Post on 19-Dec-2015
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