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 patients 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

100 90 80 70 60 50 40 30 20 10 0 0 5 10 20 30 60 120 180 minutes

concentration

IV Oral Rectal

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, E1-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

100 90 80 70 % 60 steady 50 state 40 30 20 10 0 1 2 3 4 5 Half-life

Half-life = time required for serum plasma concentrations to decrease by onehalf (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
40 35 30 25 20 15 10 5 0 w/ bolus w/o bolus

Linear Pharmacokinetics
Linear = rate of elimination is proportional to amount of drug present Dosage increases result in proportional increase in plasma drug levels
120 100 concentration 80 60 40 20 0 dose

Nonlinear Pharmacokinetics
Nonlinear = rate of elimination is constant regardless of amount of drug present Dosage increases saturate binding sites and result in nonproportional increase/decrease in drug levels
50 45 40 35 30 25 20 15 10 5 0 dose

concentration

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
30 concentration 25 20 15 10 5 0 dose phenytoin

Special Patient Populations

Renal Disease: same hepatic metabolism, same/increased volume of distribution and prolonged elimination @ o dosing interval Hepatic Disease: same renal elimination, same/increased volume of distribution, slower rate of enzyme metabolism @ q dosage, o dosing interval Cystic Fibrosis Patients: increased metabolism/ elimination, and larger volume of distribution @ o dosage, q 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 drugs 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 (cont)
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

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

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?

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

REMEMBER
No drug produces a single effect!!!

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) b) c) d) Start with a normal dose and interval for age Give a normal dose with an extended interval Give a lower dose and keep the interval normal for age Aminoglycosides are contraindicated in renal insufficiency

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) b) c) d) Continue digoxin at the current dose Decrease the digoxin dose by 50% and monitor levels Increase the digoxin dose by 50% and monitor levels Discontinue the digoxin

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) b) c) d) Increase the infusion to 0.5 mg/kg/hr Bolus with 0.1 mg/kg and increase the infusion to 0.5 mg/kg/hr Bolus with 0.4 mg/kg and increase the infusion to 0.5 mg/kg/hr Bolus with 0.1 mg/kg and maintain the infusion at 0.4 mg/kg/hr

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) b) c) Increase his phenytoin dose to 12 mg/kg/day divided bid Load him with phenytoin 5 mg/kg and increase his dose to 12 mg/kg/day 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). Add another anticonvulsant

d)

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) b) c) d) Administer phenytoin 5 mg/kg IV now Order a serum phenytoin level now Obtain an EEG now Order a total and free serum phenytoin level now

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) b) c) d) Continue her current dose of theophylline. There is no need to monitor serum concentrations. Lower her dose of theophylline and monitor daily serum concentrations Increase her dose of theophylline by 10% and monitor daily serum concentration Continue her current dose of theophylline and monitor daily serum concentrations

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) b) c) Identify the drugs which may worsen her renal function Identify the drugs which require dosage adjustment due to her renal dysfunction Identify the drugs which require serum concentrations to be monitored and project when you would obtain these levels