COMMON PHARMACOLOGY PHARMACOKINETICS Passive diffusion Distribution of drugs

COMMON PHARMACOLOGY PHARMACOKINETICS

Passive diffusion

Distribution of drugs Intensity of blood circulation in organs and tissues: · Tiopental after intravenous introduction first of all penetrates into muscular tissue which is well blood-supplied (there is necessity in repeated introduction) · Distribution and pharmacological effects of drugs can decrease in case of organic blood supply insufficiency (shock, haemostasis in large blood circulation circle based on heart insufficiency)

CONNECTION OF DRUGS WITH BLOOD PLASMA PROTEINS • Albumin, lipoproteins, 1 -acid gycoprotein and globulins • specific proteins-carriers: glucocorticosteroids – transcortin, vitamin В 12 – 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 !!!

• 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 • high level 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

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 Vd of acetylsalycylic acid – 8 litter Vd of rifampicin, lidokain, diazepam, anaprilin, digoxin – 65, 90, 210, 280, 600 litters correspondingly

Metabolism of drugs Metabolism or biotransformation 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

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

The catalytic cycle of cytochrome P 450

Drug-Induced Immune-Mediated Liver Injury - DILI

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

Enalapril, cefuroxim axetil, oseltamivir (tamiflu)

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

Presystemic elimination

Factors that influence on drug metabolism

Biotransformation of drugs into active (or more active) metabolites 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

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

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

GENERAL PHARMACOLOGY PHARMACODYNAMICS

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 an adverse reaction • Reversible and irreversible

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

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. )

Receptors - enzymes cholinesterase Cox - Cyclooxygenase MAO ACEangiotensin converting enzyme

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

thyroid hormone receptor - genes

FOOD - DRUGS

Food and bioavalability Drugs Spironolactone, hydralazine Anapriline, hydantoine, griseofulvini Furosemid, isoniaside, cefalexine absor btion bioaval ability

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

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

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

Green tea • Xanthines (Theophyllinum) – Increase of absorption, Increase of adverse reactions (insomnia, nervousness) • Indirect anticoagulants – decrease of effectivenes

Drugs and caffeine-containing products Morphine, papaverine, codeine, atropine, aminazine, haloperidol, hormonal contraceptives, ergotamine Decreas of absorption Decreas of therapeutic activity Ø Paracetamol, aspirine Ø increase of analgesic effect

Grapefruit juice • Calcium antagonist, terfenadine, ciclosporine • Decrease of biotransformation in liver, increase of their blood concentration, increase of toxicity

Diet in case of administration of IMAO It is necessary to exclude such products which contain DOPA and thiramine (which is formed from casein during the process of transforming under the influence of bacteria) Aged cheese, kefir Marinated herring Smoked meat and fish Red vine, beer, yeast Beans, oranges, tangerines, lemons, grape, chocolate, bananas, caviar (red and black)…

INFLUENCE OF BIOLOGICAL RHYTHMS • Glucocorticoids are administered between 6 and 8 in the morning • Theotard (long-acting form of theophylline) is used in the evening (exacerbation of BA at night) • Maximum effect occurs if use diuretics till 10 a. m. • Toxicity of Haloperidolum changes during the day in 5 times • Angina attacks more frequently appears from 2 to 6 p. m.