Pharmacology of drugs acting on the eye

1. Pharmacology of drugs acting on the eye Prof. Hanan Hagar Pharmacology Unit Physiology Department College of Medicine King Saud University

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

3. Eye drops 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 • Eye drops- most common • one drop = 50 µl • volume of conjunctival cul-de-sac 7-10 µl

4. Peri-ocular injections Intraocular injections • subconjunctival, 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 • Intracameral or intravitreal • E.g. • Intracameral acetylcholine (miochol) during cataract surgery • Intravitreal antibioticsin cases of endophthalmitis • Intravitreal steroid in macular edema

5. 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

6. Physiological Anatomy of the Eye

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

8. Ophthalamic Uses of Drugs • Autonomic drugs: • 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

9. Drugs used for treatment of the eye Autonomic drugs

10. 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

12. 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.

14. Autonomic control of pupil (A) and site of action of mydriatics (B) and miotics (C)

15. Accomodation

16. Sympathetic N.S. • Contraction of dilator Pupillae ( Mydriasis) α1 • Relaxation of ciliary muscles (accommodation for far vision) β receptors • Increase in intraocular pressure • Lacrimation α1 • Vasoconstriction of conjunctival blood vessels α1 • β receptors in the blood vessels of the ciliary processes →production of aqueous humour. • β antagonists reduces the production of aqueous humor • α agonists increase outflow of aqueous humor and ↓ IOP

18. Pupillary Muscles Miosis Mydriasis

19. Drugs acting on parasympathetic system Cholinergic agonists • Direct agonists • Methacholine, carbachol, pilocarpine • Indirect acting agonists (anticholinesterases) • Reversible :Physostigmine • Irreversible: Ecothiophate USES: -Glaucoma (open angle glaucoma) -Counteract action of mydriatics • To break adhesions • in accommodative esotropia (ecothiophate)

20. 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

21. Cholinergic drugs

22. Cholinergic antagonists (Muscarininc antagonists) • Passive 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

23. 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.

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

25. 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.

26. 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.

27. 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 drugs.

28. 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

29. Prostaglandins Latanoprost, 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

30. 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)

31. 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)

34. 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

35. Corticosteroids Side effects: • Glaucoma, cataract, mydriasis • Suppression of pituitary-adrenal axis • Hyperglycemia, Osteoporosis • Peptic ulcer, Psychosis, susceptibility to infections

36. 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

37. Harmful drugs for the Eye Drugs that ↑ IOP: • Mydriaticcycloplegics, tricyclic antidepressants • Chronic steroid use Cataractogenic drugs: steroids, phenothiazines, heavy metals…

38. Drugs causing corneal deposits: chloroquine, amiodarone, • Amiodarone , a cardiac arrhythmia drug • causes optic neuropathy (mild decreased vision, visual field defects) • causes corneal keratopathywhich is pigmented deposits in the corneal epithelium. • Digitalis , cardiac failure drug • Causes chromatopsia (objects appear yellow) with overdose

39. Other agents • methanol – optic atrophy and blindness • Ethambutol– optic neuropathy • Hypervitaminosis A – yellow skin and conjunctiva, retinal hemorrhage. • Hypovitaminosis A – night blindness (nyctalopia).