Timolol

Pharmacological properties

timolol is a non-selective β-adrenergic receptor blocker that does not exert a sympathomimetic or local anesthetic (membrane-stabilizing) effect. timolol inhibits β1 receptors, which are localized mainly in the heart muscle, as well as β2 receptors.

Timolol reduces the stimulating effect of catecholamines on the heart. As a result, the conductivity of the AV node slows down, heart rate and cardiac output decrease. The blockade of β-adrenergic receptors in the bronchi and bronchioles leads to an increase in airway resistance due to the lack of counteraction for parasympathetic activity.

Local action on the eyes. Arutimol eye drops reduce both elevated and normal intraocular pressure.

The exact mechanism of action of timolol, which manifests itself in a decrease in intraocular pressure, is unknown. However, fluorophotometric and tonographic studies indicate that the effect of timolol may be due to a decrease in the secretion of aqueous humor. Some studies have also shown an improvement in the outflow of aqueous humor. In some patients, after prolonged treatment, a decrease in sensitivity to timolol, as well as to other drugs that reduce intraocular pressure, was noted. Long-term studies involving 164 patients, studied for at least 3 years, showed that after achieving stabilization of intraocular pressure, no serious changes occurred. Unlike miotic agents, timolol reduces intraocular pressure without affecting the accommodation and pupil size. The absence of myosis is especially important for patients with cataracts. In the case of the patients transition from the use of miotic agents to timolol, it is necessary to carry out a correction of refraction after a decrease in myotic effect.

Pharmacokinetics The action of the drug occurs, as a rule, 20 minutes after topical administration, reaches its maximum in about 1-2 hours. The effect lasts up to 24 hours. The level of concentration of timolol in the 1st and 2nd hours after the introduction of 2 drops of timolol 0, 5% is 150 ng / 100 mg. After 7 hours, the concentration level decreased to 10 ng / 100 mg.

Radioactivity equivalent to 1–10 ng of timolol / 100 mg of tissue was recorded in the cornea, third century, iris / ciliary body.

Systemic absorption: studies have shown that timolol is absorbed after topical application to the eye. Studies have shown that timolol was detected in the urea of ​​all healthy volunteers and patients. (Timolol maleate and its metabolites are excreted mainly by the kidneys).

Blood level: the concentration of timolol in blood plasma after topical application in recommended clinical doses is often impossible to determine (less than 2 ng / ml), and not after a single dose, or after a 2-week treatment.

WITH_max in the blood plasma after applying 2 drops 2 times a day was 9.6 ng / ml. This was noted 30–90 min after application.

Indications

Increased intraocular pressure (ocular hypertension); glaucoma (chronic open-angle glaucoma); glaucoma after lens removal (glaucoma with aphakia).

Application

Bury 1 drop of arutimol 0.25% solution in the affected eye (s) 2 times a day. if the result is unsatisfactory, apply 0.5% rr.

If intraocular pressure with regular use is set at the desired level, the dose can be reduced to 1 drop of 0.25% solution or, respectively, 0.5% solution once a day. When using contact lenses, you must remove them before using Arutimol. You can put them on again no earlier than after 15 minutes.

The bottle is air and waterproof. From above, it is not tightly closed with a cap. Before first use, close the cap tightly by turning it clockwise so that the spike in the cap pierces the dropper of the vial.Then turn the cap counterclockwise.

Arutimol, eye drops, are instilled into the conjunctival sac of the eye. To do this, tilt your head back, look up and slightly pull the lower eyelid from the eye. The bottle should be kept with the hole down. By clicking on the bottle, drop the eye drops into the conjunctiva of the lower eyelid. The opening of the droplet vial should not come in contact with the eye. Immediately after using the drug, the following actions should be performed: close the eyelids and lightly press a finger on the inner corner of the eye (near the nose) for 1-2 minutes to prevent the solution from entering the lacrimal tubules and, thus, reduce the possible systemic side effect of the drug.

After use, close the vial. Drops with an open bottle should not be used for longer than 6 weeks after opening.

As a rule, treatment with Arutimol gives results after a rather long period of use. Interruption of the course or change in dosage is permissible only on the recommendation of a doctor. In case of missing the drug, it is necessary to instill the next dose, as soon as they remembered the need to use the drug. Do not double the next dose.

Contraindications

The use of arutimol, eye drops, is contraindicated in the presence of the following diseases: bronchial hypersensitivity; history of ba or ba; heavy hobble; sinus bradycardia, av blockade of the II and III degrees; heart failure; cardiogenic shock.

Arutimol, eye drops, should also not be prescribed for hypersensitivity to any of the components of the drug, severe allergic rhinitis or dystrophic disorders of the cornea. The simultaneous administration of local β-adrenoreceptor blockers, such as timolol, as well as oral or intravenous preparations of calcium antagonists in patients with heart failure should be avoided, as it may impair AV conduction, left-sided heart failure and arterial hypotension.

Timolol eye drops are not recommended for the treatment of patients who have an increase in eye pressure at night.

Side effects

When using timolol, the following adverse reactions are possible:

Disorders of a general nature and conditions associated with the injection site: headache, asthenia, chest pain.

From the cardiovascular system: bradycardia, arrhythmia, arterial hypotension, syncope, heart block, stroke, cerebral vascular ischemia, congestive heart failure, tachycardia, cardiac arrest.

From the digestive system: diarrhea, nausea.

From the nervous system: dizziness, increased objective and subjective symptoms of myasthenia gravis, paresthesia.

Mental disorders: depression.

On the part of the skin and subcutaneous tissues: hypersensitivity, including generalized and localized rash, urticaria, alopecia.

From the respiratory tract, thoracic and mediastinal disorders: bronchospasm (especially in patients with pre-existing lung diseases), respiratory failure, shortness of breath, nasal congestion, cough.

Endocrine disorders: latent symptoms of hypoglycemia in patients with insulin-dependent diabetes mellitus.

Ophthalmic disorders: objective and subjective symptoms of eye irritation, including conjunctivitis, blepharitis, keratitis, blepharoptosis, decreased sensitivity of the cornea, visual impairment, including changes in refraction (in some cases due to discontinuation of therapy with the use of miotic agents), dry eyes, diplopia, ptosis .

The following are adverse reactions that have been reported, but a causal relationship with the use of timolol has not been established.

Disorders of a general nature and condition associated with the injection site: increased fatigue.

From the cardiovascular system: AH, pulmonary edema, angina pectoris.

From the digestive system: dyspepsia, anorexia, dry mouth.

Disorders of the nervous system / mental disorders: behavioral disorders, including confusion, hallucinations, anxiety, disorientation, agitation, drowsiness, and other mental disorders.

Ophthalmic disorders: cystoid macular edema.

From the urinary system: retroperitoneal fibrosis, impotence.

The following adverse reactions have been reported in clinical practice with the oral administration of timolol maleate, and may occur with the ophthalmic use of timolol maleate.

Disorders of a general nature and condition associated with the injection site: pain in the limbs, decreased level of physical activity, decreased body weight.

From the cardiovascular system: edema, worsening of the course of arterial insufficiency, Raynauds disease, vasodilation.

From the digestive system: pain in the stomach or intestines, hepatomegaly, vomiting.

On the part of the blood and lymphatic system: purpura.

Endocrine disorders: hyperglycemia, hypoglycemia.

On the part of the skin and subcutaneous tissues: itching, skin irritation, increased pigmentation, sweating, cooling of the extremities.

From the musculoskeletal system and connective tissue: arthralgia, lameness.

From the side of the nervous system / mental disorders: dizziness, weakness, decreased sex drive, nightmares, insomnia, decreased concentration.

From the respiratory tract, thoracic and mediastinal disorders: wheezing, bronchial obstruction.

From the side of the hearing organ: tinnitus.

From the kidneys and urinary tract: difficulty urinating.

Possible adverse reactions

The following adverse reactions were recorded with the use of other β-adrenergic receptor blockers and can occur with the ophthalmic use of timolol maleate.

From the digestive system: mesenteric arterial thrombosis, ischemic colitis.

On the part of the blood and lymphatic system: agranulocytosis, thrombocytopenic purpura.

From the side of the nervous system: reversible depression, which progresses to catatonia; acute reversible syndrome, characterized by disorientation in time and space, short-term memory loss, emotional lability, slight clouding of consciousness and reduced neuropsychometry.

On the part of the immune system: erythematous rash, fever, which is accompanied by pain and inflammation of the throat, laryngospasm with respiratory failure.

From the urinary system: Peyronies disease.

There have been reports of a syndrome including a psoriasis-like rash on the skin, dry conjunctivitis, otitis media and sclerosing serositis associated with the use of β-adrenoreceptor blockers, praktolol. The occurrence of this syndrome with the use of timolol maleate was not reported.

special instructions

Topical β-adrenoreceptor blockers can be systemically absorbed. Thus, with topical application of the drug, the same adverse reactions are possible as with systemic use of β-adrenergic receptor blockers. for example, after the use of timolol, serious reactions were reported from the respiratory and cardiovascular systems, including fatal cases as a result of bronchospasm in patients with BA and rarely due to heart failure.

It has been reported that β-adrenoreceptor blockers can cause muscle weakness, which is associated with certain symptoms of myasthenia gravis (e.g. diplopia, ptosis, and general weakness). There have also been occasional reports that timolol causes muscle weakness in some patients with gravis myasthenia gravis or with symptoms of myasthenia gravis.

The main problem of treatment in patients with angle-closure glaucoma is the need to open the corner. To do this, narrow the pupil with the help of miotic agents, timolol practically does not affect the pupil.

If timolol is used to reduce elevated intraocular pressure in angle-closure glaucoma, it should be used with miotics. As with the use of other antiglaucoma drugs, some patients noted a decrease in sensitivity to timolol after prolonged therapy.

Before general anesthesia, the use of β-adrenergic receptor blockers should be gradually discontinued, since they reduce the ability of the heart to respond to stimulation of the β-adrenergic receptors of the sympathetic system.

If additionally using other ophthalmic means, it is necessary to wait 15 minutes between their use.

Risk of anaphylactic reactions: patients with atopy or with severe pathological reactions to numerous allergens in history can react more acutely to repeated random diagnostic or therapeutic doses of these allergens if they took β-adrenergic receptor blockers. Such patients may not respond to the usual dose of adrenaline, which is prescribed in case of anaphylactic reactions.

During treatment with Arutimol, regular measurements of intraocular pressure and examination of the cornea should be carried out regularly.

After surgical treatment of glaucoma and with the use of drugs that reduce the secretion of intraocular moisture, cases of detachment of the choroid of the eye were noted. Such cases have been described with timolol and acetazolamide.

Due to the possible effect of β-adrenergic receptor blockers on blood pressure and heart rate, these agents should be used with caution in patients with cerebrovascular insufficiency. If after the start of therapy with timolol signs or symptoms of decreased cerebral circulation develop, an alternative type of therapy should be used.

When using the drug Arutimol, eye drops, a positive result can be detected with doping control.

Benzalkonium chloride may cause eye irritation. Therefore, contact with soft contact lenses should be avoided. Benzalkonium chloride can cause discoloration of soft contact lenses. Contact lenses must be removed before instillation and put on again no earlier than after 15 minutes. It should be noted that with stabilization of intraocular pressure, its initial decrease can be up to 50%, after which the effectiveness of the drug may decrease (tachyphylaxis). In the period from the 3rd to the 12th month, the pressure drop stabilizes. Therefore, it is important to carry out regular monitoring of pressure during the first 5 days after the use of timolol eye drops.

When using β-adrenoreceptor blockers orally, a decrease in intraocular pressure is possible. In this case, the further need for topical application of timolol eye drops should be considered. If β-adrenergic blockers have already been used systemically, the additional effect of topical preparations is usually lower. Regular monitoring of patients who are additionally using oral β-adrenergic receptor blockers, or for whom the use of β-adrenergic receptor blockers is limited, should be carried out regularly.

Patients should not use two local ophthalmic β-adrenergic receptor blockers at the same time.

In patients with significantly pigmented iris, a decrease in pressure may be noted late and to a lesser extent.

After discontinuation of treatment, the effect of the drug may continue for several days. If treatment with timolol, eye drops, is discontinued after prolonged use, its action to reduce intraocular pressure can last 2–4 weeks.

When instilled in only one eye, β-adrenoreceptor blockers can have an effect on reducing intraocular pressure on the untreated eye.

During pregnancy and breastfeeding. Any data from clinical studies on the use of the drug in pregnant women are not available. Arutimol, eye drops, should not be used during pregnancy and lactation.

The use of the drug before childbirth can lead, like with other β-adrenoreceptor blockers, to bradycardia, hypoglycemia and respiratory depression (neonatal asphyxia) in the newborn. For other β-adrenergic blockers, cases of β-blockade have been described. For this reason, continuous monitoring of the condition of newborns during the first few days of their life should be carried out.

After instillation in the eye, timolol passes into breast milk, where it can accumulate in higher concentrations than in blood plasma. Although the amount of active ingredient that is thus obtained in breast milk probably does not pose a risk to infants, a qualitative examination is necessary to identify the symptoms of β-blockade.

Children. The effectiveness and safety of the drug in children have not been established.

The ability to influence the reaction rate when driving vehicles or working with mechanisms. Even with proper use, Arutimol can affect vision, and also worsen the reaction rate to such an extent that it can affect the ability to drive vehicles or work with mechanisms.

Interactions

With the simultaneous use of eye drops containing adrenaline, the expansion of the pupil is possible. the combined use of eye drops containing adrenaline or pilocarpine enhances the effect of timolol in relation to reducing intraocular pressure.

With the simultaneous use of β-adrenoreceptor blockers, it is possible to strengthen both local (decrease in intraocular pressure) and systemic effects (effect on the cardiovascular system). If Arutimol eye drops are used simultaneously with antihypertensive or other cardiological agents (for example, calcium antagonists, reserpine, β-adrenergic blockers), the risk of developing arterial hypotension and bradycardia is increased.

Neuromuscular blockade caused by tubocurarine can be enhanced by the action of a β-adrenergic receptor blocker.

The severity of cardiodepressive action can increase in the case of the simultaneous use of antiarrhythmic drugs with quinidine-like action.

Negative chronotropic and dromotropic effects may be enhanced in case of combined use of cardiac glycosides.

With the simultaneous use of β-adrenergic receptor blockers and β₂-sympathomimetics, the effect of the latter may decrease and bronchospasm may occur.

The combined use of insulin or other antidiabetic drugs, especially against the background of stress or physical exertion (hypoglycemia), can cause or increase the severity of latent hypoglycemia.

Overdose

Subject to the dosage and application regimen, the possibility of toxic side effects is practically excluded.

Symptoms: a marked decrease in blood pressure, the development of heart failure, cardiogenic shock, severe bradycardia, up to cardiac arrest. In addition, respiratory dysfunction, bronchospasm, gastrointestinal disturbances, confusion and convulsions may occur.

Treatment: in conditions of intensive medical care, in addition to general therapy, monitoring of vital signs should be carried out. In case of an overdose, the following antidotes are prescribed:

• atropine oxide: 0.5–2 mg iv;
• glucagon: first 1–10 mg iv, then 2–2.5 mg every hour as a prolonged infusion;
• β-sympathomimetics depending on body weight and effect: dobutamine, isoprenaline, orciprenaline or epinephrine.

With resistant bradycardia, treatment with a pacemaker should be considered. With bronchospasm, β can be prescribed₂sympathomimetics (in the form of an aerosol or, if necessary, iv) or aminophylline iv. With convulsions, a slow intravenous administration of diazepam is recommended.

Storage conditions

In a dark place at temperatures up to 25 ° c. after opening the bottle, the drug should be used for 6 weeks.