Pharmacology of drugs acting on the eye Dr.Abdul latif Mahesar Department of Medical Pharmacology College of Medicine

Routes of drug administration into the eye Drugs can be delivered to ocular tissue as: Locally (Topically): more common Eye drops Ointments Injections : Periocular injection e.g. subconjunctival, subtenon, peribulbar, or retrobulbar Intraocular injection e.g. Intracameral or intravitreal Systemically: Orally IV

Eye drops Ointment Eye drops- most common one drop = 50 µl Their contract time is low to be used several times 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 Peri-ocular injections Intraocular injections Intracameral or intravitreal E.g. Intracameral acetylcholine (miochol) during cataract surgery Intravitreal antibiotics in cases of endophthalmitis Intravitreal steroid in macular edema 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

Pharmacology of drugs acting on the eye Drugs used for the treatment of eye Drugs that can produce harmful effects on the eye

Ophthalamic Uses of Drugs Autonomic drugs: Affect production and drainage of aqueous humor Affect the size of the pupil: Miotics Mydriatics Affect accommodation (Cycloplegics). Anti-inflammatory drugs: Glucocorticoids NSAIDs Chemotherapeutics (antibacterial, antifungal and antiviral agents). Local Anesthetic drugs

Drugs used for treatment of the eye Chemotherapeutic agents Local anesthetics Anti-inflammatory drugs Miotics Mydriatics Cycloplegics 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 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

Sympathetic N.S. Parasympathetic N.S. Eye Contraction (Mydriasis) α1 No effect Contraction (miosis) M3 Iris radial muscle circular muscle Relaxation β2 Contraction M3 Ciliary muscle accommodation for far vision for near vision Accommodation Conjunctival Vasoconstriction Conjunctival Vasodilatation Conjunctival blood vessels increase Decrease Intraocular pressure(IOP)

Pupillary Muscles Miosis 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)

bronchial constriction vomiting and diarrhea  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 pectoris Incontinence Intestinal obstruction

Cholinergic drugs Ocular uses Drugs Induction of miosis in surgery Glaucoma Acetycholine Carbachol Methacholine In open angle glaucoma Pilocarpine Glaucoma, accommodative esotropia Physostigmine Ecothiophate

Cholinergic antagonists (Muscarininc antagonists) 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 Duration of effect Drugs 7-10 days 3-7 days Natural alkaloids Atropine Scopolamine (hyoscine) 1-3 days 24 hour 6 hour Synthetic atropine substitutes Homatropine Cyclopentolate Tropicamide

To prevent adhesion in uveitis & iritis 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, fever CNS effects: sedation, hallucination, excitation (toxic dose). Contraindications of antimuscarinic drugs Glaucoma (angle closure glaucoma) Tachycardia, Prostate hypertrophy in old patients. Constipation, paralytic ileus.

Drugs acting on sympathetic system Adrenergic agonists Non-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 angles α1 agonists e.g. phenylepherine mydriasis (without cycloplegia), decongestant Uses: Funduscopic examination of the eye To prevent adhesion in uveitis & iritis Decongestant in minor allergic hyperemia of eye Can cause significant increase in blood pressure

α2 agonists e.g. apraclonidine (eye drops) Uses: glaucoma treatment, prophylaxis against IOP spiking after glaucoma laser procedures Mechanism:  production of aqueous humor Side Effects: Lethargy, fatigue, dry mouth [apraclonidine is a derivative of clonidine (antihypertensive) which cannot cross BBB to cause systemic hypotension.

β blockers selective: betaxolol (beta 1 “cardioselective”) 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, headache metabolic 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)

Dehydrate vitreous body which reduce IOP significantly E.G. 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)

Corticosteroids Topical Systemic: 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

Corticosteroids Side 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 Uses 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).