1. Clinical importance of interactions

2. 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

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. Combinations of Drugs 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 Interactions Patient with Risk polymorbidity polypharmacy
Drug with Risk
narrow therapeutic window (digoxin, teophylline)
steep dose-response curve (warfarin, sulhonylurea der.)
enzyme inhibitors (azole antimycotics, erythromycin)
enzyme inducers (rifampicin, carbamazepine)
high toxic potential (aminoglycosides)
Patient with Risk
polymorbidity
polypharmacy
disorders of elimination functions
abusus
non-compliance
self-treatment

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 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.

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, SSRI, proton pump inhibitors, cimetidine, garlic, ginkgo, grepefruit juice

20. Pharmacodynamic Interactions
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. 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

22. 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 an alcoholic or not

23. 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

24. Marijuana, Hasis red eye Speed, LSD, Ecstasy, Cocaine mydriasis
                                                  
normal eye
Marijuana, Hasis red eye
Speed, LSD, Ecstasy, Cocaine mydriasis
Opiates: heroin, codeine, morphine miosis

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.
At menstruation 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.