Ocular Pharmacology Flashcards
Main pharmacokinetic parameter for ocular drugs
Absorption
Important characteristics for topical abx?
Hydrophilic enough to stay in corneal stroma, but lipophilic enough to cross corneal epithelium
What prevents systemic drugs from getting into the eye?
Blood-aqueous and blood-retinal barriers
tight junctions, p-glycoprotein efflux pumps, NON-fenestrated capillaries (Fenestrated capillaries are capillaries that have tiny openings, or pores)
Requirements for systemic ocular drugs
Requirements for topical ocular drugs?
Will systemically administered ocular drugs match in concentration once in the eye?
NO -> Drugs in the eye will always be a fraction of the concentration in the bloodstream
Like in BBB, inflammation increases concentrations
Similar to drugs getting across BBB
Pharacokinetics of ocular drugs:
- Drug Distribution
- Drug Metabolism
- Drug Elimination
What lesion locations in the eye may systemic administration be useful for?
Anterior segment (cornea, iris, lens); corneal stroma
Ocular lesions where systemic administration is not preferred // where topical is better
Corneal surface & conjunctiva
Which ABX are hydrophilic // NOT used in systemic administration?
Beta-lactams (ampicillin + sulbactam), aminoglycosides (gentamicin, tobramycin, amikacin)
Which systemic ABX are lipophilic?
Tetracyclines (doxy), Fluoroquinolones (enro), Macrolides (the -mycins -> erythro, clarithro, azithro-)
Systemic anti-fungals
Fluconazole, Voriconazole
When is topical administration not preferred?
For posterior segment disease
Topical administration can be enhanced by what method? Why is this “best”? What limits this method?
Increasing dose frequency – increases absorption and efficacy
- drug accumulates in eye over time -> results in highest concentration
- OWNER COMPLIANCE - difficult for owners to adminsiter so frequently (Q2 hours) + life-long ABX course
How come increasing topical drug concentration is limited in increasing efficacy?
Will only increase absoprtion in cornea up to a certain dose b/c of limited/small surface area of the cornea
Not enough surface area for all the drug to enter - maxes out
Method to increase topical drug absorption across the cornea without adjusting dosage?
DECREASE corneal thickness (gently scrape off diseased layers of cornea)
Topical Antibiotics
Polymyxin B
- beneficial actions & effects
- use / main species
- precautions
- Cell wall inhibitor
- Spectrum = Gram Negative
- Low doses – used for endotoxemia in horses (bactericidal drugs -> dead bacteria release endotoxins into bloodstream)
- Dose-dependent nephrotoxicity
Topical Antibiotics
Bacitracin
- beneficial actions & effects
- precautions
- Cell-wall & peptidoglycan-synthesis inhibitor
- Gram positive * Gram negatives
- nephrotoxicity prevents parenteral use
Why is corticosteroid use contrainidicated in corneal ulcerations?
Can potentiate corneal ulcer infections + cause other severe ocular infections
ALWAYS READ THE LABEL!
What is the only FDA-approved anti-fungal ophthalmic drug? Its spectrum? Indications?
Natamycin
- similar to Amphotericin B
- binds to ergosterol in fungi cell membrane => oxidative damage and cell death
- filamentous fungi! -> aspergillus, fusarium
- DOES NOT PENETRATE THE INTACT CORNEA
NATAMYCIN corneal fungal infection, VORICONAZOLE stromal/deeper
What antibiotics does Natamycin have a synergistic effect with?
Tobramycin and Cefazolin (Aminoglycoside & Cephalosporin)
Trifluridine and Idoxuridine
Use, species, effect on viruses
Herpesvirus keratitis
- cats, horses
- are virostatic -> no effect on latent viral particles
(Idoxuridine = nucleoside analogue -> gets replicated into virus DNA, but then blocks BPing)
What are the 3 main categories of anti-inflammatory ocular drugs?
Glucocorticoids, NSAIDs, Immunomodulators
MoA of topical glucocorticoids
transactivation of anti-inflamm. genes & transrepression of pro-inflamm. genes –> block arachidonic acid pathway (phospholipase A2)
When is topical glucocorticoid use contrainidicated?
Use is only indicated for anterior segment inflammation, conjunctivitis, keratitis, anterior uveitis
Presence of corneal ulcers
Topical prednisolone acetate (1%) - benefits of acetate
Acetate increases lipophilicity of the drug = increases ocluar pentration, and increases potency (increases affinity for receptor)
When is the use of Prednisolone Sodium Succinate or Phosphate indicated?
for superficial corneal diseases (b/c does NOT cross an intact cornea!)
Dexamethasone sodium phosphate (0.1%) - benefits / indications?
Higher potency than topical prednisolone acetate (0.1% vs 1.0%)
- Penetrates an intact cornea
- available in formulations combined with antimicrobials (e.g., Neo/poly/dex)
Why is hydrocortisone not preferred? When are they used?
Less potent / do not penetrate an intact cornea. Typically combined with ABX formulation.
Adverse effects of topical glucocorticoids in the eye? (4)
- potentiate infection (Fungus!!!)
- Delay re-epithelialization of corneal ulcers
- Calcific band keratopathy (chronic use)
- Long-term use associated with development of endocrine issues
Calcific band keratopathy:
Band keratopathy is defined as a disease process that occurs from sub-epithelial calcium hydroxyapatite deposition leading to an opaque, band-like horizontal plaque across the cornea. This opacity often impacts the visual axis leading to decreased visual acuity in patients.
Are topical ocular NSAIDs selective or non-selective?
Non-selective – inhibit BOTH COX-1 & COX-2
Adverse effects of topical NSAIDs (3)
- less concern for potentiating infection compared to topical GCs
- decreased corneal epithelialization, ulcer/wound healing (thimersol)
- no repported GI or renal effects (compared to systemic NSAIDs)
Ketorolac (0.5%), Diclofenac sodium (0.1%)
Thimersol-containing topical NSAID: Flurbiprofen (0.03%)
WHEN are systemic GCs and NSAIDs used for ocular disease? WHY are systemic NSAIDs used more frequently than systemic GCs?
Indication: when inflammation cannot get under control using topical
- systemic NSAIDs used more frequently (topical GC + systemic NSAID) b/c non-selective drugs are more effective in getting inflammation under control
Flunixin meglumine > firocoxib in the horse
Immunomodulator
Cyclosporine A
- MoA
- Indications
- Binds calcineurin -> blocks IL-2 production & prevents T-cell activation
- Most effective in ocular diseases mediated by lymphocytes (anterior uveitis)
- Topical: surface ocular diseases since it does NOT penetrate intact cornea (immune-mediated keratitis; eosinophilic keratitis)
- Systemic = $$$
T cells (also called T lymphocytes) are major components of the adaptive immune system. Their roles include directly killing infected host cells, activating other immune cells, producing cytokines and regulating the immune response.
What is a suprachoroidal implant used for?
Anterior Uveitis (iris +/- ciliary body)
- delivers cyclosporine A for months-to-years
Which autonomic nervous system has adrenergic vs cholienrgic receoptors?
Sympathetic: adrenergic (Alpha-1, Alpha-2, Beta-1, Beta-2)
Parasympathetic: cholinergic (Nicotinic & Muscarinic)
Phenylephrine
- indications
Sympathomimetic
- causes mydriasis -> It is used before eye examinations, before and after eye surgery, and to treat certain eye conditions.
- dogs
- can be cobined with anti-cholinergic drugs to maximize dilation
Tropicamide
- indications
Parasympatholytic
- prevents miosis
- short-acting
- more appropriate to use when diagnosing rather than for treatment!
Atropine
- indications
Parasympatholytic
- prevents miosis
- long-acting! (especially in blue eyes — 14 days!)
- used for treatment; relieves pain from pupil constriction (ciliary spasm)
- can prevent synechiae (pupil stuck in one position) and 2º glaucoma
Adverse effects of Atropine
decreased tear production –> KCS risk if tear production is not monitored (atropine antagonizes muscarinic receptor of lacrimal gland)
decreased GI motility (concern for colic in horses?)
Horses: Give q6 -> q12 -> q24 -> q48 -> PRN –> colic unlikely to occur 2º to atropine
MoA of parasympathomimetics?
Cholinergic agonists (direct or indirect)
Indications / adverse effects for parasympathomimetics?
- not many b/c of adverse effects (v+, d+, anorexia, lethargy, weakness)
- dry eye in dogs
- somestimes glaucoma (not in horses as it’s been found to actually increase IOP)
Timolol
- MoA
- Indications
- Precautions
- Species
Sympatholytic -> non-selective beta-blocker
-reduces IOP via decreasing aqueous humor production
- Precautions = Pts with cardiovascular disease (bradycardia, hypotension)
- Horses: better efficacy & fewer adverse effects (vs. dogs & cats)
Dorzolamide is a carbonic anhydrase inhibitor. - MoA?
- Indications?
- How is it adminsitered?
In the eyes, carbonic anhydrase inhibitors reduce the production of aqueous humor by the epithelium of the ciliary body by reducing the production of bicarbonate ions and presumably reducing fluid flow.
- treatment of glaucoma
- combined with beta-blockers (-olol) since not very effective alone
Carbonic anhydrase is an enzyme that assists rapid inter-conversion of CO2 and H2O => H2CO3, H+ and HCO3-
Prostaglandin analogues
- MoA?
- Indications?
Latanoprost -> GLAUCOMA TX
- LOWERs IOP via increased AH outflow (increases sclera permeability)
- DOGS and HORSES
MoA of topical / local anesthetics for corneal and conjunctival surfaces?
sodium channel blockers
- block depolarization of nerves // propagation of nerve signals
Indications for topical / local ocular anesthetics?
- Diagnostic procedures (culture, tonometry)
- Surgical procedures (analgesic – sole or adjunctive)
When are topical ocular anesthetics contraindicated?
as therapy for ulcerative keratitis!!
can also be toxic to epithelium, can destabilize tear film, inhibit normal corneal blink reflex
Most common topical ocular anesthetic used in clinical practice?
Proparacaine (effective within 1 minute; lasts 25-45 mins)
Use of local administration of anesthetics (e.g., lidocaine, bupivicaine)?
Lidocaine: rapid onset, shorter duration (45-60 mins)
Bupivicaine: longer duration (5-10 hrs)
Blockade of sensory & motor innervation (surgical and non-surgical procedures)
Topical Antiproteases
- Indications
- Topical vs Systemic
Prevent “corneal melting” in infectious-caused corneal issues by inhibitng matrix metalloproteinases (MMPs)
Topical: autologous serum, N-acetylsysteine
Systemic: tetracyclines, doxycycline in tears
Deep and melting ulcers are usually associated with Pseudomonas spp or beta-hemolytic streptococci. Proteases, hydrolases, and collagenases produced by bacteria, neutrophils, epithelial cells, dying keratocytes, and macrophages cause rapid COLLAGENOLYSIS and melting of stroma that can rapidly progress to a descemetocoele and possible corneal perforation within 24 hours. Topical (EDTA) (drops and ointment), N-acetylcysteine, and tetracyclines (oxytetracycline and doxycycline) inhibit MMPs via chlelating calcium and zinc. Undiluted topical autologous and homogenous serum or plasma has alpha 2-macroglobulin and alpha-1 proteinase inhibitor that act to inhibit MMP and serine protease. Frozen serum or plasma retain anti-protease efficacy for up to 180 days. Antiprotease drops should be applied 2–4 hours initially to inhibit melting and then can be decreased to every 4–6 hours. Oral doxycycline (10 mg/kg every 24 hours) is also effective as an antiproteolytic agent and can be combined with topical antiprotease drops.
How is autologous serum collected for use as a topical antiprotease?
Collected aseptically // maintained sterility
Why don’t systemic anti-viral drugs work
Too hydrophilic (can’t stay in corneal stroma)
