Ординатура / Офтальмология / Английские материалы / Comprehensive Ophthalmology_Khurana_2007

some gram-positive cocci. However, Pseudomonas and Streptococcus pyogenes are not sensitive to it. It is highly toxic to internal ear and kidney and hence used only topically (0.3-0.5%).

6.Framycetin. It is very similar to neomycin. It is also too toxic for systemic use and hence used only topically. It is available as 1 percent skin cream; 0.5 percent eye ointment and eyedrops.

Tetracyclines

These are broad-spectrum bacteriostatic agents with a considerable action against both gram-positive and gram-negative organisms as well as some fungi, rickettsiae and chlamydiae. This group includes tetracycline, chlortetracycline and oxytetracycline.

Chloramphenicol

It is also a broad-spectrum antibiotic, primarily bacteriostatic, effective against gram-positive as well as gram-negative bacteria, rickettsiae, chlamydiae and mycoplasma.

Its molecule is relatively small and lipid soluble. Therefore, on systemic administration, it enters the eye in therapeutic concentration. Topically it is used as 0.5% eyedrops.

Polypeptides

These are powerful bactericidal agents, but rarely used systemically due to toxicity. Clinically used polypeptides are polymyxin B, bacitracin, colistin and tyrothricin.

1.Polymyxin B and colistin. These are active against most gram-negative bacteria, notably Pseudomonas.

2.Neosporin (neomycin-polymyxin-bacitracin). It is an effective broad-spectrum antimicrobial but suffers the disadvantage of a high incidence (6- 8%) of sensitivity due to neomycin.

Fluoroquinolones

Fluoroquinolones are potent synthetic agents having broad spectrum of activity against gram-positive and gram negative-organisms.

Mechanism of action. Fluoroquinolones are bactericidal drugs. These inhibit the bacterial DNA synthesis.

Preparations. Fluroquinolones by convention have been grouped into four generations (Table 18.1).

Table 18.1. Commonly used fluoroquinolones

ANTIVIRAL DRUGS

These are more often used locally in the eye. Currently available antiviral agents are virostatic. They are active against DNA viruses; especially herpes simplex virus. Antiviral drugs used in ophthalmology can be grouped as below:

For herpes simplex virus infection

Idoxuridine

Vidarabine

Trifluridine

Acyclovir

Famiciclovir

For herpes zoster virus infection

Acyclovir

Famiciclovir

Valaciclovir

Vidarabine

Sorvudine

For CMV retinitis

Ganciclovir

Foscarnet

Zidovudin

Non selective

Interferons

Immunoglobulins

Some of the antiviral drugs are described in brief.

1. Idoxuridine (IDU, 5-iodo-2 deoxyuridine). It is a halogenated pyrimidine resembling thymidine. Mechanism of action. It inhibits viral metabolism by substituting for thymidine in DNA synthesis and thus prevents replication of virus.

Topically it is used as 10% eye drops. Preparations. It is available as 0.1 percent eye drops and 0.5 percent eye ointment.

Indications and doses: Since the intraocular penetration of topically applied IDU is very poor, it is not of much value in the treatment of chronic stromal herpetic keratitis. It is mainly used in acute epithelial herpetic keratitis. IDU drops are used one hourly during day and two hourly during night and has to be continued till microscopic staining disappears.

Side-effects include follicular conjunctivitis, lacrimal punctal stenosis and irritation with photophobia. Contraindications. It is known to inhibit corneal stromal healing, hence its use is not advisable during first few weeks after keratoplasty.

2. Adenine arobinoside (Ara-A, Vidarabine). It is a purine nucleoside. It has antiviral activity against herpes simplex, cytomegalo, vaccinia and zoster viruses. It is more potent and less toxic than IDU and is also effective in IDU resistant cases. It has no cross allergenicity with IDU or TF3 and thus can be used with IDU.

Mechanism of action: It is metabolized to triphosphate form which inhibits DNA polymerase and thus the growth of viral DNA is arrested. Preparations: It is available as 3% ophthalmic ointment.

Dose: It is used 5 times a day till epithelization occurs and then reduced to once or twice daily for 4-5 days to prevent recurrences. Side-effects are superificial punctate keratitis and irritation on prolonged application.

3.Cytosine-Arabinoside (Cytarabine). It is a purine nucleoside, Mechanism of action: It blocks nucleic acid synthesis by preventing conversion of cytosine ribose to cytosine deoxyribose.

Preparation: It is not commercially available at present. 5 percent solution used as drops has been found experimentally effective for treatment of herpes simplex keratitis.

Side-effects. It causes profound corneal epithelial toxicity with superficial punctate keratitis and iritis. So it is not recommended for clinical use.

4.Triflurothymidine (TF3). It is a pyrimidine nucleoside. It has the advantage over IDU of higher solubility, greater potency, lack of toxicity and allergic reactions. It is also effective in IDU-resistant cases. Mechanism of action: It is a DNA inhibitor with same mechanism as IDU. Preparation: It is available as 1 per cent eyedrops.

Dose: One drop is instilled 4 hourly. If no improvement occurs in 14 days, it is better to change to some other antiviral drug.

Toxicity: It is least toxic. It may cause mild superficial punctate keratitis on prolonged use.

5.Acyclovir (Acycloguanosine). It has proved to be an extremely safe and effective agent and is effective in most forms of herpes simplex and herpes zoster infections.

Mechanism of action: It inhibits viral DNA, preferentially entering the infected cells, with little effect on normal cells. It penetrates into deeper layers and thus is very effective in stromal keratitis. Preparation. It is available as 3 percent ophthalmic ointment and also as tablet for oral use and injection

for intravenous use.

Indications and doses: (a) Topical 3 percent ointment is used 5 times a day for epithelial as well as stromal herpes simplex keratitis (b) Oral acyclovir four tablets of 200 mg each, 5 times a day for 5-7 days, may be considered in following situations: (i) After penetrating keratoplasty in patients suffering from herpes simplex keratitis. (ii) Recalcitrant stromal or uveal disease caused by HSV. (iii) To reduce ocular complications of keratitis and uveitis in herpes zoster ophthalmicus. Side-effects: A few cases show slight punctate epithelial keratopathy which ceases once the drug is stopped.

6. Valaciclovir. It is used for treatment of herpes zoster ophthalmicus in a dose of 500-700 mg TDS for 7 days. It is as effective as acyclovir in acute disease and is more effective in reducing late neuralgia.

7.Famiciclovir. Its use, dose and effectivity is similar to valaciclovir.

8.Interferons. These are non-toxic, species-specific proteins possessing broad-spectrum antiviral activity. However, it is still not available for commercial use.

9.Immunoglobulins. These preparations may be useful in the treatment or prophylaxis of certain viral diseases especially in patients with immune deficiencies.

10.Ganciclovir. It is used for the treatment of CMV retinitis in immunocompromised individuals. Dose: 5 mg/kg body weight every 12 hours for 2-3 weeks, followed by a permanent maintenance dose of 5 mg/ kg once daily for 5 out of 7 days.

11.Foscarnet (Phosphonoformic acid; PFA). It is as effective as ganciclovir in the treatment of CMV retinitis in AIDS patients.

12.Zidovudin (azidothymidine; AZT). It has been recently recommended for selectedAIDS patients with non-vision threatening retinitis who have no evidence of systemic CMV infection.

OCULAR ANTIFUNGAL AGENTS

A number of antifungal agents have become available in the recent years. These can be broadly classified on the basis of their chemical structure into polyene antibiotics, imidazole derivatives, pyrimidines and silver compounds.

I. Polyene antifungals

These have been the mainstay of antifungal therapy. These are isolated from various species of Streptomyces and consist of a large, conjugated, double-bond system in a lactose ring linked to an amino acid sugar.

Mechanism of action. They work by binding to the sterol groups in fungal cell membranes, rendering them permeable. This occurrence leads to lethal imbalances in cell contents. Polyenes do not penetrate well into the cornea and are not beneficial in deep stromal keratitis.

Preparations. This group includes following drugs:

1.Nystatin. It is fungistatic and is well tolerated in the eye as 3.5 percent ointment. It has a medium level of activity in ocular infections caused by Candida or Aspergillus isolates. Because of its narrow spectrum and poor intraocular penetration its use is restricted.

2.Amphotericin B (Fungizone). This antibiotic may act as fungistatic or fungicidal depending upon the concentration of the drug and sensitivity of the fungus. Topically, it is effective in superficial infections of the eye in the concentration of 0.075 to 0.3 percent drops. Subconjunctival injections are quite painful and more than 300 mg is poorly tolerated.

Amphotericin B may be given intravitreally or/ and intravenously for treatment of intraocular infections caused by Candida, Histoplasma, Cryptococcus and some strains of Aspergillus and others. For intravenous administration a solution of 0.1 mg/ml in 5 percent dextrose with heparin is used.

3.Natamycin (Pimaricin). It is a broad-spectrum antifungal drug having activity against Candida,

Aspergillus, Fusarium and Cephalosporium. Topical application of 5 percent pimaricin suspension produces effective concentrations within the corneal stroma but not in intraocular fluid. It is the drug of choice for fusarium solani keratitis. It adheres well to the surface of the ulcer, making the contact time of the antifungal agent with the eye greater. It is not recommended for injection.

II. Imidazole antifungal drugs

Various imidazole derivatives available for use in ocular fungal infections include: miconazole, clotrimazole, ketoconazole, econazole and itraconazole.

1.Miconazole. It possesses a broad antifungal spectrum and is fungicidal to various species of

Candida, Aspergillus, Fusarium, Cryptococcus, Cladosporium, Trichophyton and many others. Topical (1%) and subconjunctival (10 mg) application of miconazole produces high levels of the drug in the cornea which is more dramatic in the presence of epithelial defect.

2.Clotrimazole. It is fungistatic and is effective against Candida, Aspergillus and many others. Its 1 percent suspension is effective topically and is the treatment of choice in Aspergillus infections of the eye.

3.Econazole. It also has broad-spectrum antifungal activity and is used topically as 1 percent econazole nitrate ointment. Becaue of its poor intraocular penetration, it is effective only in superficial infections of the eye.

4.Ketoconazole. It is effective after oral administration and possesses activity against common fungi. It is given as single oral dose of 200-400 mg daily up to at least one week after the symptoms have disappeared. It is an adjunctive systemic antifungal agent in fungal keratitis complicated by endophthalmitis.

5.Fluconazole. It is fungistatic drug active against

Candida, Aspergillus and Cryptococcus. It is available for oral use (50-100 mg tablets) and also for topical use (0.2% eyedrops).

6.Itraconazole. It is prescribed for treatment of fungal infections caused primarily by Aspergillus, Histoplasmosis, Blastomycosis. It has moderate effect against Candida and Fusarium infections. It is available for oral and topical use. Oral dose is 200 mg twice daily for a week. Topically it is used as 1% eye drops.

III. Pyridine

This group includes flucystosine, which is a fluorinated salt of pyrimidine. Its mechanism of action is not clear. The drug is very effective against Candida species and yeasts. It is used as 1.5 percent aqueous drops hourly. It can also be given orally or intravenously in doses of 200 mg/kg/day.

IV. Silver compounds

Combination of silver with sulfonamides and with other anti-microbial compounds significantly increases the activity against bacterial and fungal infections. In this context several silver compounds have been synthesized. Most frequently used is silver sulphadiazine which is reported to be highly effective against Aspergillus and Fusarium species.

MYDRIATICS AND CYCLOPLEGICS

(See pages 98, 146 and 550)

ANTI-GLAUCOMA DRUGS

Classification

A.Parasympathomimetic drugs (Miotics)

B.Sympathomimetic drugs (Adrenergic agonists)

C.β-blockers

D.Carbonic anhydrase inhibitors

E.Hyperosmotic agents

F.Prostaglandins

G.Calcium channel blockers

A. Parasympathomimetic drugs (Miotics)

Parasympathomimetics, also called as cholinergic drugs, either imitate or potentiate the effects of acetylcholine.

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: As the name indicates these drugs act indirectly by destroying the enzyme cholinesterase; thereby sparing the naturallyacting acetylcholine for its actions. These drugs have been divided into two subgroups, designated as reversible (e.g., physostigmine) and irreversible (e.g., echothiophate iodide, demecarium and diisopropyl-fluoro-phosphate, DFP3) antic-holinesterases.

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 the miotics reduce the intraocular pressure (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 these 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 noted are: bradycardia, increased sweating, diarrhoea, excessive salivation and anxiety. The only serious complication noted with irreversible cholinesterase inhibitors is ‘scoline apnoea’, i.e., inability of the patient to resume normal respiration after termination of general anaesthesia.

2.Local side-effects are encountered more frequently with long-acting miotics (i.e. irreversible cholinesterase inhibitors). These include problems due to miosis itself (e.g. reduced visual acuity in the presence of polar cataracts, impairment of

night vision and generalized contraction of visual fields), spasm of accommodation which may cause myopia and frontal headache, retinal detachment, lenticular opacities, iris cyst formation, mild iritis, lacrimation and follicular conjunctivitis.

Preparations

1. Pilocarpine. It is a direct-acting parasympathomimetic drug. It is the most commonly used and the most extensively studied miotic. Indications: (i) Primary open-angle glaucoma; (ii)Acute angle-closure glaucoma; (iii) Chronic synechial angle-closure glaucoma. Contraindications: inflammatory glaucoma, malignant glaucoma and known allergy.

Available preparations and dosage are: (a) Eyedrops are available in 1%, 2% and 4% strengths. Except in very darkly pigmented irides maximum effect is obtained with a 4 percent solution. In POAG, therapy is usually initiated with 1 percent concentration. The onset of action occurs in 20 minutes, peak 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 eyedrops. 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 percent 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

Sympathomimetics, also known as adrenergic agonists, act by stimulation of alpha, beta or both the receptors.

Classification

Depending upon the mode of action, these can be classified as follows:

1.Both alpha and beta-receptor stimulators e.g., epinephrine.

2.Direct alpha-adrenergic stimulators e.g., norepinephrine and 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 include hypertension, tachycardia, headache, palpitation, tremors, nervousness and anxiety.

2.Local side-effects are burning sensation, reactive hyperaemia of conjunctiva, conjunctival pigmentation, allergic blepharo conjunctivitis, mydriasis and cystoid macular oedema (in aphakics).

Preparations

1.Epinephrine. This direct-acting sympathomimetic drug stimulates both alpha and betaadrenergic receptors. Indications: (i) It is one of the standard drugs used for the management of POAG. (ii) It is also useful in most of the 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(Propineordipivalylepinephrine).Itisa prodrug which is converted into epinephrine after its absorption into the eye. It is 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 similarto1percentepinephrine.Itisinstilledtwicedaily.

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%). Mechanism of action. It is a selective alpha-2 adrenergic agonist and lowers IOP by decreasing aqueous production and enhancing uveoscleral outflow. It has an 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 (0.5%, 1%). It is also alpha-2 adrenergic agonist like brimonidine. It is an extremely potent ocular hypotensive drug and is commonly used prophylactically for prevention of IOP elevation following laser trabeculoplasty, YAG laser iridotomy and posterior capsulotomy. It is of limited use for long-term administration because of the high rate of ocular side-effects.

C. Beta-adrenergic blockers

These are, presently, the most frequently used antiglaucoma drugs. The 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. Betaxolol has 10 times more affinity for beta-1 than beta-2 receptors.

The drugs timolol and levobunolol lower IOP by blockade of beta-2 receptors in the ciliary processes, resulting in decreased aqueous production. The exact mechanism of action of betaxolol (cardioselective beta-blocker) is unknown.

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.

Contraindications. These drugs should be used with caution or not at all, depending on the severity of the systemic disease 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

1.Ocular side-effects are not frequent. These include burning and conjunctival hyperaemia, superficial punctate keratopathy and corneal anaesthesia.

2.Systemic side-effects are also unusually low. However, these are reported more often than ocular side-effects. These include (i) Cardiovascular effects which result from blockade of beta-1 receptors. These are bradycardia, arrhythmias, heart failure and syncope. (ii) Respiratory reactions: These include 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. These include depression, anxiety, confusion, drowsiness, disorientation, hallucinations, emotional lability, dysarthria and so on. (iv) Miscellaneous effects are nausea, diarrhoea, decreased libido, skin rashes, alopecia and exacerbation of myasthenia gravis.

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. Therefore, it is used once or twice daily. The drug is very effective, however, the phenomenon of ‘short-term escape’ and ‘longterm drift’ are well known. ‘Short-term escape’ implies marked initial fall in IOP, followed by a transient rise with continued moderate fall in IOP. The ‘long-term drift’ implies a slow rise in IOP in patients who were well controlled with many months of therapy.

2.Betaxolol. It is a cardioselective beta-blocker and thus can be used safely in patients prone to attack of bronchial asthma; an advantage over timolol. It is available as 0.5 percent suspension, and 0.25 percent suspension, and is used twice daily. Its action starts within 30 minutes, reaches peak in 2 hours and lasts for 12 hours. It is slightly less effective than timolol in lowering the IOP.

3.Levobunolol. It is available as 0.5 percent solution and its salient features are almost similar to timolol.

4.Carteolol. It is available as 1 percent and 2 per cent solution and is almost similar to timolol except that it induces comparatively less bradycardia.

5.Metipranolol. It is available as 0.1 percent, 0.3 percent and 0.6 percent solution and is almost similar to timolol in all aspects.

(D) Carbonic anhydrase inhibitors (CAIs)

These are potent and most commonly used systemic antiglaucoma drugs. These include acetazolamide (most frequently used), methazolamide, dichlorphenamide and ethoxzolamide.

Mechanism of action. As the name indicates 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. Unfortunately, 40-50 percent of patients are unable to tolerate CAIs for long term because of various disabling side-effects. These include:

1.Paresthesias of the fingers, toes, hands, feet and around the mouth are experienced by most of the patients. However, these are transient and of no consequence.

2.Urinary frequency may also be complained of by most patients due to the diuretic effect.

3.Serum electrolyte imbalances may occur with higher doses of CAIs. These may be in the form of (i) Bicarbonate depletion leading to metabolic acidosis. This is associated with ‘malaise symptom complex’, which includes: malaise, fatigue, depression, loss of libido, anorexia and weight loss. Treatment with sodium bicarbonate or sodium acetate may help to minimize this situation in many patients. (ii) Potassium depletion. It may occur in some patients, especially those simultaneously getting corticosteroids, aspirin or thiazide diuretics. Potassium supplement is indicated only when significant hypokalemia is documented. (iii) Serum sodium and chloride may be transiently reduced; more commonly with dichlorphenamide.

4.Gastrointestinal symptom complex. It is also very common. It is not related to the malaise symptom complex caused by biochemical changes in the serum. Its features include—vague abdominal discomfort, gastric irritation, nausea, peculiar metallic taste and diarrhoea.

5.Sulfonamide related side-effects of CAIs, seen rarely, include renal calculi, blood dyscrasias, Stevens-Johnson syndrome, transient myopia, hypertensive nephropathy and teratogenic effects.

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. It is available as 50 mg tablets. Its recommended dose is 25 to 100 mg three times a day. It causes less metabolic acidosis but has a sustained diuretic effect.

3.Methazolamide. It is also available as 50 mg tablets. It has a longer duration of action than acetazolamide. Its dose is 50-100 mg, 2 or 3 times a day.

4.Ethoxzolamide. It is given in a dosage of 125 mg every 6 hours and is similar to acetazolamide in all aspects.

5.Dorzolamide (2%). It is a topical carbonic anhydrase inhibitor. It is water soluble, stable in solution and has excellent corneal penetration. It decreases IOP by 22% and has got additive effect with timolol. It is administered thrice daily. Its side effects include burning sensation and local allergic reaction.

6.Brinzolamide (1%). It is also a topical CAI which decreases IOP by decreasing aqueous production. It is administered twice daily (BD).

E. Hyperosmotic agents

These are the second class of compounds, which are administered systemically to lower the IOP. These include: glycerol, mannitol, isosorbide and urea.

Mechanism of action. Hyperosmotic 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, such as 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 derivatives

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. Its sideeffects 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.

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.

Antiglaucoma drugs: Mechanism of lowering IOP at a glance

Drugs which increase trabecular outflow

Miotics (e.g., pilocarpine)

Epinephrine, Dipivefrine

Bimatoprost

Drugs which increase uveoscleral outflow

Prostaglandins (latanoprost)

Epinephrine, Dipivefrine

Brimonidine

Apraclonidine

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) Hyperosmotic agents (e.g., glycerol, mannitol, urea)

CORTICOSTEROIDS

These are 21-C compounds secreted by the adrenal cortex. They have potent anti-inflammatory, antiallergic and anti-fibrotic actions. Corticosteroids reduce inflammation by reduction of leukocytic and plasma exudation, maintenance of cellular membrane integrity with inhibition of tissue swelling, inhibition of lysosome release from granulocytes, increased stabilisation of intracellular lysosomal membranes and suppression of circulating lymphocytes.

Classification and relative anti-inflammatory drug potency

See Table 18.2

Table 18.2: Corticosteroids: equivalent antiinflammatory oral dose (mg) and relative antiinflammatory potency.

I.Glucocorticoids

1.Short acting

Hydrocortisone

Preparations and modes of administration

Corticosteroids may be administered locally in the form of drops, ointments or injections and systemically in the form of tablets or injections.

(A)Topical ophthalmic preparations used commonly are as follows:

(B)Systemic corticosteroid preparations used commonly are:

Prednisolone

Dexamethasone

Betamethasone

Ocular indications

1.Topical preparations are used in uveitis, scleritis, allergic conjunctivitis (vernal catarrh and phlyctenular conjunctivitis), allergic keratitis, cystoid macular oedema and after intraocular surgery.

2.Systemic preparations are indicated in posterior uveitis, sympathetic ophthalmia, Vogt-Koyanagi- Harada syndrome (VKH), papillitis, retrobulbar neuritis, anterior ischaemic optic neuropathy, scleritis, malignant exophthalmos, orbital pseudotumours, orbital lymphangioma and corneal graft rejections.

Side-effects

Injudicious use of topical steroids may cause glaucoma, cataract, activation of infection (if given in herpetic, fungal and bacterial keratitis), dry eye and ptosis.

Misuse of systemic corticosteroids may cause ocular and systemic side-effects. Ocular complications include cataract, glaucoma, activation of infection, delayed wound healing, papilloedema, and central retinal vein occlusion.

Systemic complications include peptic ulcer, hypertension, osteoporosis, aggravation of diabetes mellitus, mental changes, cushingoid state and reactivation of tuberculosis and other infections.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

Nonsteroidal anti-inflammatory drugs (NSAIDs), often referred to as ‘aspirin-like drugs’, are a

heterogeneous group of anti-inflammatory, analgesic and antipyretic compounds. These are often chemically unrelated (although most of them are organic acids), but share certain therapeutic actions and side-effects.

Mechanisms of action

The NSAIDs largely act by irreversibly blocking the enzyme cyclo-oxygenase, thus inhibiting the prostaglandin biosynthesis. They also appear to block other local mediators of the inflammatory response such as polypeptides of the kinin system, lysosomal enzymes, lymphokinase and thromboxaneA2; but not the leukotrienes.

Preparations

A.NSAIDs available for systemic use can be grouped as follows:

1.Salicylates e.g., aspirin.

2.Pyrazolone derivatives e.g., phenylbutazone, oxyphenbutazone, aminopyrine and apazone.

3.Para-aminophenol derivatives e.g., phenacetin and acetaminophen.

4.Indole derivatives e.g., indomethacin and sulindac.

5.Propionic acid derivatives e.g., ibuprofen, naproxen and flurbiprofen.

6.Anthranilic acid derivatives e.g., mefenamic acid and flufenamic acid.

7.Other newer NSAIDs e.g., ketorolac tromethamine, carprofen and diclofenac.

B.Topical ophthalmic NSAIDs preparations available include:

1.Indomethacin suspension (0.1%)

2.Flurbiprofen, 0.3% eyedrops

3.Ketorolac tromethamine, 0.5% eyedrops

4.Diclofenac sodium, 0.1% eyedrops

Ophthalmic indications of NSAIDs

1.Episcleritis and scleritis. Recalcitrant cases of episcleritis may be treated with systemic NSAIDs such as oxyphenbutazone 100 mg TDS or indomethacin 25 mg BD.

NSAIDs may also suppress the inflammation in diffuse and nodular varieties of scleritis, but are not likely to control the necrotizing form.

2.Uveitis. NSAIDs are usually not used as the primary agents in therapy of uveitis. They are, however, useful in the long-term therapy of recurrent anterior uveitis, initially controlled by steroid therapy. Phenylbutazone is of use in uveitis associated with ankylosing spondylitis.

3.Cystoid macular oedema (CME). Topical and/or systemic antiprostaglandin drugs are effective in preventing the postoperative CME occurring after cataract operation. The drug (e.g., 0.03% flurbiprofen eyedrops) is started 2 days preoperatively and continued for 6-8 weeks postoperatively.

4.Pre-operatively to maintain dilatation of the pupil. Flurbiprofen drops used every 5 minutes for 2 hours preoperatively are very effective in maintaining the pupillary dilatation during the operation of extracapsular cataract extraction with or without intraocular lens implantation.

5.Spring catarrh. Sodium cromoglycate 2 percent inhibits degranulation of the mast cells and thus is more useful when used prophylactically in patients with spring catarrh. Topical antiprostaglandins are effective in the treatment of spring catarrh.

6.Topical antihistaminics are helpful in cases of mild allergic conjunctivitis.

VISCOELASTIC SUBSTANCES

Use of viscous or viscoelastic substances has become almost mandatory in the modern microphthalmic surgery, especially intraocular lens implantation, which involves a risk of involuntary tissue damage due to intraocular manipulations.

Properties of viscoelastic substances

An ideal viscoelastic substance should have the following properties:

1.Chemically the material should be inert, isoosmotic, free from particulate matter, nonpyrogenic, non-antigenic, non-toxic and sterile.

2.Optically clear.

3.Viscosity of the substances should be enough to provide sufficient space for manipulation within the eye.

4.Hydrophilic and dilutable properties are necessary to irrigate the material out of the eye after the operation.

5.Protectability and maintenance of space. It should protect the endothelium, separate the tissues, maintain the space and act as a lubricant.