Day 14 (2): Ocular Pharmacology

Question 1

What are the different methods of ophthalmic drug delivery?

Answer 1

A. LOCAL Administration

1. Topical
   - Eyedrops: most common; suspension/solution
   - Ointments/Gels
   - Lid Scrubs
   - Solid Delivery Devices: SCL, collagen shields, filter paper strips, cotton pledgets
2. Periocular: around the eye
   - Subconjunctival: under the conjunctiva
   - Subtenon: under the Tenon’s capsule
   - Retrobulbar: behind the globe
   - Peribulbar: around the globe
3. Intracameral: into anterior chamber/aqueous
4. Intravitreal: into vitreous

B. SYSTEMIC Administration
- Oral
- Intravenous
- Subcutaneous
- Intramuscular

Question 2

What are examples of Topical Anesthetics?

Answer 2

Topical Anesthetics
- suppress corneal sensitivity by blocking nerve impulses
- onset: 10 - 20 sec
- duration: 10 - 20 min (may need reapplication)
- SE:
1. mild burning sensation upon instillation
2. corneal desquamation and opacification with chronic use
- indications:
1. procedures (tonometry, gonioscopy)
2. removal of foreign bodies
3. procedures requiring anesthesia of the cornea and conjunctiva

Examples:
1. Proparacaine 0.5%
- combined with fluorescein for use in applanation tonometry and to detect corneal epithelial defects
- a drop is placed in a fluorescein strip before application in the eye
2. Tetracaine 0.5%
3. Benoxinate
4. Cocaine

Question 3

Differentiate the Mydriatics vs Mydriolytics vs Cycloplegics.

Answer 3

MYDRIATICS
- MOA: adrenergic agonist/sympathomimetic
- action: dilates the pupil by stimulating the iris dilator muscle
- used to facilitate the examination of the posterior segment of the eye
- used to assess anisocoria
- contraindication: narrow-angle glaucoma

Examples:
1. Phenylephrine 2.5%: alpha-1 agonist
2. Hydroxyamphetamine and Cocaine: indirect action by increasing the release of norepinephrine from nerve synapses

MYDRIOLYTICS
- MOA: adrenergic antagonists/sympatholytic
- action: constricts the pupil by inhibiting the iris dilator muscle

Example:
Dapiprazole: alpha-1 antagonist

CYCLOPLEGICS
- MOA: muscarinic-receptor antagonists/anticholinergics/parasympatholytics
- action: dilates the pupil by inhibiting the iris sphincter and the ciliary muscles

Examples:
1. Tropicamide
2. Cyclopentolate
3. Atropine
4. Homatropine
5. Scopolamine: can affect the CNS because of ability to cross the BBB

Question 4

What are the three most common cycloplegics used?

Answer 4

Cycloplegics
- muscarinic-receptor antagonist/anti-muscarinic
- pupillary dilation: inhibit iris sphincter
- accommodation paralysis: inhibit ciliary muscle

TROPICAMIDE 0.5 or 1%
- drug of choice: routine dilation
- short-acting: 6 hours
- fastest onset

CYCLOPENTOLATE 1 or 2%
- drug of choice: routine cycloplegic refraction
- intermediate-acting: 24 hours
- less residual accommodation
- used in pediatric patients with accommodative excess or spasm

ATROPINE 1%
- drug of choice: complete cycloplegia
- long-acting: 7 - 12 days
- most potent mydriatic-cycloplegic
- used in the penalization of the eye (blurring of vision) for the treatment of accommodative esotropia and amblyopia

Question 5

What anesthetics are usually used for pain management?

Answer 5

Anesthetics
- act on cell membrane receptors to reversibly block generation of nerve impulses and pain signals to the trigeminal ganglion and brain

1. LIDOCAINE 2%
   - outpatient and minor procedures
   - faster onset: 2 - 5 minutes
   - shorter duration: 2 - 3 hours
   - may prolong effect by adding Epinephrine
2. BUPIVACAINE 0.5%
   - major operations
   - later onset: 5 - 10 minutes
   - longer duration: 4 - 8 hours
   - added with lidocaine for prolonged anesthesia

Question 6

What analgesics are usually given for acute ocular pain and inflammation?

Answer 6

A. NON-OPIOID Analgesics
- inhibits prostaglandin and thromboxane synthesis by deactivating the cyclooxygenase (COX-1 and COX-2) enzymes
- PERIPHERAL acting only

1. Paracetamol/Acetaminophen
   - acute mild to moderate pain
2. Aspirin/Acetylsalicylic Acid
   - IRREVERSIBLE NON-SELECTIVE inhibitor of COX-1 and COX-2
3. Non-Steroidal Anti-Inflammatory Drugs
   - REVERSIBLE inhibitors of COX
   - acute moderate to severe pain & inflammation
   - most effective and safest for SHORT-term use

Non-Selective (both COX-1 and COX-2)
- Mefenamic Acid
- Piroxicam/Meloxicam
- Diclofenac/Ketorolac
- Ibuprofen/Naproxen/Ketoprofen/Fenoprofen

Selective COX-2 Inhibitors
- Celecoxib
- Etoricoxib

B. OPIOID Analgesics
- mimics the effect of endorphins by acting as opioid receptor agonists in the CENTRAL nervous system
- acute severe pain
- NO ceiling effect: prone to abuse and addiction

1. Tramadol: weak agonist
2. Codeine
3. Oxycodone
4. Hydrocodone
5. Hydromorphone
6. Morphine

Question 7

What are the different ocular hypotensives used in the management of glaucoma?

Answer 7

Ocular Hypotensives:
1. Decrease aqueous production/secretion
2. Increase aqueous drainage

I. DECREASE AH PRODUCTION/SECRETION

A. Alpha-Agonists
- Alpha-1: vasoconstriction of ciliary vessels
- Alpha-2: decreased secretion by epithelium and relaxation of ciliary muscles to increase uveoscleral outflow

Examples: 3x/day
1. Apraclonidine 0.5%
- non-selective alpha-agonist
2. Brimonidine 0.15 or 0.20%
- alpha-2 agonist

B. Beta-Blockers
- Beta-2: most prevalent receptor in the epithelium; increases aqueous secretion

Examples: 2x/day
1. Timolol 0.5%, Levobunolol 0.5%
- non-selective beta-blockers
2. Betaxolol 0.5%
- beta-1 blocker
3. Metipranolol, Carteolol
- non-selective beta-blockers (unavailable)

C. Carbonic Anhydrase Inhibitors
- CA receptors: increase aqueous secretion

Examples: 3x/day
1. Acetazolamide 250 mg QID (1st Gen)
2. Methazolamide (1st Gen)
- longer half-life than acetazolamide and less renal side effects
3. Dorzolamide 2% (2nd Gen)
- avoids systemic side effects of 1st Gen
- for cases unresponsive to beta-blockers
- more painful upon instillation vs Brinzolamide
4. Brinzolamide 1% (2nd Gen)
- avoids systemic side effects of 1st Gen
- for cases unresponsive to beta-blockers

II. INCREASE AH DRAINAGE

A. Parasympathomimetics
- increases TM outflow by widening the iridocorneal angle (with pupillary constriction) and increasing the tension on the scleral spur (with ciliary muscle contraction)
- various side effects due to non-selective action

Examples: 2x/day
1. Pilocarpine 2%
- muscarinic-3 agonist
2. Carbachol 0.01%
- muscarinic-3 agonist
3. Echothiophate 0.125%
- irreversible acetylcholinesterase inhibitor

B. Prostaglandin Analogues
- prostaglandin F2-alpha receptor agonists
- induces remodelling of ECM in the ciliary muscles by dissolving Collagen type I & III through the increased activation of MMP
- this increases intercellular spaces for outflow
- SE: increased eyelash growth, iris pigmentation, periorbital hyperpigmentation

Examples: 1x/day
1. Latanoprost 0.005%
2. Travoprost 0.004%
3. Bimatoprost 0.03%
4. Tafluprost 0.0015%

Question 8

What are the usual indications for ophthalmic antibiotic use?

Answer 8

Antibiotics:
- EMPIRIC and WIDE-SPECTRUM
- should cover for the ff. organisms:
1. S. aureus
2. Coagulase (-) Streptococcus
3. H. influenzae
4. Gram (-) bacteria: coliforms
5. Pseudomonas: less likely

INDICATIONS:
1. Bacterial conjunctivitis
2. Blepharitis
3. Keratitis
4. External hordeola
5. Endophthalmitis
6. Prophylaxis pre- and post-surgery

Question 9

Discuss the different antibiotics used in ophthalmologic practice.

Answer 9

Mechanism of Action:
1. Cell wall/membrane synthesis
2. Protein synthesis
3. DNA synthesis

I. CELL WALL/MEMBRANE SYNTHESIS

A. Beta-Lactams
1. Penicillins
- penicillinase-S: Pen G & V, Amox/Ampicillin
- penicillinase-R: Naf/Oxa/Dicloxacillin
- anti-pseudomonal: Pipera/Ticar/Carbenicillin

2. Cephalosporins
   - later generation: better coverage for Gram (-) and Pseudomonas BUT lesser for Gram (+)
   - 1st Gen: Cefazolin (IV), Cefalexin (PO)
   - 2nd Gen: Cefoxitin (IV), Cefuroxime (PO)
   - 3rd Gen: Ceftriaxone, Ceftazidime, Cefixime
   - 4th Gen: Cefipime
   - 5th Gen: Ceftaroline
3. Carbapenems: Mero/Erta/Dori/Imipinem
4. Monobactam: Aztreonam

B. Glycopeptides
- Vancomycin
- Bacitracin
- Polymyxin B: cell MEMBRANE synthesis

II. PROTEIN SYNTHESIS (MALT)

A. 30S ribosomal subunit
- Aminoglycoside: Tobra/Neo/Genta/Amikacin
- Tetracycline: Doxy/Tige/Minocycline

B. 50S ribosomal subunit
- Macrolide: Erythro/Clarithro/Azithromycin
- Lincosamide: Linco/Clindamycin
- Linezolid
- Chloramphenicol

III. DNA SYNTHESIS

1. Topoisomerase inhibitor: Fluoroquinolones
   - Moxi/Gati/Oflo/Cipro/Levofloxacin
2. Folate synthesis inhibitor: Sulfonamides
   - Trimethoprim-Sulfamethoxazole
   - Pyrimethamine
3. Free radical damage: Metronidazole
4. RNA polymerase inhibitor: Rifampicin

Question 10

Discuss the different antivirals used in ophthalmologic practice.

Answer 10

MOA: inhibition of thymidine kinase needed for DNA synthesis and viral replication

HSV-1
- Acyclovir: prodrug
- Valcyclovir: prodrug but more PO bioavailable
- Famciclovir: prodrug but more PO bioavailable

Adenovirus (ser. 3, 7, 8, 19, 37)
- NO approved ocular antivirals

CMV
- NO approved ocular antivirals
- Valganciclovir: prodrug
- Ganciclovir: eye gel, oral or intravenous

Question 11

Discuss the different antifungals used in ophthalmologic practice.

Answer 11

Mechanism of Action:
1. Cell wall: Echinocandins
2. Cell membrane: Azoles, Polyenes
3. Nucleic acid & protein synthesis: Pyrimidines

I. CELL WALL SYNTHESIS

Echinocandins
- inhibit β-glucan synthesis in the fungal cell wall - similar to penicillins: β-glucan ~ peptidoglycan
- Caspo/Mica/Anidulafungin

II. CELL MEMBRANE FUNCTION INHIBITION

1. Azoles
   - disrupts ergosterol synthesis important for cell membrane integrity
   - newer triazoles: broader spectrum, better safety profile, less resistance
   - imidazole: Ketoco/Miconazole, Clotrimazole,
   - triazoles (1st Gen): Fluco/Itraconazole
   - triazoles (2nd Gen): Vorico/Posaconazole
2. Polyenes
   - binds to ergosterol in the membrane, forms pores and disrupts cell integrity
   - Natamycin/Pimaricin
   - Amphotericin B
   - Nystatin

III. DNA & PROTEIN SYNTHESIS

Flucytosine
- inhibit thymidilate synthase: DNA synthesis
- replaces uracil w/ 5-FU: protein synthesis

Question 12

What are corticosteroids?

Answer 12

Glucocorticoids
- anti-inflammatory regardless of etiology
- stimulates synthesis of lipocortin-1 which:

1. Inhibits prostaglandin and leukotriene synthesis by suppressing phospholipase A2 and cyclooxygenases
2. Suppresses inflammatory immune responses (adhesion, chemotaxis, phagocytosis)

Classification:

I. DURATION and POTENCY
- potency compared with Cortisol

A. Short-acting: < 12 hours
1. Hydrocortisone: 1.0x
2. Cortisone: 0.8x

B. Intermediate-acting: 12 - 36 hours
1. Prednisone: 3.5x
2. Prednisolone: 4.0x
3. Methylprednisolone: 5.0x
4. Triamcinolone: 5.0x

C. Long-acting: > 36 hours
1. Betamethasone: 25x
2. Dexamethasone: 30x

II. METHOD OF ADMINISTRATION

A. Topicals/Drops
- Prednisolone acetate 1%
- Dexamethasone 0.1%
- Fluorometholone 0.1%: ophthalmic use only
- Loteprednol 0.2 or 0.5%: ophthalmic use only

B. Injectables
- Triamcinolone
- Methylprednisolone

C. Systemics
- Prednisone
- Methylprednisolone
- Dexamethasone

Question 13

What is Cyclosporine?

Answer 13

• immunosuppressant drug that acts as a calcineurin inhibitor which is important in IL-2 transcription and T-lymphocyte activation and function
• used in REFRACTORY inflammatory and ocular surface diseases

Question 14

What are the common ophthalmologic allergy medications used?

Answer 14

Pathogenesis of Allergy:
1. Allergen interaction with IgE antibodies on mast cells and basophils surface
2. Cell degranulation and release of histamine
3. Histamine interacts with Histamine receptors

I. DECONGESTANTS
- induces conjunctival vasoconstriction and improves eye redness due to allergic etiologies
- long-term use NOT recommended due to rebound congestion

1. Pheniramine: antihistamine + anticholinergic
2. Naphazoline: non-selective alpha agonist
3. Oxymetazoline: non-selective alpha agonist
4. Tetrahydrozoline: alpha-2 agonist

II. ANTIHISTAMINES (H1 Receptor Antagonist)
- block the action of histamine at the H1 receptor to relieve allergic (Type I/Immediate Hypersensitivity) response

A. 1st Generation/Non-Selective
- lacks receptor selectivity: also acts on muscarinic receptors and CNS H1 receptors
- multiple side effects (sedation)

1. Diphenhydramine (IV, PO)
2. Promethazine (IV, PO)
3. Chlorpheniramine (IV, PO)
4. Pheniramine (eye drops)
5. Antazoline (eye drops)

B. 2nd Generation/Selective
- more selective for peripheral H1 receptors because unable to cross the BBB

1. Olopatadine 0.1% or 0.2% (eye drops)
   - also a mast cell stabilizer
2. Levocabastine (eye drops):
   - also a neurotensin receptor antagonist
3. Oral formulations:
   - Cetirizine/Levocetirizine
   - Loratidine/Desloratidine
   - Bilastine
   - Fexofenadine

III. MAST CELL STABILIZERS

1. Olopatadine: also an H1 receptor antagonist
2. Pemirolast 0.1%
3. Cromolyn 2% or 4%
4. Ketotifen 0.035%
5. Nedocromil 2%
6. Lodoxamide 0.1%

Question 15

What are the common medications used for Tear Film Dysfunction/Dry Eye Disease?

Answer 15

Tear Film: 2 layers
- outer lipid layer
- inner muco-aqueous layer

I. ARTIFICIAL TEARS/LUBRICANTS
- mimic the metabolic, optical and physical characteristics of natural tears
- do not contain the biologically active components found in naturally-produced tears
- indication: mild to moderate DED
- contains benzalkonium chloride (preservative)
- select preservative-free formulations if more frequent dosing (Q1) is indicated

Preparations:
1. Polyethylene glycol
2. Propylene glycol
3. Polyvinyl alcohol
4. Methylcellulose
5. Hypromellose/Hydroxypropyl Methylcellulose
6. Dextran
7. Povidone
8. Sodium hyaluronate/hyaluronan

II. NON-MEDICATED OINTMENTS
- supplements or mimics the upper lipid layer to retard evaporation of tears
- indications: moderate to severe DED, lagophthalmos, exposure keratopathy, severe corneal epithelial compromise

Preparations:
1. Petrolatum
2. Mineral oil
3. Lanolin

III. SECRETAGOGUES
- stimulates lacrimal gland function to increase tear and mucin production

A. Cholinergic Agonists
- poorly hydrolyzed by acetylcholinesterases thus the prolonged duration of action

1. Bethanechol: muscarinic receptors ONLY
2. Pilocarpine: muscarinic receptors ONLY
3. Carbachol: BOTH muscarinic and nicotinic

B. Mucolytics

1. Bromhexine
2. Ambroxol: metabolite of Bromhexine

IV. IMMUNOMODULATORS
- suppresses the underlying inflammatory process in dry eye disease
- used in refractory cases

1. Corticosteroids
2. Cyclosporine