Ocular Pharmacology And Toxicology

Objectives

• Explain the basic principals of pharmacodynamics and pharmacokinetics.

• List main drugs used in the eye and their routes of administration.

• Describe commonly encountered adverse drug effects in ocular therapeutics and diagnostics.

• Enlist agents that can cause Toxic Optic Neuropathy.

• Describe select Ocular toxicology manifestations.

Pharmacodynamics

• Study of mechanisms of drug effects

• Receptor - special types based on transduction of signal • Regulation of receptors – Down regulation Up regulation • Therapeutic index

Distribution

• Barriers concerned with distribution Blood aqueous barrier Blood retinal barrierCorneal barrier

Tissue binding

Tissue perfusion

Drugs used in the eye:• Miotics e.g. pilocarpine Hcl• Mydriatics e.g. atropine• Cycloplegics e.g. atropine• Anti-inflammatories e.g. corticosteroids• Anti-infectives (antibiotics, antivirals

and antibacterials)• Anti-glucoma drugs e.g. pilocarpine Hcl• Surgical adjuncts e.g. irrigating

solutions• Diagnostic drugs e.g. sodiumfluorescein• Anesthetics e.g. tetracaine

ADVERSE DRUG EFFECTS

SIDE EFFECTS

TOXIC EFFECTS

INTOLERANCE

TERATOGENICITY

Routes of administrationLocal- Topical – EYE DROP AND OINT

Periocular Intraocular

• Systemic oral

Injection

Topical drug methods

Eye drops

Eye ointment

Gels

Ocuserts

Soft contact lens

Drug Penetration

• Topically : -Lipid and water solubility -Contact time , viscosity , - isotonicity

• Systemically : - Lipid solubility - eye inflammation - protein binding -molecular weight

Ocular anaesthetics

MOA :- Reduce nerve impulse conduction by reducing membrane to sodium ions.

Common local anaestheitics :-

Ester type = Tetracaine 0.5 % ,

Propacaine 0.75 %

Amide type = Lidocaine 2 % ,

Bupivacaine 0.75 %

Topical anaesthetic Aim :- To block nerves of superficial cornea

Advantages :- No needle insertion

No hemorrhage

Systemic anticoagulants can use

Patient alert

Disadvantages :- No akinesia

Not adequate Anaesthesia

Adv effects :- Corneal Stinging ,Epithelial & Endothelial

Toxicity Allergy & Contact dermatitis

Contraindications :- Nystagmus , Uncooperative patients

Retrobulbar block

Aim :- To block 3rd cranial nerve in posterior intraconal space

Site of injection :- Above inferior orbital rim

midway of lateral canthus & temporal limbus

Advantages :- Excellent akinesia

quick onset of block

Disadvantages:- High complication rate

Complications :- Retrobulbar Haemorrhage

Globe perforation

Optic nerve contusion

Oculocardiac reflex

Respiratory depression

Peribulbar block

Aim :- To block extraconally the nerves

Site of injection :- midway b/w temporal limbus & lateral canthus

-Inferomedial to superior orbital notch

Advantages :- All that of retrobulbar block

Less complications

Disadvantages :- More than one injection needed

Only good akinesia , anesthesia

Longer time for anesthesia

Chemosis

Sub tenon’s block

At 1 or 2 ‘0’ clock positions from corneal limbus [7-8 mm away]

Using a 30 mm radius flexible cannula after perforating conjunctiva

Passed beyond equator b/w tenon’s capsule & sclera

Most frequent site is inferotemporal .

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Intraocular injections

• Intracameral or intravitreal• E.g.

– Intracameral acetylcholine (miochol) during cataract surgery

– Intravitreal antibiotics in cases of endophthalmitis

– Intravitreal steroid in macular edema

– Intravitreal Anti-VEGF for DR

INTRA-OCULAR INJECTIONS

Mydriatics & Cycloplegics Anticholinergic drugs :- Atropine 1 % - 1 week Homatropine 2 % - 24 hrs Cyclopentolate 1 % - 24 hrs Tropicamide 0.5 % - 4 hrs

Indications :- corneal ulcer, uveitis , cycloplegic refractionSide effects :- blurry vision, photophobia, precipitates angle closure glaucomaSympathomimetics :- Phenylephrine 5 %

Indications - Along with mydriatic in Preoperative cataract preparation, fundus examinationSide effects - Stinging , rise in Blood pressure

Cholinergic agonists Cholinergic agonists

• Directly acting agonists:– E.g. pilocarpine, acetylcholine (miochol), carbachol (miostat)

– Uses: miosis, glaucoma

– Mechanisms:• Miosis by contraction of the iris sphincter muscle • Increases aqueous outflow through the trabecular meshwork by longitudinal ciliary

muscle contraction• Accommodation by circular ciliary muscle contraction

– Side effects: • Local: diminished vision (myopia), headache, cataract, miotic cysts, and rarely

retinal detachment• Systemic side effects: lacrimation, salivation, perspiration, bronchial spasm, urinary

urgency, nausea, vomiting, and diarrhea

Cholinergic agonistsCholinergic agonists• Indirectly acting (anti-cholinesterases) :

– More potent with longer duration of action

– Reversible inhibitors

• e.g. physostigmine

• Used in glaucoma and lice infestation of lashes

• Can cause CNS side effects

Cholinergic agonistsCholinergic agonists• Indirectly acting

(anticholinesterases):

– Irreversible:

• e.g. phospholine iodide

• Uses: in accommodative

esotropia

• Side effects: iris cyst and

anterior subcapsular cataract

• C/I in angle closure glaucoma,

asthma, Parkinsonism

• Causes apnea if used with

succinylcholine or procaine

Cholinergic antagonistsCholinergic antagonists

• E.g. tropicamide, cyclopentolate, homatropine, scopolamine, atropine• Cause mydriasis (by paralyzing the sphincter muscle) with cycloplegia (by

paralyzing the ciliary muscle)

• Uses: fundoscopy, cycloplegic refraction, anterior uveitis• Side effects:

– local: allergic reaction, blurred vision– Systemic: nausea, vomiting, pallor, vasomotor collapse, constipation, urinary

retention, and confusion– Specially in children they might cause flushing, fever, tachycardia, or delerium – Treatment by DC or physostigmine

Adrenergic agonistsAdrenergic agonists

• Non-selective agonists (α1, α2, β1, β2)

– E.g. epinephrine, depevefrin (pro-drug of

epinephrine)

– Uses: glaucoma

– Side effects: headache, arrhythmia,

increased blood pressure, conjunctival

adrenochrome, cystoid macular edema in

aphakic eyes

– C/I in closed angle glaucoma

Adrenergic agonistsAdrenergic agonists• Alpha-1 agonists

• E.g. phenylepherine

• Uses: mydriasis (without cycloplegia), decongestant

• Adverse effect:

– Can cause significant increase in blood pressure specially in infant and

susceptible adults

– Rebound congestion

– precipitation of acute angle-closure glaucoma in patients with narrow

angles

Adrenergic agonistsAdrenergic agonists

• Alpha-2 agonists

– E.g. brimonidine, apraclonidine

– Uses: glaucoma treatment, prophylaxis against IOP spiking after glaucoma laser procedures

– Mechanism: decrease aqueous production, and increase uveoscleral outflow

– Side effects:• Local: allergic reaction, mydriasis, lid retraction, conjunctival blanching.

• Systemic: oral dryness, headache, fatigue, drowsiness, orthostatic hypotension, vasovagal attacks.

– Contraindications: infants, MAO inhibitors users

Alpha adrenergic Alpha adrenergic antagonistsantagonists

• E.g. thymoxamine, dapiprazole.

• Uses: to reverse pupil dilation produced by phenylepherine.

• Not widely used.

Beta-adrenergic Beta-adrenergic blockersblockers

• E.g. – Non-selective: timolol,

levobunolol, metipranolol, carteolol

– Selective: betaxolol (beta 1 “cardioselective”)

• Uses: glaucoma.

• Mechanism: reduce the formation

of aqueous humor by the ciliary body.

• Side effects: bronchospasm (less

with betaxolol), cardiac impairment.

Carbonic anhydrase Carbonic anhydrase inhibitorsinhibitors

• E.g. acetazolamide, methazolamide, dichlorphenamide, dorzolamide, brinzolamide.

• Uses: glaucoma, cystoid macular edema, pseudotumour cerebri.

• Mechanism: aqueous suppression.• Side effects: myopia, parasthesia, anorexia, GI upset, headache, altered taste and

smell, Na and K depletion, metabolic acidosis, renal stone, bone marrow suppression “aplastic anemia”.

• Contraindication:

sulpha allergy, digitalis users, pregnancy.

Prostaglandin Prostaglandin analoguesanalogues

• E.g. latanoprost, Bimatoprost, Travoprost, Unoprostone

• Uses: Glaucoma

• Mechanism: increase uveoscleral aqueous outflow

• Side effects: darkening of the iris (heterochromia iridis), lengthening and thickening of eyelashes, intraocular inflammation, macular edema.

Hypertonic agents

MOA - Raises the osmotic pressure to reduce intra

ocular pressure

Glycerol [10 % infusion /1gm /kg oral ]

Side effects : nauseating sweet taste ,

diarrhoea,headache

Mannitol [ 20 % infusion ]

Side effects : Hypervolemia , pulmunory edema

Drugs during glaucoma surgery

ANTIFIBROBLASTIC AGENTS –5 FU &MITOMYCIN-C

MOA - Inhibit collagen and protein synthesis by interfering

with DNA transcription and replication

Side effects : 5 FU – keratopathy

Mitomycin - scleral ulcer & iritis

Administration : 5 FU - 50 mg/ml Sponge / sub conjunctival

mitomycin – 0.5 mg/ml topically

Antibacterials

PENICILLINS MOA :- Bactericidal Destroys cell wall [gram + , gram – cocci,spirochetes] - penicillin G [1 lakh U/ml topical] [0.5 M U/ ml sub conj inj ] [5 M U / 4 hrs IV] - Cloxacillin [penicillinase resistant] [50-100 mg/kg] 6 hrly oral [staphylococci] - Amoxycillin [25-50 mg/kg] 6 hrly oral [ gram +,- bacteria]

Adverse eff :- Hypersensitivity reactions , rash ,

QUINOLONES

MOA :- [Bacterial] Anti DNA gyrase – inhibits division & supercoiling

[gram -- bacteria , gram + bacteria ,chlamydia, mycoplasma]

Ciprofloxacin :- 0.3 % topical , 500 mg BD oral , 5-10 mg/kg IV

200 mg /ml intravitreal

Uses :- Keratoconjunctivitis, ulcers,blepharitis,

dacryocystitis , infectious endoophthalmitis

S/E :- Arthropathy in children ,GIT irritation,

Photosensitivity ,rash, liver damage

Gatifloxacin :-

CEPHALOSPORINS

MOA :- Bactericidal – destroys cell wall

1 st generation :- gram + cocci & gram – bacilli

Cephazolin – 0.5 – 1 g/ml 8 hrly IM /IV

2000 ug Intravitreal , 100 mg S/C

Cefadroxil – 0.5 -1 g BD oral

S/E :- GIT disturbances ,hypoprothrombinemia

2 nd generation :- gram – bacteria ,some anaerobes

Cefuroxime axetil – 250-500 mg BD oral

Cefoxitin – 1-2 gm 8 hrly IM/IV

S/E :- GIT disturbances , migraines, headache

3 rd generation :- gram – bacteria

Cefixim – 200-400 mg bd oral

Ceftazidim -1-2 gm 8 hrly IM/IV

S/E: diarrhoea , neutropenia, thrombocytopenia

• 4 th generation :- against many bacteria , highly resistant to B –lactamases

Cefepime & cefpirome :- 1-2 gm 8 hrly IM/IV

S/E : allergic reactions, breathing difficulty,

swelling of face,

Uses :- Along with Aminoglycosides

In Endoophthalmitis and bacterial corneal ulcers,

Chloramphenicol

MOA :- Bacteriostatic , Inhibits Protein synthesis by binding to 50 S ribosomal subunit

[gram +,- aerobes , chlamydia,ricketssia,mycoplasma]

0.5 % ointment, 50 mg /kg 4 times oral

2 mg/ml intravitreal

Uses :- Intraocular infections

Conjunctivitis

Side effect :- Bone marrow depression

Aplastic anemia , agranulocytosis

Tetracycline

MOA :- Bacteriostatic - inhibits protein synthesis by binding to 30 S Ribosome

- 250-500 mg 4 hrly oral

- 1 % topical

Uses :- Chlamydial diseases

phlyctenular conjunctivitis

Toxoplasmosis

Ocular rosacea

Side effect :- GIT disturbances

discolouration of teeth

photosensitivity , rashes nephrotoxicity

AMINOGLYCOSIDES MOA :- Bacteriocidal - inhibits protein synthesis ,binding 30 S

Ribosome sub unit

[gram negative bacteria & staph aureus

ADR : Ototoxicity , nephrotoxicity ,corneal Retinotoxicity,

Gentamycin :- 0.3 % drops, 20 mg sub conjunctival inj

200 ug/ml intravitreal inj

Uses :- Endoophthalmitis , ocular injuries ,retained FB

conjunctival necrosis

Amikacin :- 0.3 % drops , 15 mg / kg 8 hrly IV , 0.4 mg Intravitreal

Uses :- along vancomycin in post op endophthalmitis

Tobramycin :- Including proteus,pseudomonas

0.3 % drops , 3 - 5 mg /kg /day IV , 150-200 ug /ml

SULPHONAMIDES

MOA :- Bacteriostatic - Inhibits folate synthesis

[PABA folic acid ]

[gram - ,+ bacteria] - Sulfacetamide , Sulfamethoxazole , sulfadiazine- Topically 10% ,20 % ,30 % drops- Oral 2-4 gm/day TDS

COTRIMOXAZOLE MOA :- Inhibits Dihydro folate reductase in conversion of DHF THF Sulfamethoxazole [400 mg ] + trimethoprim [80 mg]

USES :- In trachoma

Along with pyrimethamine in Toxoplasmosis

S/E :- GIT disturbances , Hypersensitivity Reactions , Urticaria ,

Renal toxicity-Crystalluria.

AntifungalsPolyene antibiotics :-

MOA - Selective action on ergosterol of fungal cell membrane

forming micropores – increase permeability

Amphotericin B–Against yeast,filamental fungi[0.25 % topical ]

[0.25mg/kg oral]

Nystatin - against candida [ 1 lakh u/gm oint]

Natamycin – against candida , aspergillus ,fusarium [ 5 % suspension]

Uses in keratomycosis and endophthalmitis[5-10 ug intravitreal]

Common side effects : allergic hypersensitivity reactions

Imidazoles :-

MOA - Block fungal cytochrome P-450 enzyme in ergosterol

[increase permeability tru membrane]

Clotrimazole :- [1 % topical]

Miconazole :- [ 1 % drops,2 % oint, 5-10 mg sub conj ]

Ketoconazole :- [200-800 mg oral daily , 0.5 mg intravitreal]

Uses :- candida,fungal , endoophthalmitis

Side effect:- liver toxicity

Triazoles :-

Fluconazole - [100-200 mg oral]

[0.2% topical]

[0.1 mg intravitreal]

Uses :- Candida,cryptococcus

Anti virals PYRIMIDINE DERIVATIVES Idoxuridine :- 0.1 % drops hrly / 0.5 % ointment TRIFLUOROTHYMIDINE :- 1 % drops

MOA : By incorporation - inhibition of viral DNA synthesis Uses :- Dendritic ulcer , herpes simplex keratoconjunctivitis

Side effects :-with corticosteroids – SPK, follicular conjunctivitis,

PURINE DERIVATIVESADENINE ARABINOSIDE MOA :- Blocking DNA synthesis of virus Acyclovir - 3 % ointment , 400-800 mg 5 times/day a week Uses :- EB virus, CMV ,Herpes zoster virus,.. S/E :- Allergic reactions,.. Valacyclovir - 1000 mg TDS Famciclovir - 500 mg TDS S/E :- GIT disturbances Ganciclovir - 5-6 mg intravitreal inj , 5 mg IV S/E :- bone marrow depression , rashes

Ocular anti-allergicsMOA – Competitive Antagonist of H1 receptors

Uses - Vernal Keratoconjunctivitis, Giant papillary conjunctivitis

Allergic conjunctivitis

CPM – 4 times /day topical

Azelastine - 2 times/day

Loratadine/ cetrizine – at bed time

Mast cell stabilizers

MOA – Stabilizes mast cells and prevent release of histmaine

Cromolyn sodium [2-4 % ] 6 hrly

Olapatadine [0.1 % ] 12 hrly

Anti-allergics Anti-allergics • Avoidance of allergens, cold compress, lubrications• Antihistamines (e.g.pheniramine, levocabastine)• Decongestants (e.g. naphazoline, phenylepherine, tetrahydrozaline)• Mast cell stabilizers (e.g. cromolyn, lodoxamide, pemirolast, nedocromil,

olopatadine)• NSAID (e.g. ketorolac)• Steroids (e.g. fluorometholone, remixolone, prednisolone)• Drug combinations

CorticosteroidsMOA :

In general : Anti inflammatory action - fibroblast formation

reduce capillary permeable

Topical steroids

1 % Prednisolone

0.1 % FML

0.1 % Dexamethasone in Conjunction to Antibiotic

Uses :

Allergic conjunctivitis , Iritis, Keratitis ,Episcleritis

Injection steroids :

40 mg Triamcinolone Acetate - Periocular

1 mg Dexamethasone - Intravitreal

Uses :

Endoophthalmitis, Cysotid Macular Edema,

Oral steroids :

1 - 2mg /kg /wt -orbital inflammation

Post operative inflammation

Panuveitis

Adverse drug reaction :

Prolonged use - Posterior Sub Capsular Cataract

Glaucoma

NSAID• E.g. ketorolac 0.5 % , flurbiprofen 0.03 %,..

• Mechanism: inactivation of cyclo-oxygenase

• Uses: postoperatively mild allergic conjunctivitis episcleritis, mild uveitis, cystoid macular edema

• Side effects: stinging , burning

Anti VEGF

• MOA : Inhibits Vascular EGF in Retinal Ischaemia Uses :Diabetic Retinopathy, Macular Edema, ROP, ARMD Intravitreal Inj - Pegaptanib [macugen ] Ranibizumab [ lucentis]

Drugs for dry eyeCharacteristics of ideal tear drops : - Soothing effect - Proper wetting agent , Viscious - No epithelial toxicity - Alkaline p H

MOA : Mucomimetic - bind to corneal epithelium form

Hydrophilic layer to stabilize tear film . Hydroxy propyl methyl cellulose – 0.5 - 1 % Polyvinyl alcohol -- 1.4 %Carboxy methyl cellulose -- 0.5 %

ViscoelasticsProperties - Optical

- Cohesive [ space maintaining

tissue manipulation in surgery]

- Dispersive [ Coating ocular surface

protecting corneal endothelium

lower surface tension]

- Elasticity

Sodium hyaluronate 1 %

Sodium hyaluronate 3 % & chondroitin sulphate 4 %

Hydroxy propyl methyl cellulose 3 %

Uses :-

- In gonioscopy

- In intra ocular surgeries

IRRIGATING SOLUTIONS Characteristics of an ideal solution :

-- Maintain moisture of & cleanse ocular tissues

-- Isotonicity electrolyte and p H same as aqueous

-- Maintain pressure of globe

-- Protect delicate ocular structures

-- Endothelial nourishment

Available preparations :- Balanced salt solution[BSS]

BSS plus

Dextran containing soln

Glucose fortified BSS plus

USES :-Intraocular – in cataract surgery

Extraocular – FB removal,tonometry,gonioscopy

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Ocular diagnostic drugs

• Fluorescein dye– Available as drops or strips – Uses: stain corneal abrasions,

applanation tonometry, detecting wound leak, NLD obstruction, fluorescein angiography

– Caution:• stains soft contact lens• Fluorescein drops can be

contaminated by Pseudomonas sp.

Ocular Diagnositic Drugs

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• Rose bengal stain– Stains devitalized epithelium– Uses: severe dry eye, herpetic keratitis

Complications of topical Complications of topical administrationadministration

• Mechanical injury from the bottle e.g. corneal

abrasion

• Pigmentation: epinephrine-adrenochrome

• Ocular damage: e.g. topical anesthetics,

benzylkonium.

• Hypersensitivity: e.g. atropine, neomycin,

gentamicin.

• Systemic effect: topical phenylephrine can

increase BP.

Amiodarone Amiodarone

• A cardiac arrhythmia drug.

• Causes optic neuropathy (mild decreased vision, visual field defects, bilateral optic disc swelling).

• Also causes corneal vortex keratopathy (corneal verticillata) which is whorl-shaped pigmented deposits in the corneal epithelium.

Chloroquines Chloroquines

• E.g. chloroquine, hydroxychloroquine

• Used in malaria, rheumatoid arthritis,

SLE.

• Cause vortex keratopathy (corneal

verticillata) which is usually

asymptomatic but can present with

glare and photophobia.

• Also cause retinopathy (bull’s eye

maculopathy).

Chorpromazine Chorpromazine

• A psychiatric drug.

• Causes corneal punctate epithelial opacities, lens surface

opacities.

• Rarely symptomatic.

• Reversible with drug discontinuation.

Thioridazine Thioridazine

• A psychiatric drug.

• Causes a pigmentary retinopathy after high dosage.

Diphenylhydantoin Diphenylhydantoin

• An epilepsy drug.

• Causes dosage-related cerebellar-vestibular

effects:

– Horizontal nystagmus in lateral gaze.

– Diplopia, ophthalmoplegia.

– Vertigo, ataxia.

• Reversible with the discontinuation of the drug.

Topiramate Topiramate

• A drug for epilepsy

• Causes acute angle-closure glaucoma (acute eye

pain, redness, blurred vision, haloes).

• Treatment of this type of acute angle-closure

glaucoma is by cycloplegia and topical steroids

(rather than iridectomy) with the discontinuation of

the drug,.

Ethambutol Ethambutol

• An anti-TB drug.

• Causes a dose-related optic neuropathy.

• Usually reversible but occasionally permanent visual damage might

occur.

HMG-CoA reductase HMG-CoA reductase inhibitors (statins)inhibitors (statins)

• Cholesterol lowering agents

• E.g. pravastatin, lovastatin, simvastatin, fluvastatin, atorvastatin, rosuvastatin

• Can cause cataract in high dosages specially if used with erythromycin

Other agentsOther agents

• Methanol – optic atrophy and blindness.

• Contraceptive pills – pseudotumor cerebri (papilledema), and

dryness (CL intolerance).

• Chloramphenicol and streptomycin – optic atrophy.

• Hypervitaminosis A – yellow skin and conjunctiva,

pseudotumor cerebri (papilledema), retinal hemorrhage.

• Hypovitaminosis A – night blindness (nyctalopia),

keratomalacia.

Select Ocular toxicology manifestations:

Digitalis :- Chromatopsia [seeing

yellow colour ]

Chloroquine :- Bull’s eye maculopathy

Ethambutol :- Optic neuropathy ,

colour vision disturbed

Corticosteroids :- Posterior sub

capsular cataracts

Thioridazine :- Pigmentary retinopathy

Copper, Gold :- Lenticular opacities

Rifabutin :- Anterior uveitis

Agents that Can Cause Toxic Optic Neuropathy

• Methanol • Ethylene glycol (antifreeze) • Chloramphenicol • Isoniazid • Ethambutol • Digitalis • Chloroquine • Streptomycin • Amiodarone • Quinine • Vincristine and methotrexate

(chemotherapy medicines) • Sulfonamides • Melatonin

• High-protein diet • Carbon monoxide • Lead • Mercury • Thallium (alopecia, skin rash, severe

vision loss) • Malnutrition with vitamin B-1

deficiency • Pernicious anemia (vitamin B-12

malabsorption • phenomenon) • Radiation (unshielded exposure to

>3,000 rads).

Key points ---systemic drugs that can cause ocular side effects