Duloxetine

Pharmachologic effect

Antidepressant, serotonin and norepinephrine (norepinephrine) reuptake inhibitor. Weakly inhibits dopamine uptake, does not have a significant affinity for histamine, dopamine, cholinergic and adrenergic receptors. The mechanism of action of duloxetine is to suppress the reuptake of serotonin and norepinephrine (norepinephrine). Duloxetine has a central mechanism for suppressing the pain syndrome, which is primarily manifested by an increased level of pain syndrome of neuropathic etiology.

Pharmacokinetics

After oral administration, duloxetine is well absorbed from the digestive tract, absorption begins 2 hours after administration, Cmax is reached 6 hours after administration. Reception simultaneously with food increases the time to reach Cmax up to 10 hours, which reduces the degree of absorption (approximately 10%), but does not affect the value of Cmax. Plasma protein binding is high (over 90%), mainly with albumin and ฮฑ1-globulin. Disorders from the liver or kidneys do not affect the degree of protein binding. Duloxetine is actively biotransformed with the participation of the isoenzymes CYP2D6 and CYP1A2, which catalyze the formation of two main metabolites (glucuronic conjugate of 4-hydroxyduloxetine, sulfate conjugate of 5-hydroxy, 6-methoxiduloxetine). Circulating metabolites do not have pharmacological activity. T1 / 2 is 12 hours. The average clearance of duloxetine is 101 l / h. It is excreted in the urine in the form of metabolites. In patients with end-stage chronic renal failure undergoing hemodialysis, the values โ€‹โ€‹of Cmax and AUC of duloxetine increased by 2 times. In this regard, the feasibility of reducing the dose of the drug in patients with clinically severe renal impairment should be considered. Patients with clinical signs of liver failure may experience a slowdown in metabolism and excretion of duloxetine. After a single dose of 20 mg of duloxetine in 6 patients with cirrhosis of the liver and moderate impaired liver function (Child-Pugh class B), the duration of T1 / 2 of duloxetine was approximately 15% higher than in healthy people of the same gender and age five an increase in average AUC. Despite the fact that Cmax in patients with cirrhosis was the same as in healthy people, T1 / 2 is approximately 3 times greater.

Indications of the active substances of the drug Duloxetine

Depression, a painful form of diabetic neuropathy.

Dosage regimen

Antidepressant, serotonin and norepinephrine (norepinephrine) reuptake inhibitor. Weakly inhibits dopamine uptake, does not have a significant affinity for histamine, dopamine, cholinergic and adrenergic receptors. The mechanism of action of duloxetine is to suppress the reuptake of serotonin and norepinephrine (norepinephrine). Duloxetine has a central mechanism for suppressing the pain syndrome, which is primarily manifested by an increased level of pain syndrome of neuropathic etiology.The recommended starting dose is 60 mg 1 time / day. If necessary, you can increase the daily dose from 60 mg to a maximum dose of 120 mg / day in 2 divided doses. In patients with severe renal impairment (CC <30 ml / min), the initial dose should be 30 mg 1 time / day. In patients with impaired liver function, the initial dose of the drug should be reduced or the frequency of administration reduced.

Side effect

From the side of the central nervous system: often - dizziness (except vertigo), sleep disturbances (drowsiness or insomnia), headache (headache was less common than with placebo); sometimes - tremor, weakness, blurred vision, lethargy, anxiety, yawning; very rarely - glaucoma, mydriasis, visual impairment, agitation, disorientation. From the musculoskeletal system: sometimes - muscle tension and / or twitching; very rarely - bruxism. From the cardiovascular system: sometimes - palpitations; very rarely - orthostatic hypotension, syncope (especially at the beginning of therapy), tachycardia, increased blood pressure, cold extremities. From the reproductive system: sometimes - anorgasmia, decreased libido, delayed and impaired ejaculation, erectile dysfunction. From the urinary system: sometimes - difficulty urinating; very rarely - nocturia. Other: sometimes - weight loss, increased sweating, hot flashes, night sweats; very rarely - anaphylactic reactions, thirst, hyponatremia, chills, angioedema, rash, Stevens-Johnson syndrome, urticaria, poor health, feeling hot and / or cold, weight gain, dehydration, photosensitivity. With cancellation, dizziness, nausea, and headache were often noted. Patients with a painful form of diabetic neuropathy may experience a slight increase in fasting blood glucose.

Contraindications

Uncompensated angle-closure glaucoma, simultaneous use with MAO inhibitors, hypersensitivity to duloxetine.

Pregnancy and lactation

The use of the drug during pregnancy is possible only in cases where the intended benefit to the mother outweighs the potential risk to the fetus, because clinical experience with duloxetine during pregnancy is not enough. If necessary, the use of the drug during lactation should decide on the termination of breastfeeding (due to lack of experience). Patients should be warned that in the event of pregnancy or planning pregnancy during the use of duloxetine, they need to inform their doctor.

Special instructions

It is used with caution in exacerbating the manic / hypomanic state, epileptic seizures, mydriasis, impaired liver or kidney function, in patients with a tendency to suicidal attempts. When prescribing serotonin reuptake inhibitors in combination with MAO inhibitors, there have been cases of serious reactions, sometimes fatal (hyperthermia, rigidity, myoclonus, various disorders with possible sharp fluctuations in vital signs of the body and changes in mental status, including marked excitement with transition to delirium and to whom). Such reactions are also possible in cases when the serotonin reuptake inhibitor was canceled shortly before the appointment of MAO inhibitors (symptoms may develop, including those characteristic of malignant antipsychotic syndrome). The effects of the combined use of duloxetine and MAO inhibitors have not been evaluated in humans or animals. The use of duloxetine simultaneously with MAO inhibitors or up to 14 days after their withdrawal is not recommended, because duloxetine is an inhibitor of the reuptake of serotonin, and norepinephrine (norepinephrine). MAO inhibitors should not be prescribed for at least 5 days after discontinuation of duloxetine. Use with caution in patients with a history of manic episodes, as well as with a history of epileptic seizures. Depressive conditions are associated with a high risk of suicidal behavior. As a result, patients with a diagnosis of depression who are taking duloxetine should inform their doctor of any disturbing thoughts and feelings. Against the background of the use of the drug, the development of mydriasis is possible, caution should be exercised when prescribing duloxetine to patients with increased intraocular pressure or in individuals at risk of developing acute angle-closure glaucoma. In patients with arterial hypertension and / or other diseases of the cardiovascular system, it is recommended to control blood pressure. Influence on the ability to drive vehicles and control mechanisms Patients taking duloxetine should be careful when engaging in potentially hazardous activities (due to the possible occurrence of drowsiness).