Medical Management of Glaucoma

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Brief Introduction:

Brief Introduction Angle of anterior chamber Role in aqueous drainage. Formed by; Root of iris Anterior-most part of ciliary body Scleral spur, Trabecular meshwork Schwalbe’s line

Flow chart depicting drainage of aqueous humour:

Flow chart depicting drainage of aqueous humour

Definition & Classification:

Definition & Classification Definition:- Group of disorders characterized by a progressive optic neuropathy resulting in a characteristic appearance of the optic disc and a specific pattern of irreversible visual field defects that are associated frequently but not invariably with raised intraocular pressure (IOP) Classification:- Clinico -etiologically glaucoma may be classified as Follows; (A) Congenital and developmental glaucomas 1. Primary congenital glaucoma (without associated anomalies) 2. Developmental glaucoma (with associated anomalies). (B) Primary adult glaucomas 1. Primary open angle glaucomas (POAG) 2. Primary angle closure glaucoma (PACG) 3. Primary mixed mechanism glaucoma (C) Secondary glaucomas

Etiology (in brief):

Etiology (in brief) Primary insults 1. Raised intraocular pressure (Mechanical theory) 2. Pressure independent factors (Vascular insufficiency theory ) i . Failure of auto-regulatory mechanism of blood flow ii. Vasospasm iii. Systemic hypotension iv. Other factors (acute blood loss and abnormal coagulability profile) Secondary insults ( Excito -toxicity theory) glutamate (excitatory toxin), oxygen free radicals, or nitric oxide which are released when RGCs undergo death due to primary insults


ANTI GLAUCOMA DRUGS Parasympathomimetic drugs ( Miotics ) Sympathomimetic drugs (Adrenergic agonists) β-blockers Carbonic anhydrase inhibitors Hyperosmotic agents Prostaglandins Calcium channel blockers

PowerPoint Presentation:

Alpha1 adrenoreceptor : constrict ciliary vessels and reduce aqueous production. (≈ Use Alpha AGONISTS) Alpha2 adrenoreceptor : located on ciliary epithelium reduces aqueous secretion. (≈ Use Alpha AGONISTS) Beta 2 receptor : located on ciliary epithelium enhance aqueous secretion via increasing CAMP. Their blockade reduces secretion. (≈ Use Beta ANTAGONISTS) Carbonic anhydrase : present within ciliary epithelial cells generate bicarbonate ion. Enhances aqueous humor production. Blockade reduces secretion. (≈ Use C.A ANTAGONISTS) Receptor activity



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Site of action of miotics in angle closure glaucoma: Contraction of sphincter pupillae , removes pupillary block and reverses obliteration of iridocorneal angle Site of action of miotics in open angle glaucoma: Contraction of ciliary muscle pulls on scleral spur and improve trabecular patency Site of alpha1 alpha2 agonist and beta blockers Site of action of prostaglandins and possibly adrenalin: I ncrease uveo-scleral outflow by altering permeability and or pressure gradients Site of action of Adrenaline : possibly increases aqueous conductivity trabecular filtering cells (Beta 2 action)

A. Parasympathomimetic drugs (Miotics) :

A. Parasympathomimetic drugs ( Miotics ) Classification Depending upon the mode of action, these can be classified as follows: 1. Direct-acting or agonists e.g., Pilocarpine . 2. Indirect-acting parasympathomimetics or cholinesterase inhibitors : I ndirect destruction of the enzyme cholinesterase; spares the naturally acting Acetylcholine for its actions. Types; ( i ) Reversible (e.g., Physostigmine ) (ii) Irreversible (e.g., Echothiophate iodide , Demecarium and Diisopropyl-fluoro-phosphate, DFP3 ) 3. Dual-action parasympathomimetics , i.e., which act as both a muscarinic agonist as well as a weak cholinesterase inhibitor e.g., Carbachol .


. Mechanism of action 1. In primary open-angle glaucoma : Miotics reduce IOP by enhancing the aqueous outflow facility. This is achieved by changes in the trabecular meshwork produced by a pull exerted on the scleral spur by contraction of the longitudinal fibres of ciliary muscle . 2. In primary angle-closure glaucoma : M iotics reduce the IOP due to their miotic effect by opening the angle. The mechanical contraction of the pupil moves the iris away from the trabecular meshwork.


.. Side-effects 1. Systemic side-effects : Bradycardia , increased sweating, diarrhoea, excessive salivation and anxiety. 2. Local side-effects: E ncountered more frequently with long-acting Miotics (i.e. irreversible cholinesterase inhibitors). Problems due to miosis itself (e.g. reduced visual acuity in the presence of polar cataract, impairment of night vision and generalized contraction of visual fields) Spasm of accommodation - Myopia and frontal headache, retinal detachment Lenticular opacities Iris cyst formation Mild iritis Lacrimation Follicular conjunctivitis.


. PREPARATIONS Pilocarpine . D irect-acting parasympathomimetic drug. Most commonly used. Indications : ( i ) Primary open-angle glaucoma (ii) Acute angle-closure glaucoma (iii ) Chronic synechial angle-closure glaucoma. Contraindications : ( i ) I nflammatory glaucoma (ii) Malignant glaucoma (iii) Known allergy. Available preparations and dosage are: (a) Eyedrops are available in 1%, 2% and 4% strengths. In POAG, therapy is usually initiated with 1 percent concentration. The onset of action occurs in 20 minutes, peaks in 2 hours and duration of effect is 4-6 hours. Therefore, the eyedrops are usually prescribed every 6 or 8 hourly. ( b) Ocuserts are available as pilo-20 and pilo-40. These are changed once in a week. Pilo-20 is generally used in patients controlled with 2 percent or less concentration of eyedrops ; and pilo-40 in those requiring higher concentration of eyedrops . ( c) Pilocarpine gel (4%) is a bedtime adjunct to the daytime medication.


.. 2. Carbachol . It is a dual-action (agonist as well as weak cholinesterase inhibitor) miotic . Indications . It is a very good alternative to pilocarpine in resistant or intolerant cases. Preparations . It is available as 0.75 percent and 3 percent eyedrops . Dosage : The action ensues in 40 minutes and lasts for about 12 hours. Therefore, the drops are instilled 2 or 3 times a day. 3. Echothiophate iodide ( Phospholine iodide). It is a long acting cholinesterase inhibitor. Indications : It is very effective in POAG. Preparations : Available as 0.03, 0.06 and 0.125 percent eye- drops. Dosage : The onset of action occurs within 2 hours and lasts up to 24 hours. Therefore, it is instilled once or twice daily. 4. Demecarium bromide . It is similar to ecothiopate iodide and is used as 0.125 percent or 0.25 per- cent eyedrops . 5. Physostigmine ( eserine ). It is a reversible (weak) cholinesterase inhibitor. It is used as 0.5 percent ointment twice a day.

B. Sympathomimetic drugs :

B. Sympathomimetic drugs Classification Depending upon the mode of action; 1. Both Alpha and Beta-receptor Stimulators e.g. Epinephrine . 2. Direct Alpha-Adrenergic Stimulators e.g. Norepinephrine Clonidine hydrochloride 3. Indirect Alpha-Adrenergic Stimulators e.g. Pargyline . 4. Beta-Adrenergic Stimulator e.g . Isoproterenol .


.. Mechanisms of action 1. Increased aqueous outflow results by virtue of both alpha and beta-receptor stimulation. 2. Decreased aqueous humour production occurs due to stimulation of alpha-receptors in the ciliary body. Side-effects 1. Systemic side-effects: H ypertension , tachycardia, headache, palpitation, tremors, nervousness and anxiety . 2. Local side-effects: Burning sensation, reactive hyperaemia of conjunctiva, conjunctival pigmentation, allergic blepharo conjunctivitis, mydriasis and cystoid macular oedema (in aphakics ).

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PREPARATIONS 1.Epinephrine. D irect-acting sympathomimetic drug stimulates both alpha and beta- adrenergic receptors. Indications : ( i ) POAG - DoC ( ii) Secondary glaucomas . Preparations : It is available as 0.5 percent, 1 percent and 2 percent eyedrops . Dosage : The action starts within 1 hour and lasts up to 12-24 hours. Therefore , it is instilled twice daily. 2. Dipivefrine ( Propine or dipivalylepinephrine ): Prodrug which is converted into epinephrine after its absorption into the eye. More lipophilic than epinephrine and thus its corneal penetration is increased by 17 times. Preparations : It is available as 0.1 percent eyedrops Dosage : Action and efficacy is similar to 1 percent epinephrine. Instilled twice daily.

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3. Clonidine hydrochloride . It is a centrally-acting systemic antihypertensive agent, which has been shown to lower the IOP by decreasing aqueous humour production by stimulation of alpha-receptors in the ciliary body. Preparations and dosage . It is used as 0.125 percent and 0.25 percent eye drops, twice daily. 4. Brimonidine (0.2%) . S elective alpha-2 adrenergic agonist . Lowers IOP by decreasing aqueous production and enhancing uveoscleral outflow. Additive effect to betablockers . Dosage : It has a peak effect of 2 hours and action lasts for 12 hours; so it is administered twice daily. 5. Apraclonidine Prophylactically for prevention of IOP elevation following laser trabeculoplasty , YAG laser iridotomyand posterior capsulotomy


. C. Beta-adrenergic blocker The most frequently used antiglaucoma drugs. Commonly used preparations are Timolol and Betaxolol . Other available preparations include Levobunolol , Carteolol and Metipranolol . Mechanism of action . Timolol and levobunolol are non-selective beta-1 (Cardiac) and beta-2 (smooth muscle, pulmonary) receptor blocking agents. The drugs timolol and levobunolol lower IOP by blockade of beta-2 receptors in the ciliary processes, resulting in decreased aqueous production. Indications . Beta adrenergic blockers are useful in all types of glaucomas , viz., developmental, primary and secondary; narrow as well as open angle. Unless contraindicated due to systemic diseases, betablockers are frequently used as the first choice drug in POAG and all secondary glaucomas .

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Contraindications . U se with caution in patients with Bronchial Asthma , Emphysema , COPD, Heart blocks, Congestive Heart Failure or Cardiomyopathy . Betaxolol is the beta blocker, of choice in patients at risk for pulmonary diseases. The other contraindication includes known drug allergies. Additive effects Beta-blockers have very good synergistic effect when combined with Miotics ; and are thus often used in combination in patients with POAG, unresponsive to the single drug . Side-effects Ocular side-effects are not frequent. These include burning and conjunctival hyperaemia, superficial punctate keratopathy and corneal anaesthesia . Systemic side-effects are also unusually low. ( i ) Cardiovascular effects which result from blockade of beta-1 receptors. These are bradycardia , arrhythmias, heart failure and syncope. ( ii) Respiratory reactions : bronchospasm and airway obstruction, especially in asthmatics . These occur due to blockade of beta-2 receptors; and thus are not known with betaxolol . ( iii) Central nervous system effects . Depression , anxiety, confusion, drowsiness, disorientation , hallucinations, emotional lability , dysarthria and so on. 3. Miscellaneous effects are nausea, diarrhoea, decreased libido, skin rashes, alopecia and exacerbation of myasthenia gravis.

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PREPARATIONS 1. Timolol. It is a non-selective beta-1 and beta-2 blocker. It is available as 0.25 per cent and 0.5 percent eye drops. The salt used is timolol maleate . Its action starts within 30 minutes, peak reaches in 2 hours and effects last up to 24 hours. 2. Betaxolol : It is a cardioselective beta-blocker and thus can be used safely in patients prone to attack of bronchial asthma . 3. Levobunolol : 0.5% 4. Carteolol : 1-2% Less Bradycardia 5. Metipranolol : 0.1, 0.3, 0.6%


. D .Carbonic anhydrase inhibitors (CAIs) Potent and most commonly used Systemic Anti-Glaucoma drugs. These include Acetazolamide (most frequently used), Methazolamide , Dichlorphenamide and Ethoxzolamide . Mechanism of action . CAIs inhibit the enzyme carbonic anhydrase which is related to the process of aqueous humour production. Thus, CAIs lower the IOP by reducing the aqueous humour formation. Indications . These are used as additive therapy for short term in the management of all types of acute and chronic glaucomas . Their long-term use is reserved for patients with high risk of visual loss, where all other treatments fail.


. Side-effects . 1. Paresthesias of the fingers, toes, hands, feet and around the mouth. 2. Urinary frequency 3. Serum electrolyte imbalance 4. GI symptoms Preparations and doses 1. Acetazolamide ( diamox ). It is available as tablets, capsules and injection for intravenous use. The acetazolamide 250 mg tablet is used 6 hourly. Its action starts within 1 hour, peak is reached in 4 hours and the effect lasts for 6-8 hours.


. 2.Dichlorphenamide 3.Methazolamide 4.Ethoxzolamide 5.Dorzolamide 6.Brinzolamide

E. Hyperosmotic agents :

E. Hyperosmotic agents Mechanism of action : Hyper-osmotic agents increase the plasma tonicity. Thus, the osmotic pressure gradient created between the blood and vitreous draws sufficient water out of the eyeball, thereby significantly lowering the IOP . Indications : These are used as additive therapy for rapidly lowering the IOP in emergency situations - Acute Angle-Closure Glaucoma or Secondary Glaucomas with very high IOP. They are also used as a prophylactic measure prior to intraocular surgery.


. Preparations and doses 1 . Glycerol. It is a frequently used oral hyperosmotic agent. Its recommended dose is 1-1.5 gm/kg body weight . It is used as a 50 percent solution. So, glycerol (50 to 80 ml in adults) is mixed with equal amount of lemon juice (preferably) or water before administering orally. Its action starts in 10 minutes, peaks in 30 minutes and lasts for about 5-6 hours. It can be given repeatedly. It is metabolised to glucose in the body. Thus, its repeated use in diabetics is not recommended. 2. Mannitol . It is the most widely used intravenous hyperosmotic agent. It is indicated when the oral agents are felt to be insufficient or when they cannot be taken for reasons such as nausea. Its recommended dose is 1-2 gm/kg body weight . It is used as a 20 percent solution. It should be administered very rapidly over 20-30 minutes. Its action peaks in 30 minutes and lasts for about 6 hours. It does not enter the glucose metabolism and thus is safe in diabetics. However, it should be used cautiously in hypertensive patients. 3. Urea. When administered intravenously it also lowers the IOP. However, because of lower efficacy and more side-effects than mannitol , it is not recommended for routine use. 4. Isosorbide . It is an oral hyperosmotic agent, similar to glycerol in action and doses. However metabolically it is inert and thus can be used repeatedly in diabetics.

F. Prostaglandin analogues :

F. Prostaglandin analogues 1. Latanoprost (0.005 %) It is a synthetic drug which is an ester analogue of prostaglandin F2-α . It is acts by increasing uveoscleral outflow and by causing reduction in episcleral venous pressure. It is as effective as timolol . It has additive effect with pilocarpine and timolol . Its duration of action is 24 hours and is, thus, administered once daily. Side-effects: include Conjunctival hyperaemia, foreign body sensation and increased pigmentation of the iris. 2. Bimatoprost (0.03%). It is a prostamide which decreases IOP by decreasing ocular outflow resistance. It is used once a day (OD). 3. Travoprost (0.004%). It is a synthetic prostaglandin F2 analogue and decreases IOP by increasing uveoscleral outflow of aqueous. 4. Unoprostive isopropyl (0.12%). It is a dolosanoid related in structure to prostaglandin F2-α . It lowers IOP by increasing uveoscleral outflow of aqueous. It also increases retinal blood flow.

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G. Calcium channel blockers Calcium channel blockers such as Nifedipine , Diltiazem and Verapamil are commonly used antihypertensive drugs. Recently, some of these have been used as anti-glaucoma drugs. Mechanism of action: The exact mechanism of lowering IOP of topically used calcium channel blockers remains to be elucidated. It might be due to its effects on secretory ciliary epithelium. Preparations: Verapamil has been tried as 0.125 percent and 0.25 percent eyedrops twice a day. Indications: Though the IOP lowering effect of verapamil is not superior than the standard topical antiglaucoma drugs, it has a place in the mangement of patients with POAG , where miotics , beta-blockers and sympathomimetics are all contraindicated e.g., in patients suffering simultaneously from axial cataract, bronchial asthma and raised blood pressure . It can also be used for additive effect with pilocarpine and timolol .

PowerPoint Presentation:

Antiglaucoma drugs: Mechanism of lowering IOP (A) Drugs which increase trabecular outflow Miotics (e.g ., Pilocarpine ) Epinephrine, Dipivefrine Bimatoprost (B) Drugs which increase uveoscleral outflow Prostaglandins ( Latanoprost ) Epinephrine, Dipivefrine Brimonidine Apraclonidine (C) Drugs which decrease aqueous production Carbonic anhydrase inhibitors (e.g., Acetazolamide , Dorzolamide ) Alpha receptor stimulators in ciliary process (e.g., Epinephrine, Dipivefrine , Clonidine , Brimonidine , Apraclonidine . Beta blockers (e.g., Timolol , Betaxolol , Levobunolol ) (D) Hyperosmotic agents Glycerol Mannitol Urea

Management in a nutshell…:

Management in a nutshell… I] PRIMARY OPEN ANGLE GLAUCOMA (a) Single Drug Therapy 1. Topical beta-blockers: DoC, 1 st line Timolol maleate, Betaxolol, Levobunolol, Carteolol 2. Latanoprost : 1 st line 3. Dorzolamide : 2 nd line 4. Pilocarpine : 2 nd line 5. Adrenergic drugs: Dipivefrine hydrochloride ( combined with beta-blockers in patients where other drugs are contraindicated ) (b) Combination topical therapy If one drug is not effective, then a combination of two drugs—one drug which decreases aqueous production ( timolol or other betablocker , or brimonidine or dorzolamide ) and other drug which increases aqueous outflow ( latanoprost or brimonidine or pilocarpine ) may be used.

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II] acute primary angle-closure glaucoma Medical therapy is instituted as an emergency and temporary measure before the eye is ready for operation; Systemic hyperosmotic agent intravenous mannitol (1 gm/kg body weight) Acetazolamide 500 mg intravenous injection followed by 250 mg tablet should be given 3 times a day. Analgesics and anti-emetics Pilocarpine eyedrops 2 percentpilocarpine should be administered every 30 minutes for 1-2 hours and then 6 hourly Beta blocker eyedrops like 0.5 percent timolol maleate or 0.5 percent betaxolol should also be administered twice a day to reduce the IOP. Corticosteroid eyedrops like dexamethasone or betamethasone should be administered 3-4 times a day to reduce the inflammation III] absolute primary angle-closure glaucoma Retrobulbar alcohol injection : It may be given to relieve pain. First, 1 ml of 2 percent xylocaine is injected followed after about 5-10 minutes by 1 ml of 80 percent alcohol . It destroys the ciliary ganglion.

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