Clinical Pharmacokinetics and Pharmacodynamics

1. Clinical Pharmacokinetics and Pharmacodynamics

2. Individualize patient drug therapy Monitor medications with a narrow therapeutic index Decrease the risk of adverse effects while maximizing pharmacologic response of medications Evaluate PK/PD as a diagnostic tool for underlying disease states Why Study Pharmacokinetics (PK) and Pharmacodynamics (PD)?

3. The science of the rate of movement of drugs within biological systems, as affected by the absorption, distribution, metabolism, and elimination of medications Clinical Pharmacokinetics

4. Must be able to get medications into the patient’s body • Drug characteristics that affect absorption: • Molecular weight, ionization, solubility, & formulation • Factors affecting drug absorption related to patients: • Route of administration, gastric pH, contents of GI tract Absorption

5. Gastrointestinal pH changes Gastric emptying Gastric enzymes Bile acids & biliary function Gastrointestinal flora Formula/food interaction Absorption in the Pediatric Patient

6. Time to Peak Concentration

7. Membrane permeability • cross membranes to site of action • Plasma protein binding • bound drugs do not cross membranes • malnutrition = albumin =  free drug • Lipophilicity of drug • lipophilic drugs accumulate in adipose tissue • Volume of distribution Distribution

8. Body Composition •  total body water & extracellular fluid •  adipose tissue & skeletal muscle • Protein Binding • albumin, bilirubin, 1-acid glycoprotein • Tissue Binding • compositional changes Pediatric Distribution

9. Drugs and toxins are seen as foreign to patients bodies Drugs can undergo metabolism in the lungs, blood, and liver Body works to convert drugs to less active forms and increase water solubility to enhance elimination Metabolism

10. Liver - primary route of drug metabolism • Liver may be used to convert pro-drugs (inactive) to an active state • Types of reactions • Phase I (Cytochrome P450 system) • Phase II Metabolism

11. Cytochrome P450 system Located within the endoplasmic reticulum of hepatocytes Through electron transport chain, a drug bound to the CYP450 system undergoes oxidation or reduction Enzyme induction Drug interactions Phase I reactions

12. Hydrolysis Oxidation Reduction Demethylation Methylation Alcohol dehydrogenase metabolism Phase I reactions types

13. Polar group is conjugated to the drug • Results in increased polarity of the drug • Types of reactions • Glycine conjugation • Glucuronide conjugation • Sulfate conjugation Phase II reactions

14. Pulmonary = expired in the air • Bile = excreted in feces • enterohepatic circulation • Renal • glomerular filtration • tubular reabsorption • tubular secretion Elimination

15. Glomerular filtration matures in relation to age, adult values reached by 3 yrs of age Neonate = decreased renal blood flow, glomerular filtration, & tubular function yields prolonged elimination of medications Aminoglycosides, cephalosporins, penicillins = longer dosing interval Pediatric Elimination

16. Steady State: the amount of drug administered is equal to the amount of drug eliminated within one dosing interval resulting in a plateau or constant serum drug level Drugs with short half-life reach steady state rapidly; drugs with long half-life take days to weeks to reach steady state Pharmacokinetic Principles

17. Steady State Pharmacokinetics • Half-life = time required for serum plasma concentrations to decrease by one-half (50%) • 4-5 half-lives to reach steady state

18. Loading Doses • Loading doses allow rapid achievement of therapeutic serum levels • Same loading dose used regardless of metabolism/elimination dysfunction

19. Linear Pharmacokinetics • Linear = rate of elimination is proportional to amount of drug present • Dosage increases result in proportional increase in plasma drug levels

20. Nonlinear Pharmacokinetics • Nonlinear = rate of elimination is constant regardless of amount of drug present • Dosage increases saturate binding sites and result in non- proportional increase/decrease in drug levels

21. Michaelis-Menten Kinetics • Follows linear kinetics until enzymes become saturated • Enzymes responsible for metabolism /elimination become saturated resulting in non-proportional increase in drug levels

22. Renal Disease: same hepatic metabolism, same/increased volume of distribution and prolonged elimination  dosing interval • Hepatic Disease: same renal elimination, same/increased volume of distribution, slower rate of enzyme metabolism  dosage,  dosing interval • Cystic Fibrosis Patients: increased metabolism/ elimination, and larger volume of distribution  dosage,  dosage interval Special Patient Populations

23. Science of assessing genetically determined variations in patients and the resulting affect on drug pharmacokinetics and pharmacodynamics Useful to identify therapeutic failures and unanticipated toxicity Pharmacogenetics

24. Study of the biochemical and physiologic processes underlying drug action • Mechanism of drug action • Drug-receptor interaction • Efficacy • Safety profile Pharmacodynamics

25. “What the drug does to the body” • Cellular level • General Pharmacodynamics

26. Cellular Level Pharmacodynamics

27. Most drugs bind to cellular receptors • Initiate biochemical reactions • Pharmacological effect is due to the alteration of an intrinsic physiologic process and not the creation of a new process Drug Actions

28. Proteins or glycoproteins • Present on cell surface, on an organelle within the cell, or in the cytoplasm • Finite number of receptors in a given cell • Receptor mediated responses plateau upon saturation of all receptors Drug Receptors

29. Action occurs when drug binds to receptor and this action may be: • Ion channel is opened or closed • Second messenger is activated • cAMP, cGMP, Ca++, inositol phosphates, etc. • Initiates a series of chemical reactions • Normal cellular function is physically inhibited • Cellular function is “turned on” Drug Receptors

30. Affinity • Refers to the strength of binding between a drug and receptor • Number of occupied receptors is a function of a balance between bound and free drug Drug Receptor

31. Dissociation constant (KD) • Measure of a drug’s affinity for a given receptor • Defined as the concentration of drug required in solution to achieve 50% occupancy of its receptors Drug Receptor

32. Agonist • Drugs which alter the physiology of a cell by binding to plasma membrane or intracellular receptors • Partial agonist • A drug which does not produce maximal effect even when all of the receptors are occupied Drug Receptors

33. Antagonists • Inhibit or block responses caused by agonists • Competitive antagonist • Competes with an agonist for receptors • High doses of an agonist can generally overcome antagonist Drug Receptors

34. Noncompetitive antagonist • Binds to a site other than the agonist-binding domain • Induces a conformation change in the receptor such that the agonist no longer “recognizes” the agonist binding site. • High doses of an agonist do not overcome the antagonist in this situation Drug Receptors

35. Irreversible Antagonist • Bind permanently to the receptor binding site therefore they can not be overcome with agonist Drug Receptors

36. Definitions Pharmacodynamics

37. Efficacy • Degree to which a drug is able to produce the desired response • Potency • Amount of drug required to produce 50% of the maximal response the drug is capable of inducing • Used to compare compounds within classes of drugs Definitions

38. Effective Concentration 50% (ED50) • Concentration of the drug which induces a specified clinical effect in 50% of subjects • Lethal Dose 50% (LD50) • Concentration of the drug which induces death in 50% of subjects Definitions

39. Therapeutic Index • Measure of the safety of a drug • Calculation: LD50/ED50 • Margin of Safety • Margin between the therapeutic and lethal doses of a drug Definitions

40. Drug induced responses are not an “all or none” phenomenon • Increase in dose may: • Increase therapeutic response • Increase risk of toxicity Dose-Response Relationship

41. What must one consider when one is prescribing drugs to a critically ill infant or child??? Clinical Practice

42. Select appropriate drug for clinical indication • Select appropriate dose • Consider pathophysiologic processes in patient such as hepatic or renal dysfunction • Consider developmental and maturational changes in organ systems and the subsequent effect on PK and PD Clinical Practice

43. Select appropriate formulation and route of administration • Determine anticipated length of therapy • Monitor for efficacy and toxicity • Pharmacogenetics • Will play a larger role in the future Clinical Practice

44. Other factors • Drug-drug interaction • Altered absorption • Inhibition of metabolism • Enhanced metabolism • Protein binding competition • Altered excretion Clinical Practice

45. Other factors (con’t) • Drug-food interaction • NG or NJ feeds • Continuous vs. intermittent • Site of optimal drug absorption in GI tract must be considered Clinical Practice

46. Absorption • PO/NG administered drugs may have altered absorption due to: • Alterations in pH • Edema of GI mucosa • Delayed or enhanced gastric emptying • Alterations in blood flow • Presence of an ileus • Coadministration with formulas (I.e. Phenytoin) Effect of Disease on Drug Disposition

47. Drug distribution may be affected: • Altered organ perfusion due to hemodynamic changes • May effect delivery to site of action, site of metabolism and site of elimination • Inflammation and changes in capillary permeability may enhance delivery of drug to a site • Hypoxemia affecting organ function • Altered hepatic function and drug metabolism Effect of Disease on Drug Disposition

48. Alterations in protein synthesis • If serum albumin and other protein levels are low, there is altered Vd of free fraction of drugs that typically are highly protein bound therefore a higher free concentration of drug • Substrate deficiencies • Exhaustion of stores • Metabolic stress Effect of Disease on Drug Disposition

49. Up regulation of receptors • Down regulation of receptors • Decreased number of drug receptors • Altered endogenous production of a substance may affect the receptors Effect of Disease on PD

50. Altered response due to: • Acid-base status • Electrolyte abnormalities • Altered intravascular volume • Tolerance Effect of Disease on PD