Drugs For Glaucoma

DRUGS FOR GLAUCOMA

Glaucoma is a group of diseases characterized by a progressive form of optic nerve damage. This is generally associated with raised (> 21 mmHg) intraocular tension (i.o.t), but the etiology is unknown and there are many risk factors. The chief therapeutic measure is to lower i.o.t. to target level, either by reducing secretion of aqueous humor or by promoting its drainage. The site of formation and pathway of drainage of aqueous humor as well as sites of action of antiglaucoma drugs is illustrated in Fig. 10.1. Major amount of aqueous (~90%) drains through the trabecular route, while ~10% fluid passes into the connective tissue spaces within the ciliary muscle—then via suprachoroid into episcleral vessels (uveoscleral outflow). Glaucoma is seen in two principal clinical forms:

A. Open Angle (Wide Angle, Chronic Simple) Glaucoma

It is probably a genetically predisposed degenerative disease affecting patency of the trabecular meshwork which is gradually lost past middle age. The i.o.t. rises insidiously and progressively. Ocular hypotensive drugs are used on a long term basis and constitute the definitive treatment in majority of cases.

1. β Adrenergic blockers

Topical β blockers are one of the first line drugs, but PG F_2α analogues are increasingly used now. In contrast to miotics, the β blockers do not affect pupil size, tone of ciliary muscle or outflow facility, but lower i.o.t. by reducing aqueous formation. This probably results from down regulation of adenylylcyclase due to β₂ receptor blockade in the ciliary epithelium and a secondary effect due to reduction in ocular blood flow. They are as effective as miotics and produce less ocular side effects. Ocular β blockers are lipophilic with high ocular capture (to reduce systemic effects) and have no/weak local anaesthetic activity (to avoid corneal hypoesthesia and damage).

Advantages of topical β blockers over miotics

·  No induced myopia which is especially troublesome in young patients

· ·  No change in pupil size: no diminution of vision in dim light and in patients with cataract

·    No headache/brow pain due to persistent spasm of iris and ciliary muscles

·        No fluctuations in i.o.t. as occur with pilocarpine drops

·        Convenient twice/once daily application sufficient

Ocular side effects of β blockers viz. stinging, redness and dryness of eye, corneal hypoesthesia, allergic blepharon-conjunctivitis and blurred vision are generally mild and infrequent. Their major limitation are the systemic adverse effects that occur due to absorption through nasolacrimal duct. Life threatening bronchospasm has been reported in asthmatics. Bradycardia, accentuation of heart block and CHF are likely, especially in the elderly. In fact all adverse effects and contraindications of systemic β blocker therapy apply to ocular β blockers as well.

Timolol It is the prototype of ocular β blockers; is nonselective (β₁ + β₂) and has no local anaesthetic or intrinsic sympathomimetic activity. The ocular hypotensive action (20–35% fall in i.o.t.) is smooth and well sustained. After chronic use, effect on i.o.t. persists for 2–3 weeks following discontinuation. This feature, in contrast to pilocarpine drops, gives a high level of clinical safety, i.e. 1 or 2 missed doses will not affect i.o.t. control. However, upto 30% cases of open angle glaucoma fail to achieve the desired level of i.o.t. with timolol alone, and may need additional medication.

GLUCOMOL,  OCUPRES,  IOTIM,  LOPRES  0.25%  and 0.5% eye drops; start with 0.25% drops BD, change to 0.5% drops in case of inadequate response.

Betaxolol It is β₁ selective blocker offering the advantage of less bronchopulmonary and probably less cardiac, central and metabolic side effects. In addition, it may exert a protective effect on retinal neurones independent of i.o.t. lowering, possibly by reducing Na⁺/Ca⁺ influx. However, it is less efficacious in lowering i.o.t. than timolol, because ocular β receptors are predominantly of the β₂ subtype. Transient stinging and burning in the eye is more common with it. Most ophthalmologists prefer to start with betaxolol and change over to timolol (or a similar drug) only if i.o.t. control is insufficient or there is local intolerance to betaxolol.

OPTIPRESS, IOBET 0.5% eye drops; 1 drop in each eye BD.

Levobunolol It has been introduced as a once daily alternative to timolol. The ocular and systemic effects are very similar to timolol except for longer duration of action.

BETAGAN 0.5% ophthalmic soln., 1 drop OD.

Carteolol and Metipranolol are the other ocular β  blockers.

2. α  Adrenergic agonists

Adrenaline Applied topically 0.5–1% Adr can lower i.o.t., but response is variable due to poor corneal penetration. The i.o.t. reduction is due to increased uveoscleral outflow and β₂ receptor mediated increased hydraulic conductivity of trabecular filtering cells. Reduction in aqueous formation can result from α₂ and α₁ receptor activation in ciliary body.

Adrenaline frequently produces ocular smarting and vasoconstriction followed by reactive hyperemia. It is not used now because of ocular intolerance and possible systemic effects.

Dipivefrine It is a prodrug of Adr; penetrates cornea and is hydrolysed by the esterases present there into Adr. Though better tolerated and longer acting than Adr, dipivefrine still produces significant ocular side effects. It is used only as add on therapy in poorly controlled patients.

PROPINE 0.1% eye drop; 1 drop in each eye BD.

Apraclonidine It is a polar clonidine congener which does not cross bloodbrain barrier, but applied topically (0.5–1%) it lowers i.o.t. by ~25%. It decreases aqueous production by primary α₂ and subsidiary α₁ action in the ciliary body. Itching, lid dermatitis, follicular conjunctivitis, mydriasis, eyelid retraction, dryness of mouth and nose are common side effects. Its use is restricted to control of spikes of i.o.t. after laser trabeculoplasty or iridotomy.

Brimonidine This recently introduced clonidine congener is more α₂ selective and more lipophilic than apraclonidine. It lowers i.o.t. by 20–27% by reducing aqueous production and by increasing uveoscleral flow. Ocular side effects are similar to but less frequent than with apraclonidine. Because of weaker α₁ action, side effects like mydriasis, eyelid retraction, conjunctival blanching—hyperemia are less prominent, but dry mouth, sedation and small fall in BP have been noted.

Brimonidine is indicated both for shortterm (prophylaxis of i.o.t. spikes post laser/post surgery) as well as longterm use in glaucoma. It is a 3rd choice/add on drug only.

ALPHAGAN, IOBRIM 0.2% eyedrops; 1 drop in each eye TDS.

3. Prostaglandin analogues

Low concentration of PGF_2α was found to lower i.o.t without inducing ocular inflammation. It acts by increasing uveoscleral outflow, possibly by increasing permeability of tissues in ciliary muscle or by an action on episcleral vessels. An effect on trabecular outflow is also possible. Ciliary body COX2 is down regulated in wide angle glaucoma indicating a physiological role of PG in aqueous humor dynamics.

Latanoprost Instilled in the eye, this PGF_2α derivative has shown efficacy similar to timolol (i.o.t. reduction by 25–35%) and the effect is well sustained over longterm. It reduces i.o.t. in normal pressure glaucoma also. Though ocular irritation and pain are frequent, no systemic side effects are reported. Blurring of vision, increased iris pigmentation, thickening and darkening of eyelashes have occurred in some cases.

Because of good efficacy, once daily application and absence of systemic complications, PG analogues have become the first choice drugs in developed countries. High cost limits their use in resource poor countries.

LACOMA, XALATAN 0.005% eye drops, one drop in each eye OD in the evening; LACOMAT with timolol 0.5% eye drops. (To be stored in cold)

Unoprostone, Travoprost and Bimatoprost are other ocular PG analogues.

4. Carbonic anhydrase inhibitors

Acetazolamide Oral treatment with acetazolamide (0.25 g 6–12 hourly) reduces aqueous formation by limiting generation of bicarbonate ion in the ciliary epithelium. It is used to supplement ocular hypotensive drugs for short term indications like angle closure, before and after ocular surgery/laser therapy. Systemic side effects—paresthesia, anorexia, hypokalaemia, acidosis, malaise and depression restrict longterm use to few cases in which target i.o.t. is not achieved even by concurrent use of 2–3 topical drugs.

Dorzolamide (2% eyedrops TDS) It is a topically useful carbonic anhydrase inhibitor developed to circumvent systemic side effects of acetazolamide. It lowers i.o.t. by ~20%; somewhat less efficacious than timolol. Ocular stinging, burning, itching and bitter taste are the side effects.

Dorzolamide is used only as add on drug to topical β blockers/PG analogues, or when these drugs are contraindicated.

DORTAS, DORZOX 2% eye drops.

Brinzolamide is another ocular carbonic anhydrase inhibitor.

5. Miotics

Till the 1970s topical pilocarpine and/or antiChEs were the standard antiglaucoma drugs. However, because of several drawbacks, they are now used only as the last option. In open angle glaucoma, they lower i.o.t. by increasing ciliary muscle tone thereby improving patency of trabeculae.

The current approach to treatment of open angle glaucoma can be summarized as—start monotherapy with latanoprost or a topical β blocker; if target i.o.t. is not attained either change over to the alternative drug or use both the above concurrently. Brimonidine/dorzolamide/dipivefrine are used only when there are contraindications to PG analogues/β blockers, or to supplement their action. Topical miotics and oral acetazolamide are added only as the last resort.

B. Angle Closure (Narrow Angle, Acute Congestive) Glaucoma

It occurs in individuals with a narrow iridocorneal angle and shallow anterior chamber. The i.o.t. remains normal until an attack is precipitated, usually by mydriasis (Fig. 10.3A,B). The i.o.t. rises rapidly to very high values (40–60 mmHg). It is an emergent condition; failure to lower i.o.t. quickly may result in loss of sight.

Vigorous therapy employing various measures to reduce i.o.t. is instituted.

·        Hypertonic mannitol (20%) 1.5–2 g/kg or glycerol (10%): infused i.v. decongest the eye by osmotic action. A retention enema of 50% glycerine is also some times used.

·        Acetazolamide: 0.5 g i.v. followed by oral twice daily is started concurrently.

·        Miotic: Once the i.o.t. starts falling due to the above i.v. therapy, pilocarpine 1–4% is instilled every 10 min initially and then at longer intervals. Contraction of sphincter pupillae changes the direction of forces in the iris to lessen its contact with the lens and spreads the iris mass centrally → pupillary block is removed and iridocorneal angle is freed (Fig. 10.3C). However, when i.o.t. is very high, the iris muscle fails to respond to miotics; tension should be reduced by other measures before miotics can act.

·        Topical β blocker: Timolol 0.5% is instilled 12 hourly in addition.

·        Apraclonidine (1%)/latanoprost 0.005% instillation may be added.

Drugs are used only to terminate the attack of angle closure glaucoma. Definitive treatment is surgical or laser iridotomy. Few cases, who have chronic narrow angle glaucoma, may be treated with a miotic/other ocular hypotensive drug for long periods, but often surgery/laser therapy is ultimately required.