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Factors Involved In Drug Activity

Factors Involved In Drug Activity. Ján Mojžiš Department of Pharmacology Medical Faculty, UPJŠ Ko š ice. I. Factor related to the drug dose way of administration drug formulation. Overview. II. Factors related to the organism age body weight gender genetic factors diseases

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Factors Involved In Drug Activity

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

  2. I. Factor related to the drug dose way of administration drug formulation Overview II. Factors related to the organism • age • body weight • gender • genetic factors • diseases • drug interactions

  3. Way of administration • Local applicationlocal effect e.g. plv, ung, crm, pst, tbl vag, gtt oph/nas/otosystemic effect. e.g. patches or spr.with analg. or hormones • Enteral administrationOrally: tbl, cps, non-steril., effect of food and pH, „first pass effect“Sublingually:tbl slg, rapid effectRectally: supp, first pass effect -/+, in vomiting, children

  4. Way of administration • Parenteral administrationIntravenously: inj. apyr. steril. H2O-solutions, bolus, infusionIntramuskularly: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. Overview Age Gender Genetics Disease Repeated (intermittent, continuous) dosing Drug interactions

  6. Age

  7. Drugs in infants and children • 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)

  8. Drugs in infants and children 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. Postnatal development of specific hepatic and renal function

  10. Drugs in infants and children 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.

  11. Drugs in elderly 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

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

  13. 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. GENDER- pregnancy • 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

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

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

  17. GENDER- pregnancy • 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

  18. GENDER- pregnancy 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

  19. Gross malformations thalidomide - phocomelia

  20. GENDER- pregnancy fetogenic state - at thisstage 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 VIIIth nerve damage

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

  22. GENDER- pregnancy 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

  23. 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. Disease • Renal failure • Cardiac failure • Liver disease

  25. Renal failure 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

  26. Cardiac failure • 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)

  27. Liver disease • 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)

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

  29. GENETIC POLYMORPHISMS Pharmacokinetic Pharmacodynamic • Receptors • Ion channels • Enzymes • Immune molecules • Transporters • Plasma protein binding • Metabolism

  30. Pharmacokinetic GP

  31. Cytochrom P450 and drug metabolism

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

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

  34. Polymorphism CYP2D6 • 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

  35. CYP2D6 – incidence (%)

  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

  37. Tramadol • moderate – severe pain • agonist of -opioid receptors • inhibition of „re-uptake“ NA • release of 5-HT

  38. Tramadol-metabolism • main metabolic pathway – demetylation to O-desmethyltramadol (CYP2D6) • 200 x  affinity to -receptorom • PM O-desmethyltramadol weak analgetic activity of tramadol 

  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

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

  41. Gene product Drug Consequence Dihydropyrimidine dehydrogenase 5-FU neurotoxicity, myelosuppresion Thiopurine methyl-transferase azatioprin, thioguanine A: myelosuppresion Ch: secondary tumors Glutathioóntransferase Alkylating drugs, TOPO II-i  sensitivity to toxic and anticancer effects Glucuronyltransferase Irinotecan diarrhea, myelosuppresion Methylene tetrahy-drofolate reductase MTX risk of mukositis

  42. Pharmacodynamic GP

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

  44. Idiosyncratic reactions

  45. 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 -receptor-polymorphism Hirota a kol., DMD , 677-680, 2003

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