1. Factors Involved In Drug Activity Ján Mojžiš Department of Pharmacology Medical Faculty, UPJŠ Košice

2. 1 Overview I. Factor related to the drug a) dose b) way of administration c) drug formulation II. Factors related to the organism a) age b) body weight c) gender d) genetic factors e) diseases f) drug interactions

3. 2 Way of administration Local application local effect e.g. plv, ung, crm, pst, tbl vag, gtt oph/nas/oto systemic effect. e.g. patches or spr. with analg. or hormones Enteral administration Orally: tbl, cps, non-steril., effect of food and pH, first pass effect Sublingually: tbl slg, rapid effect Rectally: supp, first pass effect -/+, in vomiting, children

4. 3 Way of administration Parenteral administration Intravenously: inj. apyr. steril. H 2 O-solutions, bolus, infusion Intramuskularly: inj. apyr. steril. susp., emuls. Subcutaneously: inj. Inhalatory: gas, vapour, aerosol (anesthesiology, asthma) Others: intraarterially, intrathecally, intracardially, etc. Onset of action: i.v. > i.m. > s.c. > per os

5. 4 Overview Age Gender Genetics Disease Repeated (intermittent, continuous) dosing Drug interactions

6. 5 Age ChildrenElderly Absorption HCl, empting. HCl, empting., atrophy circulation motil. Albumin bound in comparison with adults. (compet. with bilirub.) albumins Volume of distribution extracel. water. extracel. water., Metabolism conjug., plasm. ester. liver diseases Excretion glom. filtr. and tub. sekr. glom. filtr.

7. 6 children are not miniature adults in terms of drugs handling: differences in pharmacokinetics at birth extracellular volume is rather large while all renal mechanisms (filtration, secretion and reabsorption) are reduced hepatic microsomal enzymes system is relatively immature (mainly in the preterm infants) Drugs in infants and children

8. 7 plasma half-life of gentamicin eliminated by the kidney: t 1/2 hours premature infants < 48 h old 18 5-22days old 6 normal infants 1-4 weeks old 3 adults 2 chloramphenicol - gray baby syndrome

9. 8 Postnatal development of specific hepatic and renal function

10. 9 differences in pharmacodynamics higher dose of antihistamines can cause excitation of the CNS (convulsion) in children while sedation in adults Breast-feeding can lead to toxicity in the child if the drug enters the milk in pharmacological quantities milk is weakly acidic, so drugs that are weak bases are concentrated in breast milk. some drugs to be avoided: amiodarone, aspirin, benzodiazepines. Drugs in infants and children

11. 10 differences in pharmacokinetics in healthy individuals aged over 70, GF rate is <60-70 ml/min tubular function also declines with age Drugs that are mainly excreted via the kidney are likely to a c c u m u l a t e in patients in their seventies and eighties if given in doses suitable for young adults. Examples of drugs requiring dose adjustment in the elderly: aminoglycosides, atenolol, diazepam, digoxin, oral hypoglycemic agents, warfarin, NSAIDs Drugs in elderly

12. 11 Drugs in elderly differences in pharmacodynamics clotting factors synthesis by the liver is reduced and old people often require lower warfarin doses for effective anticoagulation than young people

13. 12 GENDER- pregnancy DRUGS IN PREGNANCY the use is complicated by the potential for harmful effects on the growing fetus, and altered maternal physiology. What are main conditions? In the placenta maternal blood is separated from fetal blood flow by a cellular membrane. Drugs can cross it by passive/active transport There are multiple placental enzymes, primarily involved with endogenous steroid metabolism, which may also contribute to drug metabolism.

14. 13 Factors that can influence the effects of drugs on the fetus: the stage of gestation, the type of the placenta the age of mother properties of drugs GENDER- pregnancy

15. 14 the stage of gestation fertilization and implantation organogenesis/embryonic stage fetogenic state delivery GENDER- pregnancy

16. 15 fertilization and implantation ( < 17 days) animal studies suggest that interference with the fetus causes abortion, i.e. if pregnancy continues the fetus is unharmed GENDER- pregnancy

17. 16 organogenesis/embryonic stage (17 -57 days) at this stage the fetus is differentiating to form major organs this is the critical period for teratogenesis. teratogens cause deviations or abnormalities in the development to embryo that are compatible with prenatal life and are observable postnatally drugs that interfere with organogenesis can cause gross structural defects confirmed, suspected and potencial teratogens GENDER- pregnancy

18. 17 C o n f i r m e d teratogens (in h u m a n s): thalidomide (phocomelia), cytostatics-antimetabolites, lithium (cardiac defects), warfarin (chondrodysplasia punctata), sex hormones (cardiac defects, multiple abnormalities) S u s p e c t e d teratogens (evidence is inconclusive, the impact of diseases?): antiepileptics (phenytoin, carbamazepine- craniofacial defects), P o t e n t i a l teratogens (in a n i m a l s): chemotherapeutics (metronidazole), sulphonamides- trimethoprim GENDER- pregnancy

19. 18 Gross malformations thalidomide - phocomelia

20. 19 fetogenic state - at this stage the fetus undergoes further development and maturation. Even if organogenesis is almost complete, drugs can still have significant untoward effects on fetal growth and development ACEI – fetal and neonatal renal dysfunction TTC - inhibit growth of fetal bones and stain teeth), opioids and cocaine taken regularly - fetal drug dependence warfarin - intracerebral bleeding aminoglycosides - fetal VIII th nerve damage GENDER- pregnancy

21. 20 delivery some drugs can cause particular problems pethidine – administered as an analgesic can cause fetal apnea, warfarin – it predisposes to cerebral haemorrhage during delivery GENDER- pregnancy

22. 21 Summary and recommendations Prescribing in pregnancy is a balance between the risk of unwanted effects on the fetus and the risk of leaving maternal disease untreated. The effects on the human fetus are not reliably predicted by animal experiments. However, untreated maternal disease may cause morbidity and /or mortality to mother and/or fetus GENDER- pregnancy

23. 22 THEREFORE: MINIMIZE PRESCRIBING use tried and tested drugs whenever possible to new agents use the SMALLEST EFFECTIVE DOSE warn the patient about the risks of smoking, alcohol, over-the counter drugs - OTC- and DRUGS OF ABUSE

24. 23

25. 24 Renal failure Cardiac failure Liver disease Disease

26. 25 permeability of the BBB (uremia) is enhanced - increased access of drugs to the CNS (cimetidine causes confusion) renal excretion is reduced in relation to GF Drugs (and their metabolites) excreted predominantly by the kidney accumulate in renal failure: aminoglycosides, digoxin, lithium, enalapril, atenolol, methotrexate usual doses can therefore result in elevated plasma concentrations and impaired elimination- accumulation and intoxication Renal failure

27. 26 distribution - in compounds with large Vd distribution decreases (probably caused by decreased tissue perfusion and impaired elimination). Usual doses can therefore result in an elevated plasma concentrations, producing toxicity (lidocaine, quinidine) elimination by liver and /or kidney is diminished: decreased hepatic perfusion accompanies reduced cardiac output (theophylline) reduced glomerular filtration (aminoglycosides, digoxin) Cardiac failure

28. 27 Prescribing for patients with liver disease: if possible, use drugs that are eliminated by routes other than the liver drug effects should be monitored (and therapy adjusted accordingly) predictable hepatotoxins (cytostatic drugs) should only be used for the strongest of indications avoid drugs that interfere with hemostasis (anticoagulants, aspirin) Liver disease

29. 28 PHARMACOGENETICS The study of genetically controlled variations in drug response Efficacy Toxicity

30. 29 GENETIC POLYMORPHISMS PharmacokineticPharmacodynamic Transporters Plasma protein binding Metabolism Receptors Ion channels Enzymes Immune molecules

31. 30 Pharmacokinetic GP

32. 31 Cytochrom P 450 and drug metabolism EnzymeDrug metabolised (%) CYP2A63 CYP2B63 CYP2E14 CYP2C198 CYP1A1/211 CYP2C8/916 CYP2D619 CYP3A4/536

33. 32 ROLE OF CYP ENZYMES IN HEPATIC DRUG METABOLISM RELATIVE HEPATIC CONTENT OF CYP ENZYMES % DRUGS METABOLIZED BY CYP ENZYMES

34. 33 CYP2D6 catalysis of hydroxylation or demetylation in the liver -blockers, antidysrhytmics antipsychotics, antidepresants antiemetics Analgetics – codeine, dihydrocodeine, dextrometorphan hydrocodone, oxycodone, tramadol

35. 34 Extensive metabolism (EM) – typical for most of the pts. Poor metabolism (PM) – mutation and/or deletion of both alleles – drug cummulation Ultra extensive metabolism (UEM) – increased gene amplification – increased drug metabolism Polymorphism CYP2D6

36. 35 CYP2D6 – incidence (%) WhiteAsiatsBlackS. Arabia PMUEMPMUEMPMUEMPMUEM 7-101-1010-20-2021-210-29

37. 36 Codeine - metabolism 10 % - demethylated in the liver to morphine analgetic effect PM – low rate of demethylation – weak/no analgetic efect respiratory, psychomotoric effects are also weaker Risk of dependence in PM

38. 37 Tramadol moderate – severe pain agonist of -opioid receptors inhibition of re-uptake NA release of 5-HT

39. 38 Tramadol-metabolism main metabolic pathway – demetylation to O- desmethyltramadol (CYP2D6) 200 x affinity to -receptorom PM O-desmethyltramadol weak analgetic activity of tramadol

40. 39 Tiopurine methyltransferase (TPMT) caucasoid population: cca 89% activity (homoz., wild type) 11% moderate activity (heteroz. with variant allele) 1 from 300 pts /0 activity (homoz., mutant alleles) in pts. with activity of TPMT cumulation of active metabolites (6-TGn) in haematopoetic system – risk of hematotoxcity metabolism of mercaptopurine, azatioprin, thioguanine

41. 40 Clinical consequences of TPMT polymorphism TMPT H /TMPT L heterozygotes (11%) good therapeutic effects, increased risk of myelosuppression TMPT L / TMPT L homozygotes (0,33%) high risk of toxicity secondary leukemias TMPT H / TMPT H homozygoti (89%) – variabile response

42. 41 Gene productDrugConsequence Dihydropyrimidine dehydrogenase 5-FUneurotoxicity, myelosuppresion Thiopurine methyl- transferase azatioprin, thioguanine A: myelosuppresion Ch: secondary tumors Glutathioóntransfera se Alkylating drugs, TOPO II-i sensitivity to toxic and anticancer effects Glucuronyl transferase Irinotecandiarrhea, myelosuppresion Methylene tetrahy- drofolate reductase MTX risk of mukositis

43. 42 Pharmacodynamic GP

44. 43 Abnormal reactions quantitative changes in receptor: density, structure, function, afinity ( insuline, glucocorticoids) qualitative (idiosyncratic reactions) hereditary defects of some enzymes (rare)

45. 44 Idiosyncratic reactions EnzmeDrugSide effect Deficiciency of G-6-PD Sulfonamides, dapson, nitrofurantoine Hemolytic anemia Deficiency of methemoglobine reductase Nitrites, dapsonMethemoglobinemia, hemolysis

46. 45 -receptor-polymorphism 1. patient 78-y., M, cancer larynx metastasis – back pain morphine 10 mg/day brak therapy – side effect -receptor – wild type 2. pacient 46-y. F, tumor with metastasis morphine 990 mg/day morphine 2000 mg/day epidurally – persistent moderate pain -receptor - mutation Hirota a kol., DMD, 677-680, 2003