PHAR763: Pathophysiology and Therapeutics Ophthalmic Disorders: Glaucoma June 4, Julianne E. Himstreet, Pharm.D., BCPS

Transcription

1 PHAR763: Pathophysiology and Therapeutics Ophthalmic Disorders: Glaucoma June 4, 2008 Julianne E. Himstreet, Pharm.D., BCPS Recommended Reading: Applied Therapeutics Chapter 51. I. Learning Objectives 1. Be familiar with the anatomy and physiology of the eye. 2. Know the medications used to treat primary open-angle glaucoma. 3. Describe the most common side effects of the medications used to treat primary open-angle glaucoma. 4. Know the medications used to treat closed-angle glaucoma. 5. Counsel a patient on administration and storage of medications for glaucoma including nasolacrimal occlusion. 6. Identify which systemic medications can cause ocular side effects. II. Ocular Anatomy and Physiology DIAGRAM OF THE EYE 1

2 A. Outer coat of the eye 1. sclera: white, dense, fibrous protective coating a. episclera: a thin layer of loose connective tissue covering the sclera, contains the blood vessels for the sclera 2. conjunctiva: mucous membrane covering the anterior portion of the eye and lines the eyelids 3. cornea: transparent avascular tissue that functions as a refractive and protective window membrane where light rays pass to the retina a. cornea involved in drug penetration b. best penetration through intact cornea with biphasic preparations (both fat and water soluble) B. Inner segment of the eye 1. retina: contains all sensory receptors for light transmission 2. optic nerve: transmits visual impulses from the retina to the brain 3. crystalline lens, aq ueous humor and vitreous: assist cornea with process of refraction C. Outermost part of the eye 1. eyelids and eyelashes a. protection for the eye b. eyelids contain sebaceous and sweat glands D. Innervation of the eye 1. Parasympathetic fibers a. originate from occulomotor nerve in the brain b. innervate the ciliary muscle and sphincter pupillae muscle c. involved in constriction of the pupil i. parasympathomimetics (cholinergics): miosis (contraction) ii. parasympatholytics (anticholinergics): mydriasis (dilation) and cytoplegia (paralysis of ciliary muscle and zonules that results in decreased accommodation and blurred vision) d. tear secretion by lacrimal glands controlled by parasympathetic system 2. Sympathetic fibers a. originate from the superior cervical ganglion in spinal cord b. innervate the dilator pupillae muscle, blood vessels of the ciliary body, episclera, and extraocular muscles c. involved in dilation of pupil i. sympathomimetics cause mydriasis (dilation) without affecting accommodation ii. sympatholytics cause miosis (contraction) 2

3 III. Glaucoma A. Definition: ocular disorder involving optic neuropathy with changes in the optic disk and loss of visual sensitivity and field; increased intraocular pressure (IOP) is thought to play an important role in pathogenesis of glaucoma but is not a diagnostic criterion 1. Influenced by a. production of aqueous humor by the ciliary processes b. outflow of aqueous humor through the trabecular meshwork 2. Intraocular pressure a. normal IOP: 10 to 20 mmhg b. IOP over 22 mmhg can indicate glaucoma B. Ocular Hypertension 1. Background a. IOP greater than 21 mmhg b. normal visual fields c. normal optic discs d. open angles e. absence of any ocular disease contributing to the elevated IOP 2. Treatment a. Only in pts with elevated IOP (> 30mmHg), family history of glaucoma, black patients, high myopia, and patients with one eye b. Beta blocker: timolol, levobunolol c. α 2 adrenergic agonist: brimonidine, apraclonidine d. Topical carbonic anhydrase inhibitor (CAI): brinzolamide, dorzolamide e. Prostaglandin analogue: latanoprost, travaprost, brimatoprost f. Goal of treatment: lower IOP by 25-30% to decrease risk of optic nerve damage C. Open Angle Glaucoma 1. Background a. 1.5% people over 30 years b. 2-3% of people older than 70 years c. Accounts for most cases of glaucoma 2. Primary open-angle glaucoma (POAG) a. Background i % of primary glaucomas are POAG ii. Manifests as optic nerve degeneration characterized by disk changes and visual field loss iii. Involves decreased aqueous humor outflow from anterior chamber from degenerative process in trabecular meshwork iv. IOP varies throughout the day from normal to significantly elevated v. Onset is gradual and asymptomatic until substantial visual field constriction occurs vi. Increase in IOP not required for diagnosis 3

4 b. Treatment i. First line - Beta blockers - Prostaglandin analogs ii. Alternative agents - α 2 -Adrenergic Agonists - Topical CAIs iii. Second line agents - Pilocarpine - Epinephrine or dipivefrin - Apraclonidine c. Approach to therapy i. Start with single agent in one eye to evaluate drug efficacy and tolerance ii. Monitor IOP and optic disk after 2-4 weeks, then every 1-6 months until stabilized iii. Measure visual field every 3-12 months (or after changes in drug therapy) iii. If single agent not tolerated, change to alternative agent iv. If single agent not effective at highest dose - switch to alternative agent (overlap by 1 day) or - addition of another optical drug used in combination v. If drug therapy not effective or tolerated, then surgical procedures are considered - argon laser trabeculoplasty (ALT) - surgical trabeculectomy vi. Goal - reduce IOP initially by 25-30% with goal of IOP < 21mmHg 4

5 Pharmacologic Agents used in Primary Open-angle glaucoma Mechanism of action Drug Dosing Interval Expected IOP Decreased production of aqueous humor Decrease production of aqueous humor and may increase outflow β-blockers Nonselective Timolol (Timoptic) Timolol (Timoptic XE) Levobunolol (Betagan) Metipranolol (Optipranolol) Selective Betaxolol (Betoptic) Nonselective with ISA Carteolol (Ocupress) Carbonic anhydrase inhibitors (CAIs) Dorzolamide (Trusopt) Brinzolamide (Azopt) α 2 -Adrenergic Agonists brimonidine (Alphagan) apraclonidine (Iopidine) Once daily 2-3 times daily 2-3 times daily 2-3 times daily 2-3 times daily lowering % *timolol and levobunolol have greater IOP lowering than betaxolol 5 Side effects Cautions Cost/ month Most common local effect: Stinging Betaxolol and metipranolol most common Dry eyes, blurred vision, blepharitis, corneal anesthesia Rare local effect: Conjunctivitis, uveitis, keratitis Systemic effects: Heart rate, blood pressure, bronchospasm, CNS effects May be less with betaxolol and carteolol % Most common local effects: Transient burning/stinging, ocular discomfort, transient blurred vision, tearing Superficial punctate keratitis (10-15%) Rare local effect: Conjunctivitis, lid reactions, photophobia Systemic effects: Sulfonamide so caution in sulfa allergic pts 18-27% Most common local effects: Allergic type reaction: lid edema, eye discomfort, itching, hyperemia (must d/c) 30% with alpraclonidine 8% with brimonidine Systemic effects: Dizziness, somnolence, dry mouth, Heart rate, blood pressure (more common with brimonidine) Pulmonary diseases Sinus bradycardia Second/third heart block CHF CAD DM Myasthenia gravis Pts taking oral β- blockers $12.00 $29.00 $ $16.00 $40.00 $20.00 Avoid in patients with hepatic or renal impairment $31.00 $33.00 CAD, Renal impairment Cerebrorvascular dz, Diabetes Pts taking antihypertensives, CAD drugs, MAOIs, tricyclic antidepressants Cosopt $50.00 $33.00 $74.00

6 Pharmacologic Agents used in Primary Open-angle glaucoma Mechanism of action Drug Dosing Interval Expected IOP Increased aqueous outflow Prostaglandin analogs Latanoprost (Xalatan) Travaprost (Travatan) Bimatoprost (Lumigan) Unoprostone (Rescula) Once daily Once daily Once daily lowering 25-35% Most common local effects: Iris pigmentation (15-30%) Most common in pts with light colored eyes Uveitis Caution in pts with ocular inflammatory conditions Rare local effects: Ocular irritation, conjuntival hyperemia, superficial punctate keratitis Systemic effects: Rarely occur Side effects Cautions Cost/ month $50.00 $57.00 $65.00 $47.00 Parasympathomimetics Pilocarpine (Pilocar) soln Pilocarpine (Pilocar) gel Pilocarpine ocular insert (Ocusert) Carbachol Sympathomimetics Diprivefrin (Propine) Epinephrine (Glaucon) 3-4 times daily once daily once weekly 2-3 times daily 20-30% Local effects: Miosis and decreased night vision in pts with cataracts Frontal headache/browache Periorbital pain, Eyelid twitching Conjunctival irritation Systemic effects: Diaphoresis, nausea, vomiting, diarrhea, cramping, urinary frequency, bronchospasm, heart block More with higher doses 15-25% Most common local effects: Tearing, burning, ocular discomfort, browache, conjunctival hyperemia, punctate keratopathy, allergic blepharoconjunctivitis Rare local effects: Loss of eyelashes, stenosis of nasolacrimal duct, blurred vision, pigmentation of conjuctiva and cornea (less with diprivefrin) Systemic effects: Headache, faintness, increased blood pressure, tachycardia, arrhythmia CAD Acute iritis $7.00 $46.00 CAD, cerebrovascular disease, CAG, hyperthyroidis m, diabetes, Pt undergoing anesthesia with halogenated hydrocarbons $10.00 $

7 D. Closed angle glaucoma (CAG) 1. Background a. Accounts for 5% or less of primary glaucomas b. Many times is an emergency to avoid visual loss c. Results from mechanical blockage of trabecular meshwork by the peripheral iris d. Between attacks IOP is usually normal in absence of POAG e. Occurs in pts with inherited shallow anterior chambers which produce a narrow angle between cornea and iris or tight contact between the iris and lens (pupillary block) f. Determined by visualization of the angle by gonioscopy g. Two types of classic reversible primary CAG i. CAG with pupillary block ii. CAG without pupillary block h. Symptoms i. cloudy, edematous cornea, ocular pain or discomfort, nausea, vomiting, abdominal pain and diaphoresis i. Examination i. closed-angle, narrow anterior chamber, hyperemic conjunctiva and edematous and hyperemic optic disc with IOP as high as mm HG 2. Goals of therapy a. rapid reduction of IOP to preserve vision and avoid surgical or laser iridectomy 3. Drug therapy a. Pilocarpine 2-4% 1 drop every 5 minutes for 4-6 administrations b. Hyperosmotic agents i. IV: mannitol ii. Oral: 50% glycerin g/kg or isosorbide iii. no drinking liquids since it will counteract the osmotic effects of the agents iv. Also can add acetazolamide 500mg IV c. Secretory inhibitor (β-blocker, α 2 agonist, prostaglandin F 2α analog or topical CAI) E. Drug induced Glaucoma 1. Open angle glaucoma a. patients with treated, controlled POAG are at minimal risk of increased IOP from systemic meds with anticholinergic properties or vasodilators b. patients with untreated or uncontrolled POAG can be at risk for further increases in IOP c. Topical anticholinergics (mydriasis): increase in IOP most likely with atropine or homatropine d. Inhaled, nasal, topical or oral corticosteroids may increase IOP in patients with POAG and those who do not have POAG; amount of increase in IOP is dose related 7

8 High Risk Medium Risk Low Risk Ophthalmic corticosteroids Systemic corticosteroids Vasodilators Nasal/inhaled corticosteroids Cimetidine Ophthalmic anticholinergics Succinylcholine 2. Closed angle glaucoma a. May be produced by drugs that cause mydriasis (anticholinergics) or swelling of the lens (sulfa compounds) b. Most likely with optical anticholinergics or topical sympathomimetics High-medium Risk Topical anticholinergics Topical sympathomimetics Systemic anticholinergics Heterocyclic antidepressants Low potency phenothiazines Antihistamines Ipratropium Low Risk Benzodiazepines Theophylline Vasodilators Systemic sympathomimetics CNS stimulants Tetracyclines Carbonic anhydrase inhibitors Monoamine oxidase inhibitors Topical cholinergics IV. Patient Education A. Procedure for administration of ophthalmic products 1. Wash and dry hands 2. Shake bottle if a suspension 3. With forefinger pull down on outer portion of lower eyelid to form a pocket to receive the drop 4. Grasp dropper between thumb and fingers with hand braced against cheek or nose and the head held upward 5. Place dropper over the eye while looking at the tip of the bottle then look up and place a single drop in the eye 6. The lids should be closed for 1-3 minutes after instillation to increase ocular availability of the drug (should not squeeze or rub eye) 7. Recap the bottle and store as instructed B. Nasolacrimal Occlusion (NLO) 1. Used to increase ocular bioavailability and reduce systemic absorption 2. Procedure a. For 1-3 minutes close the eyes and place the index finger over the nasolacrimal drainage system in the inner corner of the eye b. This decreases drainage of the drug thereby reducing drug available for systemic absorption 8

9 C. Practical information 1. Many patients are physically unable to administer their own eye drops 2. Use of more than one drop per dose increases costs and does not improve response significantly 3. When 2 drugs are administered, instillation should be separated by 3-5 minutes at least, preferably by 10 minutes 4. Instruct patients not to touch dropper bottle tip with eye, hands or any surface 5. Patients need to be encouraged to continue therapy despite lack of symptoms and warned about the risks of nonadherence 9

10 Eye Drop Tips from the Glaucoma Research Foundation ( Eye drops help maintain the pressure in your eye at a healthy level and are an important part of the treatment routine for most people with glaucoma. Always check with your doctor if you are having any difficulty. Follow doctor s orders. Be sure your doctor knows about any other drugs you may be taking (including over-thecounter items like vitamins and aspirin) and about any allergies you may have. Wash your hands before putting in your eye drops. Be careful not to let the tip of the dropper touch any part of your eye. Make sure the dropper stays clean. If you are putting in more than one drop or more than one type of eye drop, wait five minutes before putting the next drop in. This will keep the first drop from being washed out by the second before it has had time to work. Store eye drops and all medicines out of the reach of children. Start by tilting your head backward while sitting, standing, or lying down. With your index finger placed on the soft spot just below the lower lid, gently pull down to form a pocket. Let a drop fall into the pocket. Slowly let go of the lower lid. Blinking a few times is all right but try not to shut your eyes tight or squint. This may push the drops out of your eye. Gently press on the inside corner of your closed eyes with your index finger and thumb for two to three minutes. This will help keep any drops from getting into your system and keep them in your eye, where they are needed. Blot around your eyes to remove any excess. If you are still having trouble putting eye drops in, here are some tips that may help. If Your Hands Are Shaking: Try approaching your eye from the side so you can rest your hand on your face to help steady your hand. If shaky hands are still a problem, you might try using a 1 or 2 pound wrist weight (you can get these at any sporting goods store). The extra weight around the wrist of the hand you re using can decrease mild shaking. 10

11 Trouble Getting The Drop Into Your Eye: It may be easier to tell if the drop has gone into your eye if you keep your eye drops in the refrigerator. Your eye will feel the liquid when it s cold better than if it s at room temperature. If you are still not sure the drop actually got in your eye, put in another drop. The eyelids can hold only about one drop, so any excess will just run out of the eye. It is better to have excess run out than to not have enough medication in your eye. If pulling the lower lid out to create a pocket isn t working, try this. With your head turned to the side or lying on your side, close your eyes. Place a drop in the inner corner of your eyelid (the side closest to the bridge of your nose). By opening your eyes slowly, the drop should fall right into your eye. Trouble Holding Onto The Bottle: If the eye drop bottle feels too small to hold (in cases where a dropper isn t used and the drop comes directly from the bottle), try wrapping something (like a paper towel) around the bottle. You can use anything that will make the bottle wider. This may be helpful in some mild cases of arthritis in the hands. Products are available to assist you putting in your eye drops. 11

12 V. Ocular Side Effects of Systemic Medications Drug Class Effects Comments Analgesics Ibuprofen Indomethacin Narcotics Antiarrhythmics Amiodarone Anticholinergics Atropine, scopolamine, trihyxylphenidyl Anticonvulsants Carbamzepine Phenytoin Reduced vision Miosis Reduced vision Tearing, irregular pupils, paresis of accommodation, diplopia Keratopathy Cataracts Mydriasis, cycloplegia, decreased accommodation, photophobia Diplopia, blurred vision Nystagmus, cataracts Rare, blurred vision more common Common with therapeutic doses, secondary to Rare, also changes in color vision rarely reported CNS action on pupilloconstrictor center Effects associated with narcotic withdrawal Dose and duration related; corneal deposits are bilateral, reversible and asymptomatic; deposits occur in almost 100% of pts taking 400mg/day or more Anterior subcapsular lens opacities associated with amiodarone therapy; may progress to ultimately cover an area larger than undilated pupil s aperture Systemic and transdermal anticholinergic agents may cause mydriasis and less commonly cycloplegia. Mydriasis can cause angle-closure glaucoma; photophobia is related to the mydriasis. Ocular adverse effects when dosate > 1-2 grams/day, resolve with dose reduction Nystagmus with high blood levels (> 20μg/mL), cataracts may rarely occur with prolonged therapy Anesthetics Propofol Inability to open eyes 6/50 pts undergoing ENT procedures were unable to open eyes for 3-20 minutes after end of anesthetic administration Antidepressants Tricyclic (TCAs) Fluoxetine Antihistamines Chlorpheniramine Antihypertensives Clonidine Diazoxide Guanethidine Reserpine Mydriasis, cycloplegia Eye tics Blurred vision, mydriasis, decreased lacrimal secretions Miosis, dry itchy eyes Lacrimation Miosis, ptosis, conjunctivitis, blurred vision Miosis, conjunctivitis Mydriasis most common ocular side effect, cycloplegia is rare, reports of precipitation of angle-closure glaucoma Fluoxetine 20-40mg/day associated with paroxysmal contractions of the muscles aroung the lateral aspect of the eye; effect occurred 3-4 weeks after initiation and resolved within 2 weeks of discontinuation Blurred vision ~1%of patients taking 12-14mg/day, mydriasis rare Miosis in overdose; itchy eyes rare 20% of patients, may continue after stopping sporatically documented miosis rare; conjunctivitis common secondary to dilation fo conjunctival blood vessels 12

13 Antiinfectives Amantadine Chloramphenicol Chloroquine Ethambutol Gentamicin Isoniazid Sulfonamides Tetracyclines Corneal lesions Optic neuritis Corneal deposits Retrobulbar neuritis Pseudotumor cerebri Optic neuritis Myopia Conjunctivitis Optic neuritis Photosensitivity Myopia Papilledema Diffuse corneal opacities reported, occasionally associated with superficial punctate keratitis, onset 1-2 weeks after initiation of therapy with doses of mg/day, resolves with d/c drug Rare unless total dose of 100 gram and duration > 6 weeks exceeded, vision improves after stopping May occur after few months therapy, of no consequence At doses of 15mg/kg/day, ocular side effects not seen, at doses of 25mg/kg/day side effects are rare; for treatment of greater than 3 months need to do routine eye exams Rare but well documented with secondary papilledema and visual loss Prevalence not well defined but less than peripheral neuritis Acute, reversible, most common ocular side effect Associated with use of sulfisoxazide lid margin therapy Even in low doses, usually reversible with complete recovery of vision Associated with using sulfisoxazole lid margin therapy Appears to be acute, transient and rare More common in children and infants than adults, rare Antilipidemic agents Lovastatin Cataracts Does not appear to effect visual acuity, rare Diuretics Thiazides Myopia Acute myopia that may last from hours, may be reversible even when drug continued Estrogens Clomiphene Oral contraceptives Blurred vision Mydriasis Visual field changes Visual sensations Optic neuritis Pseudotumor cerebri Retrotubular neuritis 5-10% exeperience ocular side effects, blurred vision most common quite rare, pts with retinal vascular abnormalities use with caution Hyperuricemia Allopurinol Cataracts May be associated with anterior and posterior lens capsule changes, 42 cases reported, reports conflicting Phenothiazines Chlorpromazine Thioridazine Erectile dysfunction Sildenafil Deposits on the lens Retinal pigment deposits Pigmentary retinopathy Disturbance of color vision Increased brightness Blurred vision Nonarteritic ischemic optic neuropathy Rare when total dose < 0.5 kg, visible dose > 1kg Reported cases small Usually associated with maximal daily doses over 1000mg, daily doses up to 600mg are relatively safe Color vision alterations are mild to moderate, blurred vision does not impair visual acuity, visual alterations subside usually 4 hours after dose 13

14 Cardiac drugs Calcium channel blockers Digitalis Antineoplastic agents Busulfan Cytarabine Doxorubicin Fluorouracil Tamoxifen Vinca alkaloids Blurred vision Transient blindness Altered color vision, visual acuity Decreased intraocular pressure Catarats Keratoconjunctivitis, ocular burning, photophobia, blurred vision Conjunctivitis Excessive tearing Ocular irritation, lacrimation Corneal opacities, decreased vision Extraocular muscle paresis (EMP), ptosis Primary blurred vision, transient blindness at peak concentrations observed in several pts Changed in color vision, glare phenomenon, small number of cases of reversible reduction in visual acuity Decrease intraocular pressure seen most commonly at doses near toxic dose Reported with high doses Corneal toxicity and conjunctivitis reported with high dose therapy (3g/m 2 ) May last for several days after treatment Reversible and seldom interferes with therapy Generally in higher than normal doses for months Onset on EMP or paralysis seen as early as 2 weeks, dose related, most fully recover after stopping drug Corticosteroids Cataracts Posterior subcapsular cataracts with systemic use, dose dependent and more common in doses over 15mg/day prednisone for > 1 years; rare with nasal or oral use and cases where seen use was over 5 years in higher than recommended dose and use of periodic systemic corticosteroids Increased intraocular pressure More common with topical corticosteroids than systemic; little consequence in pts without preexisting glaucoma, monitor glaucoma pts on systemic steroids Papilledema Intracranial hypertension or pseudomotor cerebri from systemic corticosteroids well documented, incidence greater in children than adults, more common with chronic therapy Table adapted from Chapter 51 (Eye Disorders) Table Applied Therapeutics Textbook. 14