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COMMON PHARMACOLOGY PHARMACOKINETICS

COMMON PHARMACOLOGY PHARMACOKINETICS. Passive diffusion. Distribution of drugs. Intensity of blood circulation in organs and tissues :

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COMMON PHARMACOLOGY PHARMACOKINETICS

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  1. COMMON PHARMACOLOGY PHARMACOKINETICS

  2. Passive diffusion

  3. Distribution of drugs Intensity of blood circulationin organs and tissues: • Tiopental after intravenous introduction first of all penetrates into muscular tissue which is well blood-supplied (there is necessity in repeatedintroduction) • Distribution and pharmacological effects of drugs can decrease in case of organic blood supply insufficiency (shock, haemostasis inlarge blood circulation circlebased on heart insufficiency)

  4. CONNECTION OF DRUGS WITH BLOOD PLASMA PROTEINS • Albumin, lipoproteins, 1-acidgycoprotein and globulins • specific proteins-carriers: glucocorticosteroids – transcortin, vitamin В12 – transcobalamin, iron ions – transferrin, copper ions – ceruloplasmin free and bound with proteins forms of a drug stay in condition of dynamic balance drug bound with plasma proteins is pharmacologically inactive !!!

  5. in case of hypoalbuminemia (liver diseases, kidney disease, protein starvation, elderly): increasing of free fraction of a drug, increasing of pharmacological activity, development of toxic effects • highlevel of connection to blood proteins: diazepam, butamid, difenin, indometacin, furosemid, quinidine • competition for binding with plasma proteins: sodium valproate forces out difenin – increasing of free fraction of the last - toxic effects • high level of sulfadimetoxin, sulfapirydasin binding with blood proteins causes prolongation of their action

  6. VOLUME OF DISTRIBUTION volume of distribution – imaginary volume in which the drug is distributed in organism, if to let that organism is a single space (single-camera model), and concentration of the drug in blood plasma is equal to concentration in tissues Distribution volume is calculated according to a formula Vd =total quantity of the drug in organism concentration of the drug in blood plasmа Vdof acetylsalycylic acid– 8 litter Vdof rifampicin, lidokain, diazepam, anaprilin, digoxin – 65, 90, 210, 280, 600 litterscorrespondingly %

  7. Metabolism of drugs Metabolism orbiotransformation - complex of processes which provide decreasing of toxicity and accelerate excreting of the molecule of a drug or other foreign substance after its incoming into the organism

  8. ORGANS OF DRUGS METABOLISM • liver • kidneys • muscle tissue • intestinal wall • lungs • skin • blood

  9. The catalytic cycle of cytochrome P450

  10. Drug-Induced Immune-Mediated Liver Injury - DILI

  11. Metabolism in the intestinal wall Synthetic and nonsynthetic reactions take place • Isadrin – conjugation with sulfate • Hydrlalasin - acetylation • Penicillin, aminazin – metabolism with nonspecific enzymes • Methotrexat, levodopa – metabolism with intestinal bacteria

  12. Enalapril, cefuroxim axetil, oseltamivir (tamiflu)

  13. PRESYSTEMIC ELIMINATION presystemic elimination – extraction of the drug form blood circulatory system during it’s first going through the liver (first pass metabolism) – it leads to decreasing of bioavailability (and therefore, decreasing of biological activity) of drugs propranolol (anaprilin), labetolol, nitroglycerin, aminazin, acetylsalicylic acid, hydralasin, isadrin, cortizone, lidokain, morphin, pentasocin, organic nitrates, reserpin

  14. Presystemic elimination

  15. Factors that influence on drug metabolism

  16. Initial drug Allopurinol Amitriptilin Acetylsalicylic acid Butadion Diazepam Digitoxin Codein Cortizol Methyldopa Prednison Novocainamid Propranolol Active metabolite Aloxantin Nortriptilin Salicylic acid Oxyfenbutazon Dismethyldiazepam Digoxin Morphine Hydrocortizon Methylnoradrenalin Prednisolon N-acetylnovocainamid N-oxypropranolol Biotransformation of drugs into active (or more active) metabolites

  17. Elimination of the drugs drugs can be excreted in forms of metabolites or unchanged forms through different ways:kidneys, liver, lungs, intestines, sweat and mammary glands etc.

  18. Elimination through kidneys filtration, canalicular secretion and canalicular reabsorption • filtration(relative molecular weight of drugs is less than 90, if 90-300 – with urine and bile): ampicillin, gentamicin, urosulfan, novokainamid, digoxin • Disorders of filtration – shock, collapse (due to decreasing of blood circulation and hydrostatic pressure of blood plasma in glomerular capillaries) • furosemid (closely connected with plamsa proteins) is not filtrated in glomerular capilaries • canalicular secretion – active process (with the aid of enzyme system and using energy): penicillins, furosemid, salicilates, chinin • Disorders of canalicular secretion – in case of disorders of energetic metabolism in kidneys: hypoxia, infections, intoxications

  19. GENERAL PHARMACOLOGY PHARMACODYNAMICS

  20. PHARMACOLOGICAL EFFECTS • Local:astringent, covering, irritating, local anesthesia, necrotizing, adsorbing • Reflectory: as a result of local irritating (Sol. Ammonii caustici, Validolum, Charta Sinapis, expectorants of plant origin) • Resorbtive(systemic – after drug absorption or its introduction to blood): 1) direct (primary)and 2) indirect(secondary): cardiac glycosides: 1 – on heart, 2 – diuretic effect • Selective action (salbutamol, celecoxyb, doxazosin) • Nonspecific action – on all cells of the organism: drugs for general anesthesia, salts of heavy metals • Basic (beneficial) action anadverse reaction • Reversibleandirreversible

  21. Receptors – specific cell sites GABAc receptors Opiate receptors steroid-receptor Serotonine receptor

  22. TYPES OF RECEPTORS Receptors-enzymes: acethylcholinestherase (Proserine), monoaminoxydase in neurons of CNS (Nialamid), angiotensin converting enzyme (ACE-blockers– Captopril, Enalapril), K-,Na- ATPase (cardiac glycosides - Digoxin), H-,K-ATPase (proton pump) (Omeprasol), COG-1, COG-2 (nonsteroidal antiinflammatory agents – Diclofenac, Indometacin, Piroxycam, Meloxicam etc.)

  23. Receptors - enzymes MAO cholinesterase Cox - Cyclooxygenase ACEangiotensin converting enzyme

  24. Receptors – ionic channels sodium (Na+) channels Voltage-dependent potassium channels calcium channels

  25. thyroid hormone receptor - genes

  26. FOOD - DRUGS

  27. Food and bioavalability

  28. Glucocorticosteroids: prednisolone, dexamethasone NSAID: voltaren, butadion, indometacine Antibiotics: tetracyclines, fluoroquinolones Increase of absorption Decrease of absorption Decrease of absorption Drugs and milk

  29. Macrolides (erythromycine, spiromycine, klaritromycine) Linkosamides (linkomycine, clindamycine) Tetracyclines Decreas of absorption Decreasof activity Antibiotics and tonic drinks

  30. Alkaloids (papaverine, platyphylline, codeine, reserpine) Neuroleptics of phenothiazine and buthyrophenone groups (aminazine, haloperidole etc.) Decreas of absorption Decreasof therapeutic activity Tannin-containing products tea

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