Clinical importance of interactions

1. Clinical importance of interactions

2. Interactions = whenadministrationof 1 drug (specific type offood) influences by anywaytheeffectofanotherdrug resultofinteractionis: - quantitativechange - qualitativechange oforganismresponse to drug

3. Interactions Possitive interaction: summation 1+1=2 potentiation 1+1=3 Negative interaction: decreased effect

4. Interactions drug – drug drug – food wanted –  therapeutic effect  toxicity unwanted – most of them, can be reason of ADRs or therapy failure

5. CombinationsofDrugs wanted: hypertension severe infections TBC malignity unwanted: result in limitation of usage + iatrogenic damage

6. 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

7. 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

8. 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 DrugInteractions

9. Drugs with High Risk • Peroral antidiabetics • Peroral anticoagulants • Heart glykosides • Antiepileptic drugs • Antimanic drugs • NSA • Antibiotics

11. Division according to the level at which they arise: • pharmaceutic – physical and chemical incompatibility • pharmacocinetic – absorption distribution biotransformation excretion • pharmacodynamic

12. Absorption • pH in GIT – antacids • motility of GIT – prokinetics antidiarrhoea drugs drugs causing obstipation

13. 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

14. Distribution • Insufficiency of plasmatic proteins – hepatopathy • Binding to plasmatic proteins • Benzodiazepine site • Warfarin site

15. Distribution • limitation of drug binding to plasma proteins • competitive displacementof 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.

16. 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

18. 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

19. 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

20. PharmacodynamicInteractions • antagonism:opioids-naloxon, benzodiazepines-flumazenil, warfarin-vit. K, caffeine+hypnotics, acetylcholine+atropine neutralization of the effect • synergism:alcohol-antihistamines, antidepressants, ACEI-diuretics, ASA-warfarin, analgesics-antidepressants amplification of the effect

21. PharmacodynamicInteractions • 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

22. InteractionswithAlcohol • 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 an alcoholic or not

23. InteractionswithAlcohol • 80-89% of alcohol is metabolized in liver alcohol dehydrogenase(ADH) to acetaldehydethan  aldehyde dehydrogenase (ALDH) to acetate (innoxious acetic acid) • Disulfiraminhibits ALDH=> acetaldehyde => ADRs: tachycardia, feeling hot, nausea and vomiting  effective even 14 days after stopping of treatment

25. 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. Atmenstruation appeared serious bleeding, INR - 4. After reducing warfarin dose to one half (2.5 g), INR was stabilized to 2.5.

26. 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.