Toxicokinetics

1. Toxicokinetics Steve Lan Feb 5, 2004 Preceptor: Dr. D.Johnson

2. Overview • Pharmacokinetics vs toxicokinetics • Absorption • Distribution • Metabolism and Elimination • Clinical examples

3. Mr. M • 35 yo M presents with OD attempt • Tyl ES 200 tabs 30 min ago • APAP level has already been sent and comes back “non toxic” • What’s wrong with this level?

4. Pharmacokinetics vsToxicokinetics • Pharmacokinetic principles applied to a poisoned patient

5. Absorption • Definition – extent and rate of substance movement from outside the body to the intravascular compartment

6. Absorption

7. Absorption - Factors • Factors • Route of exposure (GI, skin, lung, IV, intranasal, etc) • Concentration of substance • Chemical/physical properties (state of molecule, non-ionized >ionized, molecule size, pKa, etc.) • Co- ingestions • Medical conditions

8. Example #1 - Cocaine

9. Example #1 - Cocaine Verebey, K. Gold, M. The effect of dose and routes of administration in abuse liability. Psyc Ann. 1988; 18:513-520.

10. Ingestions – GI absorption • Generally passive absorption (Fick’s law) • Key influence – ionization (pKa) • Basic substance – absorbed in small intestine • Acidic substance – absorbed in stomach

11. Fick’s Law dc/dt = k x (C1 – C2) D = diffusion coeffecient A = surface area of absorption membrane K = partition coeffecient H = thickness of membrane D x A x K h K = WBI and cathartics – main principle is to decrease the amount of time the substance is in contact with the absorptive surface

12. GI absorption - alterations • co-ingestion • may increase/decrease gastric emptying (eg maxeran, anticholinergics) therefore alters rate • Binds substance (eg charcoal) • May or may not change amount of drug absorbed • Other factors – • medical conditions (eg CHF and shock which may decrease flow to GI), • concretions (unpredictable breakdown and absorption

13. Activated Charcoal • Significant a decrease in absorption • Depends on • stereochemical/electrochemical characteristics • potential for contact • amount of charcoal compared to substance • time elapsed since the ingestion

14. First Pass Metabolism • Hepatic extraction ratio- proportion of drug metabolized in one pass through the liver • Enzymes may be saturated in overdose • Other changes – cirrhosis, shock, oxidase inducer • Example – Propanolol has extensive 1st pass metabolism

15. First Pass Metabolism-Clinical example • Midazolam for sedation in peds • intranasal ~0.2 mg/kg vs oral ~0.5 mg/kg • larger dose if taken orally b/c of 1st pass effect • also greater variability in clinical effect via oral (difference d/t hepatic metabolism)

16. Bioavailability • percent of active drug that will be absorbed into plasma (takes into account GI absorption and 1st pass) • Expressed as F value

17. Bioavailability- effect of preparation Example - Digoxin

18. Review

19. Distribution • Drugs distribute to different tissues at different rates and extents • Factors • Tissue perfusion • pH • Protein and tissue binding

20. Compartments • Central compartment – • plasma and organs into which drugs rapidly distribute (liver, lung, kidney) • Peripheral compartment (muscle, bone, fat) • Clinical toxicity depends on where sensitive receptors are • Dilantin - Load >50mg/min leads to toxicity as drug rapidly distributes in central compartment

21. Case 1 • 3 yo male • Congenital heart disease • dig level of 12 nMol • K 4.5 • Clinically stable • What is the key question?

22. Case 1 (con’t) • Blood level drawn 1 h after last dose! • Need level after initial distribution phase (level during beta phase) • ~6 h after dose

23. Distribution Alpha Beta Distribution + Elimination IV bolus (1st-order elimination)

24. Volume of Distribution (Vd) Amount of Drug serum [] Amount of drug Vd • Sole determinant of size of loading dose • important determinant of T 1/2 • less variation between individuals • affected by • age • plasma proteins • other drugs competing for binding sites Vd = Serum [] =

25. Volume of Distribution

26. Example #3 – Changin’ the Vd • Digoxin • Large Vd (5-6L/kg) which indicates more drug in tissue than plasma • Fab will bind drug in plasma pulling it out of tissues • Vd is decreased to 0.3L/kg

27. Protein Binding • Plasma proteins – Albumin, glycoprotein, globulins • Protein-binding decreases Vd, tissue binding increases Vd • Most labs measure total drug conc (bound + unbound) • Examples – • Phenytoin, theophylline both highly protein bound • Normal serum levels in hypoalbuminemic pt may be toxic

28. Tissue Binding • Tissues generally have the most pharmocologically active receptor sites • Little known about changes in binding in toxic scenario

29. Lipid Solubility • Highly lipophilic substances • Larger Vd (better penetration of membranes) • Longer duration of action (accumulate in fat, then release)

30. Example #4 – Lipophilic effects • Thiopental – highly lipophilic • Rapid onset of action d/t high initial brain concentration • Rapid distribution into other tissues/fat • If fat compartment “saturated” T1/2 increases to ~9h

31. Review

32. Elimination • Main route – metabolism via different pathways and renal excretion • Others – GI, lungs, sweat, tears • Liver - Max amt of drug metabolized per unit time occurs when enzymes saturated • Kidney – either conc dependent or enzyme mediated

33. Case 2 • 4 yo male with seizure disorder, on dilantin • 3/12 ago • 5.0 mg/kg/d • level 32 mcgMol • increased to 7.0 mg/kg/d • 1/12 ago • level 44 mcgMol • dilantin increased to 9.0 mg/kg/d • Today nystagmus and ataxia (level – 88 mcgMol)

34. Case 2 – what happened? • Normally (@ theraputic level): • Cl is constant, so  infusion =  [] • In this case Cl decreases and serum [ ] ’d more than expected • Elimination changes from 1st order to zero order Infusion rate Serum drug [ ] Clearance =

35. Dilantin kinetics

36. Kinetics • First order (linear) – decline in drug levels is equal to a constant percentage of the remaining drug; enzyme system is not saturated • Zero order – amount of change is constant; enzyme system is saturated • Nonlinear (Michaelis-Menten) – mixture of first and zero-order elimination

37. First order elimination 0.693 Ke T1/2 = Ke = slope

38. 1st Order Absorption and Elimination

39. Comparison of elimination

40. Elimination in Overdose Courtesy of Dr. D Johnson

41. Clearance Infusion rate serum [ ] • Volume of drug cleared per unit time • mainly by kidney (excretion) and liver (biotransformation) • significant intersubject variation • 1st order kinetics - clearance is constant despite varying [ ] Cl =

42. Half life (T 1/2) • For a given drug, T 1/2 variation between pts is mainly d/t variation in Cl Vd Cl T 1/2 

43. T 1/2, Vd, and Cl 2 – ASA 6 – morphine 23 – digoxin 29 – warfarin 32 - phenobarb T 1/2

44. Case 3 • 14 yo female admitted with sickle cell crisis • morphine bolus 0.1 mg/kg • infusion 20 mcg/kg/h • initially comfortable but 1.5h later ++pain • infusion increased to 30 mcg/kg/h

45. Case 3 (con’t) • Pain persists and infusion increased to 40 mcg/kg/h • 2h later pt comfortable • 10 h later - resp arrest • Why?

46. Case 3 1st order kinetics - equilibrium achieved after ~5 half lives T 1/2 morphine - 3+/- 1h

47. Enhancing Renal Elimination • Modifying urine pH • Increases the percentage of drug in renal tubles in the ionized state • Example: alkalinization of urine in ASA toxicity; in theory could acidify urine in amphetamine OD but too risky • Antidotes • Digibind, deferoxamine, cyanide antidote kit all require functioning kidneys to work

48. Hepatic Clearance • Phase 1 – oxidation, reduction, hydrolysis and conjugation with sulfhydryl or amide groups • Can produce hepatotoxins (eg APAP, isoniazid, carbon tetrachloride) • Phase 2- acetylation, sulfation, glucuronidation • Increase polarity of metabolites - increased urinary or biliary elimination

49. Example # 5 – TCA metabolism • TCAs can be classified into tertiary amines (amitriptyline) or secondary amines (desipramine) • Significance – tertiary amines are initially metabolized by N-demethylation into secondary amines • “Dual toxicity”

50. Another Review