nene
07-06-03, 10:11 PM
[Glaucoma
Glaucoma continues to be a major cause of irreversible visual disability all over the word. At present, there approximately 7.5 million diagnosed cases of blindness, of which glaucoma accounts for 10-20%. It is estimated that there are about 2.47 million cases of primary open angle glaucoma in United States alone, the commonest type of glaucoma in the West.
Glaucoma refers to a group of disorders in which elevated intraocular pressure leads to atrophy of the optic nerve. After being produced by the ciliary body, aqueous humor enters the posterior chamber (the space between the iris and zonules) before passing through the pupil to the anterior chamber (between the iris and the cornea).
From that site, it then drains into veins by way of the trabecular meshwork and the Schlemm canal (Fig.1-7). A delicate balance between the production and drainage of aqueous humor maintains the intraocular pressure within its physiologic range (10-20 mm Hg).
In certain pathologic states, however, aqueous humor accumulate within the eye, and intraocular pressure becomes elevated. Temporary or permanent impairment of vision results from pressure-induced degenerative changes in the retina and optic nerve head and from corneal edema and opacification.
Types of Glaucom .l
Congenital Glaucoma : This type of glaucoma result from an obstruction of the aqueous drainage by developmental anomalies, even though the intraocular pressure may not become elevated until infancy or childhood.
· Primary Open-Angle Glaucoma: The intraocular pressure becomes elevated insidiously and asymptomatically, and with time, damage to the retina and optic nerve causes an irreversible loss of peripheral vision. The angle of the anterior chamber is open and appears to be normal, but an increased resistance to the outflow of aqueous humor is present within the vicinity of the Schlemm cannal.
· Primary Closed-Angle Glaucoma: Primary closed-angle glaucoma occurs after the age of 40 years. It afflicts persons whose peripheral iris is displaced anteriorly toward the trabecular meshwork, thereby creating an abnormally narrow angle. When the pupil is constricted (miotic), the iris remains stretched, so that the chamber angle is not occluded.when the pupil dilates (mydriasis), however, the iris obstructs the anterior chamber angle, thereby impairing aqueous drainage and resulting in sudden episodes of intraocular hypertension. Acute closed-angle glaucoma is an ocular emergency, and it is essential to begin hypotensive treatment within the first 24 to 48 hours if vision is to be maintained.
· Secondary Glaucoma: The causes of secondary glaucoma are many, and include inflammation, hemorrhage, neovascularization of the iris, and adhesions. in secondary glaucoma, the anterior chamber angles may by open or closed. Because the underlying disorder is generally limited to one eye.
Reference: Essential Pathology, Third Edition, Edited by: Emmanul Rubin, MD, LIPPINCOT WILLIAMS & WILKINS.
Diagnosis:
The older the individual, greater the risk of glaucoma. Because glaucoma does not cause symptoms in most cases, those who are 40 or older should have an annual examination including a measurement of the intraocular pressure. Those who are glaucoma suspects may need additional testing.
Pharmacotherapy of Glaucoma:
Prevention or modification of risk factors, particularly the raised intraocular pressure is the primary goal in the management of glaucoma. The disease needs to be managed medically, by laser therapy or by conventional surgery as the case may be.
Classification of antiglaucoma agents:
Depending on their route of administration antiglaucoma agents may be classified as:
Topical drugs:
Cholinergic agents e.g. Pilocarpine, Carbachol, and Echothiophate iodide.
Adrenergic agonists e.g. Epinephrine, Dipivefrin, Brimonidine and Apraclonidine.
Beta blockers e.g. Timolol, Carteolol, Levobunolol and Metoprolol.
Prostaglandin analogs e.g. PGF2α, Latanoprost and Unoprostone.
Carbonic anhydrase inhibitors e.g. Dorzolamide and Brinzolamide.
Systemic drugs:
Carbonic anhydrase inhibitors e.g. Acetazolamide and Methazolamide.
Osmotic agents e.g. Glycerine, Mannitol and Urea.
Mechanism of action of antiglaucoma agents:
The antiglaucoma agents act on the aqueous humor dynamics to reduce the intraocular pressure mainly by three mechanisms:
ý Decrease aqueous production in the ciliary body.
ý Increase aqueous humor outflow through the trabecular meshwork and
ý Increase aqueous humor outflow via the uveoscleral pathway.
1. Cholinergic drugs:
In the past, miotics were the drugs of first choice for the management of most types of glaucoma but currently due to their high side-effects, their use has declined.
Miotics can be divided into two groups:
ý Direct acting miotics e.g. Pilocarpine.
ý Cholinesterase inhibitors e.g. Carbachol is a dual action parasympathomimetic due to its week anticholinesterase activity.
They act by opening up the inefficient drainage channels in the trabecular meshwork resulting from contraction or spasm of the ciliary muscle.
Used in the management of raised intraocular pressure include carbachol and pilocarpine.
Should be used with caution in cardiac disease, hypertension, asthma, peptic ulceration, urinary-tract obstruction, and Parkinson's disease.
Contraindicated in condition where pupillary constriction is undesirable such as acute iritis, and some forms of secondary glaucoma.
Side-effects of miotic drugs are ciliary spasm leads to headache which may be more in the initial 2-4 weeks of treatment.
Ocular side-effects: burning, itching, lens changes with chronic use.
Systemic side-effects: are rare following application to the eye.
Delivery systems for pilocarpine:
Drug delivery systems aim to achieve the desired pharmacological effect with the least amount of drug and to prolong the duration of therapeutic effect thereby decreasing the frequency of instillation and associated side effects.
a) Soluble polymers: Polymers like methylcellulose and polyvinyl alcohol increase the conjunctival sac retention time and increase corneal penetration.
b) Pilocarpine gel: The equivalent of 4% pilocarpine hydrochloride in a highly viscous acrylic vehicle when applied once daily at bed time has been reported to produce a significant reduction in IOP for 24 hours.
c) Membrane-controlled delivery systems: This is an insert device placed in the cul-de-sac where it gradually releases pilocarpine at the rate of 20μg/hour or 40μg/hour, which is roughly equivalent to 2% and 4% eye drops respectively. This is effective for 7 days and the constant rate of release provides good control of IOP throughout the day.
d) Pilocarpine soaked soft contact lenses: Not as yet recommended for general clinical use.
e) Transdermal drug delivery system: A new non ocular pharmaceutical device has been tested for pilocarpine.
f) Electronic medication alarm device: Another device which enhances the compliance in glaucoma patient taking pilocarpine is the electronic medication alarm device.
Cholinesterase inhibitors:
Cholinesterase inhibitors are another class of miotics which act by increasing the levels of endogenous acetylcholine by inhibiting the enzyme acetylcholinesterase. Physostigmine, neostigmine, and demecarium are short acting cholinesterase inhibitors whereas ecothiophate and isofluorophate are long acting cholinesterase inhibitors.
Physostigmine and neostigmine are useful in angle closure and open angle glaucoma, though their use has declined due to the high incidence of allergic reactions. Ecothiophate iodide and demecarium bromide are no longer used in glaucoma. Isofluorophate is more oculotoxic than ecothiophate and demecarium.
In general, the use of anticholinesterase medications for the treatment of open angle glaucoma is reserved for cases in which the patient has become intolerant to pilocarpine or carbachol or when the pressure lowering effect of these agents is inadequate. Also these agents are more effective in secondary glaucoma.
2. sympathomimetics (adrenergic agonists):
a) Epinephrine:
Adrenaline (epinephrine) probably acts both by reducing the rate of production of aqueous humour due to its α-adrenergic effect, and by increasing the outflow through the trabecular meshwork by stimulating β2-adrenergic receptors.
Onset of action occurs at 1 hr with a peak effect at 4 hours and ocular hypotensive effect may last upto 72 hours.
Epinephrine may be used as initial or adjunctive glaucoma therapy.
It is contraindicated in angle-closure glaucoma because it is a mydriatic.
Side-effects include severe redness of the eye; adrenaline should be used with caution in patients with hypertension and heart disease.
b) Dipivefrin:
Dipivefrin is a pro-drug of adrenaline (which undergoes biotransformation to epinephrine within the cornea).
Due to increased lipophilicity its penetration across the cornea 17 times more than epinephrine, and lesser doses are needed to be administered as compared to epinephrine.
It is better tolerated than epinephrine, the onset of its ocular hypotensive action is within 30 minutes and beak effect is observed in 1 hour.
Its advantages over epinephrine are lower cardiovascular side effects.
Like epinephrine it can be used in patient of asthma, in young patient intolerant to miotics and in those with cataracts.
c) Brimonidine:
Brimonidine, a selective α2-adrenoceptor stimulant, is licensed for the reduction of intra-ocular pressure in open-angle glaucoma or ocular hypertension in patients for whom beta-blockers are inappropriate.
It is the drug of choice in chronic treatment of glaucoma and in patients with cardiopulmonary disease and who have contraindications to β-blockers.
It has lower incidence of ocular side effects because of α2-selectivity.
Its peak IOP reduction efficacy is comparable to that of timolol and does not cause cardiopulmonary side effect as reported with timolol. However, there are reports suggesting similar efficacy of brimonidine with that of timolol but with a greater incidence of adverse local reactions.
3. Beta-blockers:
These drugs usually are the first line agents for the medical therapy of all kinds of glaucoma.
Topical applications of a beta-blocker to the eye reduce intra-ocular pressure effectively in chronic simple glaucoma, probably by reducing the rate of production of aqueous humour (block the β-receptor in the iris and ciliary body).
This class of drugs has several advantages over both cholinergic and adrenergic agonist; majority of patient can be treated solely by β-blockers.
Unlike miotics, β-blocker have little effect on pupil size or accommodation, eliminating the problems of dim vision, decreased night vision and blurred vision.
Unlike adrenergic agonists, β-blockers do not cause pupil size changes or hyperemia. β-blockers also have a significant additive action when combined with pilocarpine or other antiglaucoma.
Depending on their selective receptor inhibition, they are classified as β1-selective and non-selective β-blocker respectively.
ý Selective β1-blockers: Betaxolol, atenolol and metoprolol.
ý Non-selective β-blockers: Timolol, maleate, nadolol, carteolol and labetalol.
a) Timolol:
It is being used extensively worldwide as a first line agent for the treatment of patients with open angle glaucoma and ocular hypertension and has been shown to be more effective in lowering IOP than pilocarpine. It is instilled as one drop of 0.25% or 0.5% solution twice a day and the duration of action exceeds 7 hours. At this dose timolol produces a significant reduction in IOP in most cases.
b) Metoprolol:
It is a cost effective, selective β1-adrenergic antagonist similar to timolol in clinical efficacy. It reduces the IOP in normal eyes, chronic open angle glaucoma and ocular hypertensive patients.
c) Levobunolol:
It reduces intraocular pressure by reducing aqueous humor formation as well as by enhancing the outflow facility. It is as effective in reducing IOP as timolol maleate, metoprolol and carteolol. The potential advantage of levobunolol is once daily due to longer duration of action.
Levobunolol is contraindicated in patients predisposed to cardiac or respiratory disease. Caution is required in diabetics and those undergoing major surgery.
Systemic absorption may follow topical application therefore eye drops containing a beta-blocker are contra-indication in patients with bradycardia, heart block, or uncontrolled heart failure.
Important: for a warning to avoid in asthma.
Local side-effects of eye drops include ocular stining, burning, pain, itching, dry eyes.
4. Carbonic anhydrase inhibitors:
· These are the reserved group of drugs and are given orally (with the exception of dorzolamide and brinzolamide which are available for topical administration) as an adjunct when IOP is not controlled adequately with topical medication.
· Approximately 50% patients have shown intolerable side effects with the use of systemic carbonic anhydrase inhibitors. Therefore these drugs are currently used to control IOP in patients waiting for surgery or till the time topical drugs become effective.
a) Acetazolamide:
· This is the most widely prescribed carbonic anhydrase inhibitor. However, approximately 50% patients stop treatment with acetazolamide as a consequence of intolerable side effects due to extraocular inhibition of carbonic anhydrase.
· It reversibly blocks the enzyme carbonic anhydrase in the ciliary body and thus suppresses aqueous humor production.
· Acetazolamide is asulphonamide; is given by mouth or by intravenous injection, blood disorders, rashes and other sulphonamide-related side-effects occur occasionally.
b) Methazolamide:
· It is more potent than acetazolamide and has structural similarity to it.
· It is indicated in patients of chronic open angle glaucoma where IOP is not controlled adequately with acetazolamide or topical medications.
· Its penetration across blood aqueous barriers is 50 times that of acetazolamide due to its good lipid solubility and low plasma protein binding.. its dose is 25-50 mg three times daily.
c) Dorzolamide and brinzolamide:
They are topical carbonic anhydrase inhibitors, licensed for use in patient resistant to Beta-blockers or whom beta-blockers are contra-indicated.
5. Osmotic agents:
· These agents act by enhancing the osmotic pressure of plasma with respect to intraocular structures thereby setting an osmotic gradient.
· Consequently the fluid moves from the eye to hyperosmotic plasma of ocular blood vessels, thereby reducing the vitreous volume which is responsible for lowering of IOP.
· Mannitol, glycerol, urea, isosorbide etc are the osmotic agents used for short term reduction of IOP.
· The use of these drugs is currently limited to short term emergency situations such as acute angle closure glaucoma or pre-operative control of raised IOP.
· The side effect of these drugs includes nausea, vomiting, diuresis, headache, diarrhea, chills and fever.
6. Miscellaneous agents:
a) Forskolin:
Forskolin is derived from methanolic extract of the roots of Coleus forskohlii. It has been shown to be an effective ocular hypotensive agent both experimentally and clinically.
It is a potent stimulator of adenylate cyclase and does not require cell membrane bound receptors. The ocular hypotensive effect of forskolin is directly proportional to the extent of stimulation of adenylate cyclase.
No significant ocular or systemic side effects were observed.
The combination of 1% forskolin and 0.25% timolol had an additive effect which was more than the additive effect of 1% forskolin plus 2% pilocarpine.
b) Angiotensin converting enzyme inhibitors:
Components of the renin angiotensin system are present in peripheral tissues, including the eye and may play a role in controlling aqueous humor production, retinal blood flow or retinovascular disease.
Angiotensin II receptors of the retinal vasculature may play a significant role in the autoregulation of blood supply to the retina and optic nerve head.
Topical angiotensin converting enzyme (ACE) inhibitors have been shown to lower IOP in rabbits, monkeys and humans.
Experimental evidence suggests that ACE inhibitors might inhibit breakdown of bradykinin, promote formation of endogenous prostaglandins and also enhance uveoscleral outflow. Thus, inhibitors of ACE activity might be useful pharmacological agents in the medical therapy of glaucoma.
c) Ocular hypotensive lipids (OHL):
These compounds contain a neutral substituent for the carboxylic acidic group of PGF2α and are not fatty acids. These are relatively ****bolically stable unlike the prodrug latanoprost and the esterified PGF2α analogue that is readily ****bolized into active PGF2α.
These compounds have different pharmacological profiles yet are potent ocular hypotensive agents. Clinical trials were conducted on these OHL in open angle glaucoma and ocular hypertension cases.
Twice daily dosing at concentration of 0.01% produced significant IOP lowering and was superior to that of timolol (0.5%bd).
These new compounds continue to produce a significant IOP lowering effect upto 24 hours after the last drug instillation.
These compounds will be an excellent alternative as a first and second line IOP lowering agent for the therapy of ocular hypertension and open angle glaucoma.
7. Prostaglandin analogue:
a) Latanoprost:
· A prostaglandin analogue, it is licensed for open-angle glaucoma and ocular hypertension when other drugs are inappropriate.
· Its response seems to be mediated by prostanoid receptors. And it is more selective than PGF2α in this respect and thereby has superior therapeutic profile.
· It is available as 0.005% ophthalmic solution and requires to be instilled once at night. A single dose of topical 0.005% latanoprost is equi-effective to that of 0.5% timolol (bd dose) in patients suffering from primary open angle glaucoma and ocular hypertension and has a duration of action ranging from 20-24 hours. It is well tolerated with no detectable systemic side effects.
· Patients should be monitored for any changes to eye coloration since latanoprost may increase the brown pigment in the iris.
b) Unoprostone:
· Unoprostone isopropylate is the first docosanoid derivative for glaucoma therapy. It acts by enhancing uveoscleral outflow without affecting aqueous humor production.
· Its oculohypotensive effect is similar to or slightly inferior to that of timolol 0.5%.
Monotherapy versus combination therapy:
β blockers are the most commonly prescribed first line therapy though the use of latanoprost and brimonidine as primary therapy is also increasing in the west. Latanoprost, brimonidine and topical carbonic anhydrase inhibitors are effective as early adjunctive therapy in cases where a single drug alone is inadequate to control IOP.
Adrenergic agonists and miotics are also useful as secondary or tertiary therapy but their use in the west is declining due to their significant topical and systemic side effects. It is thus evident that when therapy with a single agent is inadequate to control IOP, combined treatment is indicated. The additive benefit of two drugs depends to some extent on whether they reduce IOP by similar mechanisms.
Miotics and carbonic anhydrase inhibitors in combination may be useful, probably because miotics increase aqueous outflow, whereas carbonic anhydrase inhibitors reduce inflow.
It must be stressed that if the initial agent is only slightly effective at lowering IOP, it should be discontinued and other drugs tried individually before going on to combination therapy. The combination therapy in contrast to monotherapy has the possibility of delaying the need for surgery.
In emergency or before surgery, mannitol 20% should be given by slow intravenous infusion until the intra-ocular pressure has been satisfactorily reduced. Acetazolamide by intravenous injection may also be used for the emergency management of raised intra-ocular pressure.
References:
1. Indian Journal of Pharmacology 2002; 34: 71-85, educational forum, Rohit Saxena, Jai Prakash, Priya Mathur, Suresh Kumar Gupta.
2. BNF 42 September 2001, BNF. Org, British national formulary, British medical Association, Royal Pharmaceutical Society of Great Britain.
Glaucoma continues to be a major cause of irreversible visual disability all over the word. At present, there approximately 7.5 million diagnosed cases of blindness, of which glaucoma accounts for 10-20%. It is estimated that there are about 2.47 million cases of primary open angle glaucoma in United States alone, the commonest type of glaucoma in the West.
Glaucoma refers to a group of disorders in which elevated intraocular pressure leads to atrophy of the optic nerve. After being produced by the ciliary body, aqueous humor enters the posterior chamber (the space between the iris and zonules) before passing through the pupil to the anterior chamber (between the iris and the cornea).
From that site, it then drains into veins by way of the trabecular meshwork and the Schlemm canal (Fig.1-7). A delicate balance between the production and drainage of aqueous humor maintains the intraocular pressure within its physiologic range (10-20 mm Hg).
In certain pathologic states, however, aqueous humor accumulate within the eye, and intraocular pressure becomes elevated. Temporary or permanent impairment of vision results from pressure-induced degenerative changes in the retina and optic nerve head and from corneal edema and opacification.
Types of Glaucom .l
Congenital Glaucoma : This type of glaucoma result from an obstruction of the aqueous drainage by developmental anomalies, even though the intraocular pressure may not become elevated until infancy or childhood.
· Primary Open-Angle Glaucoma: The intraocular pressure becomes elevated insidiously and asymptomatically, and with time, damage to the retina and optic nerve causes an irreversible loss of peripheral vision. The angle of the anterior chamber is open and appears to be normal, but an increased resistance to the outflow of aqueous humor is present within the vicinity of the Schlemm cannal.
· Primary Closed-Angle Glaucoma: Primary closed-angle glaucoma occurs after the age of 40 years. It afflicts persons whose peripheral iris is displaced anteriorly toward the trabecular meshwork, thereby creating an abnormally narrow angle. When the pupil is constricted (miotic), the iris remains stretched, so that the chamber angle is not occluded.when the pupil dilates (mydriasis), however, the iris obstructs the anterior chamber angle, thereby impairing aqueous drainage and resulting in sudden episodes of intraocular hypertension. Acute closed-angle glaucoma is an ocular emergency, and it is essential to begin hypotensive treatment within the first 24 to 48 hours if vision is to be maintained.
· Secondary Glaucoma: The causes of secondary glaucoma are many, and include inflammation, hemorrhage, neovascularization of the iris, and adhesions. in secondary glaucoma, the anterior chamber angles may by open or closed. Because the underlying disorder is generally limited to one eye.
Reference: Essential Pathology, Third Edition, Edited by: Emmanul Rubin, MD, LIPPINCOT WILLIAMS & WILKINS.
Diagnosis:
The older the individual, greater the risk of glaucoma. Because glaucoma does not cause symptoms in most cases, those who are 40 or older should have an annual examination including a measurement of the intraocular pressure. Those who are glaucoma suspects may need additional testing.
Pharmacotherapy of Glaucoma:
Prevention or modification of risk factors, particularly the raised intraocular pressure is the primary goal in the management of glaucoma. The disease needs to be managed medically, by laser therapy or by conventional surgery as the case may be.
Classification of antiglaucoma agents:
Depending on their route of administration antiglaucoma agents may be classified as:
Topical drugs:
Cholinergic agents e.g. Pilocarpine, Carbachol, and Echothiophate iodide.
Adrenergic agonists e.g. Epinephrine, Dipivefrin, Brimonidine and Apraclonidine.
Beta blockers e.g. Timolol, Carteolol, Levobunolol and Metoprolol.
Prostaglandin analogs e.g. PGF2α, Latanoprost and Unoprostone.
Carbonic anhydrase inhibitors e.g. Dorzolamide and Brinzolamide.
Systemic drugs:
Carbonic anhydrase inhibitors e.g. Acetazolamide and Methazolamide.
Osmotic agents e.g. Glycerine, Mannitol and Urea.
Mechanism of action of antiglaucoma agents:
The antiglaucoma agents act on the aqueous humor dynamics to reduce the intraocular pressure mainly by three mechanisms:
ý Decrease aqueous production in the ciliary body.
ý Increase aqueous humor outflow through the trabecular meshwork and
ý Increase aqueous humor outflow via the uveoscleral pathway.
1. Cholinergic drugs:
In the past, miotics were the drugs of first choice for the management of most types of glaucoma but currently due to their high side-effects, their use has declined.
Miotics can be divided into two groups:
ý Direct acting miotics e.g. Pilocarpine.
ý Cholinesterase inhibitors e.g. Carbachol is a dual action parasympathomimetic due to its week anticholinesterase activity.
They act by opening up the inefficient drainage channels in the trabecular meshwork resulting from contraction or spasm of the ciliary muscle.
Used in the management of raised intraocular pressure include carbachol and pilocarpine.
Should be used with caution in cardiac disease, hypertension, asthma, peptic ulceration, urinary-tract obstruction, and Parkinson's disease.
Contraindicated in condition where pupillary constriction is undesirable such as acute iritis, and some forms of secondary glaucoma.
Side-effects of miotic drugs are ciliary spasm leads to headache which may be more in the initial 2-4 weeks of treatment.
Ocular side-effects: burning, itching, lens changes with chronic use.
Systemic side-effects: are rare following application to the eye.
Delivery systems for pilocarpine:
Drug delivery systems aim to achieve the desired pharmacological effect with the least amount of drug and to prolong the duration of therapeutic effect thereby decreasing the frequency of instillation and associated side effects.
a) Soluble polymers: Polymers like methylcellulose and polyvinyl alcohol increase the conjunctival sac retention time and increase corneal penetration.
b) Pilocarpine gel: The equivalent of 4% pilocarpine hydrochloride in a highly viscous acrylic vehicle when applied once daily at bed time has been reported to produce a significant reduction in IOP for 24 hours.
c) Membrane-controlled delivery systems: This is an insert device placed in the cul-de-sac where it gradually releases pilocarpine at the rate of 20μg/hour or 40μg/hour, which is roughly equivalent to 2% and 4% eye drops respectively. This is effective for 7 days and the constant rate of release provides good control of IOP throughout the day.
d) Pilocarpine soaked soft contact lenses: Not as yet recommended for general clinical use.
e) Transdermal drug delivery system: A new non ocular pharmaceutical device has been tested for pilocarpine.
f) Electronic medication alarm device: Another device which enhances the compliance in glaucoma patient taking pilocarpine is the electronic medication alarm device.
Cholinesterase inhibitors:
Cholinesterase inhibitors are another class of miotics which act by increasing the levels of endogenous acetylcholine by inhibiting the enzyme acetylcholinesterase. Physostigmine, neostigmine, and demecarium are short acting cholinesterase inhibitors whereas ecothiophate and isofluorophate are long acting cholinesterase inhibitors.
Physostigmine and neostigmine are useful in angle closure and open angle glaucoma, though their use has declined due to the high incidence of allergic reactions. Ecothiophate iodide and demecarium bromide are no longer used in glaucoma. Isofluorophate is more oculotoxic than ecothiophate and demecarium.
In general, the use of anticholinesterase medications for the treatment of open angle glaucoma is reserved for cases in which the patient has become intolerant to pilocarpine or carbachol or when the pressure lowering effect of these agents is inadequate. Also these agents are more effective in secondary glaucoma.
2. sympathomimetics (adrenergic agonists):
a) Epinephrine:
Adrenaline (epinephrine) probably acts both by reducing the rate of production of aqueous humour due to its α-adrenergic effect, and by increasing the outflow through the trabecular meshwork by stimulating β2-adrenergic receptors.
Onset of action occurs at 1 hr with a peak effect at 4 hours and ocular hypotensive effect may last upto 72 hours.
Epinephrine may be used as initial or adjunctive glaucoma therapy.
It is contraindicated in angle-closure glaucoma because it is a mydriatic.
Side-effects include severe redness of the eye; adrenaline should be used with caution in patients with hypertension and heart disease.
b) Dipivefrin:
Dipivefrin is a pro-drug of adrenaline (which undergoes biotransformation to epinephrine within the cornea).
Due to increased lipophilicity its penetration across the cornea 17 times more than epinephrine, and lesser doses are needed to be administered as compared to epinephrine.
It is better tolerated than epinephrine, the onset of its ocular hypotensive action is within 30 minutes and beak effect is observed in 1 hour.
Its advantages over epinephrine are lower cardiovascular side effects.
Like epinephrine it can be used in patient of asthma, in young patient intolerant to miotics and in those with cataracts.
c) Brimonidine:
Brimonidine, a selective α2-adrenoceptor stimulant, is licensed for the reduction of intra-ocular pressure in open-angle glaucoma or ocular hypertension in patients for whom beta-blockers are inappropriate.
It is the drug of choice in chronic treatment of glaucoma and in patients with cardiopulmonary disease and who have contraindications to β-blockers.
It has lower incidence of ocular side effects because of α2-selectivity.
Its peak IOP reduction efficacy is comparable to that of timolol and does not cause cardiopulmonary side effect as reported with timolol. However, there are reports suggesting similar efficacy of brimonidine with that of timolol but with a greater incidence of adverse local reactions.
3. Beta-blockers:
These drugs usually are the first line agents for the medical therapy of all kinds of glaucoma.
Topical applications of a beta-blocker to the eye reduce intra-ocular pressure effectively in chronic simple glaucoma, probably by reducing the rate of production of aqueous humour (block the β-receptor in the iris and ciliary body).
This class of drugs has several advantages over both cholinergic and adrenergic agonist; majority of patient can be treated solely by β-blockers.
Unlike miotics, β-blocker have little effect on pupil size or accommodation, eliminating the problems of dim vision, decreased night vision and blurred vision.
Unlike adrenergic agonists, β-blockers do not cause pupil size changes or hyperemia. β-blockers also have a significant additive action when combined with pilocarpine or other antiglaucoma.
Depending on their selective receptor inhibition, they are classified as β1-selective and non-selective β-blocker respectively.
ý Selective β1-blockers: Betaxolol, atenolol and metoprolol.
ý Non-selective β-blockers: Timolol, maleate, nadolol, carteolol and labetalol.
a) Timolol:
It is being used extensively worldwide as a first line agent for the treatment of patients with open angle glaucoma and ocular hypertension and has been shown to be more effective in lowering IOP than pilocarpine. It is instilled as one drop of 0.25% or 0.5% solution twice a day and the duration of action exceeds 7 hours. At this dose timolol produces a significant reduction in IOP in most cases.
b) Metoprolol:
It is a cost effective, selective β1-adrenergic antagonist similar to timolol in clinical efficacy. It reduces the IOP in normal eyes, chronic open angle glaucoma and ocular hypertensive patients.
c) Levobunolol:
It reduces intraocular pressure by reducing aqueous humor formation as well as by enhancing the outflow facility. It is as effective in reducing IOP as timolol maleate, metoprolol and carteolol. The potential advantage of levobunolol is once daily due to longer duration of action.
Levobunolol is contraindicated in patients predisposed to cardiac or respiratory disease. Caution is required in diabetics and those undergoing major surgery.
Systemic absorption may follow topical application therefore eye drops containing a beta-blocker are contra-indication in patients with bradycardia, heart block, or uncontrolled heart failure.
Important: for a warning to avoid in asthma.
Local side-effects of eye drops include ocular stining, burning, pain, itching, dry eyes.
4. Carbonic anhydrase inhibitors:
· These are the reserved group of drugs and are given orally (with the exception of dorzolamide and brinzolamide which are available for topical administration) as an adjunct when IOP is not controlled adequately with topical medication.
· Approximately 50% patients have shown intolerable side effects with the use of systemic carbonic anhydrase inhibitors. Therefore these drugs are currently used to control IOP in patients waiting for surgery or till the time topical drugs become effective.
a) Acetazolamide:
· This is the most widely prescribed carbonic anhydrase inhibitor. However, approximately 50% patients stop treatment with acetazolamide as a consequence of intolerable side effects due to extraocular inhibition of carbonic anhydrase.
· It reversibly blocks the enzyme carbonic anhydrase in the ciliary body and thus suppresses aqueous humor production.
· Acetazolamide is asulphonamide; is given by mouth or by intravenous injection, blood disorders, rashes and other sulphonamide-related side-effects occur occasionally.
b) Methazolamide:
· It is more potent than acetazolamide and has structural similarity to it.
· It is indicated in patients of chronic open angle glaucoma where IOP is not controlled adequately with acetazolamide or topical medications.
· Its penetration across blood aqueous barriers is 50 times that of acetazolamide due to its good lipid solubility and low plasma protein binding.. its dose is 25-50 mg three times daily.
c) Dorzolamide and brinzolamide:
They are topical carbonic anhydrase inhibitors, licensed for use in patient resistant to Beta-blockers or whom beta-blockers are contra-indicated.
5. Osmotic agents:
· These agents act by enhancing the osmotic pressure of plasma with respect to intraocular structures thereby setting an osmotic gradient.
· Consequently the fluid moves from the eye to hyperosmotic plasma of ocular blood vessels, thereby reducing the vitreous volume which is responsible for lowering of IOP.
· Mannitol, glycerol, urea, isosorbide etc are the osmotic agents used for short term reduction of IOP.
· The use of these drugs is currently limited to short term emergency situations such as acute angle closure glaucoma or pre-operative control of raised IOP.
· The side effect of these drugs includes nausea, vomiting, diuresis, headache, diarrhea, chills and fever.
6. Miscellaneous agents:
a) Forskolin:
Forskolin is derived from methanolic extract of the roots of Coleus forskohlii. It has been shown to be an effective ocular hypotensive agent both experimentally and clinically.
It is a potent stimulator of adenylate cyclase and does not require cell membrane bound receptors. The ocular hypotensive effect of forskolin is directly proportional to the extent of stimulation of adenylate cyclase.
No significant ocular or systemic side effects were observed.
The combination of 1% forskolin and 0.25% timolol had an additive effect which was more than the additive effect of 1% forskolin plus 2% pilocarpine.
b) Angiotensin converting enzyme inhibitors:
Components of the renin angiotensin system are present in peripheral tissues, including the eye and may play a role in controlling aqueous humor production, retinal blood flow or retinovascular disease.
Angiotensin II receptors of the retinal vasculature may play a significant role in the autoregulation of blood supply to the retina and optic nerve head.
Topical angiotensin converting enzyme (ACE) inhibitors have been shown to lower IOP in rabbits, monkeys and humans.
Experimental evidence suggests that ACE inhibitors might inhibit breakdown of bradykinin, promote formation of endogenous prostaglandins and also enhance uveoscleral outflow. Thus, inhibitors of ACE activity might be useful pharmacological agents in the medical therapy of glaucoma.
c) Ocular hypotensive lipids (OHL):
These compounds contain a neutral substituent for the carboxylic acidic group of PGF2α and are not fatty acids. These are relatively ****bolically stable unlike the prodrug latanoprost and the esterified PGF2α analogue that is readily ****bolized into active PGF2α.
These compounds have different pharmacological profiles yet are potent ocular hypotensive agents. Clinical trials were conducted on these OHL in open angle glaucoma and ocular hypertension cases.
Twice daily dosing at concentration of 0.01% produced significant IOP lowering and was superior to that of timolol (0.5%bd).
These new compounds continue to produce a significant IOP lowering effect upto 24 hours after the last drug instillation.
These compounds will be an excellent alternative as a first and second line IOP lowering agent for the therapy of ocular hypertension and open angle glaucoma.
7. Prostaglandin analogue:
a) Latanoprost:
· A prostaglandin analogue, it is licensed for open-angle glaucoma and ocular hypertension when other drugs are inappropriate.
· Its response seems to be mediated by prostanoid receptors. And it is more selective than PGF2α in this respect and thereby has superior therapeutic profile.
· It is available as 0.005% ophthalmic solution and requires to be instilled once at night. A single dose of topical 0.005% latanoprost is equi-effective to that of 0.5% timolol (bd dose) in patients suffering from primary open angle glaucoma and ocular hypertension and has a duration of action ranging from 20-24 hours. It is well tolerated with no detectable systemic side effects.
· Patients should be monitored for any changes to eye coloration since latanoprost may increase the brown pigment in the iris.
b) Unoprostone:
· Unoprostone isopropylate is the first docosanoid derivative for glaucoma therapy. It acts by enhancing uveoscleral outflow without affecting aqueous humor production.
· Its oculohypotensive effect is similar to or slightly inferior to that of timolol 0.5%.
Monotherapy versus combination therapy:
β blockers are the most commonly prescribed first line therapy though the use of latanoprost and brimonidine as primary therapy is also increasing in the west. Latanoprost, brimonidine and topical carbonic anhydrase inhibitors are effective as early adjunctive therapy in cases where a single drug alone is inadequate to control IOP.
Adrenergic agonists and miotics are also useful as secondary or tertiary therapy but their use in the west is declining due to their significant topical and systemic side effects. It is thus evident that when therapy with a single agent is inadequate to control IOP, combined treatment is indicated. The additive benefit of two drugs depends to some extent on whether they reduce IOP by similar mechanisms.
Miotics and carbonic anhydrase inhibitors in combination may be useful, probably because miotics increase aqueous outflow, whereas carbonic anhydrase inhibitors reduce inflow.
It must be stressed that if the initial agent is only slightly effective at lowering IOP, it should be discontinued and other drugs tried individually before going on to combination therapy. The combination therapy in contrast to monotherapy has the possibility of delaying the need for surgery.
In emergency or before surgery, mannitol 20% should be given by slow intravenous infusion until the intra-ocular pressure has been satisfactorily reduced. Acetazolamide by intravenous injection may also be used for the emergency management of raised intra-ocular pressure.
References:
1. Indian Journal of Pharmacology 2002; 34: 71-85, educational forum, Rohit Saxena, Jai Prakash, Priya Mathur, Suresh Kumar Gupta.
2. BNF 42 September 2001, BNF. Org, British national formulary, British medical Association, Royal Pharmaceutical Society of Great Britain.