Azarga

Azarga is an ophthalmic drug. Included in the category of β-blockers. Used as a myotic and antiglaucoma medication.

[1]

Indications Azarga

It is shown to lower the level of intraocular pressure - to patients with open-angle glaucoma or ocular hypertension, the use of monotherapy in which it was not possible to lower the intraocular pressure to the required value.

[2]

Release form

Issued in the form of eye drops in bottles-droppers (the so-called drop-teiners) with a volume of 5 ml.

Pharmacodynamics

In drops for the eyes of Azarga contains 2 active ingredients - it is Brinzolamide, as well as timolol maleate. They help to lower the high level of intraocular pressure. This effect is developed by reducing the secretion of intraocular fluid - this process is carried out by means of several different mechanisms of action. When combining the properties of these substances, a more effective reduction in WTO occurs (compared to the effect achieved when using these elements separately).

Brinzolamide is a potent inhibitor of CA-II, considered the dominant eye enzyme. When the carbonic anhydrase is inhibited within the ciliary eye, the secretion of the fluid decreases. This occurs, mainly by inhibiting the formation of bicarbonate ions, and further slowing down the process of sodium transfer with the liquid.

Timolol is an indiscriminate blocker of β-adrenergic receptors. It does not possess internal sympathomimetic, as well as membrane-stabilizing activity, and besides it does not have a direct suppressive effect on the myocardium. The conducted fluorophotometric testing, as well as the tonography procedure, confirmed that the effect of this element is mainly related to the slowing down of the production of the intraocular fluid, and besides, with a slight acceleration of its outflow processes.

[3], [4], [5]

Pharmacokinetics

After local use, the active components are absorbed into the systemic blood flow through the eye cornea.

In the process of drug pharmacokinetics study, healthy volunteers used orally in a dosage of 1 mg 2 times a day for 2 weeks - this was necessary to reduce the period of achieving stable concentration before starting the use of the drug. After using eye drops twice a day for 13 weeks, the average index of brinzolamide within the red blood cells was 18.8 ± 3.29 μM, and in addition 18.1 ± 2.68 μM, as well as 18.4 ± 3 , 01 μM later, respectively, 4 and 10, as well as 15 weeks. This indicates that within the CGT the level of this component remains stable.

With a stable level of concentration of active substances after the use of drops, the mean C max of timolol within the blood plasma, as well as the AUC-time (0-12 hours) are lower (by 27 and 28%), and are, respectively: Cmax 0.824 ± 0.453 ng / ml; AUC 0-12 hours 4.71 ± 4.29 ng · h / ml in comparison with the use of timolol in a volume of 5 mg / ml (C max is 1.13 ± 0.494 ng / ml, and AUC 0-12 hours: 6 , 58 ± 3.18 ng · h / ml).

Weak systemic action of timolol after the use of the drug is not clinically important. The average Cmax value within the blood plasma after instillation of droplets of timolol reaches approximately 0.79 ± 0.45 hours.

Brinzolamide is synthesized with plasma protein in moderate amounts (about 60%). A high affinity with the element CA-II, and in addition a less strong one with the element CA-I, helps the brenzolamide to pass into the CTP. The active product of the decay of this substance is N-desethylbenzenamide, which also accumulates inside the CGT, mainly being associated with CA-I. Due to the affinity of Brinzolamide and its metabolite with CKT and CA tissues, a low plasma concentration index is formed.

Information on the distribution within rabbit eye tissues shows that timolol can be quantified in the intraocular fluid within 48 hours after the use of drops. After achieving a stable concentration, the component is determined in the human blood plasma for 12 hours after using the drug.

The metabolic processes of brinzolamide include N-, as well as O-dealkylation, and in addition the oxidation of its N-propyl side chain. When tested in vitro, it was found that the process of metabolism of brinzolamide is mainly associated with the element CYP3A4, and in addition with at least 4 other isoenzymes (these are elements of CYP2A6 and CYP2B6, and in addition CYP2C8 with CYP2C9).

Metabolism of timolol substance is carried out in 2 stages. During the first one, an ethanolamine side chain is formed in the thiodiazole ring, and during the second an ethanol side chain is formed inside the morpholinazite, and also another similar chain connected to the carbonyl group that is adjacent to nitrogen. The metabolic processes of this active component are mainly associated with the element CYP2D6.

Brinzolamide removal is mainly through the kidneys (approximately 60%). About 20% of the dosage can be determined in urine (as a decay product). Brinzolamide with N-desethylbenzenamide are the main elements found in the urine. It also contains traces of N-demethoxypropyl decomposition products, and in addition O-desmethyl (less than 1%).

Timolol along with its decay products are mainly excreted through the kidneys. About 20% of the dose of timolol is excreted unchanged together with urine. Removal of the remains of the component is also carried out together with urine in the guise of disintegration products.

The half-life of timolol within the blood plasma occurs 4,8 hours after the use of the drug.

[6]

Dosing and administration

Dosages for adult patients (also elderly): 1 drop in the eye conjunctival sac twice per day.

Reduce systemic absorption by pressing on the site of the nasolacrimal hole or by closing the eyelids for 2 minutes. This method helps reduce the risk of developing systemic side effects, and also increases local drug activity.

When a dose is missed, it is necessary to continue treatment according to the scheme of application. The daily dosage can be no more than 2 drops in one eye bag.

In the event that Azarga replaced another anti-glaucoma ophthalmic drug, the use of the latter should be canceled. Starting the application of Azarga is necessary from the next day.

[10], [11]

Use Azarga during pregnancy

There is no relevant information on the use of timolol and brinzolamide components during pregnancy. When testing brinzolamide on animals, a toxic effect on the reproductive system was revealed. Therefore, pregnant women are not recommended to use Azarg's medicine.

Contraindications

Among the contraindications:

• presence of bronchial asthma (also in anamnesis);
• severe obstructive pulmonary pathologies in chronic form;
• cardiogenic shock;
• sinus form of bradycardia;
• bronchial hyperopic;
• AV blockade of 2-3 degrees;
• severe heart failure;
• allergic form of the cold in severe degree;
• severe renal failure (creatinine clearance is less than 30 ml / min);
• closed-angle type of glaucoma;
• compound with ingested inhibitors of carbonic anhydrase;
• lactation period;
• age less than 18 years;
• intolerance of elements from the category of β-adrenoblockers, and in addition acidosis of hyperchloremic type;
• hypersensitivity to sulfanilamide drugs, but in addition to the active substances of the drug.

[7], [8]

Side effects Azarga

The use of this drug may cause the following side reactions:

• local: in 1-10% of all cases, blurred vision occurs, there is irritation or pain in the eye area, and in addition a sense of presence in it of a foreign object. Approximately in 0.1-1% of all situations, the following disorders develop: corneal erosion, Thyesson's keratitis, dry keratoconjunctivitis, and in addition itching or discharge from the eyeballs; In addition, blepharitis (including allergic) or allergic form of conjunctivitis, redness of the eye mucosa, outflow into the anterior eye chamber may develop; also crusts can be formed on the edges of the eyelids, discomfort in the eye area, develop erythema of the eyelids, or visual fatigue;
• systemic: about 1-10% of all cases develop dysgeusia. About 0.1-1% of all cases - the development of insomnia, obstructive pulmonary pathologies in chronic form, a drop in blood pressure, pain in the oropharynx and cough, as well as a violation of the process of hair growth, rhinorrhea, as well as flat lichen.

Local reactions to the action of brinzolamide: the development of keratopathy or keratitis, diplopia, photophobia, meibomite, photopsy, dry keratoconjunctivitis, and besides mydriasis, pterygium and conjunctivitis. Also, IOP can be increased, DZN excavation increased, eye hypesthesia observed, and in addition subconjunctival cyst and scleral pigmentation. Possible effects such as visual impairment, eye allergy or edema (eye or eyelid), increased lacrimation, as well as visual impairment. Reactions on the cornea - the appearance of defects on it and in its epithelium, the development of edema, and the appearance of deposits on it.

Systemic reactions: a state of depression or apathy, a feeling of drowsiness or nervousness, the appearance of nightmares, and in addition motor dysfunctions. Memory may also worsen and amnesia or frustration develop in the central nervous system, and in addition, the libido may decrease.

As a treatment: it is necessary to immediately rinse the eyes with water. Further, supportive treatment and therapy aimed at eliminating symptoms are required. It is necessary to monitor the pH of the blood, as well as electrolytes. The procedure of hemodialysis does not give the necessary result.

[9]

Overdose

Due to the occasional oral intake of the contents of the bottle, overdose of β-blockers can occur, such as heart failure, hypotension, bronchial spasm, and bradycardia.

Supportive and symptomatic therapy is prescribed to eliminate these symptoms. Since the drug contains brinzolamide, it is possible to disturb the balance of electrolytes, the development of the acidosis state, and also the negative effect on the central nervous system. It is required to closely monitor the electrolyte index in the blood serum (especially potassium), as well as the pH value of the blood. According to studies, it is noted that it is rather difficult to remove timolol from the body with dialysis.

[12],

Interactions with other drugs

There have been no studies on drug interactions with other drugs. It is forbidden to combine it with internal inhibitors of the carbonic anhydrase element, because there is a risk of intensifying manifestations of systemic negative reactions.

The processes of the metabolism of brinzolamide are carried out using the isoenzymes of the hemoprotein P450: it is CYP3A4 (most often), and in addition CYP2A6 and CYP2B6, and together with them CYP2C8 with CYP2C9. It is necessary to carefully appoint in combination with Azarga LS, which slow the isoenzyme CYP3A4 (itraconazole, ketoconazole, ritonavir, and clotrimazole with troleandomycin), since they can inhibit the process of metabolism of brenzolamide. Caution is also needed when combining the drug with inhibitors of isoenzyme CYP3A4. The probability of accumulation of brenzolamide in the body is rather low, because it is excreted through the kidneys. This component is not an inhibitor of iso-enamels of the hemoprotein P450.

There is a risk of an increase in the hypotensive effect, but in addition to the development of bradycardia (severe form) in the case of timolol and oral Ca blockers, and in addition to guanethidine, β-blockers, antiarrhythmic drugs, parasympathomimetics, and cardiac glycosides.

In the event of an abrupt cessation of the use of clonidine against the background of the use of β-adrenoblockers, hypertension can develop.

An increase in the systemic effect of β-blockers (slowing the frequency of cardiac contractions) is possible due to the combination of timolol with inhibitors of the element CYP2D6 (such as cimetidine or quinidine).

β-adrenoblockers are able to increase the hypoglycemic properties of antidiabetic drugs. In addition, these elements have the ability to mask the manifestations of hypoglycemia.

When combined with other local ophthalmic drugs, the gap between the use of these drugs should last at least 15 minutes.

[13], [14]

Storage conditions

To store drugs do not require special conditions. Keep out of reach of young children. Temperature indices are within 2-30 ° С.

Shelf life

Azarga can be used for 2 years since the manufacture of drugs. In this case, after opening the bottle, the medicine can be used for a maximum of 1 month.

[15], [16]