Clinical Pharmacokinetics and Pharmacodynamics

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

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

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

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

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

Time to Peak Concentration

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Pharmacodynamics Cellular Level

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

Pharmacodynamics Definitions

Definitions • 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 • 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 • 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

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

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

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

Clinical Practice • 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

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

Clinical Pharmacokinetics and Pharmacodynamics