Mechanism of action

Dorzolamide is a potent inhibitor of human carbonic anhydrase II (CA-II) the predominant isoenzyme in the ciliary processes. This enzyme plays an important role in the transfer of sodium and thereby fluid production in the aqueous humor. Inhibition of CA-II by dorzolamide suppresses the production of aqueous humor and brings about a reduction in IOP.

Dorzolamide blocks the transformation of carbon dioxide (CO2, a well-known vasodilator) to bicarbonate and therefore, has two beneficial effects. Increased CO2 in the eye improves ocular blood flow and less bicarbonate in the eye reduces aqueous humor production, thus lowering IOP as well.

Dorzolamide is an ampholytic compound (hydrophilic and lipophilic properties) and has high corneal penetration. This ensures adequate drug levels at the site of action. Studies have shown that peak levels are reached in two hours after instillation.

The pharmacokinetic properties of topical dorzolamide have been investigated in vivo in pigmented rabbits. Peak concentrations were recorded as given in Table 1.

Table 1: In vivo pharmacokinetic properties in pigmented rabbits

The high concentration in cornea demonstrates the depot effect achieved by dorzolamide. This effect is presumably responsible for reaching a sufficient concentration in the ciliary epithelium and maintaining it for a long time. The concentration of topical dorzolamide in the retinal tissue may be one reason for its effect on retinal blood flow.

After systemic absorption, dorzolamide is preferentially bound to CA-II in red blood cells (RBC). However, there is virtually no resultant effect on RBCs and other systemic functions. About 25 percent of the drug is bound to plasma proteins.

Dorzolamide is extensively metabolised in the cytochrome P450 system and is excreted through the urinary system. The half-life of dorzolamide in RBCs is 120 days approximately, which raises the question of drug accumulation. Although no such effect is seen in actual usage, this must be considered when monitoring patients on long-term treatment with dorzolamide. The drug should not be used in patients with renal impairment and must be used with caution in patients with hepatic impairment.

Dorzolamide as monotherapy

Clinical trials, using dorzolamide 2% three times a day, in patients with primary open angle glaucoma (POAG) and ocular hypertension (OHT), have shown IOP reduction by 4 to 6 mm at peak drug levels and about 3 to 4.5 mmHg at trough levels. Though there are other drugs with higher degrees of IOP control both at peak and trough, studies show that dorzolamide is almost as effective as beta-blockers (see Figure 1) and probably superior to brimonidine. Dorzolamide would be a good alternative where beta-blockers and brimonidine are contraindicated.

Dorzolamide as an adjunctive

Studies have shown an additional 15 percent reduction in IOP when dorzolamide is used as an adjunct to timolol or betaxolol. When used with latanoprost, there has been an additional reduction of about 20 percent as compared to latanoprost monotherapy. This was much higher than the results obtained when brimonidine was used as an adjunct with latanoprost (Figure 2).

Usage of dorzolamide 2% as an adjunctive to brimonidine in POAG patients brought about a significant additional reduction of about 7 mmHg in IOP.

In place of acetazolamide

Studies have proved that dorzolamide, when substituted for acetazolamide, maintained the IOP-lowering efficacy. In addition, dorzolamide improved the patient's quality of life.

A three-month prospective study conducted in 39 patients showed that within four weeks of switching from oral acetazolamide to dorzolamide, the well-being of glaucoma patients who had systemic CAI-related side effects improved significantly. There was no change in IOP control as given in table 2.

Studies have reported a significant reduction of IOP in normal tension glaucoma (NTG) with elevation of contrast sensitivity (Figure 3). It is not yet clear if the two are related. The drug has been shown to accelerate retinal arteriovenous passage time without changing major arterial or venous diameters. It is not clear if the elevation of contrast sensitivity was because of increased perfusion at the macular and parafoveal areas or because of the reduction in IOP.

A prospective randomised clinical trial studied the effect of systemic acetazolamide, topical dorzolamide and no medication on IOP. The study involved 59 patients undergoing cataract surgery, routine phacoemulsification with IOL.

Four hours after surgery, the mean IOP was higher in all the three groups. The least increase was in the dorzolamide group. The rise was statistically significant in the acetazolamide and control groups
.

Dorzolamide recently received FDA approval for paediatric use based on a 12-week multicentre trial.

Dorzolamide 2% is safe for use in paediatric population below the age of six years for the treatment of increased IOP due to glaucoma or ocular hypertension.

Side effects

Although administered topically, some systemic absorption does take place. Dorzolamide being a sulphonamide, there is a possibility of hypersensitivity reactions like Stevens-Johnson syndrome, TEN (toxic epidermal necrolysis), hepatic necrosis and coma and aplastic anaemia with blood dyscrasias. However, these effects have not been reported in published literatures.

The most common ocular side effect is mild burning and stinging, which is transient in nature.

Since safety and efficacy has not been studied in pregnant and lactating mothers, the drug is best avoided in these situations.

Drug interactions

Drug interactions of dorzolamide have not been studied widely. The risk of electrolyte imbalance should be considered. Caution should be exercised in high dose salicylate therapy.

Indications

Dorzolamide is indicated for use in primary open angle glaucoma or ocular hypertension.

Dosage

Three times a day as monotherapy and two times a day as an adjunctive.

Place in therapy

From all available accounts, timolol continues to be the mainstay of therapy in glaucoma. However, where timolol is contraindicated, dorzolamide could prove to be a valuable substitute. When used in conjunction with timolol, a pressure drop of about 6 mmHg is anticipated. Perhaps, dorzolamide could be an alternative to prostaglandin analogues.

Tachyphylaxis has been reported with timolol and betaxolol but not with dorzolamide. Thus, dorzolamide may be a good alternative to beta blockers in long term therapy. Aphakic glaucoma, where prostaglandins have been reported to induce CME could be a good indication for dorzolamide.

Dorzolamide is an additive to all classes of drugs. It is safe and effective when used in combination with other topical medications. Unlike prostaglandins (except bimatoprost), with dorzolamide there are no problems of cold chain maintenance and of storage at very low temperatures. Hence its use could be more widespread, especially in moderate glaucomas with or without timolol.

As more and more Indian practitioners use dorzolamide, we will have more information about the molecule. Will the drug change the primary approach to glaucoma management? Only time and data will tell...

Mrs. P.G. a 62 year female reported to the OPD with sudden deterioration of vision in the right eye. On taking her history she reported that she had 3 similar episodes in the same eye in the last 2 years. Previous records showed that she had an Inferior temporal branched retinal vein occlusion in right eye which was lasered.

In addition she had an anterior chamber reaction with fine keratic precipitates. A diagnosis of vitreous haemorrhage from a possible neovascularisation was made. An ultrasound of the right eye showed retina to be betached through a vitreous haemorrhage. On measuring IOP her pressure was recorded as 22 mm Hg. She was asked to take total rest with head elevation and use prednisolone acetate eye drops 4 times/day with Glucoptic eye drops 2 times/day. She was asked to report back after 3 weeks. On recording her IOP was found to be 30 mmHg and there was no improvement in her vision. The anterior chamber reaction though was less had a faint trace of reaction. Thinking on the lines of a strong steroid response, prednisolone acetate was cut down to 2 times/day tapered off over the next 3 weeks. Dorzolamide 2% (Dorzox) was started and she was asked to report after 2 weeks. Repeat IOP showed 16 mmHg. Though vision had not improved. A vitreoretinal surgeons opinion was asked for he advised a vitrectomy + endolaser as the haemorrhage had not resolved at all. She eventually underwent the same after about 3 weeks, a weaker steroid (fluorometholone) antibiotic combination was used post-operatively along with dorzolamide and monitored for the next 8 weeks. IOP remained stable between 16-18 mmHg. It was decided to withdrew dorzolamide at this point. She remained stable even after 3 weeks of discontinuing the same and is presently under follow up.

Discussion

Dorzolamide is an effective way of countering steroid response which is quite often a problem dealing with especially in the scenario of the age group most ophthalmologists deal with (with coexistent systemic problems like asthma, cardiac problems etc.).

Dr. Tapas Paul

Kolkata

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