drug delivery: injections (intraocular)

• Absorption: prompt

• Special: anterior segment surgery, infections

• Limitations/precautions: corneal toxicity, intraocular toxicity, relatively short duration of action

Ocular drug delivery: intravitreal injection or device

• Absorption: circumvented, immediate local effect, potential sustained effect

• Special: endophtalmitis, retinitis, age-related macular degenration

• Limitations/precautions: retinal toxicity

What does the rate and extent of absorption of ocular drugs depend on?

• cul-de-sac and preconeal tear film

• nasolacrimal drainage

• drug binding to tear/tissue proteins

• diffusion across cornea and conjunctiva

Macrolides

• Azithromycin, Erythromycin (most common)

• MOA: inhibits synthesis at 50S ribosome

• Uses: bacterial conjuctivitis

• Adverse: eye irritation, hypersensitivity

Trimethoprim/Polymyxin B solution

• MOA: Tri= inhibits folic acid synthesis; Poly= binds to phospholipids → alters membrane’s permeability

• Uses: bacterial conjunctivitis

• Adverse: ocular irritation

Sulfacetamide (ointment/solution)

• MOA: inhibits folic acid synthesis via antagonism of PABA

• Uses: bacterial conjunctivitis

• Adverse: ocular, irritation, allergic reactions (avoid in pts w/ sulfa allergy)

Bacitracin ointment

• MOA: inhibits bacterial cell wall synthesis

• Uses: bacterial conjunctivitis

• Adverse: ocular irritation

Fluoroquinolones

• Cipro, Ofloxacin, levofloxacin, moxi, gatifloxacin

• MOA: inhibits DNA-gyrase & topoisomerase 4 → breaks DNA

• Uses: conjunctivitis, corneal ulcers, cover pseduomonas, preferred for contact lens wearers

• Adverse: ocular irritation, white precipitate, unpleasant taste after instillation

Aminoglycosides

• gentamicin, tobramycin

• MOA: inhibits 30S ribosome sythesis

• Uses: conjunctivitis

• Adverse: ocular irritation, corneal ulceration, reactive keratoconjunctivitis

Trifluridine (Viroptic)

• MOA: interferes w/ viral replication by inhibiting thymidylate

• Uses: keratoconjunctivitis due to HSV

• Adverse: ocular irritation, punctate keratopathy

Ganciclovir (Zirgan)

• MOA: interferes w viral DNA synthesis by binding deoxyguanosine triphosphate to DNA polymerase

• Uses: herpetic keratitis, CMV retinitis

• Adverse: ocular irritation, punctate keratitis

• Cytovene: IV, oral; Vitrasert: intravitreal implant

Natamycin

• MOA: inc cell membrane permeability in fungi by binding to sterol

• Uses: conjunctivitis: keratitis -Aspergillus, candida, cephalosporium, fusarium, penicillium

• Adverse: ocular irritation

H1 receptor antagonist

• MOA: inverse agonists - causes histamine receptor inactivation

• dec capillary dilation, itch, swelling; act w/in minutes; preferred over MCS

• Azelastine, Alcaftadine, Bepotastine, Emedastine, Epinastine, Ketotifen, Olopatadine

• Adverse: ocular irritation, HA, inc ocular dryness

Mast Cell Stabilizers

• MOA: inhibit mast cell degranulation, limit release of histamine tryptase, prostaglandin D2, inhibit leukocyte activity, dampen mediator release from pro-inflammatory cells

• cromyln, lodoxamide, nedocromil

• Adverse: ocular irritation, unpleasant taste, HA

Vasoconstrictor/Antihistamine

• MOA: activates postjunctional a-adrenergic receptors on blood vessels → dec conjuctival edema

• tetrahydrozoline, naphazoline, pheniramine, naphazoline

• good for short term use; prolong → hyperemia post d/c

Imidazoline Derivatives

• systemically will target a-2 receptors

• locally will act on a-1 receptors

NSAIDS

• MOA: block action of COX, inhibits conversion of arachidonic acid to prostaglandins and thromboxanes (pro-inflammatory agents)

• Bromfenac, diclofenac, flurbiprofen, ketoralac, nepafenac

• Uses: postoperative inflammation/pain & allergic conjunctivitis

• Adverse: lacrimation, keratitis, IOP inc, ocular irritation

Glucocorticoids

• MOA: suppress late phase allergic reaction: dec formative of pro-inflammatory mediators; inhibits fibrin/collagen deposition → no scar

• Uses: severe ocular allergy, anterior uveitis, external eye inflammation, inflammation following ocular surgery, cataract formation, elevated IOP, ulcers, infections, delayed wound healing

• Dexamethasone, prednisolone, difluprednate, fluorometholone*, Loteprednol*, Rimexolone*, Triamcinolone

*= have lower IOP risk

Therapy for Dry Eyes

• tx the disease first

• Physical: punctal plugs, surgical occlusion of lacrimal drainage

• Tear subs: hypo-isotonic solutions, balanced salt solution, carboxymethylcellulose (Refresh), Hydroxyproply cellulose, polyvinvyl alcohol (artifical tears)

Immunomodulators

• Cyclosporine (restasis)

• MOA: inhibits production/release of interleukin II → less T cell activation

• eye: dec inflammatory markers in lacrimal, inc tear production, improve vision and comfort

• Uses: chronic dry eye associated w/ inflammation (keraconjuct sicca)

• Adverse: ocular burning, FB sensation, blurred vision

Glaucoma & ocular HTN

• inc aqueous outflow

  • prostaglandins (1st line agents)

  • a-adrenergic agonists

  • cholinergic agonists

• dec aqueous production

  • a-adrenergic agonists

  • B blockers (2nd line agents)

  • carbonic anhydrase inhibitors

Prostaglandins

• MOA: analogs of PGF2a, binds to prostaglandin receptors & lowers IOP by inc aqueous outflow

• Uses: most commonly glaucoma

• latanoprost, travoprost, bimatoprost, tafluprost

• Adverse: conjunctival hyperemia, ocular irritation, changes in eyelash length and iris color

Beta Blocking Agents

• MOA: blocks B receptors in ciliary body → less catecholamine activation → dec cAMP → less aqueous production

• Uses: oc HTN or glaucoma

• Beta 1 selective: Betaxol (primarily heart, better for asthma pts)

• non-selective: carteolol, timolol, levobunolol (affect B 1 & 2)

  • more efficacious, but more side effects

• Adverse: worsening HF, bradycardia, heart block, inc airway resistance

Alpha Adrenergic Agonists

• MOA: alpha 2 agonist; presynaptically: dec catecholamine release to dec aqueous production and inc outflow; postsynaptically: alpha 2 activation dec aqueous production

• Uses: oc HTN or glaucoma

• apraclonidine, brimonidine

• Adverse: ocular irration, hyperemia, pruritus, allergic conjunctivitis

• contradicted in children <2 yrs

Carbonic Anhydrase Inhibitors

• MOA: inhibits carbonic anhydrase in ciliary body epithelium → dec production of bicarb → dec fluid transport and IOP

• Uses: oc HTN or glaucoma

• dorzolamide, brinzolamide

• Adverse: bitter taste, burning/stinging after administration, allergic conjunctivitis

Cholinergic Agonists

• MOA: activates muscarinic receptors causing ciliary muscle contraction facilitating aqueous outflow

• Uses: oc HTN or glaucoma

• acteylcholine, carbachol, pilocarpine

• Adverse: fixed/small pupils, myopia, visual disturbances, HA

• poor compliance due to side effects and frequent admin, visual burning in young pts

Combination Products

• Uses: oc HTN or glaucoma

• brimonidine w/ timolol (Combigan), brinzolamide w brimonidine (simbrinza), dorzolamdie w/ timolol (cosopt)

• Synergistic IOP lowering by targeting multiple routes

• few drops to administer → inc compliance

Glaucoma tx

• start w/ prostaglandin or B blocker

• can start in one eye to determine efficacy/tolerability

• w/o risk factor → monitor until changes occur

• w/ risk factor → treat

• goal: 20-30% reduction in IOP

Ocular Anesthetics

• MOA: inhibit Na influx into the neuron preventing signal propagation

• tetracaine, proparacaine

• Uses: tonometry, FB removal, superficial corneal surgery

• Adverse: hypersensitivity, burning sensation

• will be numb for 10-20 minutes -no blink reflex

Cycloplegic Agents: antimuscarinics

• Uses: diagnostically (fundoscopic), uveitis (prevent synechiae, relive ciliary spasm)

• MOA: block muscarinic acetylcholine receptors, cause mydriasis

• Atropine, Cyclopentolate, Tropicamide

• Adverse: photosensitivity, blurred vision

Cycloplegic Agents: sympathomimetics

• Uses: diagnostically (fundoscopic), uveitis (prevent synechiae, relive ciliary spasm)

• MOA: adrenergic receptor agonist, cause mydriasis, more reactive to light

• Phenylephrine

• Adverse: photosensitivity, conjunctival hyperemia

Fluorescein

• MOA: reveals epithelial defects of the cornea and conjunctiva

• Uses: anterior segment staining, disclosing corneal injury

• Adverse: hypersensitivity, burning sensation