1. Practicals: pharmacokinetics MUDr. P. Potměšil, Ph.D. 1)Quiz 2)Clin. examples and solutions 3)Demonstrations in computer programme 4)Theory

2. Quiz – questions 1/ What is a biological half-life of drug ?

3. Quiz – answers, explanations 1/ What is a biological half-life of drug? After one half-life the concentration of drug will have fallen to half of the initial concentration; after two half-lives it will have fallen to one quarter of the initial concentration and so on.

4. Quiz – questions 2/ What is a biological availability (bioavailability)

5. Quiz – answers, explanations 2/ What is a biological availability (bioavailability) Bioavailability is the fraction of the administered dose of a drug that reaches the systemic circulation.

6. Quiz – answers, explanations 2/ What is a bioavailability Bioavailability can be calculated by comparing the plasma concentration achieved by giving an i.v. dose with the plasma concentration over time following administration of the same dose of a drug given orally. Rate of drug absorption and first-pass metabolism in the liver are main influences on bioavailability.

7. Quiz – questions 3/ What is a distribution volume?

8. Quiz – answers, explanations 3/ What is a distribution volume? The volume in which a drug would need to be uniformly distributed to produce the same concentration throughout the body as found in plasma. V d = Dose / concentration in plasma

9. Distribution volume (apparent) V d is arbitrary value useful as a guide when comparing the relative concentration of the drug in plasma with the rest of the body and should not be thought of as an actual physical volume of fluid.

10. Distribution volume Low Vd indicates drug is mainly distributed in plasma, larger indicates drug has been distributed to additional compartments.

11. Features of drugs that cause them to predominate in each fluid compartment Intravascular (plasma = 4L) Interstitial fluid (14 L) High mol. weight, bound to albumin: Warfarin Benzodiazepines Penicilin Low mol. weight, hydrophilic Epinephrine

12. Features of drugs that cause them to predominate in each fluid compartment Intracellular ( = 42L) Tissue binding (49 L) Low mol. Weight, hydrophobic: ethanol Binds to high affinity site in tissues, high lipid solubility Digoxin Tetracyclines

13. Quiz – questions 4/ What is TDM?

14. Quiz – answers, explanations 4/ What is TDM? Therapeutic drug monitoring For ex.: Digoxin (inotropic drug) Gentamicin (aminoglycoside antibiotic) Valproate (antiepileptic, mood stabiliser) Lithium (mood stabiliser)

15. Clinic example 1: A 53 yrs old man has swollen ankles, shortness of breath, fatigue upon mild exercise. He is observed: -severe pitting edema of lower extremities, distended neck veins with prominent pulsation -Sinus tachycardia 105 beats/min. at rest, normal blood pressure He is diagnosed as being in congestive heart failure renal function is normal (creatinine CL=115 mL/min)

16. Clin. Example 1 - continued If treatment is begun with oral digoxin (inotropic drug) with a maintenance dose 0,25mg once daily how long should you wait before increasing the dose if his initial response appears inadeaquate? You know that biological half-life of digoxin is approx. 36 hours. a/ approx. 2 hours b/ approx. 1 day c/ approx. 2 days d/ approx. 1 week

17. Clin. Example 1 - solution Summary of dosing regimen with digoxin without use of loading dose Initial (starting) dose 0,25mg Maintenance dose 0,25mg Dosing interval: 24 hrs. (once daily) Biol. half life approx. 36 hrs. (1,5 day) Calculation: steady state concentration wil be in plasma after time of 4-5 biol. half-lives 4 x 36/ 24 = 6 days Correct answer in test is: d/ approx. 1 week

18. Clin. Example : solution using programme PK-SIM

19. Graph of digoxine dosing without loading dose (in programme PK-SIM)

20. Dosing of digoxine with loading dose, normal renal function (progr. PK-SIM )

21. Graph of digoxine dosing with loading dose normal renal function (in progr. PK-SIM)

22. Graph of digoxine dosing with loading dose, if renal failure is present (progr. PK-SIM)

23. Graph of digoxine dosing with reduced loading and maintenance dose and prolonged dosing interval, severe renal failure is present

24. Graph of digoxine dosing with reduced loading and maintenance dose and dosing interval 24 hrs, severe renal failure is present

25. Clinical example 2: Cooperating patient with problems of addiction to alcohol desires to try treatment with acamprosate instead of disulfiram. How often should be appropriate to use acamprosate, if we know that biol. half-life of acamprosate is approx. 13 hours? multiple choice test a/ once daily b/ twice daily c/ three times daily

26. Accumulation: dose, dose interval and fluctuation of plasma level

27. Plasma concentrations of drugs with irregular dosing

28. Genetic variants in PK

29. Where can be PK data found? In section 5.2 „Pharmacokinetic properties“ of SPC = summary of product characteristics 5. Pharmacologic properties 5.1 Pharmacodynamic prop. 5.2 Pharmacokinetic prop. SPC is available on the EMA (european medicines agency) web www.ema.europa.eu or web pages of marketing authorisation holder www.ema.europa.eu

30. Recommended literature Rang, Dale, Ritter: Pharmacology 7ed., 2012 Mark A. Simmons: Pharmacology - an illustrated review, 2012

31. Acknowledgements and used literature (information sources) Lectures, presentations: Prof. M. Kršiak MUDr. J. Šedivý, CSc. Prof. J. Bultas Books: Lullman, Mohr: Color atlas of pharmacology, 2011 M. A. Simmons: Pharmacology - illustrated review, 2012

32. Lecture on pharmacokinetics

33. 1. Fate of drugs in the body 1.1 absorption 1.2 distribution - volume of distribution 1.3 elimination - clearance 2. The half-life and its uses 3. The uses of the half-life 4. Plasma concentration-effect relationship M. Kršiak Department of Pharmacology, Third Faculty of Medicine, Charles University in Prague, 2008

34. ABSORPTION DISTRIBUTION ELIMINATION FATE OF DRUGS IN THE BODY ADMINISTERED ABSORBED „HIDDEN“ ELIMINATED ACTING WHAT HAPPENS TO DRUGS INSIDE THE BODY

35. 1.1 ABSORPTION Depends on: lipid solubility ionization (depends on pH) non-ionized (non-polar), local changes in the pH routes of administration - per os - presystemic elimination FIRST-PASS EFFECT - pharmaceutical technology BIOAVAILABILITY, bioequivalence - parenteral

36. FIRST-PASS EFFECT: loss of a drug by a metabolism mostly in the liver that occurs en route from the gut lumen to the systemic circulation e.g. in nitroglycerin, morphine

37. Clinical consequence of the first-pass effect: limited effect after oral administration great interindividual differences in dosage

38. BIOAVAILABILITY: the proportion of drug that reaches the systemic circulation It is usually calculated from the AUC (Area Under the Curve)

39. ABSORPTION DISTRIBUTION ELIMINATION FATE OF DRUGS IN THE BODY ADMINISTERED ABSORBED „HIDDEN“ ELIMINATED ACTING WHAT HAPPENS TO DRUGS INSIDE THE BODY

40. - membrane penetration - protein binding -plasma proteins -tissue proteins ONLY A FREE DRUG ACTS! The bound drug is inactive. Free and bound drug are in equilibrium. Displacement: drug-drug interactions 1.2 DISTRIBUTION Depends on:

41. ABSORPTION DISTRIBUTION ELIMINATION FATE OF DRUGS IN THE BODY ADMINISTERED ABSORBED „HIDDEN“ ELIMINATED ACTING WHAT HAPPENS TO DRUGS INSIDE THE BODY

42. 1.3 ELIMINATION: METABOLIC (biotransformation) mostly in the liver ENZYME INDUCTION/ INHIBITION oxidase enzymes - cytochrom P450 (CYP2D6 etc) GENETIC POLYMORPHISM EXCRETION kidneys metabolites or unchanged (almost completely unchanged e.g. digoxin, gentamycin) GIT... enterohepatic circulation e.g. tetracyclines

43. ABSORPTION depends on - membrane penetration which depends on -lipid solubility - ionization (depends on pH) - routes of administration DISTRIBUTION depends on: ELIMINATION ONLY A FREE DRUG ACTS! FIRST-PASS EFFECT BIOAVAILABILITY - membrane penetration - protein binding - metabolic - excretion FATE OF DRUGS IN THE BODY ADMINISTERED ABSORBED „HIDDEN“ ELIMINATED ACTING WHAT HAPPENS TO DRUGS INSIDE THE BODY

44. protein binding -plasma proteins -tissue proteins ONLY A FREE DRUG ACTS! The bound drug is inactive. Free and bound drug are in equilibrium. Displacement: drug-drug interactions VOLUME OF DISTRIBUTION Depends on:

45. Because the result of the calculation may be a volume greater than that of the body, it is an APPARENT (imaginary, not actual) volume For example, V d of digoxin is about 645 liters for a 70 kg man (i.e. about 9 times bigger than his actual volume) VOLUME OF DISTRIBUTION V d = Amount of drug in body / Concentration of drug in plasma

46. Clinical importance of volume of distribution: When V d of a drug is big it takes long time to achieve effective plasma concentration of the drug. In such cases a loading dose may be given to boost the amount of drug in the body to the required level. This is followed by administration of lower maintenance dose.

47. METABOLIC (biotransformation) mostly in the liver the drug is made more hydrophilic – this increases its excretion in the urine EXCRETION mostly by the kidneys metabolites or unchanged GIT... enterohepatic circulation e.g. tetracyclines

48. CLEARANCE Clearance (CL) is the volume of plasma totally cleared of drug in unit of time (ml/min/kg) CL tot total CL R renal CL H hepatic CL NR nonrenal (= Cl tot - CL R )

49. Bathtube in a hotel with two holes, no plugs, and a plate indicating Vd= 1000 L, CL = 100 mL/min How would you regulate supply of water (water tap) to fill the bath in order to take a bath soon and for a longer time? Example – analogy for utilization of information on volume of distribution (Vd) and clearance (CL):

50. the half-life is the time taken for the plasma concentration to fall by half [plasmatic half-life]

51. Linear kinetics (First order) [t 1/2 is stable] In most drugs after therapeutic doses: plasma concentration falls exponentially The rate of elimination is proportional to the concentration

52. In most drugs after therapeutic doses: plasma concentration falls exponentially because elimination processes are not saturated [some robustness to dose increase ] Elimination is the bigger the higher is the level C max C min Linear kinetics (First order) The rate of elimination is proportional to the concentration

53. Elimination processes are saturated e.g.: in alcohol, after higher doses of phenytoin, theophyllin [unstable t 1/2 ] Non-linear (Zero-order, saturation) kinetics For example, in alcohol the rate of metabolism remains the same at about 1 g of alcohol for 10 kg of body weight per hour The rate of elimination is constant

54. In a few drugs at therapeutic doses or in poisoning, elimination processes are saturated elimination is constant, limited C max C min Non-linear (Zero-order, saturation) kinetics [low robustness to dose increase]

56. T 1/2 as a guide to asses: 1/ At a single-dose: duration of drug action 2/ During multiple dosing: to asses whether a drug is accumulated in the body (it is - if the drug is given at intervals shorter than 1,4 half-lifes) and when a steady state is attained (in 4-5 half-lifes) 3/ After cessation of treatment: to asses the time taken for drug to be eliminated from the body (in 4-5 half-lifes)

57. [t 1/2 = 1 - 2 h] Ampicillin - single dose

58. T 1/2 as a guide to asses: 1/ At a single-dose: duration of drug action 2/ During multiple dosing: to asses whether a drug is accumulated in the body (it is accumulated if the drug is given at intervals shorter than 1,4 half-lifes) and when a steady state is attained (in 4-5 half- lifes) 3/ After cessation of treatment: to asses the time taken for drug to be eliminated from the body (in 4-5 half-lifes) THE USES OF THE HALF-LIFE

59. „PRINCIPLE OF 4-5 HALF-LIFES“: If a drug is administered in intervals shorter than 1.4 half-life, then a steady state is attained after approximately 4-5 half-lifes The time to attain the steady state is independent of dose. Steady state t 1/2 Plasma concentration

60. Attainment of steady state (SS) during multiple dosing of drug at intervals of 1 half- life Why Stead State is attained after 4-5 half-lifes?

61. T 1/2 as a guide to asses: 1/ At a single-dose: duration of drug action 2/ During multiple dosing: to asses whether a drug is accumulated in the body (it is - if the drug is given at intervals shorter than 1,4 half-lifes) and when a steady state is attained (in 4-5 half-lifes) 3/ After cessation of treatment: to asses the time taken for drug to be eliminated from the body (in 4-5 half-lifes) THE USES OF THE HALF-LIFE

62. Elimination of a drug during 5 half-lifes of initial level % of total elimination

63. TIME TO STEADY STATE ( attained after 4-5 half-lifes) independen of dose FLUCTUATIONS proportional to dose intervals blunted by slow absorption STEADY-STATE LEVELS (CONCENTRATIONS) proportional to dose t 1/2 REPEATED ADMINISTRATION OF DRUGS

64. Steady-state concentrations are proportional to dose Linear kinetics - diazepam plasma concentrations daily Time (days) toxic therapeutic

65. Time (days) therapeutic toxic plasma concentrations Non-linear, saturation kinetics - phenytoin daily

66. TIME TO STEADY STATE ( attained after 4-5 half-lifes) independen of dose FLUCTUATIONS proportional to dose intervals blunted by slow absorption STEADY-STATE LEVELS (CONCENTRATIONS) proportional to dose t 1/2 REPEATED ADMINISTRATION OF DRUGS

67. How to reduce fluctuations in drug concentrations? by administering drugs slowly, continually, e.g.: slow i.v. injection, infusion, sustained–release (SR) tablets, slow release from depots (e.g. from patches transdermally, depot antipsychotics injected i.m.) by administering a total dose (e.g. a daily dose) in parts at shorter intervals (mostly inconvenient) or

68. Effects of drug correlate with plasma concentrations Therapeutic Drug Monitoring (TDM) (eg. gentamicin, lithium, some antiepileptics) do not correlate with plasma concentrations - „hit and run“ - tolerance or sensitisation - active metabolites

69. The *.ppt set of this lecture will appear at: http://vyuka.lf3.cuni.cz 1st Teaching Unit (ID9234)