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Doxycycline

Pharmacodynamics

Semisynthetic tetracycline, broad-spectrum bacteriostatic antibiotic. Penetrating into the cell, it acts on intracellular pathogens. Suppresses the synthesis of proteins in the microbial cell, disrupts the connection of transport aminoacyl-RNA with the 30S subunit of the ribosomal membrane. Gram-positive microorganisms are highly sensitive to it: Staphylococcus spp. (including Staphylococcus aureus, Staphylococcus epidermidis), Streptococcus spp. (including Streptococcus pneumoniae), Clostridium spp., Listeria spp .; Actinomyces israeli; and gram-negative microorganisms: Neisseria gonorrhoeae, Neisseria meningitidis, Haemophilus influenzae, Klebsiella spp., Escherichia coli, Shigella spp., Enterobacter, Salmonella spp., Bordetella pertussis. Bacteroides spp., Treponema spp. (including strains resistant to other antibiotics, such as modern penicillins and cephalosporins). The most sensitive are Haemophilus influenzae (91-96%) and intracellular pathogens. Doxycycline is active against most causative agents of dangerous infectious diseases: plague (Yersinia spp.), Tularemia (Francisella tularensis), anthrax microbes (Bacillus anthracis), Legionella (Legionella spp.), Brucella (Brucella spp.), Vibrio cholera cholera cholera , rickettsia (Rickettsia spp.), pathogens of glanders (Actinobacillus mallei), chlamydia (causative agents of ornithosis (Chlamydia psittaci), psittacosis (Rickettsiaformis psittacosi), trachoma (Chlamydia trachomatis), granulomatous venereal disease; dysentery (Entamoeba histolytica). It does not act on most strains of Proteus, Pseudomonas aeruginosa and fungi. To a lesser extent than other antibiotics of the tetracycline series, it inhibits the intestinal flora, differs from them in more complete absorption and a longer duration of action. Doxycycline surpasses natural tetracyclines in the degree of antibacterial activity. In contrast to tetracycline and oxytetracycline has a higher therapeutic efficacy, which is manifested in the treatment 10 times lower doses and longer duration of action. There is cross-resistance to other tetracyclines as well as penicillins.

Pharmacokinetics

Absorption is fast and high (about 100%). Reception of food does not significantly affect the degree of absorption. It has a high degree of lipid solubility and low affinity for binding calcium ions (Ca2 +). After oral administration of 200 mg, the time to reach the maximum concentration in blood plasma is 2.5 hours, the maximum concentration in blood plasma is 2.5 μg / ml, 24 hours after administration is 1.25 μg / ml. The connection with plasma proteins is 80-93%. Penetrates well into organs and tissues; 30-45 minutes after ingestion, it is found in therapeutic concentrations in the liver, kidneys, lungs, spleen, bones, teeth, prostate gland, eye tissues, in pleural and ascitic fluids, bile, synovial exudate, maxillary and frontal sinus exudate, in fluid gingival grooves. Poorly penetrates into the cerebrospinal fluid (10-20% of the plasma level). Penetrates through the placental barrier, is determined in human milk. The volume of distribution - 0.7 l / kg. Metabolized in the liver 30-60%. The half-life is 10-16 hours (mostly 12-14 hours, on average 16.3 hours). With repeated administrations, the drug may accumulate. It accumulates in the reticuloendothelial system and bone tissue. In bones and teeth, it forms insoluble complexes with calcium ions (Ca2 +). It is excreted in the bile, where it is found in high concentration. Undergoes intestinal-hepatic recirculation, excreted by the intestines (20-60%); 40% of the dose taken is excreted by the kidneys within 72 hours (of which 20-50% - unchanged), with severe chronic renal failure - only 1-5%. In patients with impaired renal function or azotemia, gastrointestinal secretion is an important route of elimination.

Contraindications

  • hypersensitivity to doxycycline, drug components, other tetracyclines;
  • lactase deficiency;
  • lactose intolerance;
  • glucose-galactose malabsorption;
  • porphyria;
  • severe liver failure;
  • leukopenia;
  • children's age (up to 12 years - the possibility of the formation of insoluble complexes with calcium ions (Ca2 +) with deposition in the bone skeleton, enamel and dentin of the teeth);
  • children over the age of 12 with a body weight of up to 45 kg.
  • Pregnancy and lactation

    The use of the drug during pregnancy is contraindicated, since, penetrating through the placenta, the drug can disrupt the normal development of teeth, inhibit the growth of the bones of the fetal skeleton, and also cause fatty liver infiltration. During lactation, the use of doxycycline is contraindicated. If it is necessary to use the drug, breastfeeding should be discontinued for the period of treatment.

    Side effects

    From the nervous system: a benign increase in intracranial pressure (decreased appetite, vomiting, headache, swelling of the optic nerve head), toxic effects on the central nervous system (dizziness or instability), Metabolic disorders: anorexia. On the part of the hearing and vestibular apparatus: ringing in the ears. From the side of the organs of vision: blurred vision, scotoma and diplopia as a result of increased intracranial pressure. From the digestive system: nausea, constipation or diarrhea, abdominal pain, glossitis, dysphagia, esophagitis (including erosive), gastritis, ulceration of the stomach and duodenum 12, pseudomembranous colitis, enterocolitis (due to the proliferation of resistant strains of staphylococcus) ). Allergic reactions: maculopapular rash, pruritus, skin flushing, angioedema, anaphylactoid reactions, medicinal lupus erythematosus, erythematous rash, exfoliative dermatitis, urticaria, anaphylaxis, anaphylactic shock, anaphylactic Stevens-Jones syndrome. From the side of the cardiovascular system: pericarditis, lowering blood pressure, tachycardia, erythema multiforme. From the side of hematopoiesis: hemolytic anemia, thrombocytopenia, neutropenia, leukopenia, eosinophilia, decreased prothrombin index. From the hepatobiliary system: liver dysfunction, increased hepatic transaminases, autoimmune hepatitis, cholestasis. Musculoskeletal system: arthralgia, myalgia. Dysfunction of the kidneys and urinary tract: an increase in the level of residual urea nitrogen. Others: photosensitivity, superinfection; persistent discoloration of tooth enamel, inflammation in the anogenital zone. Candidiasis (vaginitis, glossitis, stomatitis, proctitis), dysbiosis, a syndrome similar to serum sickness, toxic epidermal necrolysis.

    Interaction

    Absorption is reduced by antacids containing salts of aluminum (Al3 +), calcium (Ca2 +) and magnesium (Mg2 +), preparations of iron (Fe), sodium bicarbonate, laxatives containing magnesium salts (Mg2 +), cholestyramine and colestipol, therefore, their use should be separated at intervals of 3 hours. Due to the suppression of the intestinal microflora, it reduces the prothrombin index, which requires a dose adjustment of indirect anticoagulants. When combined with bactericidal antibiotics that disrupt the synthesis of the cell wall (penicillins, cephalosporins), the effectiveness of the latter decreases. Reduces the reliability of contraception and increases the frequency of bleeding "breakthrough" while taking estrogen-containing oral contraceptives. Ethanol, barbiturates, rifampicin, carbamazepine, phenytoin and other stimulants of microsomal oxidation, accelerating the metabolism of doxycycline, reduce its concentration in plasma. With simultaneous use with methoxyflurane, it is possible to develop acute renal failure, up to a lethal outcome. The simultaneous use of retinol increases intracranial pressure.

    Dosage and administration

    Inside, in adults and children over 12 years old with a body weight of more than 45 kg, the average daily dose is 200 mg on the first day (divided into 2 doses - 100 mg 2 times a day), then 100 mg / day. For chronic infections of the urinary system - 200 mg / day throughout the entire period of therapy. In the treatment of gonorrhea, it is prescribed according to one of the following schemes: acute uncomplicated urethritis - a course dose of 500 mg (1 dose - 300 mg, the next 2 - 100 mg each with an interval of 6 hours) or 100 mg / day until complete recovery (in women) or 100 mg 2 times a day for 7 days (in men); in complicated forms of gonorrhea, the course dose is 800-900 mg, which is divided into 6-7 doses (300 mg - 1 dose, then with an interval of 6 hours for 5-6 subsequent doses). In the treatment of syphilis - 300 mg / day for at least 10 days. For uncomplicated infections of the urethra, cervix and rectum caused by Chlamydia trachomatis, appoint 100 mg 2 times a day for at least 7 days. Male genital infections - 100 mg 2 times a day for 4 weeks. Treatment of chloroquine-resistant malaria - 200 mg / day for 7 days (in combination with schizontocidal drugs - quinine); prevention of malaria -100 mg once a day 1-2 days before the trip, then daily during the trip and within 4 weeks after returning; Diarrhea of ​​"travelers" (prevention) - 200 mg on the first day of the trip (for 1 dose or 100 mg 2 times a day), 100 mg 1 time a day during the entire stay in the region (no more than 3 weeks). Treatment of leptospirosis - 100 mg orally 2 times a day for 7 days; prevention of leptospirosis - 200 mg once a week during a stay in a disadvantaged area and 200 mg at the end of the trip. Prevention of infections after medical abortion - 100 mg 1 hour before the abortion and 200 mg - 30 minutes after. With acne - 100 mg / day, course - 6-12 weeks. The maximum daily doses for adults are up to 300 mg / day or up to 600 mg / day for 5 days in severe gonococcal infections. In the presence of severe hepatic impairment, a decrease in the daily dose of doxycycline is required, since it gradually accumulates in the body (risk of hepatotoxic action).

    Overdose

    Symptoms: when high doses are administered, especially in patients with impaired liver function, neurotoxic reactions may appear: dizziness, nausea, vomiting, seizures, impaired consciousness due to increased intracranial pressure. Treatment: drug withdrawal, gastric lavage with activated charcoal, symptomatic therapy, antacids and magnesium sulfate are prescribed orally to prevent the absorption of doxycycline. There is no specific antidote. Hemodialysis and peritoneal dialysis are ineffective.

    Special instructions

    To prevent local irritating effects (esophagitis, gastritis, ulceration of the mucous membrane of the gastrointestinal tract), it is recommended to take it in the daytime with a large amount of liquid and food. In connection with the possible development of photosensitivity, it is necessary to limit insolation during treatment and for 4-5 days after it. With prolonged use, periodic monitoring of liver function and hematopoietic organs is necessary.It can mask the manifestations of syphilis, and therefore, if a mixed infection is possible, a monthly serological test is necessary for 4 months. All tetracyclines form stable complexes with calcium ions (Ca2 +) in any bone-forming tissue. In this regard, reception during the period of tooth development can cause long-term staining of teeth in a yellow-gray-brown color, as well as enamel hypoplasia.A false increase in the level of catecholamines in the urine is possible when they are determined by the fluorescent method. When examining a biopsy specimen of the thyroid gland in patients who have been receiving doxycycline for a long time, dark brown staining of tissue in micropreparations is possible without impairing its function. The experiment established that doxycycline can have a toxic effect on fetal development (delayed skeletal development) - it blocks metalloproteases (enzymes that catalyze the degradation of collagen and proteoglycans) in the cartilage, leading to a decrease in lesions in deforming osteoarthritis. When the dose is increased above 4 g, the pharmacokinetics of doxycycline does not depend on the dose and the concentration in the blood does not increase. When using the drug, both while taking it and 2-3 weeks after stopping treatment, diarrhea caused by Clostridium difficile may develop. In mild cases, it is sufficient to discontinue treatment and use ion-exchange resins (cholestyramine, colestipol), in severe cases, it is indicated to replace the loss of fluid, electrolytes and protein, the appointment of vancomycin, bacitracin or metronidazole. Do not use drugs that inhibit intestinal peristalsis. Influence on the ability to drive vehicles and use mechanisms Patients should refrain from all types of activities requiring increased attention, rapid mental and motor activity.

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