This document discusses clinical pharmacokinetics and pharmacodynamics. It defines pharmacokinetics as how the body affects a drug through absorption, distribution, metabolism and elimination. Factors like age can impact these processes in pediatric patients. It also discusses pharmacodynamics, how drugs act on the body, and how pharmacokinetics and pharmacodynamics together can help individualize drug therapy and decrease adverse effects.

1. Clinical Pharmacokinetics and Pharmacodynamics Janice E. Sullivan, M.D. Brian Yarberry, Pharm.D.

2. Why Study Pharmacokinetics (PK) and Pharmacodynamics (PD)? 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

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

4. Absorption 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

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

6. Time to Peak Concentration

7. Distribution 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

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

9. Metabolism 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

10. Metabolism 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

11. Phase I reactions 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

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

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

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

15. Pediatric Elimination 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

16. Pharmacokinetic Principles 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

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. Special Patient Populations 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

23. Pharmacogenetics 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