Dorzolamide, Timolol

Pharmacological properties

The composition of the drug includes two active substances: dorzolamide hydrochloride and timolol maleate. each of these components reduces increased intraocular pressure by reducing the secretion of intraocular fluid, but due to a different mechanism of action.

Dorzolamide hydrochloride is a potent type II carbonic anhydrase inhibitor. Inhibition of the carbonic anhydrase of the miliary body leads to a decrease in the secretion of intraocular fluid by slowing the formation of bicarbonate ions, which, in turn, leads to a decrease in sodium and fluid transport.

Timolol maleate is a non-selective beta-adrenergic receptor blocker. The exact mechanism of action of timolol, which manifests itself in a decrease in intraocular pressure, is still unknown. Fluorimetric and tonographic studies indicate that the effect of timolol is due to a decrease in the secretion of humoral fluid. In addition, timolol can enhance the outflow of moisture.

The combination of the actions of the two components leads to a more pronounced decrease in intraocular pressure than monotherapy with these drugs.

After topical application, Dorzitim reduces intraocular pressure, regardless of whether its increase is associated with glaucoma. Elevated intraocular pressure plays a significant role in the pathogenesis of damage to the optic nerve and the loss of visual fields in glaucoma.

Dorzitim reduces intraocular pressure without the development of side effects characteristic of miotic agents, such as night blindness, accommodation spasm, pupil constriction.

Pharmacokinetics Dorzolamide hydrochloride. When applied topically, dorzolamide enters the systemic circulation. With prolonged use, dorzolamide accumulates in red blood cells as a result of binding to type II carbonic anhydrase, maintaining very low concentrations of free drug in blood plasma. Due to metabolism, dorzolamide forms the only N-desetyl metabolite that blocks block II carbonic anhydrase less pronounced compared to its original form, but also inhibits type I carbonic anhydrase - a less active isoenzyme. The metabolite also accumulates in red blood cells, where it binds predominantly to type I carbonic anhydrase. Approximately 33% of dorzolamide binds to plasma proteins. Dorzolamide is excreted unchanged in the urine and as a metabolite. After discontinuation of the drug, dorzolamide is derived nonlinearly from red blood cells, characterized by an initial rapid decrease in concentration and the subsequent phase of slow elimination with T_½ about 4 months

Timolol maleate. After topical administration, timolol is absorbed systemically. The systemic exposure of timolol was determined after topical administration of an ophthalmic 0.5% solution 2 times a day. C_max in the blood plasma after applying the morning dose was 0.46 ng / ml, and after applying the evening dose - 0.35 ng / ml.

Indications

Increased intraocular pressure in patients with open-angle glaucoma or pseudoexfoliation glaucoma, when topical use of beta-adrenoreceptor blockers alone is insufficient.

Application

Dorzitim is prescribed 1 drop in the conjunctival sac 2 times a day.

1. Before the first use of the drug, make sure that the cap is not damaged.

2. To open the bottle, unscrew the cap by turning it counterclockwise.

3. Tilt your head back and pull the lower eyelid down for the appearance of space between the eyelid and the eye.

4. Turn the bottle upside down and gently press the thumb and forefinger on the walls of the bottle until one drop falls into the space between the eyelid and the eye.

Do not touch the surface of the eyes or eyelids with the tip of the vial.

If used improperly, the vial can become infected and cause serious infectious damage to the eyes, followed by loss of vision.

5. Repeat steps 3 and 4 for both eyes, if prescribed by your doctor.

6. Close the bottle cap, tighten it tightly. Do not press the cap very hard, as this could damage the bottle or cap.

The drug can be used for a long time. It is known that in patients after initial stabilization of intraocular pressure there were no significant changes in the average pressure indicator, which would indicate a decrease in sensitivity to the drug.

Contraindications

Hypersensitivity to one or both active substances or to any of the auxiliary components of the drug; respiratory tract diseases, including BA and severe hobl; sinus bradycardia, degree II or III ventricular block, severe heart failure, cardiogenic shock; severe renal impairment (creatinine clearance 30 ml / min) or hyperchloremic acidosis; pregnancy and lactation, childrens age.

Side effects

From the musculoskeletal system and connective tissue: timolol maleate, eye drops: systemic lupus erythematosus.

From the nervous system: dorzolamide hydrochloride, eye drops: headache *; dizziness *, paresthesia *; timolol maleate, eye drops: headache *; dizziness *, depression *; insomnia *, nightmares *, memory loss, paresthesia *, increased symptoms of myasthenia gravis, weakening libido *, stroke *.

From the side of the organ of vision: Dorzitim: burning and tingling; conjunctival injection, blurred vision, erosion of the cornea, sensation of itching in the eye, lacrimation; dorzolamide hydrochloride, eye drops: inflammation of the eyelids *, irritation of the eyelids *; iridocyclitis *; eye irritation, including redness *, eye pain *, peeling of the eyelids *, temporary myopia (disappears after discontinuation of treatment), corneal edema *, decreased eye pressure *, detachment of the choroid (followed by filtering operation) *; timolol maleate, eye drops: symptoms of eye irritation, including blepharitis *, keratitis *, decreased sensitivity of the cornea, dry eye mucosa *; visual impairment, including changes in refraction (in some cases, due to the cancellation of myotic agents) *; ptosis, diplopia, choroid detachment of the eye (followed by filtering operation) *.

On the part of the hearing organ: timolol maleate, eye drops: ringing in the ears *.

From the cardiovascular system: timolol maleate, eye drops: bradycardia *, syncope *; arterial hypotension *, chest pain *, palpitation *, edema *, arrhythmia *, congestive heart failure *, heart block *, cardiac arrest *, cerebral ischemia, intermittent claudication, Raynauds phenomenon *, sensation of coldness in the hands and feet * .

From the respiratory system, chest and mediastinal organs: Dorzitim: sinusitis; shortness of breath, respiratory failure, rhinitis; dorzolamide hydrochloride, ophthalmic drops: nosebleeds *; timolol maleate, eye drops: shortness of breath *; bronchospasm (mainly in patients with an existing bronchospastic disease) *, cough *.

From the alimentary system: Dorzitim: change in taste; dorzolamide hydrochloride, ophthalmic drops: nausea *; irritation in the throat, dry mouth *; timolol maleate, eye drops: nausea *, dyspepsia *; diarrhea, dry mouth *.

On the part of the skin: Dorzitim: contact dermatitis; dorzolamide hydrochloride, eye drops: rash *; timolol maleate, eye drops: alopecia *, psoriatic rash or exacerbation of psoriasis *.

From the kidneys and urinary tract: Dorzitim: urolithiasis.

From the reproductive system and mammary glands: timolol maleate, eye drops: Peyronies disease *.

Violations of the general condition and violations associated with the method of use of the drug. Dorzitim: symptoms of allergic reactions, including angioedema, urticaria, pruritus, rash, anaphylaxis, bronchospasm; dorzolamide hydrochloride, ophthalmic drops: asthenia / weakness *.

* Adverse reactions, which were also observed with the use of Dorzitim.

Laboratory indicators. The use of the drug was not accompanied by significant disturbances in the electrolyte balance.

special instructions

Before using the medicine, wash your hands thoroughly.

Reactions from the cardiovascular and respiratory system. Like other topical preparations, Dorzitim can be absorbed systemically. Since timolol is a beta-adrenergic receptor blocker, the development of adverse reactions that occur with the systemic use of such drugs, including worsening of Prinzmetals angina pectoris, severe central and peripheral circulation disorders, and also arterial hypotension, is possible. In case of heart failure, it is necessary to conduct appropriate monitoring before prescribing the drug Dorzitim. Patients with a history of severe heart disease should be observed regarding the onset of symptoms of heart failure, and heart rate should be checked. The development of reactions from the respiratory system and the heart, including death due to bronchospasm and rarely death due to heart failure, after the use of timolol maleate, has been reported.

Impaired liver function. Since there is no data on the use of the drug in patients with impaired liver function, a drug should be prescribed with caution.

Immunological reactions and hypersensitivity reactions. Like other topical drugs, Dorzitim can be absorbed systemically. Dorzolamide, like sulfonamides, contains a sulfonamide group, so it is possible to develop adverse reactions that are observed with the systemic use of sulfonamide drugs. If signs of serious reactions or hypersensitivity reactions appear, discontinue use of the drug.

When using the drug, local side reactions from the organ of vision were observed, which are similar to reactions with the use of dorzolamide hydrochloride. With the development of such reactions, consideration should be given to the abolition of Dorzitim.

Patients with an atopy or anaphylactic history of multiple allergens with a history of beta-adrenergic blockers may be more sensitive to such allergens in case of accidental, diagnostic or therapeutic repeated contact. For such patients, the usual dose of epinephrine to eliminate allergic reactions may be ineffective.

Discontinuation of treatment. As with the use of systemic beta-adrenergic blockers, the use of ophthalmic timolol should be gradually discontinued if it is necessary to discontinue the drug in patients with coronary artery disease.

Additional effects of beta-adrenergic blockers. The use of beta-adrenoreceptor blockers can mask certain symptoms of hypoglycemia in patients with diabetes mellitus or hypoglycemia, as well as symptoms of hyperthyroidism. The sudden cessation of beta-adrenergic blockers can lead to worsening symptoms. Treatment with beta-adrenergic blockers can exacerbate the symptoms of myasthenia gravis.

Additional effects of inhibition of carbonic anhydrase.The use of carbonic anhydrase inhibitors is associated with the development of urolithiasis as a result of violations of the acid-base balance, especially in patients with a history of urolithiasis. Although violations of the acid-base balance were not observed with the use of Dorzitim, the development of urolithiasis was rarely reported. Since a carbonic anhydrase inhibitor is systemically absorbed when applied topically, patients with a history of urolithiasis may have a higher risk of developing urolithiasis when using the drug Dorzitim.

Other features. The treatment of patients with acute open-angle glaucoma requires the use of other therapeutic agents in addition to drugs that reduce eye pressure.

The use of the drug Dorzitim in patients with acute open-angle glaucoma has not been studied.

With the use of dorzolamide, the appearance of corneal edema and irreversible decompensation of corneal diseases in patients with pre-existing chronic corneal pathologies and / or an intraocular surgical history was reported. Topical dorzolamide should be prescribed with caution in these patients.

The development of choroid detachment, which was accompanied by ocular hypotension, was reported after filtration procedures with the appointment of treatment with water suppressants.

The use of contact lenses. The composition of the drug includes benzalkonium chloride, which can cause eye irritation. Contact lenses should be removed before instillation of the drug and put on at least 15 minutes after application of the drug. It is known that benzalkonium chloride can change the color of soft contact lenses.

As with other anti-glaucoma drugs, a decrease in sensitivity to timolol maleate for topical administration with long-term treatment has been reported. It is known that in patients there was no significant difference in the average intraocular pressure after initial pressure stabilization.

Use during pregnancy and lactation. The drug is not used during pregnancy.

It is not known whether dorzolamide is excreted in breast milk. Timolol is secreted in breast milk. Therefore, for the period of treatment should stop breast-feeding.

Children. Do not use.

The ability to influence the reaction rate when driving vehicles or other mechanisms. Studies of the effect of the drug on the ability to drive vehicles or work with other mechanisms have not been conducted. However, given the above adverse reactions, one should refrain from driving vehicles and working with other mechanisms.

Interactions

In the case of concomitant use of other local ophthalmic medicines, dorzitim must be used with an interval of at least 10 minutes.

Special studies of the interaction of Dorzitim and other drugs have not been conducted. There were no interactions with the simultaneous use of the drug Dorzitim and other groups of systemic drugs: ACE inhibitors, calcium channel blockers, diuretics, NSAIDs (including acetylsalicylic acid) and hormones (estrogens, insulin, thyroxine).

However, there is the possibility of additional effects and arterial hypotension and / or severe bradycardia with the simultaneous use of timolol maleate with calcium channel blockers for oral use, drugs that reduce the production of catecholamine, or beta-adrenergic receptor blockers, antiarrhythmic drugs (including amiodarone), digitalis glycosides, parasympathomimetics, narcotic drugs and MAO inhibitors.

With the simultaneous use of CYP 2D6 inhibitors (for example, quinidine selective serotonin reuptake inhibitors) and timolol, potentiation of systemic beta blockade (decreased heart rate, depression) was reported.

Although Dorzitim as a monotherapy has little effect on the size of the pupil of the eye, mydriasis has sometimes been reported due to the simultaneous use of timolol maleate and local epinephrine (epinephrine).

Beta-adrenoreceptor blockers may enhance the hypoglycemic effects of antidiabetic drugs.

Beta-adrenergic blockers for oral administration can provoke the development of rebound hypertension with the abolition of clonidine.

Overdose

With an overdose of timolol, systemic effects of an overdose of beta-adrenergic blockers of systemic use are possible: dizziness, headache, shortness of breath, bradycardia, bronchospasm and cardiac arrest. the most expected symptoms of an overdose of dorzolamide are electrolyte imbalance, acidosis and a possible effect on the central nervous system.

There is limited evidence regarding an accidental or intentional overdose of dorzolamide hydrochloride. Drowsiness after oral administration has been reported. When applied topically, nausea, dizziness, headache, weakness, unusual dreams, dysphagia were noted.

Treatment: symptomatic and supportive. Monitoring plasma electrolytes (mainly potassium) and blood pH. Timolol is not completely excreted during dialysis.

Storage conditions

In the original packaging at a temperature not exceeding 25 ° C.