FACTORS INFLUENCING DRUG EFFECT. ADVERSE EFFECTS. DRUG-DRUG INTERACTIONS. DRUG DEVELOPMENT. Department of Pharmacology MU FACTORS INFLUENCING DRUG EFFECT - RELATED TO THE DRUG - RELATED TO THE PATIENT - RELATED TO BOTH (DRUG AND PACIENT) FACTORS RELATED TO THE DRUG • PHYSICS AND CHEMICAL PROPERTIES • MOLECULE SIZE, CHEMICAL CONFIGURATION, WEAK ACID/BASE, LIPOPHILICITY… • DRUG DOSAGE FORM • FOOD • LIPIDS TEND TO SLOW DOWN INTESTINAL ABSORPTION • DRUG+ION COMPLEX FORMATION • PH CHANGES FACTORS RELATED TO THE PACIENT 1. AGE 2. SEX 3. BODY WEIGHT 4. CIRCADIAN RHYTHMS 5. PATOLOGICAL CONDITION 6. GENETIC FACTORS 1. AGE • CHILDREN • DOSE ADJUSTMENT DEPENDENT ON BW OR BODY SURFACE AREA • NEWBORNS – INMATURE LIVER AND KIDNEY PROCESSES, LEAKY BBB • SENIORS • POLYMORBIDITY, POLYPRAGMASY •  T1/2 OF ELIMINATION • PHARMACODYNAMICS – DIFFERENT TARGET SENSITIVITY – OFTEN PARADOXICAL AND HYPERERGIC REACTIONS   DOSING tubulární sekrece glomerulární filtrace konjugace s aminokyselinami glukuronidace acetylace porod 10 20 30 2 3 4 5 6 dny měsíce 2. SEX • WOMENT TEND TO EXPERIENCE STRONGER EFFECTS • SENSITIVITY TO DRUGS ACTING IN THE BRAIN IS ALTERED BY MENSTUAL CYCLE / MENOPAUSE • PREGNANCY AND BREAST FEEDING 3. BODY WEIGHT •DOSES ARE USUALLY CALCULATED FOR MALE PACIENT WITH 70 KG OF BW •BODY COMPOSITION •BETTER FITTING – DOSE PER METER SQUARE OR BW 4. CIRCADIAN RHYTHMS • BIOLOGICAL RHYTHMS OF PHYSIOLOGICAL FUNCTIONS (GLUCOCORTICOIDS, ETC.) • CHRONOPHARMACOLOGY, CHRONOTHERAPY 5. PATHOLOGICAL CONDITION • IMPAIRMENT OF ORGANS RESPONSIBLE FOR METABOLISM OR EXCRETION (LIVER, KIDNEY)  DOSE ADJUSTMENT • SOMETIMES THE PATHOLOGY IS NECESSARY TO OBSERVE THE EFFECT •ANTIPYRETICS, INHLALATION GLUCOCORTICOIDS IN ASTHMA… 6. GENETIC FACTORS •FARMAKOGENETICS • GENETIC POLYMORPHISMS OF CYP450 • SLOW VS. EXTENSIVE METABOLISERS FACTORS RELATED TO BOTH, DRUG AND PACIENT 1. DOSE 2. REPEATED DRUG ADMINISTRATION 3. COMBINATION OF DRUGS 4. LATE EFFECTS 1. DOSE 2. REPEATED DRUG ADMINISTRATION • MAY LEAD TO STRONGER EFFECT • CUMULATION • RECEPTOR SENZITIZATION • MAY LEAD TO WEAKER EFFECT • TOLERANCE • TACHYPHYLAXIS 3. COMBINATIONS OF DRUGS • SEE INTERACTIONS LATER 4. LATER EFFECTS • THERE IS A LONG INTERVAL BETWEEN THE DOSE AND THE EFFECT • TERATOGENICITY • MUTAGENICITY • CANCEROGENICITY ADVERSE EFFECTS OF DRUGS ADVERSE EFFECTS (AE) OF DRUGS = ANY UNINTENDED ADVERSE REACTION TO ANY DOSE ADMINISTRATION ▪ ADVERSE EFFECTS OF DRUGS ARE THE CAUSE OF UP TO 6 % OF ALL HOSPITALISATIONS AE FREQUENCY - SPC • VERY COMMON (WITH OCCURRENCE FREQUENCY ≥10 %) • COMMON (1 %- 10 %) • UNCOMMON (0.1 % - 1 %) • RARE (0.01 %- 0.1 %) • VERY RARE (< 0,01 %) ADVERSE EFFECTS 1. TYPE A (AUGMENTED) - DOSE-DEPENDENT, PREDICTABLE 2. TYPE B (BIZARRE) - DO NOT FOLLOW FROM THE MECHANISM OF ACTION 3. TYPE C (CONTINUING, CONTINUOUS, CHRONIC) CONSEQUENCE OF LONG-TERM DRUG USE 4. TYPE D (DELAYED) - MANIFESTED AFTER A LONGER INTERVAL FROM THE DRUG ADMINISTRATION 5. TYPE E (END OF USE) - MANIFESTED AFTER THE DRUG DISCONTINUATION TYPE A - AUGMENTED • INTENSIFIED “NORMAL”, OR NATURAL DRUG EFFECTS OBSERVED FOR USUAL THERAPEUTIC DOSES • PREDICTABLE • BREATHING ATTENUATION BY OPIOIDS, BLEEDING AFTER WARFARIN ADMINISTRATION, ETC. TYPE B - BIZARRE • UNEXPECTED DRUG RESPONSES • DO NOT FOLLOW FROM THE MECHANISM OF ACTION • OCCURRENCE IS RARE • INCLUDE ALLERGIC REACTIONS OR IDIOSYNCRASY ABNORMAL DRUG RESPONSE DUE TO A GENETIC DEVIATION TYPE C – CHRONIC ADMINISTRATION • CONSEQUENCE OF LONG-TERM DRUG USE • MAY BE ADDITIVE BY NATURE (CUMULATIVE EFFECT OF LONG-TERM USE OF EVEN LOW THERAPEUTIC DOSES) • NEPHROTOXICITY OF CERTAIN NON-STEROIDAL ANTIPHLOGISTICS (MAINLY PHENACETIN) OR OSTEONECROSIS OF THE JAWBONE AFTER ADMINISTRATION OF BISPHOSPHONATES TYPE D - DELAYED • MANIFESTED AFTER A LONGER INTERVAL FROM THE DRUG ADMINISTRATION • THEIR CAUSALITY IS DIFFICULT TO PROVE • LEUCOPENIA FOLLOWING ADMINISTRATION OF CYTOSTATIC LOMUSTINE OR LATE PROCARCINOGENIC AND TERATOGENIC EFFECTS OF SOME CYTOSTATICS OR HORMONES TYPE E – END OF USE • REBOUND PHENOMENON - CAUSED BY ADAPTATION MECHANISMS ON THE RECEPTOR SIDE AFTER LONGTERM ADMINISTRATION OF RECEPTOR ANTAGONISTS (CAUSING UP-REGULATION, OR RECEPTOR NUMBER INCREASE). • INSOMNIA AND ANXIETY AFTER DISCONTINUATION OF BENZODIAZEPINES OR HYPERTENSION AFTER DISCONTINUATION OF BETA BLOCKERS DRUG-DRUG INTERACTIONS DRUG-DRUG INTERACTIONS • EFFECT OF A CONCURRENTLY ADMINISTERED DRUG ON ANOTHER DRUG • ALSO INCLUDES INTERACTIONS BETWEEN DRUGS AND FOOD SUPPLEMENTS OR BETWEEN DRUGS AND FOOD DRUG INTERACTIONS ▪ADITIVE: 1+1=2 ▪SYNERGISTIC: 1+1=3 ▪POTENCIATION OF EFFECT: 1+0=2 ▪ANTAGONISTIC: 1+1=0 DRUG-DRUG INTERACTIONS •INTERACTIONS CAN BE DIVIDED TO PHARMACEUTICAL, PHARMACOKINETIC AND PHARMACODYNAMIC PHARMACEUTICAL DRUG-DRUG INTERACTIONS •OCCUR ALSO OUTSIDE OF THE BODY •E.G. IN AN INFUSION BAG PHARMACODYNAMIC DRUG-DRUG INTERACTIONS •OPPOSITE MECHANISM OF ACTION •E.G. SYMPATOMIMETIC AND PARASYMPATOMIMETIC DRUG TOGETHER PHARMACOKINETIC DRUG-DRUG INTERACTIONS • MOST COMMON • ON LEVEL OF: • ABSORPTION (INHIBITION OF ENTEROHEPATAL RECIRCULATION) • DISTRIBUTION (BINDING TO PLASMA PROTEINS) • METABOLISM (CYP) • EXCRETION (COMPETITION ON TUBULAR TRANSPORTERS) INTERACTIONS ON CYP INDUCERS OF CYP 450 • DEXAMETHASONE • PHENOBARBITAL • RIFAMPICINE • PHENYTOINE • ST. JOHNS WORT (HYPERICUM PERFORATUM) INHIBITORS OF CYP 450 • ANTIDEPRESSANTS (FLUOXETINE) • CHININE, CHINIDINE • CHLORAMPHENICOL, ERYTROMYCINE • KETOKONAZOLE, ITRAKONAZOLE • GRAPEFRUIT JUICE DRUG DEVELOPMENT DRUG DEVELOPMENT 1. SYNTHESIS • NATURAL RESOURCES • HERBS • ANIMAL TISSUES (HEPARIN) • MICROORGANISMS (PENICILIN) • HUMAN CELLS • BIOTECHNOLOGY (INSULIN) • DRUG DESIGN = BASED ON STRUCTURE – EFFECT RELATIONSHIP 2. PRECLINICAL TESTING • CELL CULTURES • ISOLATED ORGANS • ANIMALS 3. CLINICAL TRIALS • PHASE 1 – HEALTHY VOLUNTEERS • PHASE 2 – SMALL GROUP OF PATIENTS • PHASE 3 – BIG TRIALS • PHASE 4 – AFTER MARKETING (WHEN THE DRUG REACHED MARKET) PHASE 1 – HEALTHY VOLUNTEERS • ESTABLISHING THE EFFECXT OF THE DRUG ON BODILY FUNCTIONS • PHARMACOKINETIC DETAILS • SAFETY! • DOSE SELECTION • ACUTE DOSE ONLY • PARTICIPANTS MAY RECEIVE MONEY PHASE 2 – PILOT STUDY • FIRST ADMINISTRATION TO REAL PATIENTS • ASSESSMENT OF DRUG EFFICACY, ADVERSE REACTIONS, PHARMACOKINETICS IN PATIENTSM REPEATED ADMINISTRATION • DEFINITION OF INDICATIONS, CONTRAINDICATIONS • NO FINANTIAL REWARD PHASE 3 – EXTENSIVE CLINICAL TRIAL • HUNDREDS TO THOUSANDS OF PATIENTS • ASSESSMENT OF EFFICACY AND SAFETY COMPARED TO ACTIVE TREATMENT OR PLACEBO = CONTROLLED CLINICAL TRIAL • RANDOMIZED • SINGLE X DOUBLE BLIND OR OPEN LABEL • MULTICENTRIC • REQUIRED FOR SPC REDACTION AND MARKETING AUTHORIZATION PHASE 4 – POSTMARKETING STUDY • AT LEAST 5 YEARD FROM REGISTRATION • VERIFICATION OF EFFICACY • DETAILED ASSESSMENT OF ADVERSE EFFECTS IN MANY DIFFERENT PACIENT POPULATIONS • COMPARISON TO STANDARD TREATMENT • POSSIBILITY OF MARKET WITHDRAWAL • FIELD OF PHARMACOLOGY: PHARMACOVIGILANCE