Buspirone

Pharmacological properties

Buspirone is an anxiolytic drug used to treat anxiety conditions of different origin, especially neurosis, which is accompanied by a feeling of anxiety, anxiety, tension, irritability. the mechanism of action of buspirone has not been fully established, but it is known that it differs from the mechanism of action of benzodiazepines and other anxiolytic agents. Buspirone exhibits a high affinity for presynaptic 5nt1a receptors and is a partial agonist of postsynaptic 5nt1a receptors in the central nervous system. In a series of preclinical studies on experimental models, buspirone found the presence of properties characteristic of anxiolytics and antidepressants. buspirone does not have significant activity against benzodiazepine receptors and does not affect the binding of gamma. unlike benzodiazepines, buspirone does not exhibit anticonvulsant and muscle relaxant effects, is not addictive, and after completion of the course of treatment there are no withdrawal symptoms. the action of buspirone develops gradually. the therapeutic effect begins to appear between the 7th and 14th days of therapy, and the maximum effect is achieved only about 4 weeks after the start of treatment.

Pharmacokinetics After use, the drug is rapidly and almost completely absorbed in the digestive tract. An equilibrium concentration in blood plasma can be achieved approximately 2 days after the start of regular use of the drug.

Buspirone undergoes an intensive metabolism of the first passage through the liver. Systemic bioavailability is 4%. WITH_max the drug metabolite in blood plasma is also reached after 60–90 minutes.

About 95% of buspirone binds to plasma proteins. T_½ from blood plasma is 2-3 hours. The pharmacological parameters of the drug do not change with continuous use of the drug (no cumulation).

The main pharmacologically active metabolite of buspirone is 1- [2-pyrimidinyl] piperazine (1-PP).

Its anxiolytic activity is 4–5 times lower than that of the starting substance, but the concentration in blood plasma is higher and T_½ 2 times longer than buspirone.

About 29–63% of buspirone and its metabolites are excreted in the urine for 24 hours, 18–38% - with feces. In case of impaired renal and hepatic function, elimination of buspirone and its metabolites is reduced.

Simultaneous eating slows down the absorption of buspirone in the digestive tract.

Buspirone passes into breast milk. There are no data on the penetration of buspirone through the placenta.

Elevated plasma concentrations of buspirone and AUC, as well as T elongation_½ possible with impaired liver function. As a result of excretion of unchanged compound with bile, a second peak may appear in the plasma concentration curve of buspirone. Patients with cirrhosis should receive the drug in lower individual doses or in the same doses, but less often.

Renal failure can reduce buspirone clearance by 50%. In patients with renal failure, buspirone should be prescribed with caution and at lower doses.

In the elderly, the pharmacokinetics of buspirone does not change.

Indications

Symptomatic treatment for anxiety conditions with dominant symptoms: anxiety, internal anxiety, tension.

Application

Doses are determined by the doctor individually for each patient, depending on the state of the disease. at the beginning of therapy, 5 mg of buspirone hydrochloride is prescribed 3 times a day. to achieve the maximum therapeutic effect, the daily dose is gradually increased to 20-30 mg of buspirone, distributed in several separate doses.

The maximum single dose should not exceed 30 mg.

The maximum daily dose should not exceed 60 mg.

Food increases the bioavailability of buspirone.Tablets should be taken at the same time of the day, without chewing, with a small amount of liquid, before or after a meal.

If it is necessary to divide the tablet into two halves, it should be placed on a hard surface with a dash up and lightly pressed with the thumb.

If buspirone is used in combination with a powerful CYP 3A4 inhibitor, the initial dose of buspirone should be reduced and gradually increased only after a medical examination of the patient (see INTERACTIONS).

Grapefruit juice increases the level of buspirone in blood plasma. Patients during treatment are not recommended to consume large quantities of grapefruit juice.

Special Patient Groups

Renal failure. In renal failure of mild to moderate severity (creatinine clearance - 20–49 ml / min / 1.72 m²) a single use of buspirone causes an increase in its level in blood plasma without increasing T_½. These patients are recommended to use buspirone with caution and in lower doses, take the drug 2 times a day. Care must be taken to monitor the response to treatment and symptoms in the patient before increasing the dose. In patients with anuria, a single use of the drug leads to an increase in the level of 1-PP metabolite in the blood, their dialysis did not have any effect on the concentration of either buspirone or 1-PP. Buspirone should not be used in individuals with creatinine clearance of 20 ml / min / 1.72 m², especially in patients with anuria due to the possibility of increasing the concentration of buspirone and its metabolites.

Liver failure. The use of drugs such as buspirone for the treatment of patients with impaired liver function leads to a reduced effect of the first passage of drugs through the liver. With cirrhosis of the liver, a single use of buspirone causes an increase in the concentration of its unchanged form in blood plasma with an increase in T_½. It is recommended that these patients use buspirone with caution and after individual titration of doses to reduce the risk of serious adverse reactions that may occur due to the use of buspirone in high doses. An increase in doses should be considered after a thorough examination of the patient and only 4–5 days after the previous dose.

Elderly patients. Available data do not indicate the advisability of changing the dosage regimen depending on the age and gender of the patient.

Duration of treatment. Tranquilizers can not be used without medical supervision for a long time. Therefore, the duration of treatment with buspirone 5 mg and / or 10 mg should not exceed 4 months. Doses are determined by the doctor individually for each patient, depending on the state of the disease. If long-term use of the drug is required (up to 6 months), careful medical monitoring should be carried out.

It should be remembered that psycho-and sociotherapeutic measures are combined with treatment with buspirone.

Contraindications

Hypersensitivity to buspirone or to any other component of the drug. severe liver disease, severe liver failure (prothrombin time 18 s); severe renal failure (glomerular filtration rate (SCF) 10 ml / min); epilepsy; acute intoxication with alcohol, sleeping pills, analgesics and antipsychotics.

Concomitant treatment with MAO inhibitors and within 14 days after the withdrawal of an irreversible MAO inhibitor or within 1 day after the withdrawal of a reversible MAO inhibitor.

Side effects

Side effects occur, as a rule, at the beginning of treatment, and their severity usually decreases with prolonged use. in some cases, a dose reduction is necessary. Adverse reactions from the nervous system, such as dizziness, insomnia, nervousness, drowsiness, fainting, as well as from the digestive tract, such as nausea, as well as other undesirable effects, such as headache and fatigue, were most often noted.

Anger and hostility, confusion, blurred vision, diarrhea, pain in muscles and bones, numbness, paresthesia, impaired coordination of movements, tremors and skin rashes, dry mouth, weakness, asthenia, increased sweating, clammy skin were less frequently detected.

The frequency of adverse reactions: very often (≥1 / 10), often (≥1 / 100, 1/10), infrequently (≥1 / 1000, 1/100), rarely (≥1 / 10,000, 1/1000), very rarely (1/10 000), unknown (frequency cannot be estimated due to lack of data).

Infections and infestations: frequency unknown - fever.

From the cardiovascular system: often - nonspecific chest pain, tachycardia / feeling of palpitations; infrequently - temporary loss of consciousness, arterial hypotension and / or hypertension; rarely - cerebrovascular accident, heart failure, myocardial infarction, cardiomyopathy, bradycardia, cerebrovascular disorders.

On the part of the blood system: rarely - changes in blood counts (eosinophilia, leukopenia, thrombopenia).

From the psyche: often - nightmares, insomnia, nervousness, decreased attention span, emotional arousal, irritability, hostility, confusion, depression; infrequently - depersonalization, discomfort, pathological increased perception of ordinary sounds, euphoria, hyperkinesia, anxiety, loss of interest, impaired associative perception, hallucinations, suicidal thoughts, dysphoria, fear; rarely - a sharp change in mood, claustrophobia, stupor, illegible speech, psychosis, passing memory problems, serotonin syndrome, affective lability.

From the side of the central nervous system: very often - dizziness, headache, drowsiness; often - numbness, paresthesia (for example, tingling, sensation of pain), blurred vision, impaired coordination, tremor; infrequently - numbness, epileptic seizures, dysgeusia, dysosmia, lengthening the reaction time; rarely, spontaneous movements, lethargy, extrapyramidal symptoms, including early and late dyskinesia, impaired tone, parkinsonism, akathisia, dystonia, syncope, amnesia, ataxia, serotonin syndrome, muscle rigidity like a gear, restless legs syndrome, excited state.

From the side of the organ of vision: often - blurred vision; infrequently - redness and itching in the eye area, conjunctivitis; rarely - photophobia, sensation of intraocular pressure, pain in the eyes, narrowed field of vision, increased intraocular pressure.

On the part of the hearing organ: often - tinnitus; rarely - damage to the inner ear.

From the respiratory system: often - sore throat, nasal congestion, pain in the pharynx and larynx; infrequently - rapid breathing, shortness of breath, feelings of compression in the heart, hyperventilation, feeling of lack of air; rarely - nosebleeds, burning sensation of the tongue.

From the digestive tract: often - nausea, xerostomia, epigastric pain, diarrhea, constipation, vomiting; infrequently - flatulence, lack of appetite, increased appetite, hypersalivation, colon irritation syndrome, rectal bleeding.

From the urinary system: infrequently - frequent urination, urinary retention; rarely - enuresis, nightly urination.

On the part of the skin: often - cold sweat, rash; infrequently - edema, urticaria, hyperemia, the occurrence of hematomas, baldness, dry skin, eczema, facial swelling, blisters, increased skin vulnerability, itching; rarely - allergic reactions, ecchymosis, acne, thinning nails.

From the musculoskeletal system: often - musculoskeletal pain; infrequently - spasm and muscle stiffness, myalgia, arthralgia; rarely - myasthenia gravis.

From the endocrine system: rarely - galactorrhea, gynecomastia, thyroid dysfunction.

Metabolic disorders: infrequently - anorexia, increased appetite; frequency unknown - weight gain, weight loss.

General disorders: often - asthenia; infrequently - fever, ringing in the head, malaise, increased fatigue, impaired sense of smell and taste, increased sweating, hot flashes, cold hyperesthesia; rarely - a tendency to abuse alcohol, impaired blood coagulation, loss of voice, hiccups, glossalgia.

From the hepatobiliary system: infrequently - increased liver enzymes.

From the reproductive system: infrequently - menstrual irregularities, decreased or increased libido; rarely - amenorrhea, inflammation of the genitourinary organs, decreased ejaculation, impotence.

Laboratory studies: increased levels of transaminases in plasma.

special instructions

Liver failure. Buspirone undergoes extensive metabolism in the liver. in a pharmacokinetic study, the use of buspirone in a single dose of 30 mg in patients with cirrhosis increased the concentration of buspirone in the blood plasma, increased the auc value and lengthened t½ of buspirone. due to the excretion of the substance into bile, a second peak in the concentration of buspirone in the blood plasma is possible. the use of the drug is contraindicated in patients with severe liver failure. persons with liver cirrhosis should be prescribed the drug in lower doses or in the same doses, but with an increased interval between doses of the drug.

Renal failure. With moderate or severe renal failure, the clearance of buspirone can be reduced by 50%. The drug is contraindicated in patients with severe renal failure (GFR 10 ml / min). In case of mild (GFR 30 ml / min) and moderate (GFR 10-30 ml / min) renal failure, buspirone can be prescribed, but caution should be exercised and used in reduced doses.

Elderly patients. There is no need to clarify the dose, but caution should be exercised when using the drug (for example, due to a possible decrease in kidney and / or liver function and increased sensitivity to side effects of the drug). Patients should be prescribed the drug in the minimum effective dose, and if the dose is increased, the patients health should be carefully monitored.

Patients should be advised not to consume grapefruits or drink grapefruit juice in significant quantities during treatment, as these products can increase the level of buspirone in the blood plasma and lead to an increase in the frequency or severity of side effects.

Transfer patients from benzodiazepines to buspirone. Buspirone cannot resolve the withdrawal symptoms of benzodiazepines. If the patient is transferred to buspirone therapy after prolonged benzodiazepine therapy, buspirone should be prescribed only after the period of gradual reduction in the dose of benzodiazepines is completed.

Buspirone is not addictive to the drug, but its use in patients with a known or suspected propensity for drug dependence requires careful medical supervision. Since the anxiolytic effect of the drug appears after 7-14 days of use, and the full therapeutic effect develops after 4 weeks, patients with severe anxiety require careful medical supervision at the initial stage of therapy.

During the course of treatment with buspirone, alcohol should be avoided.

Buspirone is not intended to relieve withdrawal symptoms caused by the use of benzodiazepines or other sedatives / hypnotics. Therefore, before starting treatment with buspirone, the use of these drugs should be gradually discontinued. This is especially true for patients taking drugs that depress the central nervous system. Buspirone should not be used in monotherapy for depression, as it can mask the clinical symptoms of depression.

Clinical and experimental studies have not revealed any signs that buspirone is a risk of addiction or dependence, however, the purpose of the drug should be justified.

The use of buspirone in patients taking MAO inhibitors can be dangerous. There are reports of increased blood pressure with the combined use of these drugs.

Buspirone should be taken with caution in patients with acute angle-closure glaucoma, myasthenia gravis, drug addiction.

In patients with a history of epilepsy attacks, do not prescribe buspirone.

Buspirone Sandoz contains lactose, so it should not be prescribed to patients with rare hereditary forms of galactose intolerance, lactase deficiency or glucose-galactose malabsorption syndrome.

Long term toxicity. Since the mechanism of action is not fully understood, prolonged toxic effects on the central nervous system or other organ systems may be unpredictable.

Use during pregnancy and lactation. There are no data on the use of buspirone during pregnancy, so the drug can only be prescribed in cases where the expected benefit for the pregnant woman outweighs the potential risk to the fetus. Buspirone passes into breast milk, therefore, breastfeeding during treatment should be discontinued.

Children. Buspirone is not prescribed for children due to the lack of data on the safety and effectiveness of the drug in this category of patients.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. During treatment, one should refrain from driving vehicles or working with mechanisms, since adverse reactions from the central nervous system and psyche are possible (see ADVERSE EFFECTS).

Interactions

Due to the lack of relevant clinical data, the combined use of buspirone with antihypertensive, antipsychotic drugs, antidepressants, antidiabetic drugs, anticoagulants, oral contraceptives and cardiac glycosides is possible only under strict medical control. Buspirone is not used concomitantly with benzodiazepines and other sedatives.

Combination with MAO inhibitors is not recommended due to the risk of hypertensive crisis.

Since buspirone is mainly metabolized by cytochrome P450, potent inhibitors of this enzyme can increase the bioavailability of buspirone.

Nefazodon. The simultaneous use of buspirone (2.5 or 5 mg 2 times a day) and nefazodone (250 mg 2 times a day) led to an increase in C_max buspirone in blood plasma by 20 times and AUC by 50 times and a statistically significant decrease (by about 50%) in the metabolite of buspirone, 1-pyrimidinyl piperazine, in blood plasma. In the case of the use of buspirone in a dose of 5 mg 2 times a day, there was a slight increase in the AUC of nefazodone (23%) and its metabolites - hydroxynephazodone (HO-NEF) (17%) and mCPP (9%). Observed a slight increase in C_max for nefazodone (8%) and its metabolite HO-NEF (11%).

The profile of adverse reactions in patients taking buspirone at a dose of 2.5 mg 2 times a day and nefazodone at a dose of 250 mg 2 times a day did not differ from the profile of adverse reactions in patients taking individually any of these drugs. Adverse reactions in individuals using buspirone at a dose of 5 mg 2 times a day and nefazodone at a dose of 250 mg 2 times a day included fainting, asthenia, dizziness and drowsiness. A dose reduction of buspirone is recommended while it is used with nefazodone.

Erythromycin. The combined use of buspirone (single dose - 10 mg) and erythromycin (1.5 mg once a day for 4 days) led to an increase in C_max Buspirone 5 times and AUC 6 times. If necessary, the simultaneous use of buspirone and erythromycin is recommended to use buspirone in a low dose (for example, 2.5 mg 2 times a day).

Itraconazole. The simultaneous use of buspirone (a single dose of 10 mg) and itraconazole (200 mg once a day for 4 days) led to an increase in C_max Buspirone 13 times and AUC 19 times. If necessary, the simultaneous use of buspirone and itraconazole is recommended to use buspirone in a low dose (for example, 2.5 mg once a day).

Diltiazem. The simultaneous use of buspirone (single dose - 10 mg) and diltiazem (60 mg 3 times a day) led to an increase in C_max Buspirone 5.3 times and AUC 4 times. It is possible to enhance the action and increase the toxicity of buspirone, if necessary, the simultaneous use of buspirone and diltiazem.

Verapamil. The concomitant use of buspirone and verapamil led to an increase in C_max and Buspirone AUC 3.4 times. The enhanced effect and increased toxicity of buspirone with the simultaneous use of buspirone and verapamil are possible.

Cimetidine. The combined use of buspirone and cimetidine leads to an increase in C_max buspirone 40%, Tmax - 2 times, but the AUC practically does not change.

When using buspirone together with the above funds, the therapeutic effect and toxicity of buspirone are increased, therefore it is recommended to reduce the dose of the drug (for example, 2.5 mg 2 times a day). The next dose adjustment should be based on the clinical response to treatment with each of these drugs.

Baclofen, lofexidine, nabilon, antihistamines can enhance any sedation.

Rifampicin. The simultaneous use of buspirone (a single dose of 30 mg) and rifampicin (600 mg once a day for 5 days) led to a decrease in C_max buspirone by 83.9% and AUC by 89.6%.

Inhibitors and inducers of CYP 3A4. Ketoconazole or ritonavir inhibit the metabolism of buspirone and increase its concentration in blood plasma. When using buspirone with a CYP 3A4 inhibitor, its dose should be reduced.

CYP 3A4 inducers, such as dexamethasone, phenytoin, phenobarbital or carbamazepine, can increase the metabolic rate of buspirone. In this case, it is necessary to increase the dose of buspirone to maintain its anxiolytic effectiveness.

Serotonin reuptake inhibitors. Not a single case of the dangerous use of buspirone in combination with antidepressants, selective serotonin reuptake inhibitors has been identified. There were isolated reports of seizures during their prolonged use with buspirone.

Haloperidol. The simultaneous use of buspirone and haloperidol led to an increase in the concentration of haloperidol in blood plasma.

Trazodone. There were reports that in some patients with the simultaneous use of trazodone with buspirone, AlAT activity increased 3 times. However, such an increase in hepatic transaminases has not been confirmed by clinical studies.

Diazepam. With the simultaneous use of diazepam and buspirone, the level of the first in the blood plasma rises slightly, and side effects can also occur: dizziness, headache, nausea.

During treatment with buspirone should refrain from drinking alcoholic beverages.

Fluvoxamine Short-term buspirone therapy concomitantly with fluvoxamine administration led to a double increase in the concentration of buspirone in the blood plasma compared with buspirone monotherapy.

Digoxin. In humans, approximately 95% of buspirone binds to plasma proteins. In vitro, buspirone does not displace from plasma protein binding sites drugs that tightly bind proteins (such as warfarin). However, in vitro buspirone can displace from the sites of protein binding drugs that bind proteins insufficiently firmly (for example, digoxin). The clinical significance of this property is unknown.

An increase in prothrombin time has been reported after the addition of buspirone to therapy involving warfarin treatment.

During treatment, patients are not recommended to consume large amounts of grapefruit juice (double dose of 200 ml for 2 days), as this can lead to an increase in the concentration of buspirone in the blood plasma and to an increase in the frequency or severity of side effects.

Overdose

Symptoms: nausea, vomiting, dizziness, increased fatigue, drowsiness, loss of consciousness, miosis (constriction of the pupils) and impaired gastrointestinal function. more severe complications in humans were not observed even with the introduction of a daily dose of up to 2400 mg.

Treatment: gastric lavage, monitoring of respiration, pulse, blood pressure. Symptomatic TherapyThere is no specific antidote. Buspirone is not excreted by hemodialysis. Based on the experience gained with the use of the drug, a high dose overdose (single dose of 375 mg buspirone orally) does not necessarily cause severe symptoms.

Storage conditions

It does not require special storage conditions.