Course Outline PHARMACOLOGY FOR TECHS. Pharmacokinetics. Eyedrops. Punctal occlusion. Eye drop administration 4/6/2016

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1 Course Outline Examine common ophthalmic medications - topical and systemic, diagnostic, therapeutic Indications/usage Dosage and means of administration Side effects Examine systemic medications and their ophthalmic side effects PHARMACOLOGY FOR TECHS Vincent K. Young, MD Albert Einstein Medical Center Philadelphia, PA Vision Expo East 2016 Pharmacokinetics To achieve a therapeutic effect a drug must reach its site of action in sufficient concentration with minimal side effects. Drug concentration, viscosity, lipid solubility, preservatives, ph, tonicity. Eyedrops High concentrations delivered to cornea, conjunctiva, and anterior chamber Avoid systemic side effects Limitations poor retention of drug in the cul-desac, rapid turnover of tear reservoir, especially if tearing Difficult application for some Eye drop administration Punctal occlusion Clean hands Technique Punctal occlusion Compliance Economics Understanding Side effects Missed doses Refrigeration 1

2 Other routes of administration Diagnostics Ointments Periocular injections Intraocular injections Oral Intravenous Ophthalmic dyes Fluorescein (topical) Stains defects of corneal or conj epithelium Evaluation of tear film (TBUT, tear lake) Applanation tonometry Seidel test Rose Bengal Lissamine Green Diagnostics Fluorescein (IVFA) For the study of retinal and choroidal circulation, abnormal retinal pigment epithelium Indocyanine Green Side effects of IVFA Fluorescein allergy uncommon Rash, nausea. Anaphylaxis (rare) NO IODINE ICG has iodine Topical anesthetics Topical anesthetics Anesthetic Proparacaine Tetracaine Fluress (Benoxinate) Properties Onset - 15 sec. Duration 20 mins. Longer onset / duration More corneal toxic (stings) For use in tonometry Foreign body removal Glaucoma testing Corneal abrasion dx. Retards corneal healing NEVER give bottle to patients 2

3 Local Anesthetics Autonomic nervous system Lidocaine (Xylocaine) with / without Epi For injection and mucosal anesthesia Onset 5 mins. Duration 1 to 2 hours Clear corneal cataract surgery Carbocaine Duration 2 to 3 hours Marcaine Duration 8 hours Neurotransmitters Sympathetic Epinephrine (Adrenaline) Norepinephrine (Noradrenaline) Parasympathetic Acetylcholine (also the neurotransmitter for somatic nerves) Dilating agents Sympathomimetics Phenylephrine 2.5%, 10% Actions Stimulates iris dilator Iris sphincter is stronger Caution blood pressure Don t use 10% Careful in infants Dilating agents Dilating agents Anticholinergics Tropicamide 0.5 or 1% Cyclogyl 1 or 2% Homatropine 2 or 5% Scopolamine 1/4% Atropine 1% Anticholinergics actions Blocks iris sphincter Paralyzes ciliary muscle Relieves pain from iritis Allows accurate refraction in children Caution may elevate IOP Systemic absorption flushing, fever, tachycardia, delirium, urinary retention, nausea 3

4 Color coding for eyedrops Red dilating agents Green constricting agents Yellow Beta blockers (0.5%) Dark blue - (0.25%) Orange carbonic anhydrase inhibitors Turquoise prostaglandins Pink steroids (not all) Constricting agent for office use Dapiprazole HCl (Rev- Eyes) Blocks stimulation of pupil dilator muscle Reverses mydriasis in 30 mins. No effect on cycloplegia Therapeutics (topical) Allergy Allergy Anti infective Corticosteroids Glaucoma Dry Eye NSAID Acular Alamast Alocril Alomide Alrex Crolom Elestat Bepreve Livostin Lastacaft Optivar Patanol/Pataday Vasocon-A Zaditor Allergic conjunctivitis Allergy Hypersensitivity reaction where allergens couple to antibodies (IgE) on the surface of mast cells leading to release of histamines and other mediators of inflammation. Histamine causes capillary dilation, permeability, nerve stimulation Conjunctival hyperemia, chemosis, itching Ocular decongestants Naphcon Visine Clear Eyes All ineffective at relieving itching Get the red out Mask other problems 4

5 Allergy Allergy Anti-histamines Vasocon-A, Bepreve Histamine release blockers Cromolyn Na (Crolom, Opticrom) Histamine receptor blockers Livostin Mast cell stabilizers Alocril, Alomide Mast cell stabilizer and H2 receptor blocker Patanol, Lastacaft NSAID s Acular Antibiotics Principles of antibiotic therapy Bacitracin Bleph-10 Ciloxan Garamycin Ilotycin Neosporin Polysporin Ocuflox Polytrim Besivance Tetracycline Tobrex Vigamox Zymar/Zymaxid Treat aggressively Do not taper For severe infections ointment at bedtime If no improvement in 2 to 3 days Noncompliance, subtherapeutic dosing, wrong drug, wrong diagnosis Allergic reactions occur after 5 10 days Antibiotics - aminoglycosides Gentamycin, Tobramycin, Neomycin Gram negative bacteria (Proteus, Pseudomonas, Klebsiella, Enterobacter) Staph aureus, staph epidermidis Resistance is increasing Inexpensive High toxicity 10% of population allergic to Neomycin Antibiotics penicillins/cephalosporins No proprietary topical preparations Do not penetrate the eye well, easily transported out of the eye Fortified Ancef useful in corneal ulcer treatment when gram positives suspected 5

6 Antibiotics - fluoroquinolones Antibiotics - fluoroquinolones All drugs within this class are excellent against most organisms Little difference between them Less resistance development with 4 th generations First choice for bacterial corneal ulcers, severe bacterial conjunctivitis 3 rd generation Ocuflox Ciloxan 4 th generation Zymaxid Vigamox Besivance Antibiotics - tetracyclines Antibiotics - erythromycin Most often used for neonatal prophylaxis against Chlamydia, Neisseria gonorrhea, and Syphilis ocular infection from passage through the birth canal. Severe blepharitis, acne rosacea Oral tetracycline, minocycline, doxycycline Only available as ointment (Ilotycin) Gentle on cornea Good for prophylaxis Active against gram positives Well tolerated in infants Antibiotics Polymyxin B Antibiotics - sulfonamides Effective against gram negatives Good in combinations Polytrim with Trimethoprim Non toxic Good in children active against H. Influenza and Streptococcus Polysporin with Bacitracin Broad spectrum, non toxic Sulfa drugs once a mainstay of treatment Broad spectrum, inexpensive Now, high rate of resistance among staph, pseudomonas Severe sensitivity reactions such as Stevens-Johnson syndrome have been reported Poor choice of antibiotics 6

7 Antifungals Natacyn 5% - only commercially available antifungal Effective against the majority of fungal pathogens e.g., fusarium, candida, aspergillus Fungal ulcers seen in CL wearers, diabetics Frequent dosing q 1 hour Amphotericin B for difficult cases More corneal, renal toxic than Natamycin Antivirals Herpes Simplex Virus Trifluridine (Viroptic) Dosing q 2 hours for 4 to 5 days, then qid Use with oral acyclovir 400 mg 5 times/day Highly corneal toxic Ganciclovir Gel (Zirgan) Less toxic, more easily dosed Antivirals Corticosteroids Herpes Zoster Ophthalmicus (shingles) - for relief of post herpetic neuralgia Zovirax (acyclovir) 800 mg 5 times/day x 1 wk Famvir (famciclovir) 500 mg tid x 1 wk Valtrex (valacyclovir) 1000 mg tid x 1 wk Also used in H Simplex Kidney function must be intact Steroids for ocular involvement Alrex Omnipred Fluor-Op FML Forte Durezol Inflamase Forte Lotemax Maxidex Pred Forte Vexol Corticosteroids Corticosteroids Effectiveness based on penetrability, strength Dosing dependent on condition, severity In general, start with pulse dosing then taper Indications post op inflammation, uveitis, trauma, corneal disease Side effects - IOP, susceptibility to infection, cataracts Prednisolone 1% Gold standard for years - effective suspension (shake well) Lotemax Less potential for side effects Durezol Powerful, no need to shake Higher rate of IOP elevation 7

8 Combination steroid/antibiotic Glaucoma - prostaglandins Blephamide Cortisporin FML-S Maxitrol Polypred Pred-G Tobradex, Tobradex ST Zylet First line glaucoma therapy Improves aqueous humor outflow Highly effective at lowering IOP (30%) Once/day dosing (bedtime) Side effects hyperemia, lash growth, iris color change, irritation Contraindicated in inflammatory glaucomas Glaucoma - prostaglandins Glaucoma alpha agonists Xalatan Travatan Z Lumigan 0.1% Reduce aqueous humor production Significant conjunctival redness, irritation TID dosing inconvenient Systemic side effects fatigue, dry mouth, Rapid acting Good for post-op IOP spikes with laser tx. Rescula Glaucoma alpha agonists Glaucoma beta blockers Alphagan, Alphagan P, Alphagan.1% Iopidine Epifrin Propine Reduce aqueous humor production BID dosing (once/day probably OK) Usually available in 0.25, 0.5 % AM dose most important Contraindicated in asthma, emphysema, CHF 8

9 Glaucoma beta blockers Glaucoma topical CAI s Betagan Betimol Betoptic Ocupress Optipranolol Timoptic Timoptic XE Reduce aqueous humor production TID dosing Stinging, irritation Sulfa based, allergy concern Glaucoma topical CAI s Glaucoma combination drops Carbonic anhydrase inhibitors Azopt Cosopt timolol/dorzolamide Trusopt Combigan timolol/brimonidine Simbrinza dorzolamide/brimonidine Glaucoma cholinergic agonists Glaucoma - cholinergic agents Causes ciliary body contraction, opens TM Constricts pupil, stretches iris Also helpful in closed angle glaucoma Prior to laser iridotomy QID dosing Side effects brow ache, VA, induced myopia, risk of RD, cataracts Carbachol Pilocarpine 1 6% Phospholine Iodide Physostigmine 9

10 Dry Eye Therapy Dry Eye Therapy Artificial tears and emollients form a film to lubricate and protect the eye from drying. Active ingredients polyvinyl alcohol, cellulose, methylcellulose Multidose units contain preservatives Benzalkonium chloride, thimerosol, others Require frequent dosing poor compliance Dry Eye Therapy Dry Eye Therapy Artificial tears Refresh tears, Genteal, Systane, Advanced Eye Relief, Visine Tears, Tears Plus, Tears Naturale, Artificial tear ointments nighttime, exposure Lacrilube, Genteal Gel, Refresh PM Oral agents TheraTears Nutrition, Omega-3 FA s, flaxseed oil, doxycycline Restasis (cyclosporine 0.05%) Inflammatory damage to tear producing glands thought to reduce production of normal tear film. BID dosing Burns on instillation Takes up to 3 months to have full effect Castor oil in carrier (Refresh Endura) improves symptoms NSAID s NSAID s Work by inhibiting cyclooxygenase, an enzyme leading to prostaglandin release TID or QID dosing Limited anti-inflammatory activity Good pain relief Post op usage to reduce macular edema Acular, Acuvail Voltaren Ocufen Nevanac Xibrom Ilevro 10

11 Therapeutics (systemic) Other ophthalmic drugs Oral/IV/intraocular steroids Prednisone Solumedrol Kenalog Oral/IV antiglaucoma meds Diamox, neptazane Glyrol, Isosorbide, Mannitol Anti-VEGF meds angiogenesis inhibitors used in diseases with pathologic vascular proliferation AMD, DME, NVG Pegaptanib (Macugen) Bevacizumab (Avastin) Ranibizumab (Lucentis) Proteases activity against proteins at the vitreoretinal interface- prevents traction Ocriplasmin may be retino-toxic Other ophthalmic drugs Other ophthalmic drugs Light sensitized drugs Visudyne Neurotoxins Botox Antifibrotic agents Mitomycin C, 5 Fluorouracil adjuncts to glaucoma surgery Hyperosmotics Muro 128 drops, ointment for corneal edema Viscoelastics Healon, Viscoat, Amvisc Systemic medication and their ocular side effects What are drugs used to prevent clot formation in the disease associated with the EKG below? 11

12 ANTICOAGULANTS Aspirin (salicylate) Coumadin (warfarin) Heparin Lovenox (enoxaparin sodium) Plavix (clopidogrel) Pradaxa (dabigatran etexilate mesylate) What drugs would this person be using, and what side effects might she have? Ocular Side Effects Subconjunctival and retinal hemorrhage Recommend to be discontinued for a week prior to eye surgery INR > 5 prone to bleed Chronic use of ASA may cause yellowing of vision Anti allergy agents Claritin (Loratadine) Zyrtec (cetirizine) Allegra (fexofenadine) Singulair (Montelukast sodium) Benadryl (Diphenhydramine HCl) Sudafed (pseudoephedrine) Ocular Side Effects: Dry eye, keratitis sicca Contact lens intolerance Mydriasis glare, blurring of vision Angle closure glaucoma or narrow angle glaucoma Anti allergy agents mechanism of ocular side effects Block Histamine-1 (H1) receptors Weak atropine action (cholinergic antagonist), causing mydriasis, anisocoria, blurred vision Inhibit glandular secretion and reduce mucous and tear secretion which aggravate keratitis sicca and contact lens wear intolerance Other histamine receptor blockers Anti-ulcer drugs Drugs that treat this condition ANTI-MIGRAINE AGENTS Topamax (topiramate) Indicated for migraines, seizures, mood disorder, weight loss Mechanism of action: blockage of sodium channels, an augmentation of GABA activity at some of the GABA receptors, inhibition of the carbonic anhydrase enzyme 12

13 Topamax Other anti-migraine agents Ocular side effects Acute Closed Angle Glaucoma Diplopia Acute Myopia 6-8 diopters Suprachoroidal Effusion Dry Eyes Sulfa Allergy Symptoms within days to weeks of beginning the drug Serotonin receptor antagonist Imitrex Corneal opacity, blurred vision Beta Blockers Reduce tear lysozyme levels and immunoglobulin IgA Dry eye, contact lens intolerance Medications to treat depression ANTI-DEPRESSANTS Prozac (fluoxetine) Zoloft (sertraline) Paxil (paroxetine) Celexa (citalopram) Effexor (venlafaxine hydrochloride) Anticholinergic effects blocking the binding of the neurotransmitter acetylcholine to its receptor in nerve cells Ocular Side Effects Blurred vision Cycloplegia Photophobia Dry eye Drugs to treat the following symptom Anti-anxiety meds Xanax (Alprazolam) Valium (Diazepam) Binds to the benzodiazepine receptor site on the GABA receptor and modulates function Ocular Side Effects Blurred Vision Diplopia Mydriasis Conjunctivitis 13

14 What are some medications used for the following associated with CHF? Anti-arrhythmics Amiodarone (Cordarone) Photosensitizer, tendency towards lipid storage in the cornea and lens Dose and duration dependent, usually reversible Ocular side effects Vortex Keratopathy Nearly 100% pts treated greater than 6 months <10% bothered by blurred vision or haloes Anterior and posterior subcapsular lens changes Optic neuropathy Cardiac meds Digoxin Inhibition of Na+K+ ATPase which plays a vital role in maintaining normal cone receptor function and ciliary epithelium responsive for active transport of sodium necessary for aqueous secretion What class of drugs would you use to treat the following condition? Ocular Side Effects Affects cone receptor function 11-25% of patients red-green color defects Yellow tinged vision (xanthopsia) Snowy, hazy, or dimming vision Flickering or flashes of light, and colored spots Reduces aqueous secretion and IOP Diuretics Thiazides or diuretics are often used to treat congestive heart failure and HTN Hydrochlorothiazide (HCTZ) Furosemide (Lasix) What systemic condition is associated with the following picture? What drugs are used to treat this? Ocular Side Effects: Dry eye reduced aqueous layer Myopic shift Band keratopathy 14

15 Antihyperlipidemics Antihyperlipidemics Statins -Mevacor (lovastatin) -Lipitor (atorvastatin) -Zocor (simvastatin) The enzyme HMG-CoA reductase is inhibited, thereby preventing a step in the pathway of cholesterol synthesis. Ocular Side Effects: Localized myositis in the extraocular muscles or levator palpebrae superioris muscles Diplopia reversible on discontinuation of the statin as evidenced by the 62 positive rechallenge case reports. Ptosis Lid edema Lens opacities Dry eye Blurred vision Pseudo-cystoid macular edema Meds for glycemic control which have significant ocular side effects? Metformin Avandia/Actos Avandia (rosiglitazone) Actos (pioglitizone) Thiazolidinedione class Thiazolidinediones act as insulin sensitizers. They reduce glucose, fatty acid, and insulin blood concentrations. Ocular Side Effect Macular edema What is a common drug to treat the following process? What ocular side effects are there? Flomax (tamsulosin) Flomax (tamsulosin) for Benign Prostatic Hypertrophy (BPH) alpha-adrenergic blocker, relaxes the muscles in the prostate and bladder neck, making it easier to urinate Ocular Side Effects Loss of tone in iris dilator smooth muscle causing poor pupil dilation Iris prolapse during cataract surgery Floppy Iris Syndrome 15

16 Tamoxifen citrate What drug is prescribed to treat and/or reduce the incidence of breast cancer among high-risk women that has well known ocular side effects? Tamoxifen citrate competitively binds to estrogen receptors on tumor cells and other tissue targets, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects Ocular Side Effects: Crystalline retinopathy Treatment involves withdrawal of the drug as it is reversible Ocular complications are rare (0.6%) What are the ocular effects of birth control pills? Estrogen or Progesterone Estrogen or Progesterone Decreased aqueous production, microvacular occlusions from enhanced platelet adhesiveness, or increase in fibrinogen and clotting factors. Ocular Side Effects Microvascular complications - artery and venous occlusions Dry Eye Contact Lens Intolerance Optic neuritis Macular Edema TIA (Transient ischemic attack) Pseudotumor cerebri What common drug used to treat this teenager has ocular complications? DERMATOLOGIC AGENTS Accutane (isoretinoin) This retinoid (a form of vitamin A) is used to treat psoriasis, cystic acne, and various other skin conditions. Ocular Side Effects: Swollen optic discs - "papilledema - the result of increased intracranial pressure (pseudotumor cerebri). Symptoms are headache and transient black-outs of vision upon assuming the upright posture. Visual black-outs caused by postural drops in BP and secondary compromise of blood flow to the retina through the tightly packed optic disc. Night blindness Retinotoxicity Keratitis Deficiency of the normal lipid layer in the tear film 16

17 DERMATOLOGIC AGENTS Minocycline For severe acne vulgaris Ocular side effect Pseudotumor cerebri Papilledema A patient travels back to the U.S. with night sweats and is given meds with potential ocular side effects Anti-tuberculosis drugs Anti-tuberculosis drugs Ethambutol HCL Isoniazid Rifampin Ophthalmic examinations are recommended by the PDR every month for doses of ethambutol greater than 15mg/kg/day. Chelates copper, so the decreased levels impair mitochondrial activity of axonal transport in optic nerve, leading to optic neuropathy Ocular side effects Optic neuritis/neuropathy and blindness. Change tears, sweat, saliva, urine, feces and contact lenses a redorange color. Optic neuropathy can occur at any dose despite regular ophthalmic exams and the vision loss can be severe and irreversible. Obtain a baseline exam to include a visual field test, color vision test, dilated fundus and optic nerve exam, and visual acuity. If any visual symptoms occur, patients should discontinue the medication and see an ophthalmologist/optometrist. Name a drug used to treat the following conditions Visual field test results obtained 3 months after onset of visual symptoms. Both the left (A) and right (B) visual fields show central scotoma with inferior temporal quadrant defects. 17

18 Antimalarials Antimalarials Plaquenil (hydroxychloroquine) Aralen (chloroquine) Treats malaria, rheumatoid arthritis, and systemic lupus erythematosis High affinity to melanin, toxic to the retinal pigment epithelium Ocular Side Effects: Bull s-eye maculopathy starts as fine pigmentary mottling within the macular area. The end result can range from reduced vision to blindness Patients at greatest risk for toxicity from Plaquenil Using longer than 5 years Renal or liver disease Elderly, thin patients may also be overdosed, as may obese patients. Dosage exceeds 6.5 mg/kg Examination A baseline exam should be performed before the patient starts treatment Eye exam including Fundus Photos, HVF-10 (red-white), OCT, Amsler grid, and color vision Plaquenil follow-up recommendations Chloroquine follow-up recommendations Age <40 who are not higher risk follow-up every 2-4 years Patients between 40 and 64 years: follow-up every 2-4 years Age 64 and older: follow-up every 1-2 years Obtain tests as plaquenil exam. See patients at least annually if dosage is less than 3.0 mg/kg of ideal body weight. Annual eye examinations should be considered in: Patients on Plaquenil therapy for longer than 5 years obese, or lean and small (especially in elderly patients progressive macular disease of any type significant renal or liver disease, dosage exceeds 6.5 mg/kg See every 6 months if dosage is greater than 3.0 mg/kg body weight, or if patients are short, obese, or have renal and/or liver impairment. Corticosteroids Prednisone, Solumedrol To treat inflammatory and allergic conditions. They are very effective for acute disease states as well as chronic conditions Ocular Side Effects Posterior subcapsular cataract Elevated intraocular pressure Papilledema Exacerbation of herpetic keratitis Corticosteroids Cataracts resulting from steroid use are well known and occur with topical, systemic, and nasal administration. The development of cataract is related to the cumulative dose of prednisone; 25% of patients who use 15 mg/day for 1 year or more will get cataracts that interfere enough with vision to require surgical removal The etiology is unknown, the drug may react with amino groups of crystalline lens fibers causing protein complexes to aggregate 18

19 What drugs are used for the treatment/prevention of osteoporosis? Bisphophonates FOSAMAX AREDIA ACTONEL ZOMETA BONIVA DIDROCAL Bisphosphonate molecules preferentially "stick" to calcium and bind to it. They accumulate to a high concentration in bones, resulting in maintained or increased bone density and strength Ocular Side Effects Scleritis/Episcleritis Blurred vision Hyperemia Anterior uveitis What class of drugs is used to treat hepatitis and multiple sclerosis? Interferons - Avonex/Pegasys) Interferons Delayed type hypersensitivity reaction. In many infectious and systemic diseases, the deposition of immune complexes with subsequent complement activation is a major pathogenic mechanism for the development of uveitis Ocular Side Effects: Cotton wool spots Optic neuritis Ocular pain Conjunctivitis Pronounced dry eye Dilated Eye exam prior to treatment and 2-4 weeks after treatments A man reports discoloration of vision after taking a medication last night ERECTILE DYSFUNCTION Viagra (sildenafil citrate) Cialis (tadalafil) Levitra (vardenafil) Stendra (avanafil) These drugs inhibit phosophodiesterase-5 (PDE-5) which results in vasodilation of smooth muscle. Ocular Side Effects Objects have color tinges usually blue or blue-green 11% of patients on 100mg perceive a blue haze up to four hours Dark colors appear darker Visual disturbances NAION 19

20 ERECTILE DYSFUNCTION Herbal Medicines and Nutritional Supplementation The side effects based on dosage with sildenafil start minutes after ingestion of the drug, peak 60 minutes after ingestion Patients who should not take phosphodiesterase type 5 inhibitors previously suffered ischemic optic neuropathy (NAION) in one eye anyone who experiences transitory visual loss while on these medications. These patients may be more prone to developing NAION in the same or fellow eye if sildenafil or other medicines in this class are ingested. Canthaxanthine Tanning crystalline retinopathy Chamomile Allergic conjunctivitis one of the most ancient medicinal herbs known to mankind. terpenoids and flavonoids Used for hay fever, inflammation, muscle spasms, menstrual disorders, insomnia, ulcers, wounds, gastrointestinal disorders, rheumatic pain, and hemorrhoids. Essential oils of chamomile are used extensively in cosmetics and aromatherapy Herbal Medicines and Nutritional Supplementation Herbal Medicines and Nutritional Supplementation Datura angel s trumpet Mydriasis from tropane alkaloids, atropine/scopolamine properties Poisonous Ginkgo biloba Dementia, Alzheimer s, memory Anticoagulant properties Spontaneous hyphema, retinal hemorrhage Echinacea purpurea Conjunctivitis Used for URI, yeast infection, and many other ailments Licorice Visual loss associated with migraine-like symptoms Vasospasm Hypertension Herbal Medicines and Nutritional Supplementation Summary Niacin Cystoid macular edema Dry eyes, discoloration of the eyelids, eyelid edema, proptosis, loss of eyebrows and eyelashes superficial punctate keratitis A careful and detailed case history is important to reveal a patient s medication history. The ocular and visual side effects from a patient s systemic medication can range from mild to severe. Vitamin A Intracranial hypertension when taken in large doses, causing papilledema Recognition of ocular and visual side effects is important for prompt management to prevent and minimize serious complications. 20