Transcript drug
Interactions = when administration of 1 drug (specific type of food) influences by any way the effect of another drug result of interaction is: - quantitative change - qualitative change of organism response to drug Interactions Possitive interaction: summation 1+1=2 potentiation 1+1=3 Negative interaction: decreased effect Interactions drug – drug drug – food wanted – therapeutic effect toxicity unwanted – most of them, can be reason of ADRs or therapy failure Combinations of Drugs wanted: hypertension severe infections TBC malignity unwanted: result in limitation of usage + iatrogenic damage 5R • Right drug – drug for the diagnosis • Right dose – estimated therapeutic dose • Right time – drugs at developped disease loose effectivity • Right form - drugs as insulin must be administered as s.c. injection, if administered perorally, they dissolve in GIT • Right patient – is the one who needs the drug and we know his risk profile Factors Increasing Risk of Drug Interactions • • • • • • • Polypharmacy Polymorbidity Treatment lasting long time Chronic disease Combination of drugs with similar effect Low therapeutic index Simultaneous ordination of more drugs by different physicians • Abuses • Self-treatment Drug Interactions Drug with Risk • narrow therapeutic window (digoxin, teophylline) • steep dose-response curve (warfarin, sulhonylurea der.) • enzyme inhibitors (ketoconazole, erythromycin) • enzyme inducers (rifampicin, carbamazepine) • high toxic potential (aminoglycosides) Patient with Risk • polymorbidity • polypharmacy • disorders of elimination functions • abusus • non-compliance • self-treatment Drugs with High Risk • • • • • • • Peroral antidiabetics Peroral anticoagulants Heart glykosides Antiepileptic drugs Antimanic drugs NSA Antibiotics Division according to the level at which they arise: • pharmaceutic – physical and chemical incompatibility • pharmacocinetic – absorption distribution biotransformation excretion • pharmacodynamic Absorption • pH in GIT – antacids • motility of GIT – prokinetics antidiarrhoea drugs drugs causing obstipation Absorption • some drugs in combination with other substances or food form insoluble and non-absorbable complexes /tetracyclines + antacids, black tea + iron/ • reduced absorption of several drugs after milk intake • parenteral administration of vasoconstricting additives – slowing down of absorption from the site of i.m. or s.c. injection Distribution • Insufficiency of plasmatic proteins – hepatopathy • Binding to plasmatic proteins • Benzodiazepine site • Warfarin site Distribution • limitation of drug binding to plasma proteins • competitive displacement of substances at biding site – a substance with higher affinity is displacing a substance with a lower affinity to receptors – increasing the portion of free molecules = more intense and shorter effect • mainly substances with high protein binding – more than 90% + with small distribution volume • warfarín, sulfonylurea der. Biotransformation • the most frequent interactions • some drugs were deregistered for this type of interactions (mibefradil, astemizole, terfenadine...) => serious ADRs, even death • cytochrome P450 – change of activity = change in rate of activation and inactivation of drugs • stimulation of met. = enzyme induction • inhibítion of met. = enzyme inhibítion Biotransformation Inductors of cyt. P450 - barbiturates, benzodiazepines, hydantoin antiepileptics, glucocortikoids, rifampicin, griseofulvin, St. John´s wort, smoking, grilled meat, chronic alcohol intake – increase biotransformation = decrease the effect of several drugs, e.g. cardiotonics, steroid hormones, coumarin anticoagulants Biotransformation • Inhibitors of cyt. P450 - some macrolides, quinolones, sulfonamides, some antimycotics (e.g. ketoconazole, fluconazole), isoniazid, metronidazole, chloramphenicol, amiodarone, verapamil, diltiazem, quinidine, SSRI, proton pump inhibitors, cimetidine, garlic, ginkgo, grepefruit juice Pharmacodynamic Interactions • antagonism: opioids-naloxon, benzodiazepines-flumazenil, warfarin-vit. K, caffeine+hypnotics, acetylcholine+atropine neutralization of the effect • synergism: alcohol-antihistamines, antidepressants, ACEI-diuretics, ASAwarfarin, analgesics-antidepressants amplification of the effect Pharmacodynamic Interactions • Most often potentiation of sedative effect on CNS (benzodiasepines and alcohol) • Also potentiation of bradycardia (verapamil a betablockers) • Dangerous simultaneous administration of warfarin and aspirin Interactions with Alcohol • Character a intensity depends on type and ammount acute, chronic intake • Chronic alcoholism: – Enzyme induction – absorption and utilization of vitamines – Adaptive changes in neurotransmitters (DOPA system) • Genetic polymorphism - atypical ADH Japanese, Chinese sensitivity • Acute intoxication: – Rather inhibits CYP; depents whether the individual is Interactions with Alcohol • 80-89% of alcohol is metabolized in liver alcohol dehydrogenase (ADH) to acetaldehyde than aldehyde dehydrogenase (ALDH) to acetate (innoxious acetic acid) • Disulfiram inhibits ALDH => acetaldehyde => ADRs: tachycardia, feeling hot, nausea and vomiting effective even 14 days after stopping of treatment normal eye Marijuana, Hasis red eye Speed, LSD, Ecstasy, Cocaine mydriasis Opiates: heroin, codeine, morphine miosis Case Young 35 year old woman, who previously took contraceptive therapy, after a broken leg had thromboembolic events. Followed anticoagulant therapy (warfarin 5 mg; INR - 2.5). At regular controll found hypertriglyceridemia and started was therapy with gemfibrozil 1.2 g daily. At menstruation appeared serious bleeding, INR - 4. After reducing warfarin dose to one half (2.5 g), INR was stabilized to 2.5. Case Gemfibrozil is an inhibitor of CYP3A4 and reduced biotransformation of warfarin, resulting in increased plasma levels of warfarin to values with the risk of bleeding.