The primary goal in the treatment of glaucoma is to prevent or retard the loss of visual function caused by damage to the optic nerve. Our therapeutic approaches, however, are currently limited to reducing IOP. This approach of lowering a potentially harmful pressure will apply to patients with documented optic nerve damage and visual field loss as well as those with elevated IOP or other well-described risk factors so that treatment is indicated to prevent the onset of damage. We now have five major randomized glaucoma clinical trials stating that intraocular pressure is important for protecting the susceptible optic nerve in patients with glaucoma.
Before going into the details of the drugs used in glaucoma, let us have a look at the basic pharmacologic principles in topical ocular treatment.
Bioavailability of topical ocular medications:
- The penetration of topically applied medication into the eye is proportional to the concentration of the drug that comes in contact with the cornea over time, which gets diluted by tears and gets washed out into the lacrimal drainage system.
- The half-life of various drugs in the tears is said to be 2-20 mins.
- Alteration of the molecule or vehicle in a way that increases the half life, such as increasing the viscosity will increase the efficacy and duration.
- Normal volume of the conjunctival sac is 7 micro liters. After installation of an eye drop it increases to 30 micro liters.
- Most drugs are available between 30 to 70 micro liters. Thus a single drop will exceeds the capacity.
Tear Film: Under normal circumstances, the turnover of tear films is 15% per minute, when an eye drop is installed this increases to 30% per minute, which helps in the drug getting drained off faster. Also every drop added cause an increasing in blinking, squeezing which propels tears towards the sac. It is possible to stop this by placing pressure on the canaliculi and closing the eye lids gently after eye drops.The drugs that pass on to the lacrimal sac come directly in contact with the nasolacrimal system, were it gets absorbed rapidly and gets directly into the system, which means, they bypass the liver, thereby, causing systemic effects. For this reason, the installation of multiple eye drops over a short period is not recommended. For example:- when saline is instilled in rabbits eye 30 seconds after pilocarpine administration the effect of the drug is reduced by 45%, if administered within 2 minutes - 17% after 5 minutes there is little loss to pilocarpine.
Cornea: The one thing to remember about the cornea as a barrier is that it is like a lipid - water - lipid sandwich. The lipid content of the epithelium and the endothelium is 100 times more than that of stroma. And therefore allow lipophilic than to hydrophilic substance. Because of the dual nature of the corneal barriers, drugs possessing both lipid and water solubility penetrate the cornea more readily.
Drug Elimination: Most of the drug is lost in the cui de sac, because of the over flow.
Once in the anterior chamber the drug is eliminated with the bulk flow of the aqueous humor via the trabecular mesh work or the uvea scleral out flow. Some of them through the limbal, conjunctival and scleral vessels. There are many enzymes which metabolize the drugs in the cornea. This metabolic capability is used by the prodrug dipivefrin.
It can be grouped into the following categories:-
- Alpha - Adrenergic receptor agonists
- Beta-Adrenergic receptors antagonist or beta-blockers
- Carbonic anhydrase inhibitors
- Prostaglandin related agents or hypotensive lipids.
- Calcium channel Blockers.
- Neuroprotection and other investigational Antiglaucoma drugs.
- Cholinergic agents.
- Acetylcholine chloride.
- Pilocarpine hydrochloride and nitrate Pilocarpine combination.
Cholinergic agents:The cholinergic drugs are the oldest effective medical treatment for glaucoma. More than 100 years ago, Laqueur used physostigmine (eserine) an extract from the calabar or ordeal bean for the treatment of glaucoma and Weber described the effects of pilocarpine. Basic Considerations: Acetylcholine (ACh) is the neuro transmitter at autonomic preganglionic, parasympathetic, postganglionic and some motor nerve endings. Endogenously released ACh is hydrolised rapidly by acetylcholinesterase located in cholinergic nerves. Cholinergic drugs either act directly by stimulating cholinergic receptors or indirectly by inhibiting the enzyme cholinesterase thereby protecting endogenous acetylcholine. Topical administration of cholinergic drugs in the eye produces pupillary constriction, dilatation of conjunctival and iris blood vessels and increase aqueous out flow.
Acetylcholine: It is used only for intraocular (intracameral route) administration to induce miosis during ocular surgery. It produces complete miosis during ocular surgery. It is used in Cataract surgery, Penetrating keratoplasty, Peripheral Iridectomy and other anterior segment surgery.
Dosage: it is available as powder and fresh ophthalmic solution (1:100 acetyl choline chloride). Usually 0.5 - 2 ml of this solution is required to produce good miosis. Solution need not be washed as it has a short duration 10-20 mins.
Pilocarpine: Pilocarpine, the oldest and most widely used cholinergic agent, derived from the plant Pilocarpus microphylus. Pilocarpine is well absorbed by the cornea and released slowly in to the aqueous.
Topically administered, produces a reduction in IOP that starts after one hour and lasts for 4 - 8 hours. The drug is administered every 6 hours to ensure good reduction in IOP.
Mechanism of action in various types of Glaucoma: In OAG - By increasing the outflow, by stimulating the ciliary muscles, pulling traction on the scleral spur and the trabecular mesh work. This action separates the trabecular sheets and the schlem’s canal is kept open. In ACG - for short term management of angle closure glaucoma till laser or surgery is done. It helps in constricting the pupil, tighten the iris, and decrease the volume of iris in the periphery away from the trabecular tissue.
Dosage: It is available in topical ophthalmic solutions, ocuserts and gel form.
- Topical solution is available in two salts:
- Pilocarpine hydrochloride in the strengths of 0.25, 0.50, 1, 2, 3, 4, 6, 8, 10%.
- Pilocarpine nitrate in the strengths of 1, 2 & 4%.
- Gel Doses: Available in 4% and also 1-2% onset of action is 10-30mins and duration is 4-6 hours.
- Pilocarpine can be given in ocusert form. Ocusert P - 20, P - 40 or by soft contact lens.
- Pilocarpine when given with a polmer vehicle (1.6% polyvinyl pyrolidine) has a prolonged duration of action.
- Ocuserts are changed weekly and have to be kept in refrigeration at 2°- 8° centigrade.
It has been clinically shown that ocusert 20 mcg is roughly equal to 0.5% to 1% and 40 mcg is about 2 - 4%. Ocuserts initially release the drugs at 3 times the rated value in 151 hours and declines to the rated value approximately 6 hours. During the reminder of the 7 days period the release rate is within 20% the rated value. It is advised that it is placed in the night to avoid myopic shift in the first few hours.
The disadvantages include increased cost, foreign body sensation. Occasional burst can cause myopic shift and intense miosis.
Adrenergic Antagonist: Epinephrine compounds produce additional IOP reduction when combined with pilocarpine. However, the effect of either combination is less than the additive effect of the two drugs.
Available as E-Pi101 - E-Pi106 concentration from 1 to 6%. This is also true for the alpha 2 agonists apraclonidine and brimonidine.
Adrenergic Antagonists: Timolol has also shown to have a partially additive effect with pilocarpine, which is also true for all the other topical β blockers.
Prostaglandin Agonists: Even though pilocarpine reduces and prostaglandin increases the uvea scleral outflow, there is an additive IOP lowering effect.
Pilocarpine and Physostigmine combination: Available in pilocarpine 2% and 0.25% physostigmine salicylate.
Carbonic Anhydrase Inhibitors: Pilocarpine in combination with CAI reduces the IOP effectively.
Antibiotic and Corticosteroids Ointments: It is supposedly to bring down the efficacy of the drug. However, whether it is due to the drug or the ointment not very sure. But it is advisable to use the drug after 5 minutes.
Other Miotics: Have no adding effect, but may interact with them to bring down the potency.
Side effects of Pilocarpine
Periorbital and Conjunctiva.
Orbicularis muscle spasm and lid twitching Allergic Blepharoconjunctivitis.
Vascular Dilatation and conjunctival hyperemia.
Corneal epithelial staining and vascularisation atypical band keratopathy.
- Iris and ciliary body:
Pigment epithelial cyst formation.
Ciliary muscle spasm.
Post-operative iritis and synechae formation.
Increase lens thickness - myopia
- Posterior segment:
Retinal hole, detachment and vitreous hemorrhage.
Inverse glaucoma in a few cases.
Systemic Side Effects: Sweating, salivation and lacrimation, nausea, vomiting and abdominal cramps, weakness, fatigue and muscle spasm, paraesthesia, nightmare, depression & delusion, prolonged respiratory paralysis after GA, bronchial spasm, asthma and pulmonary edema.
Other Cholinergic Agents
- It is a synthetic derivative of choline.
- It is dual action parasympathomimetic which produces direct motor end plates stimulation and at pre synaptic receptors to release acetylcholine. They are longer acting than pilocarpine. Thus greater stabilizing effect on diurnal pressure and myopia fluctuations.
- Comes in 0.75% to 3% concentration administered 3 to 4 times a day.
- Can be used in patients who are allergic to pilocarpine.
- It is also a synthetic derivative rarely used because it is unstable.
- It was used in 2% to 10% concentration.
- A synthetic agent directly inhibits cholinesterase.
- Acts directly on the muscarinic end plates.
- It is weaker than pilocarpine and induces less miosis and accommodation than pilocarpine.
Originally anticholinesterase agents were classified into reversible and irreversible enzyme inhibitors. Now it is better to classify them as weak/short-acting and strong/long-acting inhibitors.
Physostigmine (Eserine) is a short-acting inhibitor of cholinesterase. It comes in aqueous solution in the concentration of 0.25% to 1% and is administered every 4 to 6 hours. (Preparation of salicylate & sulfate).
Physostigmine solutions are unstable decompose with Ph changes or after exposure to light.
It reduces IOP by increasing out flow.
Indications are in primary glaucoma's especially aphakia, chronic synechial angle closure glaucoma and following cyclodialysis surgery.
- It is a potent, stable long acting cholinesterase inhibitor.
- The mechanism of action is similar to that of physostigmine.
- In addition to the indication already mentioned it is also used in accommodative esotropia.
- It is available in concentration of 0.125% and 0.25%. It is to be used twice daily because of its prolonged effect.
- It is a potent inhibitor of both true cholinesterase and pseudo cholinesterase.
- It depresses both plasma and erythrocyte cholinesterase.
- It has a much longer duration of action than pilocarpine and controls IOP in some eyes which are resistant to pilocarpine. (Irreversible)
- It is available in the concentration of 0.03% to 0.25% and administered every 12 to 48 hours.
- It is unstable in room temperature and therefore it has to be refrigerated.
- It is a potent cholinesterase inhibitor and like Ecothiophate it depresses both plasma and erythrocyte cholinesterase.
- It is usually administered in ointment form in concentration of 0.025% in a polyetheylene mineral gel. It also has a prolonged action so has to be used once or twice daily.
- Wash hands immediately after administering as in the presence of water it will turn to form hydrofluric acid.
- Keep ointment tightly closed. It causes allergic reactions and it has to be refrigerated.
Alpha Adrenergic Agonists:
- Clonidine Apraclonidine
- Brimonidine Tartrate (Alphagan)
Clonidine: The first such α2 adrenergic agonist, an imidazole derivative, it is used as an anti-hypertensive agent. The drug acts principally on the centrally and peripheral α2 agonist, thereby inhibiting norepinephrine release and suppressing sympathetic outflow to the cardiovascular system.
Applied topically to normal and glaucomatous eye in concentration of 0.125% and 0.5% it lowers IOP for 6 to 8 hours. When it is applied to the eye it is partially absorbed in to the system causing hypotension. Therefore not used alone.
Apraclonidine:It is a relatively selective α2 adrenergic agonist. When installed in the eye it reduces the IOP and has minimal systemic effects.
The mechanism of action is not clearly understood but it is thought to be that β2 receptors stimulation that results in decrease aqueous humor formation.
Dosage: It is available as topical 0.5% ophthalmic solution (5 ml packs) and 1% in a single dose 0.25% pack. Usually dosage is 1 drop before and after laser procedure.
- It is used to control increase of IOP after anterior segment surgery.
- Acute raise in IOP.
- And now most recently as adjuvant to other antiglaucoma drugs.
Contraindications: It includes hypersensitivity to the drug and also cardiac disease with untreated arteriovenous block or bradycardia.
Adverse Reactions: On topical use after laser surgery-
- Upper lid elevation.
- Conjunctival blanching.
- Burning or itching sensation.
- Subconjunctival hemorrhage.
Systemic effects: Gastrointestinal reactions, Bradycardia, Vasovagal attack, Palpitation, Orthostatic hypotension, CNS disturbances, Irritability and decrease libido, which are all transient.
Brimonidine Tartrate (Alphagan):
- It is a recently introduced 2nd generation α-adrenergic receptor agonist, with high degree selective to α2 receptors.
- It has a dual action.
- It decreases aqueous humor production like β-blockers and also increases the uveo scleral out flow like prostagladins.
- It has binding sites in the iris epithelium, ciliary epithelium, ciliary muscle, retina and retinal epithelium and choroid.
- After administration its peak plasma level is achieved in 2-4 hours, and declines with a systemic half life period of approximately 3 hours.
Dosage: It is available in 0.2% solution (5, 10, 15ml Packs). Instill one drop twice daily.
Open-Angle Glaucomas and OHT. The IOP decreasing ability decreases over a period of time so one must keep this in mind while treating patients.
Contraindications: In hypersensitivity to brimonidine tartrate, in patients receiving MAO inhibitor therapy, it should be used in caution with patients with depression and coronary insufficiency. Caution while using it in pregnant and lactating mothers.
Caution in contact lens users. They have to wait for at least 20 mins before using the lens as it gets absorbed into the lens.
Adverse reactions: Lid crusting, burning and stinging sensation, ocular hyperemia, headache, oral dryness, blurring, fatigue, Hypertension, depression, anxiety, abnormal taste, palpitation and syncope.
Dapiprazole hydrochloride is α adrenergic blocker. It blocks α adrenergic receptors in the smooth muscles and produces miosis. It brings about safe and fast reversal of mydriasis. It is used for iatrogenically induced mydriasis. It has not much effect on IOP in normal people or in patients with raised IOP.
It is a non-selective α and β adrenergic agonist. Its mechanism of action is not fully understood. It is said to have three stages:-
- β- adrenergic stimulation of the ciliary muscle may increase uveoscleral outflow (the major effect) and trabecular outflow.
- β- adrenergic stimulation of the adenoreceptors in the ciliary epithelium increases the aqueous outflow.
- α adrenergic stimulation may result in reduction of aqueous flow.The net result is that IOP is lowered.
Preparation and Dosage: Epinephrine hydrochloride drugs are stable and are available in concentrations of 0.25, 0.50, 1.0 and 2%. They contain antioxidants to prevent oxidation.
Borate solutions are less irritating and less stable than hydrochloride or bitartrate solutions.
Epinephrine polymeric matrix releases the drug osmotically over 12 hours period at a rate of 1 to 4 mgm.
Its effect on IOP is proportional to the concentration of the drug. Its onset of action is at 1 hour, with a peak effect at 4 hours, its effect lasts up to 12 hours.
Additive Effects: It has an additive effect when used with pilocarpine and CAI. It is more effective with betaxolol, maybe because it has less effect on IOP than other β blockers.
It has an advantage over miotics in patients with cataract or in young patients as it does not induce myopia. It can be used in asthmatics.
Contradictions: Severe hypertensive, cardiac disease, thyrotoxicosis, patients taking MAO inhibitors.
Lid and conjunctiva
Hyperemia, Burning, Tearing, Skin
Epithelial oedema, Endothelial toxicity,
blanching, Adrenochrome deposits,
Epithelial erosion, Adrenochrome
Madrosis, Ocular Pemphigoid
deposits, Stain soft contact lens
Iris and uveal tract
Punctal stenosis, epidermalisation of
Mydriasis and angle closure, visual
puncta, lacrimal stones
Distortion, photophobia and iridocyclitis.
Systemic side effects:
Headache / Browache, tachycardia, premature ventricular contractions, palpitations, tremor, increased BP, Cerebrovascular accidents, myocardial infarctions.
It is a prodrug of epinephrine, used to enhance corneal penetration and minimize toxicity by lowering the concentration of epinephrine. The penetration is 17 times more than epinephrine. Its 0.1% is equal to 1% of epinephrine. Side effects are much less when compared to epinephrine. Indicated as the 1st line of therapy in open-angle glaucomas and OHT.
Adrenergic Blocking Agents
- Timolol Maleate.
Basic Considerations: These drugs compete with sympathomimetic substances for access to receptors, reducing sympathetic activity. They have little effect on pupil size, accommodation. They lower IOP by decreasing aqueous production β-2 receptors (sympathetic activity cause - production of aqueous).
Inhibition of chloride ion pump.
1. Betaxolol: It is a relatively cardio, selective β-1 adrenergic agonist. It is thought to decrease IOP by reducing aqueous formation through blockade of the β-1 receptors. However, the ciliary epithelium is made up of only β-2 receptors. Therefore it may be that it might not be totally a β-1 blocker but also, it may have β-2 blocking properties or it may reduce because of high concentration it may block β-2 receptors.
Comes in a dosage of 0.25 and 0.50%, dosage, 1 – 2 times a day.
Its wash out time is also 2 weeks this may be due to depots in the iris. The IOP lowering response may require a few weeks to stabilize so IOP should be checked after 1 month. IOP lowering effect is 21%.
2. Cartelol: It is a non selective β blocker; its mechanism of action is by decreasing the production of aqueous production. It also has intrinsic sympathomimetic activity possible resulting in few side effects. It also lacks Timolol tendency to raise serum cholesterol and lower high density lipoprotein, a factor to consider in cardiovascular patients.
It is available as topical solution of 1 % used once or twice a day.
Used in all the glaucomas.
IOP lowering effect is 32%.
3. Levobunolol: It is a non selective β blocker. Systemic administration of this agent is used in cardiovascular disorders. Its mechanism of action is to decrease the production of aqueous. It increases the ocular pulse while achieving better IOP control. The long term drift is a little less than timolol.
It is available in 0.5% solution and used once or twice daily. Onset of action is about 1 hour after application. IOP lowering effect is 25-30%.
4. Metipranolol: It is a non selective β-1 and 2 antagonist, given twice daily in a concentration of 0.3 and 0.6%.
It is similar to Timolol, except for the rare production of granulomatous uveitis, especially with 0.6%. IOP lowering effect is 21%
5. Timolol Maleate: It is one of the most common and oldest β blockers available. It is a non-selective β blocker. It acts directly on the ciliary epithelium to reduce aqueous production. It lowers IOP both in normal and ocular hypertensive patients.
The drug can lower IOP in the untreated contralateral eye because of systemic absorption which is known as cross over effect.
Timolol penetrates the eye rapidly and its effect is seen in 30 to 60 minutes and lasts upto 24- 48 hours.
Short term escape: The initial dose of timolol produces the maximum effect about 40% or more, followed by a partial decline over the following days or weeks. This may be due to alterations in the β adrenergic receptors in the ocular tissues may be an increase in the no of receptors. The best time to evaluate the effect it is after 1 month.
Long term drift: The IOP slowly increases over a period of time in patients who have well controlled IOP. This may be due to partial adaptation of the ciliary body to long term administration of timolol may be due to a decrease in cellular sensitivity.
Preparation & Dosage: It is available in 0.25% and 0.5%. Administered once or twice daily. The maximum action takes place by 2 hours. The washout period for timolol is 14 hours.
It is also available as a gel format applied once daily. It comes in 0.5% concentration. It is more effective with light colors than dark color iris, maybe due to its binding effect with melanin. It reduces IOP by 25 to 30%.
Additive effect with other drugs: Pilocarpine and CAIs have an additive effect, where as there is a very small additive effect with epinephrine.
Uses and Side effects:The β adrenergic blockers are useful in all types of glaucomas. They are better tolerated by patients and they don't affect the pupil or the accommodation.
- Burning sensation (B).
- Superficial Punctate Keratitis.
- Corneal Anesthesia.
- Allergic Blepharoconjunctivitis (L)
- Dry eye
- Corneal erosion
- Visual disturbance
- Dilated Pupil in case of epinephrine
- Nervous system: Depression, Anxiety, Confusion, Hallucination, Fatigue, Tinnitus, Abnormal taste sensation, Diplopia, Lightheadedness, Cerebrovascular accidents, Psycosis.
- Cardiovascular: Bradycardia, Heart failure, Arrhythmia, Raynaud's phenomenon, Hypotension, Hypertension, Syncope, MI, Death.
- Pu1monary: Dyspnea, Airway obstruction, pulmonary failure, Apnea especially in children (sleep).
- Gastrointestinal: Nausea, Vomiting, Diarrhea, Abdominal cramps
Background: Prostaglandins are biological active products of arachidonic acid, a fatty acid that is bound to phospholipids in the cell membrane. The enzyme cyclooxygenase converts arachidonic acid to PGs, which acts like local hormones in different organs.
The biological effects of the PGs depend on the amount present and the organ or tissue it is expressed.
In physiological process, the PG and other eicosonaids are produced in small amounts, and are involved in hormonal effects and neurotransmission.
Larger amounts of these molecules may lead to pathologic events involved in inflammatory effects.
Experiments with rabbits and IOP: Four agents that are available now:
Latanoprost – 1996; Unoprostone – 2000; Travoprost – 2001; Bimatoprost – 2001.
Many important chemical modifications were made to the lipid molecule to improve the bioavailability of the drug.
Addition of Phenyl ring to the omega chain The C - 1 carboxyl group was modified with an ethyl amide in the case of brimatoprost or an Iso - propyl ester for latanaprost, travoprost and unoprostone to make the molecule more soluble.
Mechanism of action: The PGs derivates primarily lower IOP by enhancing the conventional outflow pathway, uveoscleral outflow of the eye. In most of the studies, the ocular hypotensive effects of PGs were not explained by reducing aqueous production, reducing the venous pressure, or increasing the conventional out flow. It is still not fully understood. Two possible mechanism exists that have been studied are relaxation of the ciliary muscle and remodelling the extra cellular matrix of the ciliary muscle. This means either the ciliary muscle was relaxed so that there was enough space for the aqueous to go towards the uveoscleral space or the narrowing of the ciliary muscle fiber bundles or enzymatically mediated lysis of the intramuscular connective tissue, both of which could enhance the movement of fluid from the anterior chamber through the muscle into the suprachoroidal space.
Indications: It is indicated for reduction of elevated IOP in patients with open angle glaucoma and OHT.
Dosage: It is available as 0.005% topical solution. To be stored in the refrigerator till it is open, once open it can be stored in room temp for 6 weeks. Usual dosage is once daily. It should not be used more than once a day. Reduction of IOP starts after 3 - 4 hours and maximum action is reached in 12 hours.
IOP reduction is about 27 - 35%. It is now available in combination with timolol. It is said that it improves compliance.
Adverse reactions: Blurred vision, burning and stinging sensation, conjunctival hyperemia, itching, increased iris pigmentation and punctate epithelial keratopathy. Other rare side effects are - tearing, lid crusting, lid edema, lid erythemia, diplopia and photophobia.
It is a pharmacologically unique compound of PG group which mimic the prostamides. The prostamides are members of the fatty acids amide family. It is very stable and is well preserved outside, not undergo hydrolytic conversion.
Mechanism of action: Its primary ocular hypotensive action is due to reduction in tonographic resistance to outflow. That is on the episcleral venous pressure. And also by the other method that is the uveoscleral pathway.
Indications They are open angle glaucomas and OHT. It is available as a 0.03% topical solution.
Side effects: Iris pigmentation, conjunctival hyperemia, hypertrichiosis, burning and stinging sensations, FB sensation, ocular pain, eyelid edema.
Systemic side effects: Nausea, abdominal pain, dizziness, sinusitis. It is not recommended in pregnant and lactating mothers also not in children.
It is a recently launched drug, released in Japan for the treatment of POAG. It’s a PGF2 α-analogue. It is the first docosanoid. It lowers the IOP by increasing the Uveoscleral outflow. It also increases the blood supply to the back of the eye.
Dose: It is 0.12%. Used once or twice daily.
Side effects: Iris pigmentation, conjunctival hyperemia, ocular irritation, burning and stinging sensation and ocular pruritus.
It is also a recently launched drug. It is highly selective affinity for FP receptors and is equally effective.
Commercially it is available as 0.004% ophthalmic solution.
Dose: Used once or twice a day.
Side effects: Ocular hyperemia, iris pigmentation, decreased visual acuity, eye discomfort, FB sensation, ocular pain.
Carbonic Anhydrase Inhibitors
Carbonic Anhydrase Inhibitors (CAI): CAIs were first shown to decrease IOP in 1954. Since then CAIs are been prescribed even though of their side effects. It is used as a monotherapy or as an adjunctive therapy.
These agents are non-bacteriostatic sulphoamides that non competitively inhibit the enzyme carbonic anhydrase in the ciliary epithelium directly. By this decrease, the production of aqueous hence decreases IOP.
This action is independent of systemic acid base balance. By inhibiting the hydrogen ion in the renal tubules it causes K+, Na, Bicarbonate excretion causing alkaline diuresis.
Acetazolamide: It was introduced in clinical practice in 1954 and till now it is used as the only systemic agent for the long-term treatment of glaucoma. It is useful in all types of glaucomas even when the anterior chamber angle is sealed.
Preparation and dosage: Available as 125mg, 250mg tabs and 500mg sustained release. Given lower dose first, then higher does later on. Good IOP control is best achieved with 250mg QID. It reduces IOP in 2 - 4 hours with a duration of 12 hours. Sustained release act for 24 hours. Pediatric dose is also available in 5-10mg. IV preparations are also available in 500mg ampules, which can be dissolved in 10ml of distilled water. Very useful in acute glaucomas. It is also used in pseudotumour cerebri.
Methazolamide: Mechanism of action is similar to that of acetazolamide. Available in 25mg and 50mg tabs 2 - 3 times a day. Usually it is given in the least dosage. It penetrates the eye and the CNS so the side effects are more common in the CNS. Other side effects are similar to that of acetazolamide.
Ethoxzolamide: Its mechanism of action is similar to that of acetazolamide. It is one of the most potent agents but its activity is reduced by high plasma protein binding capacity. It is available in 125mg tabs and is administered 3-4 times a day. Precaution vision may be blurred, caution while driving or using machinery.
Dichlorophenamide: It is a molecule containing two sulfonamide groups. It causes less metabolic acidosis. But there is continued loss of chloride and potassium depletion. Dosage is 100 - 200mg initially. Available in 50mg tabs.
Dorzolamide: Dorzolamide is a topical ophthalmic solution. Locally acting on the ciliary body inhibits carbonic anhydrase minimizing systemic side effects. It was first made commercial in 1995.
Indications: It is used in most of the acute primary and secondary glaucomas as a monotherapy or combined with other drugs. It is available in 2% ophthalmic solution or in combination with timolol (2% and 0.5%). If it is only dorzolamide then it is used 3 times a day. If it is in combination with timolol then it is twice a day. If it is used in combination with other drugs it has to be put at 10 mins apart.
Adverse reactions: It has least side effects. Ocular side effects includes: burning and stinging sensation, irritation. Taste abnormalities. The concomitant administration of local and systemic administration is not good because of its additive side effects.
Its activity is absorbed both in cytoplasm and plasma of the endothelium.
Note: Dorzolamide alone is supposed to decrease IOP by 20% and combination with timolol is said to be about 43%.
Brinzolamide: It is a recently introduced antiglaucoma drug. It has the same amount of reduction of IOP as dorzolamide. But it is more comfortable than dorzolamide. It is available in 1 % solution. Applied 1 - 3 times a day. Rest all it is similar to topical dorzolamide.
Side effects: Transient myopic shift, interference with treatment of myasthenia. Paresthesia of fingers toes. Dyspnea, leg cramps, hearing loss, birth defects.
- Electrolyte disturbance: Metabolic disturbances, K+ depletion, chloride depletion, uric acid retention.
- Gastrointerstinal: Abdominal cramps, metallic taste, nausea, diarrhea, anorexia, weight loss, constipation.
- Renal: Nocturia, polydypsia, Impotence, hypersensitivity nephropathy, urolithiasis.
- CNS: Drowsiness Excitement, Fatigue, Vertigo, Tremor, Confusion Headache, Irritability, Elevated cerebrospinal fluid, Depression Insomnia,
- Dermatological: Exfoliative dermatitis, Hair loss, Flushing, Steven Johnson syndrome.
- Oral Glycerol (Glycerine)
- Ethyl Alcohol
Hyperosmotic agents are used for more than 30 years now. They are a great value in reducing the IOP rapidly.
Mechanism of Action: These agents lower IOP by increasing plasma tonicity sufficient to draw the water out of the eye. Another mechanism is thought to be that – acting on the CNS path in the hypothalamus (receptors). Ideal the drug should not enter the eye. Should have lower molecular weight and should stay in the extra cellular space.
1. Oral Glycerol (Glycerine): Oral glycerol is one of the most widely used drug. It is available as 50% and 75% lime flavored oral solution (in 126ml or 220ml pack). Standard dosage is 1.0 - 1.5/kq body weight given 1 to 1 ½ hr before surgery. If not for surgery it can be given in other condition in the dose of 2 - 3 ml of body weight, if well tolerated 2 - 3 times a day. Caution: Must be exercised while treating diabetics as it is high in calories. It is metabolized in the liver and gives out 4.32 kcal/g.
Topical Glycerin is a viscous solution, that when applied on to the cornea can clear the edema so that the intra ocular structures can be visualized clearly.
2. Isosorbide: It is available as 45% mint flavored solution in 220ml pack with a dosage of 1 - 2g/Kg body weight given 2 - 4 times a day. It is dihydric alcohol derived from sorbital. And it is different from isosobide nitrate. It does not have much calories so can be given safely in diabetics. However, one of the side effects include diarrhea.
3. Ethyl Alcohol: It has unwanted effects on the CNS so not used clinically. It acts by inhibiting the anti-diuretic hormone
IV agents: These act rapidly and are more effective.
4. Mannitol: It is available from 5 - 25% hyperosmotic agent in 50,100,150,500 & 1000 ml pack. Most commonly used are the 20% in 100 or 200 ml (less irritating to the blood vessel). Standard dose is 0.5 - 2.0g/kg body weight.
The onset is 30 minutes and lasts for 6 hours (it can be stopped when IOP comes down). It is secreted in the urine unchanged. In low temperatures it gets crystallized. When crystals are observed warm the bottle and then it can be given IV.
Advantages of IV mannitol: It penetrates the eye poorly. Extravasation of the drug from IV line will not cause necrosis. More effective and it have rapid action. Can be used in diabetic patients. It is not contraindicated in renal failure patients.
Disadvantages: Greater likelihood of cellular dehydration, potassium depletion. Cardiovascular overload and pulmonary edema are more common.
5. Urea: It is less effective than mannitol. It penetrates the eye readily. It is administered as 30% solution in a dose of 2 to 7 ml/kg. But this drug is not used very often, because of its disadvantages.
Disadvantages: When the drug is cleared in the circulation rebound increase of IOP occurs. Old solutions decompose to ammonia. Urea is contraindicated in renal failure. If the drug extravasates it can cause thrombophlebitis and skin necrosis.
Uses of Hyperosmotic agents: Angle Closure Glaucoma, Secondary Glaucomas, Malignant Glaucoma.
Precautions: It should be used in caution in cardiac hepatic and renal patients. Cellular dehydration can cause disorientation. Especially in the cerebral area it can cause subdural hemotama.
Side Effects of Hyperosmotic agents:
- Gastrointestinal: Nausea, Vomiting, Diarrhea, Abdominal Cramps.
- CNS: Headache, Confusion, Disorientation, Fever, Subdural hemotama.
- Cardiovascular: Angina, Congestive, Heart Failure, Pulmonary edema
- Renal: Diuresis, Loss of potassium, Urinary retention, Anuria.
- Miscellaneous: Arm Pain, Acidosis, Diabetic Ketoacidosi, Laryngeal edema, Anaphylactic reaction, Hyphema, Thrombophlebitis.
Calcium Channel Blockers:
Calcium channel blockers such as diltiazem, nifedipine, and verapamil which inhibit calcium influx in vascular smooth muscle, decrease vascular tone and increase blood flow.
Recent studies have indicated that these oral calcium channel blockers are useful in low tension glaucoma by increasing the blood flow to the optic nerve.
1. 5–Fluorouracil (5FU): It is a fluorinated pyrimidine analogue that inhibits the enzyme thymidylate synthetase, which catalyzes the conversion of deoxyuridine phosphate to thymidine phosphate. Thus impending DNA synthesis. It acts selectively on the S-phase of the cell cycle.
Indications: It is used as adjuvant in glaucoma filtering surgery both intra operatively and post operatively to control IOP. 5FU is increasingly used as a single intra operative application.
A 3 x 2 mm of cellulose sponge soaked with 50mg/ml 5FU is placed under the conjunctival flap, avoiding the cut edges of the conjunctiva for about 1-2 minutes (depending upon the case upto 3 minutes). The sponge is removed and is then irrigated with 5-10 ml of ringer lactate solution.
5FU can also be given subconjunctival route during filtration surgery or bleb formation. (0.5 cc of 5mqm of 5FU prepared from commercially available 50mg/ml in physiological saline.
Complications of 5FU: Corneal and conjunctival epithelial toxicity, superficial punctate keratopathy, epithelial corneal defects and conjunctival wound leak are common to 5FU which occur after two weeks and heal after another two weeks.
Other complications include filamentary keratitis, dellen, sterile corneal ulcer and perforation. Bleb rupture, endothelial cell toxicity, lens epithelial toxicity, and retinal toxicity have been reported.
Contraindications: 5FU is contraindicated in eyes with pre-existing corneal epithelium edema, endothelial dysfunctions, or other pre-existing corneal abnormalities such as keratoconjunctivitis sicca or exposure keratopathy. Eyes with poor lid closure, trichiasis, or lid scaring. Reduced limbal cell count either to burns or scars.
2. Mitomycin-C (MMC): It is an alkylating, anti-tumor antibiotic that interrupts DNA replication and thus inhibits mitosis and protein synthesis. It is active on all cells regardless to the phase of the cell cycle. Its potency is 100 times that of 5FU. It has a toxic effect on the overlying conjunctiva, inhibits the angiogenic activity of blood vessels.
MMC has a greater effect than 5FU in reducing post operative IOP, delayed healing helps in doing suture lysis after 2 - 3 weeks.
Dose: A sponge soaked in 0.2 - 0.5 mg/ml MMC is applied to the filtering site from 30 seconds to 5 minutes. The sponge is placed between the conjunctiva and sclera without exposing the conjunctival edge of the wound to the antimetabolite. The drug is thoroughly irrigated with balanced salt solution. Complications are serious and more common than with 5FU. They are the same as with 5FU. MMC frequently forms a large thin walled bleb.
Other anti-metabolites tested for intra operative use during glaucoma filtering surgery are:.
- Daunorubicin (is already in use)
Recent advances in Glaucoma therapy: Continuous and exciting research is going on for a typical anti glaucoma drug. Some of these are launched or are about to launch in the near future are:
- Ocular hypotensive Lipids
- Neuroprotective agents
Ocular Hypotensive Lipids (OHL): Two new agents that are termed as OHL. They are AGN - 191129 and AGN - 192024. Are similar to the existent prostaglandins and decrease IOP by uveoscleral outflow. It comes in a dose of 0.1 % and is supposed to be superior to most of the drugs.
Neuro protective agents: Even though we all agree that reducing IOP is a key factor in reducing the damage to the optic nerve head. We also agree that there are other factors also affecting the ONH. One of these is the theory of apoptosis.
These drugs are supposedly to reduce or alter the pathway of cell death.
They are α-2 agonists, calcium channel blockers, nitric oxide inhibitors, neurotrophic factors, free radical scavengers, NMDA channel blockers, NMDA agonists