1. DRUG INTERACTIONS

2. Definition „ pharmacological or clinical response to the administration of a drug combination is different from that anticipated from the known effects of the two agents given alone“ „whwn the effects of one drug are changed by the presence of another drug, food, drink or by some chemical environmental agent“

3. Therapeutic DI - potentiation Post-transplantation immunosupression –corticosteroids, cyclosporine, azathioprine Malignancy –alkylating agents (cyclophosphamide), antimetabolites (methotrexate, fluorouracil) Hypertension Asthma

4. Incidence Incidence of potential prescription …… 4-5 % Hospital admissions……………………..1 % ! Most in ambulatory (outpatients) settings ! UNDERESTIMATION ! Geriatric patients - polypharmacy, polymorbidity

5. Documentation and reliability Interactions in animals Case-reports - one or a few patients reposted spontaneously Trials of drug combiantions in healthy volunteers Terapeutic RCT (randomised placebo- controlled trials)

6. Individual variation Drug metabolism - susuceptibility to microsomal enzyme induction genetic activity of P-450: –poor x extensive; slow x fast metabolisers –digoxin x antibiotics - in only about 10 % patients

7. Drug interactions Pharmaceutical –incompability prior to administration (syringes, infusions) Pharmacodynamic –competition at receptor sites, physiological system Pharmacokinetic –absorption, distribution, metabolism, elimination phase

8. Combination of mechanisms Aspirin - interferation with absorption and renal tubular secretion of drugs; increasing toxicity of oral anticoagulants; gastroinestinal erosions Amiodarone - increasing the serum digoxin by: –inhibition of renal excretion –inhibition of hepatobiliary excretion –displacement from tissue binding sites

9. Induction of metabolism Enzyme-inducing agents: –barbiturates, phenytoin, carbamazepine, aminoglutethimide, alcohol, rifampicin, cigarette smoking Stimulation of metabolism of –warfarin, paracetamol, oral contraceptives

10. Inhibition of metabolism Enzyme inhibitors: –cimetidine –CCB (diltiazem, verapamil) –amiodarone –macrolide antibiotics (ery, clar, trol) –azole antifungals (keto, itra, mico) –SSRI (fluoxetine, fluvoxamine) –grapefruit juice