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Clinical Pharmacokinetics and Pharmacodynamics

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Slide 1 :

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

Slide 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

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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

Slide 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

Slide 5 :

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

Slide 6 :

Time to Peak Concentration

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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

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

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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

Slide 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

Slide 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

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

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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

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

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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

Slide 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

Slide 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

Slide 18 :

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

Slide 19 :

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

Slide 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

Slide 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

Slide 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

Slide 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

Slide 24 :

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

Slide 25 :

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

Slide 26 :

Pharmacodynamics Cellular Level

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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

Slide 28 :

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

Slide 29 :

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”

Slide 30 :

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

Slide 31 :

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

Slide 32 :

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

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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

Slide 34 :

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

Slide 35 :

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

Slide 36 :

Pharmacodynamics Definitions

Slide 37 :

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

Slide 38 :

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

Slide 39 :

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

Slide 40 :

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

Slide 41 :

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

Slide 42 :

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

Slide 43 :

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

Slide 44 :

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

Slide 45 :

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

Slide 46 :

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)

Slide 47 :

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

Slide 48 :

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

Slide 49 :

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

Slide 50 :

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

Slide 51 :

Management of Drug Therapy “Target-effect” strategy Pre-determined efficacy endpoint Titrate drug to desired effect Monitor for efficacy If plateau occurs, may need to add additional drug or choose alternative agent Monitor for toxicity May require decrease in dose or alternative agent

Slide 52 :

Management of Drug Therapy “Target-concentration” strategy Pre-determined concentration goal Based on population-based PK Target concentration based on efficacy or toxicity Know the PK of the drug you are prescribing Presence of an active metabolite? Should the level of the active metabolite be measured? Zero-order or first-order kinetics? Does it change with increasing serum concentrations?

Slide 53 :

Management of Drug Therapy Critical aspects of “target-concentration” therapy Know indications for monitoring serum concentrations AND when you do not need to monitor levels Know the appropriate time to measure the concentration If the serum concentration is low, know how to safely achieve the desired level Be sure the level is not drawn from the same line in which the drug is administered Be sure drug is administered over the appropriate time AND Treat the patient, not the drug level

Slide 54 :

REMEMBER No drug produces a single effect!!!

Slide 55 :

Case #1 JB is a 5 y.o. male with pneumonia. He has a history of renal insufficiency and is followed by the nephrology service. His sputum gram stain from an ETT shows gram negative rods. He needs to be started on an aminoglycoside. Currently, his BUN/SCr are 39/1.5 mg/dL with a urine output of 0.4 cc/kg/hr. You should: a) Start with a normal dose and interval for age b) Give a normal dose with an extended interval c) Give a lower dose and keep the interval normal for age d) Aminoglycosides are contraindicated in renal insufficiency

Slide 56 :

Case #2 MJ is a 3 y.o. female with a history of congenital heart disease. She is maintained on digoxin 10 mcg/kg/day divided bid. She has a dysrhythmia and is started on amiodarone. You should: a) Continue digoxin at the current dose b) Decrease the digoxin dose by 50% and monitor levels c) Increase the digoxin dose by 50% and monitor levels d) Discontinue the digoxin

Slide 57 :

Case #3 AC is a 4 y.o male on a midazolam infusion for sedation in the PICU. He is currently maintained on 0.4 mg/kg/hr. You evaluate the child and notice that he is increasingly agitated. You should: a) Increase the infusion to 0.5 mg/kg/hr b) Bolus with 0.1 mg/kg and increase the infusion to 0.5 mg/kg/hr c) Bolus with 0.4 mg/kg and increase the infusion to 0.5 mg/kg/hr d) Bolus with 0.1 mg/kg and maintain the infusion at 0.4 mg/kg/hr

Slide 58 :

Case #4 JD is a 10 y.o. child on phenytoin NG bid (10 mg/kg/day) for post-traumatic seizures but continues to have seizures. He is on continuous NG feeds. His phenytoin level is 6 mcg/ml. You should: a) Increase his phenytoin dose to 12 mg/kg/day divided bid b) Load him with phenytoin 5 mg/kg and increase his dose to 12 mg/kg/day c) Change his feeds so they are held 1 hr before and 2 hrs after each dose, give him a loading dose of 10 mg/kg, continue his current dose of 10 mg/kg/day and recheck a level in 2 days (sooner if seizures persist). d) Add another anticonvulsant

Slide 59 :

Case #5 LF is a 12 y.o. with sepsis and a serum albumin of 1.2 mg/dL. She has a seizure disorder which has been well controlled with phenytoin (serum concentration on admission was 19 mcg/ml). You notice she is having clonus and seizure-like activity. You should: a) Administer phenytoin 5 mg/kg IV now b) Order a serum phenytoin level now c) Obtain an EEG now d) Order a total and free serum phenytoin level now

Slide 60 :

Case #6 KD is a 12 y.o. child admitted with status asthmaticus who is treated by her primary physician with theophylline (serum concentration is 18 mcg/ml). Based on her CXR and clinical findings, you treat her with erythromycin for presumed Mycoplasma pneumoniae. You should: a) Continue her current dose of theophylline. There is no need to monitor serum concentrations. b) Lower her dose of theophylline and monitor daily serum concentrations c) Increase her dose of theophylline by 10% and monitor daily serum concentration d) Continue her current dose of theophylline and monitor daily serum concentrations

Slide 61 :

Case #7 BJ is a 13 y.o. S/P BMT for ALL. She is admitted to the PICU in septic shock. She has renal insufficiency with a BUN/SCr of 45/2.1 mg/dL and is on fluconazole, cyclosporine, solumedrol, vancomycin, cefepime and acyclovir in addition to vasopressors. a) Identify the drugs which may worsen her renal function b) Identify the drugs which require dosage adjustment due to her renal dysfunction c) Identify the drugs which require serum concentrations to be monitored and project when you would obtain these levels

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Inhibit or block responses caused by agonists; Competitive antagonistCase #2 MJ is a 3 y.o. female more Inhibit or block responses caused by agonists; Competitive antagonistCase #2 MJ is a 3 y.o. female with a history of congenital heart disease. less

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