Pharmacokinetics and Pharmacodynamics.pptx

Basics of Pharmacokinetics and Pharmacodynamics

1. Principles of Pharmacokinetics and pharmacodynamics Dr. Georgie A. Martin, Jr. Level I Resident

2. To define Pharmacokinetics and Pharmacodynamics Identify biologic and pharmacologic factors that influence the Absorption, Distribution, and Elimination of Drugs Identify factors that determine the relationship between drug concentration and pharmacologic effect Apply these concepts to describe clinically important drug-drug interaction Apply the principles of Pharmacokinetic and Pharmacodynamics to determine the target concentration of drugs for adequate anesthetic state

3. Relationship between Drug Concentration and Time Relationship between Drug Concentration and Effect

4. PHARMACOKINETIC PATHWAY Major processes involved in: ABSORPTION DISTRIBUTION METABOLISM ELIMINATION

5. PHARMACOKINETIC PATHWAY Major processes involved in: ABSORPTION DISTRIBUTION METABOLISM ELIMINATION

6. PHARMACOKINETIC PATHWAY Major processes involved in: ABSORPTION DISTRIBUTION METABOLISM ELIMINATION

7. Principles of pharmacokinetics Drugs n e ed t o c r os s c e ll me m bra n es i n o r der t o p r odu c e their effects Lipophilic Compounds Hydrophilic Compounds

8. Principles of pharmacokinetics Drugs n e ed t o c r os s c e ll me m bra n es i n o r der t o p r odu c e their effects Lipophilic Compounds Hydrophilic Compounds Lipophilic Compounds Passive diffusion Concentration gradient decreased by transporters p-glycoprotein Organic anion polypeptide transporters

9. Principles of pharmacokinetics Drugs n e ed t o c r os s c e ll me m bra n es i n o r der t o p r odu c e their effects Lipophilic Compounds Hydrophilic Compounds Hydrophilic Compounds Passive diffusion thru Nonspecific hydrophilic channels

10. Principles of pharmacokinetics Drugs n e ed t o c r os s c e ll me m bra n es i n o r der t o p r odu c e their effects Hydrophilic Compounds in the CNS Shuttle compound against its concentration gradient Active Transport – requires energy Facilitated Diffusion – does not require energy

11. PHARMACOKINETIC PATHWAY: administration INTRAVENOUS ADMINISTRATION Immediate delivery with 100% Bioavailability Bioavailability - relative amount of a drug dose that reaches the systemic circulation unchanged and the rate at which this occurs

12. ORAL ADMINISTRATION Safest and most convenient method Absorption rate is dependent on gastrointestinal tract Extensive First Pass Metabolism and Bioavailability is reduced PHARMACOKINETIC PATHWAY: administration

13. TRANSCUTANEOUS ADMINISTRATION Few lipophilic drugs – sufficient enough to penetrate intact skin. Available as drug patches. The time taken to achieve therapeutic level limits its practical use and preferred for maintenance therapy. PHARMACOKINETIC PATHWAY: administration

14. INTRAMUSCULAR AND SUBCUTANEOUS ADMINISTRATION Dependent upon drug dose and blood flow on area of administration Intramuscular > Subcutaneous Subcutaneous – variation in onset and duration PHARMACOKINETIC PATHWAY: administration

15. INHALATIONAL ADMINISTRATION Large surface area of the pulmonary alveoli and large amount of blood flow PHARMACOKINETIC PATHWAY: administration

16. PHARMACOKINETIC PATHWAY Major processes involved in: ABSORPTION DISTRIBUTION METABOLISM ELIMINATION

17. PHARMACOKINETIC PATHWAY: distribution Tissue group Composition Body mass % Cardiac output % Vessel rich Brain,heart,liver, kidney , endocrin e gl a nds 10 75 Muscle Muscle,skin 50 19 Fat Fat 20 6 Vesselpoor Bone, ligament, cartilage 20

18. PHARMACOKINETIC PATHWAY: distribution

19. PHARMACOKINETIC PATHWAY: distribution COMPARTMENTAL PHARMACOKINETIC A mathematical model – divides the body into compartments and characterize the blood concentration of the drug Use to quantify drug distribution and elimination – volume of distribution, clearance and half-lives Does not include cardiac output as a parameter

20. PHARMACOKINETIC PATHWAY: distribution ONE COMPARTMENT MODEL The body is a single homogenous compartment Drug distribution is instantaneous Drug elimination is constant

21. PHARMACOKINETIC PATHWAY: distribution

22. PHARMACOKINETIC PATHWAY: distribution ONE COMPARTMENT MODEL

23. PHARMACOKINETIC PATHWAY: distribution TWO COMPARTMENT MODEL Central compartment where the drug is administered Peripheral compartment where some of the drug is distributed

24. PHARMACOKINETIC PATHWAY: distribution

25. PHARMACOKINETIC PATHWAY: distribution TWO COMPARTMENT MODEL

26. PHARMACOKINETIC PATHWAY: distribution THREE COMPARTMENT MODEL Highly fat soluble drug Fat compartment acts as reservoir for the drug

27. PHARMACOKINETIC PATHWAY: distribution THREE COMPARTMENT MODEL

28. PHARMACOKINETIC PATHWAY: distribution VOLUME OF DISTRIBUTION Quantifies the extent of the drug distribution Physiologic factor: Overall uptake capacity of the tissue Capacity of the blood Relates the total amount of drug present in the concentration observed in the central compartment

29. PHARMACOKINETIC PATHWAY: distribution VOLUME DISTRIBUTION Lipophilic drugs have larger volume of distribution than hydrophilic drugs  

30. PHARMACOKINETIC PATHWAY: distribution VOLUME DISTRIBUTION Loading dose can be calculated by rearranging the equation  

31. PHARMACOKINETIC PATHWAY Major processes involved in: ABSORPTION DISTRIBUTION METABOLISM ELIMINATION

32. PHARMACOKINETIC PATHWAY: metabolism Pharmacologically active lipid soluble drugs are converted into water soluble and often pharmacologically inactive metabolites Sites of metabolism Liver is the most metabolically active tissue Gut wall, Lungs, Kidney and Plasma

33. PHARMACOKINETIC PATHWAY: metabolism PHASE I REACTIONS Hydrolysis – insertion of a molecule of water into another molecule Oxidation – removes electrons from a molecule; inserts hydroxyl group (-OH) into the drug molecule Dealkylation – removal of a carbon group Deamination – removal of nitrogen containing group Reduction – adding an electron molecule

34. PHARMACOKINETIC PATHWAY: metabolism PHASE I REACTIONS Cytochrome P45O Enzyme – catalyze most Phase I reactions CYP3A4 accounts for 40% to 45% of all CYP mediated drug metabolism Found in: Smooth endoplasmic reticulum of hepatocytes Membrane of upper intestinal enterocytes

35. PHARMACOKINETIC PATHWAY: metabolism PHASE I REACTIONS Cytochrome P45O Enzyme – catalyze most Phase I reactions Two fundamental characteristics: Broad substrate specificity Induction of different CYP Isoenzymes Inhibited by substrate competing with the drug-binding site

36. PHARMACOKINETIC PATHWAY: metabolism PHASE II REACTIONS Conjugation or synthetic reactions Endogenous compounds: glucuronic acid, acetate and amino acid Produces conjugates that are polar, and water soluble

37. PHARMACOKINETIC PATHWAY Major processes involved in: ABSORPTION DISTRIBUTION METABOLISM ELIMINATION

38. PHARMACOKINETIC PATHWAY: excretion CLEARANCE Volume of plasma from which drug is completely and irreversibly removed in a given time interval Clearance depends on the drug, blood flow and condition of the organs of elimination.  

39. PHARMACOKINETIC PATHWAY: excretion The total clearance is the sum of each clearance by metabolic organs Major organs involved in Drug Clearance: Kidney (Renal Clearance) Liver (Hepatic Clearance)

40. PHARMACOKINETIC PATHWAY: excretion RENAL DRUG CLEARANCE Excrete through the urine unchanged, hydrophilic and hepatic metabolites from Phase I and Phase II reactions of lipophilic drugs Dependent on renal function

41. RENAL DRUG CLEARANCE Proximal tubule – actively transport organic acids and bases Tubular reabsorption – passive reabsorption of lipophilic drug and active, carrier mediated reabsorption of hydrophilic drugs PHARMACOKINETIC PATHWAY: excretion

42. PHARMACOKINETIC PATHWAY: excretion HEPATIC DRUG CLEARANCE Depends on the intrinsic ability of the liver to metabolize drug Amount of drug available to diffuse into the liver Assumes that all drug delivered to liver is available for extraction The elimination is constant fraction per unit of time

43. PHARMACOKINETIC PATHWAY: excretion Hepatic Extraction Ratio: Fraction of blood passing through the liver Where:  

44. PHARMACOKINETIC PATHWAY: excretion Total Hepatic Clearance: Function of the hepatic blood flow and the ability of the liver to extract drug from the blood Where:  

45. PHARMACOKINETIC PATHWAY: excretion HEPATIC DRUG CLEARANCE The ability to extract drug depends on: Activity of drug metabolizing enzyme Capacity of hepatobiliary excretion – the intrinsic clearance of the liver Intrinsic clearance – ability of the liver to remove drug from the blood in the absence of any limitations imposed by blood flow or drug binding

46. PHARMACOKINETIC PATHWAY: excretion Intrinsic Clearance: Where:  

47. PHARMACOKINETIC PATHWAY: excretion Intrinsic Clearance: Where:  

48. PHARMACOKINETIC PATHWAY: excretion HEPATIC DRUG CLEARANCE Hepatic clearance and extraction are determined by two independent variable: Intrinsic Clearance Hepatic blood Flow

49. PHARMACOKINETIC PATHWAY: excretion ELIMINATION KINETICS Zero Order Kinetics - e limination of a constant quantity per time unit of the drug quantity present in the organism. First Order Kinetics - e limination of a constant fraction per time unit of the drug quantity present in the organism. The elimination is proportional to the drug concentration.

50. PHARMACOKINETIC PATHWAY: excretion Zero-order elimination kinetics : The plasma concentration – time profile during the elimination phase is linear. For example 1.2 mg are eliminated every hour, independently of the drug concentration in the body. Zero order elimination is rather rare, mostly occurring when the elimination system is saturated. An example is the elimination of Ethanol.

51. PHARMACOKINETIC PATHWAY: excretion First-order elimination kinetics : For first order elimination, the plasma concentration – time profile during the elimination phase shows an exponential decrease in the plot with linear axes and is linear if plotted on a semi-logarithmic plot (plasma concentration on logarithmic axis and time on linear axis). For example, 1% of the drug quantity is eliminated per minute. Many drugs are eliminated by first order kinetics.

52. PHARMACOKINETIC PATHWAY: excretion First-order elimination kinetics : For first order elimination, the plasma concentration – time profile during the elimination phase shows an exponential decrease in the plot with linear axes and is linear if plotted on a semi-logarithmic plot (plasma concentration on logarithmic axis and time on linear axis). For example, 1% of the drug quantity is eliminated per minute. Many drugs are eliminated by first order kinetics.

53. PHARMACOKINETIC PATHWAY: excretion First order Zero order Curve in the plasma concentration vs. time plot after IV bolus Exponential decay Linear Curve in the log plasma concentration vs. time plot after IV bolus Linear Non-linear Relation between elimination rate and drug concentration Elimination rate is proportional to drug concentration Elimination rate saturates with higher drug concentration< Term in clinical pharmacology Linear kinetics Non linear kinetics Concerns 95 % of drugs, at therapeutic concentrations The remaining 5 %, and ethanol

54. pharmacodynamic PATHWAY Physiologic effect of drugs and the molecular mechanisms by which those effects are produced What drugs do to the body? How do they do it?

55. Agonist and antagonist Target Structure/s Effect Drug Type Endogenous Substance Enzymes Receptors Activation Agonist Effector Signaling molecule Inhibition Antagonist Inhibitor

56. Agonist and antagonist AGONIST – drugs that binds to receptors and produce an effect DIRECT AGONIST – binds to receptor and mimics effect of endogenous signaling molecule INDIRECT AGONIST – enhances the effect PARTIAL AGONIST – drugs not capable of producing maximal effect

57. Agonist and antagonist ANTAGONIST – compounds that bind receptors without producing any changes in cellular function COMPETITIVE – bind reversibly to receptors; can be overcome by high concentration of agonist NONCOMPETITIVE – bind irreversibly to receptors; reversed only by synthesis of new receptors

58. Agonist and antagonist

59. pharmacodynamic PATHWAY EFFICACY Maximal response a drug can produce Depend on the number of drug receptor complexes formed and the efficiency they produce a cellular action A compound may bind to a receptor and have a zero efficacy. Not elicit a response, and may act as antagonist

60. pharmacodynamic PATHWAY POTENCY A measure of how much drug is required to elicit a given response The lower the dose required for a given response the more potent the drug

61. TOXICITY CURVE LETHAL DOSE the amount of drug that is lethal IN 100% of exposed population

62. Therapeutic index THERAPEUTIC INDEX important measure of the safety of the drug

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