The nonselective beta -blocker timolol and the carbonic anhydrase inhibitor dorzolamide both lower intraocular pressure (IOP), Timolol and dorzolamide have different mechanisms of action and their effects are additive when administered together. Therefore, the 2 drugs are frequently used concomitantly to treat patients with open-angle glaucoma who have not adequately responded to first-line therapy. A barrier to good compliance with concomitant therapy is the need to administer 5 or 6 drops of medication on 2 or 4 occasions during the day. Timolol 0.5% and dorzolamide 2.0% have therefore been combined in a single formulation, reducing the number of administrations required to 2 per day. Clinical trials in patients with glaucoma have demonstrated that dorzolamide 2%/timolol 0.5% (dorzolamide/timolol) is superior to monotherapy with the individual components. When dorzolamide/timolol administered twice daily was compared with concomitant treatment with dorzolamide 2% and timolol 0.5%, each administered twice daily for 90 days, both regimens resulted in marked lowering of trough IOP (measured just before the morning dose) compared with baseline (reduction in IOP = 4.2mm Hg). The effect of the 2 regimens on IOP at all time points, both before treatment and at peak effect (2 hours after treatment), were virtually indistinguishable. When the combined formulation was compared with a concomitant regimen that included dorzolamide 2% 3 times daily and timolol 0.5% twice daily the concomitant regimen was slightly more efficacious than the combined regimen at trough after 90 days: IOP was lowered by 3.6mm Hg in the combined group versus 4,lmm Hg in the concomitant group. Dorzolamide/timolol has been compared with concomitant administration of timolol 0.5% and the IOP lowering miotic drug, pilocarpine 2.0%. This non-blind patient-preference study found that both regimens reduced IOP. However, the dorzolamide/timolol combination was preferred by the patients because of reduced frequency and severity of adverse effects and less frequent administration. Dorzolamide/timolol was well tolerated in clinical trials, the adverse effects reflected those of the individual components, and no additional tolerability issues were identified. However, the potential for timolol to cause cardiorespiratory effects must be considered when prescribing this combination. Furthermore, dorzolamide is a sulfonamide and can cause allergic reactions in those who are hypersensitive to this class of drug. Conclusions: Dorzolamide/timolol is a well tolerated and effective fixed combination for lowering IOP in the treatment of open-angle glaucoma and is likely to be useful in those patients who do not respond adequately to first-line monotherapy. Compared with concomitant therapy with the same 2 drugs the primary advantage is convenience, which may lead to improved compliance. Studies of compliance and comparisons with other currently available combination therapies would be useful to fully define the value of the formulation. Nonetheless, dorzolamide combined with timolol in a single applicator system will be a useful addition to the treatment options for glaucoma, a leading cause of preventable blindness. Dorzolamide is a sulfonamide and a carbonic anhydrase (CA) inhibitor while timolol is a nonselective beta -blocker. As there is no direct interaction between the 2 drugs, their pharmacodynamics will be considered independently. Timolol is a nonselective beta -blocker which has no local anaesthetic, membrane stabilising or sympathomimetic properties. However, the precise mechanism by which timolol lowers intraocular pressure (IOP) is not known. Timolol lowers IOP by inhibiting aqueous humour production rather than by increasing outflow of aqueous humour and it has been suggested that timolol down-regulates adenylate cyclase by inhibiting beta (2)-adrenoceptor sites at the ciliary process. Dose-response studies in volunteers showed that timolol 0.5 to 1.5% significantly reduced IOP by up to 28% 2 to 5 hours after drug administration. Topically instilled timolol is absorbed systemically and statistically significant decreases in resting heart rate have been reported after a year or more of treatment with timolol. Slight decreases in blood pressure have also been noted. Dorzolamide is a highly selective inhibitor of CA-II, an isoenzyme present on the ciliary process in the eye. Inhibition of CA-II slows local bicarbonate production, decreases sodium and fluid transport and, consequently, decreases aqueous humour production and lowers IOP. Reduction of IOP has been demonstrated after topical administration of dorzolamide to the eyes of healthy volunteers and patients with open-angle glaucoma or ocular hypertension. Topically applied dorzolamide can enter the systemic circulation: CA-II activity in erythrocytes of patients with glaucoma was reduced to 12% of baseline after treatment with dorzolamide 2% for 12 months. However, research suggests that <1% of CA-II activity is required to maintain physiological function. There is emerging evidence that, in addition to inhibiting production of aqueous humour, dorzolamide may also improve intraocular blood flow. Timolol is absorbed systemically after topical ocular administration. In 6 patients, the mean peak plasma concentration of timolol after twice daily topical administration of a 0.5% solution was 0.46 <mu>g/L after the morning dose, and 0.35 mg/L after the afternoon dose. In rabbits, peak concentrations after topical ocular administration of timolol 0.5% were 13-fold higher in aqueous humour than in plasma. After oral (0.1 to 0.4 mg/kg) or intravenous (0.02 mg/kg) administration of timolol to healthy volunteers, the apparent volume of distribution of the drug was 1.3 to 1.7 L/kg. After topical ocular administration of timolol 0.5% (2 drops in each eye) in 11 volunteers, 5 to 46% of the calculated absorbed dose was excreted renally over 24 hours. After an oral dose in volunteers, elimination was primarily renal (73% in 3 days); only 6.4% was excreted in faeces. Dorzolamide is absorbed systemically after topical ocular administration. However, in healthy volunteers, plasma concentrations of dorzolamide remained below detection levels (5 mug/L) after either a single dose of 3 drops of dorzolamide 2% or after instillation 4 times daily of 1 drop of dorzolamide 3% for 14 days; both treatments to both eyes. However, in another study a mean plasma concentration of 11 mug/L was reported after 6-month therapy of dorzolamide 2% 1 drop 3 times daily in 4 patients with glaucoma. After systemic absorption, dorzolamide is preferentially taken up by erythrocytes as a result of binding to CA-II. The mean erythrocyte concentration of the drug in 56 patients with glaucoma or ocular hypertension were 20.5 mu mol/L after 12 months' treatment with dorzolamide 2% eye drops 3 times daily. Approximately 24 to 32% of systemically absorbed dorzolamide is bound to plasma proteins. In rat liver microsomes dorzolamide is hepatically metabolised to N-desethyl-dorzolamide by the cytochrome P450 system. N-desethyldorzolamide inhibits CA-II less effectively than the parent drug, but also inhibits CA-I (also present on erythrocytes). Systemically absorbed dorzolamide is primarily excreted in the urine. Both dorzolamide and its metabolite were identified in the urine of patients who had received topical ocular dorzolamide 2% 3 times daily for 28 days (mean 140 and 18 mug, respectively, over 8 hours). The terminal elimination half-life of dorzolamide in erythrocytes is greater than or equal to 120 days, so there is potential for systemic accumulation during long term administration. However, in patients with glaucoma treated with dorzolamide 2% 3 times daily, plasma concentrations after 12 months were similar to those after 6 months (approximate to 20 mu mol/L). Large, double-blind, randomised multicentre trials in patients with open-angle glaucoma or ocular hypertension have shown that dorzolamide 2%/timolol 0.5% (dorzolamide/timolol) is superior to monotherapy with the individual components, and equivalent to therapy with dorzolamide 2% and timolol 0.5% given concomitantly. When dorzolamide/timolol administered twice daily was compared with concomitant timolol 0.5% and dorzolamide 2.0%, each administered twice daily, both regimens resulted in marked lowering of trough IOP (measured just before the morning dose) compared with baseline after 90 days of treatment (change in IOP = 4.2mm Hg). The effect of the 2 regimens on IOP at all time points, both before and 2 hours after treatment (peak effect), were virtually indistinguishable. When the combined formulation was compared with a concomitant regimen of twice daily timolol and 3 times daily dorzolamide, the concomitant regimen was slightly more efficacious than the combined regimen at the trough measurement after 90 days: IOP was lowered by 3.6mm Hg in the combined group versus 4.1mm Hg in the concomitant group. A 9-month open-label extension of this study, where all patients received combined dorzolamide/timolol therapy showed that reductions in IOP seen with dorzolamide/timolol at the end of the double-blind phase were maintained for up to 1 year. Although no direct comparisons of combined ocular hypotensive medications have been carried out, the dorzolamide/timolol combination has been compared with concomitant timolol 0.5% and pilocarpine 2.0%. This non-blind patient-preference study found that both regimens resulted in a similar lowering of IOP. However, the dorzolamide/timolol combination was better tolerated and preferred by the patients because of reduced frequency and severity of adverse effects and the need for less frequent administration. Dorzolamide/timolol was well tolerated in clinical trials and adverse effects were generally localised. However, both drugs are absorbed systemically, and systemic effects can also occur. The tolerability profile of dorzolamide/timolol reflects that of the individual components. In clinical trials, the most common adverse effects were those relating to the eye and taste. In 1 study burning and/or stinging in the eye was the most frequently reported ocular adverse effect in patients using dorzolamide/timolol and eyelid pain or discomfort occurred in 6% of dorzolamide/timolol-treated patients Versus 1% of those on concomitant therapy. Taste perversion was a common local adverse effect in patients receiving combined therapy. A number of instances of irreversible corneal decompensation have been reported in dorzolamide-treated patients with pre-existing corneal abnormalities or those who have undergone corneal transplant, and caution is advised when dorzolamide is prescribed to patients with compromised corneas. No systemic adverse effects that might have been associated with the beta -blocking properties of timolol were reported in clinical trials of dorzolamide/timolol. However, patients with cardiorespiratory disease were excluded from these trials and shortness of breath and respiratory failure have been reported in patients using dorzolamide and timolol concomitantly. Therefore, physicians and patients need to be alert to the possibility of systemic adverse effects developing during therapy with this preparation. Headache and nausea reported in patients receiving combined therapy are likely to have been associated with dorzolamide. Also, dorzolamide is a sulfonamide derivative and, in common with most carbonic anhydrase inhibitors, has the potential to cause hypersensitivity. For the treatment of glaucoma or ocular hypertension, the dose of dorzolamide/timolol is 1 drop twice daily in the affected eye. If additional topical ophthalmic formulations are being used, they should be administered 10 minutes apart. Dorzolamide/timolol should be used with caution in those with hepatic insufficiency and is not recommended in patients with severe renal impairment. Dorzolamide/timolol is contraindicated in patients with a history of bronchial asthma, severe obstructive pulmonary disease, cardiac failure, sinus bradycardia, atrioventricular block or cardiogenic shock. The formulation should not be used in patients with known hypersensitivity to either of the components (e.g. sensitivity to sulfonamide).
