Dr.Abdul latif MahesarDepartment of Medical

PharmacologyCollege of Medicine

Pharmacology of drugs acting on the eye

• Drugs can be delivered to ocular tissue as:– Locally (Topically): more common

1) Eye drops2) Ointments3) Injections :

–Periocular injection e.g. subconjunctival, subtenon, peribulbar, or

retrobulbar– Intraocular injectione.g. Intracameral or intravitreal

– Systemically:• Orally• IV

Routes of drug administration into the eye

Eye drops

• Eye drops- most common• one drop = 50 µl• Their contract time is low

to be used several times

Ointment

Increase the contact time of ocular medication to ocular surface thus better effect

Disadvantages The drug has to be high lipid soluble with some water solubility to have the maximum effect as ointment

Intraocular injections

• Intracameral or intravitreal• E.g.

– Intracameral acetylcholine (miochol) during cataract surgery

– Intravitreal antibiotics in cases of endophthalmitis

– Intravitreal steroid in macular edema

Peri-ocular injections

• subconjunctival, subtenon, peribulbar, or retrobulbar

• reach behind iris-lens diaphragm better than topical application

• bypass the conjunctival and corneal epithelium which is good for drugs with low lipid solubility (e.g. penicillins)

• steroid and local anesthetics can be applied this way

Systemic drugs• Oral or IV• Factor influencing systemic drug penetration

into ocular tissue:– lipid solubility of the drug: more penetration with

high lipid solubility– Protein binding: more effect with low protein

binding– Eye inflammation: more penetration with ocular

inflammation

Physiological Anatomy of the Eye

• Drugs used for the treatment of eye

• Drugs that can produce harmful effects on the eye

Pharmacology of drugs acting on the eye

Ophthalamic Uses of Drugs Autonomic drugs: Affect production and drainage of aqueous humor

Affect the size of the pupil: Miotics MydriaticsAffect accommodation (Cycloplegics).

Anti-inflammatory drugs: Glucocorticoids NSAIDs

Chemotherapeutics (antibacterial, antifungal and antiviral agents).

Local Anesthetic drugs

Drugs used for treatment of the eye

Autonomic drugs

Autonomic Nerve supply of the Eye

Parasympathetic N.S. Constriction of the pupillary sphincter muscle (miosis) Contraction of the ciliary muscle (accommodation for

near vision). Decrease in intraocular pressure ↓ IOP. increases aqueous outflow through the trabecular meshwork into

canal of Schlemm by ciliary muscle contraction Increased lacrimation Conjunctival Vasodilatation

The aqueous humor is secreted by the ciliary body. Produced by a combination of active transport of ions and ultrafiltration of interstitial fluid. The fluid flows over the surface of the lens, out through the pupil into the anterior chamber. Flows through the trabecular meshwork into Schlemm’s canal and is collected in the scleral veins.

Accomodation

Eye Parasympathetic N.S. Sympathetic N.S.

Iris radial musclecircular muscle

No effectContraction (miosis)

M3

Contraction (Mydriasis) α1 No effect

Ciliary muscle Contraction M3 Relaxation β2

Accommodation for near vision accommodation for far vision

Conjunctival blood vessels

Conjunctival Vasodilatation

Conjunctival Vasoconstriction

Intraocular pressure(IOP)

Decrease increase

Pupillary MusclesMiosis

Mydriasis

Drugs acting on parasympathetic system

Cholinergic agonists• Direct agonists

– Methacholine, carbachol, pilocarpine• Indirect acting agonists (anticholinesterases)

– Reversible :Physostigmine– Irreversible: Ecothiophate

USES:-Glaucoma (open and closed angle)-Counteract action of mydriatics- To break adhesions- in accommodative esotropia (ecothiophate)- In lice infestation of lashes (physostigmine)

 Adverse Effects of cholinergic agonists: Miosis Salivation Sweating bronchial constriction vomiting and diarrhea CNS effects: high doses (physostigmine & pilocarpine)

Ocular side effects: diminished vision (myopia), headache,

Contraindications of cholinergic agonists:Bronchial asthma.Peptic ulcer.Angina pectorisIncontinenceIntestinal obstruction

Cholinergic drugsDrugs Ocular usesAcetycholineCarbacholMethacholine

Induction of miosis in surgeryGlaucoma

Pilocarpine In open angle glaucoma

Physostigmine Glaucoma, accommodative esotropia

Ecothiophate Glaucoma, accommodative esotropia

Mydriasis due to relaxation of circular muscles

Cycloplegia (loss of near accommodation) due to relaxation of ciliary muscles

Loss of light reflex. increased I.O.P # glaucoma. Lacrimal secretion sandy eye

Drugs Duration of effect

Natural alkaloids Atropine Scopolamine (hyoscine)

7-10 days3-7 days

Synthetic atropine substitutes Homatropine Cyclopentolate Tropicamide

1-3 days24 hour6 hour

Cholinergic antagonists (Muscarininc antagonists)

USES:- To prevent adhesion in uveitis & iritis - Funduscopic examination of the eye- Measurement of refractive error

Side effects: blurred vision, tachycardia, constipation, urinary retention, dryness of mouth , dry sandy eyes, feverCNS effects: sedation, hallucination, excitation (toxic dose).

Contraindications of antimuscarinic drugsGlaucoma (angle closure glaucoma)Tachycardia, Prostate hypertrophy in old patients.Constipation, paralytic ileus.

Drugs acting on sympathetic systemAdrenergic agonistsNon-selective agonists (α1, α2, β1, β2), eye drops• e.g. epinephrine, depevefrin (pro-drug of epinephrine)• Uses: open angle glaucoma• Mechanism: uveoscleral outflow of aqueous humor• Side Effects: cardiovascular arrhythmia, tachycardia • C/I in closed angle glaucoma in patients with narrow anglesα1 agonists e.g. phenylepherine• mydriasis (without cycloplegia), decongestantUses: - Funduscopic examination of the eye- To prevent adhesion in uveitis & iritis - Decongestant in minor allergic hyperemia of eye

• C/I in closed angle glaucoma in patients with narrow angles• Can cause significant increase in blood pressure

α2 agonists e.g. apraclonidine (eye drops)

Uses: glaucoma treatment, prophylaxis against IOP spiking afterglaucoma laser procedures

Mechanism: production of aqueous humor

Side Effects: Lethargy, fatigue, dry mouth [apraclonidine is aderivative of clonidine (antihypertensive) which cannot crossBBB to cause systemic hypotension.

β blockers– non-selective: timolol, carteolol– selective: betaxolol (beta 1 “cardioselective”)– Given topically as eye drops

Uses: open angle glaucoma

Mechanism: Act on ciliary body to production of aqueous humor

Advantages can be used in patients with hypertension/ischemic heart disease

Contraindications• Bronchospasm (less with betaxolol)• Cardiovascular (bradycardia, hypotension, asystole, syncope)• Depression• C/I in asthmatic patients or patients with pacemaker.

Treatment of open angle glaucoma (chronic)

The main goal is to decrease IOP and this can be obtained by:

Decreasing production of aqueous humor Beta blockers Alpha-2 agonists Carbonic anhydrase inhibitors

Increasing outflow of aqueous humor Prostaglandins Adrenergic agonists, nonspecific Parasympathomimetics

Prostaglandins and Beta blockers are the most popular

Carbonic anhydrase inhibitors

e.g. acetazolamide (oral), dorzolamide (topical)

Mechanism: production of aqueous humor by blocks carbonic anhydrase enzyme required for production of bicarbonate ions (transported to posterior chamber, carrying osmotic water flow).

Side Effects: myopia, malaise, anorexia, GI upset, headachemetabolic acidosis, renal stone, bone marrow suppression “aplastic anemia”Contraindication: sulpha allergy, digitalis users, pregnancy

Prostaglandins

Latanoprost (Most preferred dru due to lesser adverse effects,

they have replaced beta blockers

They are used once a day

travoprost Are prostaglandins F2α analogs

Mechanism:

uveoscleral outflow by relaxing ciliary body muscle

Uses: open angle glaucoma

Administration: Topical drops

Side Effects: Iris color change

Drug Therapy of acute angle closed glaucoma(narrow angle)

• Is associated with occlusion of the outflow drainage pathway• Acute, painful increases of pressure • emergency situation that require treatment before surgery

(Iridectomy)

The use of drugs is limited to : • Oral Acetazolamide• Topical cholinomimetics e.g.: pilocarpine• Dehydrating agents: IV infusion Of hypertonic solution

( Mannitol, Glycerol)• Analgesics: pethidine or morphine (for pain)

Osmotic agents

• Dehydrate vitreous body which reduce IOP significantly

• E.G. – glycerol 50% syrup (cause nausea, hyperglycemia)– Mannitol 20% IV (cause fluid overload and not

used in heart failure)

Anti-inflammatory

corticosteroid NSAID

Corticosteroids

• Mechanism: inhibition of arachidonic acid release from

phospholipids by inhibiting phosphlipase A2

• Topical– E.g. prednisolone, dexamethasone, hydrocortisone– Uses: postoperatively, anterior uveitis, severe allergic

conjunctivitis, scleritis, prevention and suppression of corneal graft rejection

• Systemic:– E.g. prednisolone, cortisone– Uses: posterior uveitis, optic neuritis

CorticosteroidsSide effects: – Glaucoma, cataract, ptosis, mydriasis, scleral melting,

skin atrophy– Suppression of pituitary-adrenal axis– Hyperglycemia, Osteoporosis– Peptic ulcer, Psychosis, susceptibility to infections

NSAID• E.g. ketorolac, diclofenac• Mechanism: inhibition of cyclo-oxygenase • Uses: postoperatively, mild allergic conjunctivitis,

episcleritis, mild uveitis, cystoid macular edema, preoperatively to prevent miosis during surgery

• Side effects: stinging

Harmful drugs for the Eye

Drugs that ↑ IOP: Mydriatic cycloplegics, tricyclic antidepressants Chronic steroid use

Cataractogenic drugs: steroids, phenothiazines, heavy metals…

Oxygen : 40 % O2 for prolonged periods in premature infants causes Retrolental fiboplasia

Drugs causing corneal deposits: chloroquine, amiodarone,•Amiodarone , a cardiac arrhythmia drug•causes optic neuropathy (mild decreased vision, visual field defects)•causes corneal keratopathy (corneal verticillata) which is pigmented deposits in the corneal epithelium.

•Digitalis , cardiac failure drug•Causes chromatopsia (objects appear yellow) with overdose

Antibiotics • Penicillins, Cephalosporins, macrolides• Sulfonamides, Tetracyclines, chloramphenicol• Aminoglycosides, Fluoroquinolones, Vancomycin

Uses Conjunctivitis (inflammation of conjunctiva) Keratitis (corneal inflammation) Blepharitis (eye lid inflammation) Endophthalmitis (intraoculatr tissue inflammation). Used topically in prophylaxis (pre and postoperatively) and

treatment of ocular bacterial infections. Used orally for the treatment of preseptal cellulitis

e.g. amoxycillin with clavulonate Used intravenously for the treatment of orbital cellulitis e.g. gentamicin, cephalosporin, vancomycin Can be injected intravitrally for the treatment of endophthalmitis

Antibiotics• Trachoma can be treated by topical and systemic

tetracycline or erythromycin, or systemic azithromycin.

• Bacterial keratitis (bacterial corneal ulcers) can be treated by topical fortified penicillins, cephalosporins, aminoglycosides, vancomycin, or fluoroquinolones.

• Bacterial conjunctivitis is usually self limited but topical erythromycin, aminoglycosides, fluoroquinolones, or chloramphenicol can be used

Local anesthetics• Topical

– E.g. propacaine, tetracaine– Uses:removal of corneal foreign bodies, removal of

sutures, examination of patients who cannot open eyes because of pain

– Adverse effects: toxic to corneal epithelium, allergic reaction rare

• Orbital infiltration– peribulbar or retrobulbar– cause anesthesia and akinesia for intraocular surgery– e.g. lidocaine, bupivacaine

Other agents

• methanol – optic atrophy and blindness

• Ethambutol – optic neuropathy

• Chloramphenicol and streptomycin – optic atrophy

• Hypervitaminosis A – yellow skin and conjunctiva,

pseudotumor cerebri (papilledema), retinal

hemorrhage.

• Hypovitaminosis A – night blindness (nyctalopia).