الفهرس 
IntroductionOnly 14 pages are availabe for public view
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Abstract
For glaucoma therapy to be the most efficacious, the most important principle to remember is that regardless of the type of medication prescribed, it is imperative for success that patients be provided with instructions for proper administration of these drugs.
Topical 13-blockers are the most widely used treatment for glaucoma. To date comparative trials in patients with elevated IOP demonstrated that carteolol, levobunolol, metipranolol and timolol have similar degree and maintenance of IOP lowering (20%-30%). Betaxolol appears to have slightly less 10P lowering efficacy. Approximately 50% of glaucoma patients on a 13-blocker require additional glaucoma medications to control their IOP adequately. The additivity of epinephrine compounds to 0-blockers is variable with some studies, suggesting that additivity is greater with betaxolol than timolol, at least there is mean reduction of IOP of I to 2 mmHg with a small proportions of patients showing a greater reduction of IOP and significant proportion showing no change in IOP. A wide variety of systemic side effects has been reported with the use of topical fl-blockers including cardiopulmonary, central nervous system and metabolic side effect. Betaxolol, which is cardioselective, has the advantage of causing less systemic B2-blockade. Ocular adverse reactions are relatively uncommon with topical B-blockers. There are some variations in ocular side effects but in general the side effects of the different B-blockers are similar. The variations in ocular side effects may reflect the different vehicles used, pHs and concentrations of the drugs.
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a2 agonists are relatively new antiglaucoma agents. Their mechanisms of action include decreasing aqueous formation, increasing trabecular outflow (apraclonidine) and increasing uveoscleral outflow (brimonidine).
Apraclonidine 1.0% is already well established as the treatment of choice to prevent intraocular pressure spikes following laser therapy and a future role to prevent intraocular pressure rise after cataract surgery seems likely. For longer term application 0.5% solution with a small DROP size and a 12 hours dosage schedule is probable. Mild side effects such as conjunctival blanching, foreign body sensations, dryness of the nose and mouth, fatigue and allergic reactions are common which limits its use as a long term antiglaucoma drug. No significant reduction of blood pressure has been noted.
Brimonidine tartarate 0.2% is a more recent highly selective a2- agonist (23 to 32 times more selective for a2-receptors than apraclonidine). Due to the duration of action of brimonidine it is approved for three times a day dosing. It lowers intraocular pressure by not only reducing aqueous humour production, but also by increasing uveoscleral outflow. Recently researches have shown that a2-agonists may confer neuroprotection in animal models specifically in cerebral ischemia. The most frequent ocular side effects reported with brimonidine are dry mouth, ocular allergy with conjunctival follicles, burning and stinging which appear to be dose related. Systemic side effects include fatigue and drowsiness as it is a highly lipophilic drug that possess the ability to pass blood brain barrier. Another side effect is systemic hypotension. Brimonidine has an important place in management of
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chronic glaucoma because of its lower rate of localised effects, sustained 1013 lowering and better additivity to other antiglaucoma medications.
Because of the high incidence of systemic side effects with oral carbonic anhydrase inhibitors (CAIS) investigators have long searched for active topical CAIs. A series of topical CAIs have been developed and three of them have undergone clinical trials. The most important of these agents, is dorzolamide. Dorzolamide is effective in inhibiting isoenzymes II and IV with a somewhat weaker effect on isoenzyme ISO it reduces intraocular pressure by decreasing aqueous production. Dose response studies of 0.7%, 1.4% and 2% have shown that the 2% solution is the most effective producing peak and trough IOP reductions of 21% and 13% respectively with twice daily usage and slightly better trough reduction with dosing three times daily. Dorzolamide is additive to other aqueous suppressants as timolol and to drugs acting on the outflow system as pilocarpine. Dorzolamide is available commercially as a 2% solution to be used every 8 hours as monotherapy and every 12 hours as adjunctive therapy. There have been no significant clinical side effects reported with the use of topical carbonic anhydrase inhibitors. This is to be expected because less than 1% of the total dose of the oral preparation is being administered.
Prostaglandins in very small doses produce an intraocular pressure lowering effect that is dose dependent and of relatively long duration. They decrease intraocular pressure by increasing the uveoscleral outflow with no effect on aqueous secretion. The isopropyl ester form of PGF2a penetrates the cornea better than does the free acid and acts as a prodrug. To avoid intolerance a submaximal dose is selected but the hypotensive effect becomes enhanced after several doses. Side effects include a mild
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to moderate ocular irritation or foreign body sensation and hyperaemia. Both of which are dose dependent and become more frequent with sustained use. Clinically significant breakdown of the blood aqueous barrier and inflammation have not been noted, but because of the external ocular symptoms, it is unlikely that the drug will be sufficiently tolerated in its present form. A new prostaglandin analogue, PHXA41 (latanoprost) produce less conjunctival hyperaemia and discomfort than PGF2a-IE. Latanoprost may be used as a primary medical treatment when the patient is unlikely to tolerate (3-blocker therapy and when the convenience of once-daily dosing is important. However the patient should be willing to accept the possiblity of permanent iris colour change which may occur especially in unilateral cases. It certainly should be considered as a second-line medication if 13-blockers therapy does not provide adequate 10P control or produces significant side effects.
Isopropylunoprostone is another drug derived from a pulmonary metabolite of PGF2. It reduces 10P in normal volunteers without significant side effects for at least 2-weeks period. It is given twice daily and this was equivalent to the effect produced by timolol twice daily. Side effects of isopropyl unoprostone included a dose-dependent conjunctival hyperaemia, corneal epithelial defect and headache. The indications and cautions for latanoprost apply to unopostone as well.
Calcium channel blockers have ocular effects that may benefit glaucoma patients particularly with low-tension glaucoma. These drugs generally cause a mild reduction of 10P especially with topical administration in some low-tension glaucoma patients, calcium channel blockers slow the rate of glaucomatous progression possibly by increasing optic nerve blood flow, reducing vasopasm or causing
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neuroprotective effect. Blood pressure should be monitored in patients who are treated with these drugs and arterial hypotension can be avoided by adjusting the dosing of the medication. Systemic calcium channel blockers therapy is potentially useful in select patients with low-tension glaucoma. Topical calcium-channel blockers which have a consistent-albeit moderate-ocular hypotensive effect are under investigations.
One modern promise of neuroprotection reveals around excitotoxicity caused by glutamate and other agents with the promise that inhibition of these agents may block or reduce their negative effects on the ganglion cells and/or optic nerve. Glutamate an excitatory amino acid transmitter is a well-known mediator of traumatic and ischemic neuronal injury within the CNS. For some time, glutamate has been known to facilitate ganglion cell death in the inner retina. Recent reports of elevated glutamic acid levels in the vitreous of gluacomatous humans and monkeys suggest that an elevated vitreal glutamate level may induce glaucomatous damage.
Glutamate can be toxic to retinal ganglion cell neurons via over stimulation of various subtypes of excitatory amino acid receptors. The predominant form of injury appears to be mediated by the NMDA subtype of these receptors. Moreover, clinically tolerated CNS-permeant NMDA antagonists directed to controlling glutamate-induced excitotoxicity have been described recently. These agents include the amantadine derivative memantine and nitric acid generating agents such as nitroglycerin, in addition clinically available voltage-dependent calcium channel blockers such as nimodipine which permeate the blood brain barrier have been shown recently to partially a meliorate NMDA receptor mediated neutrotoxicity of retinal ganglion cells at least in vitro.
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Recent work with the NMDA blocking effect of brimonidine has shown the neuroprotective ability of this drug.
The following approach to medical treatment of most chronic glaucoma is suggested by Stamper et aL (1999). Most physicians would start with a B-blocking agent unless the patient has respiratory or cardiovascular conditions that might represent contraindications to their use. Betaxolol, a selective B-blocker is somewhat safer than are non-selective B-blockers in patient with a history of asthma or cardiovascular diseases.
Latanoprost, a prostaglandin analogue has achieved as first-line therapy in scandinavia and Japan (in the united states, it is currently approved only as a second-line drug). If the LOP fails to respond to the initial agent, discontinue it and start another agent, preferably one belonging to a different class. If the IOP responds insufficiently to reach the target pressure, a second agent of a different type may be added. Medical escalation should proceed from the least toxic agents to the more potentially toxic ones.