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
Clinical Pharmacokinetics
• The science of the rate of movement of
drugs within biological systems, as affected
by the adsorption, 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
Time to Peak Concentration
100
90
80
70
60 IV
50 Oral
40 Rectal
30
20
10
0
0 min 5 min 10 min 20 min 30 min 60 min 120 180
min min
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 CP450 system undergoes
oxidation or reduction
• Enzyme induction
• Drug interactions
Phase I reactions types
• Hydrolysis
• Oxidation
• Reduction
• Demethylation
• Methylation
• Alcohol dehydrogenase
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
100
90 required for serum
80
70 plasma concentrations
% 60
steady 50
to decrease by one-
state 40 half (50%)
30
20 • 3-5 half-lives to reach
10
0 steady state
1 2 3 4 5
Half-life
Loading Doses
• Loading doses allow 40
rapid achievement of 35
therapeutic serum 30
levels 25 w/ bolus

• Same loading dose used 20

w/o
regardless of 15 bolus

metabolism/elimination 10

dysfunction 5
0
Linear Pharmacokinetics
• Linear = rate of 120
elimination is 100
proportional to amount
80
of drug present
60
• Dosage increases
result in proportional 40

increase in plasma 20
drug levels 0
Nonlinear Pharmacokinetics
• Nonlinear = rate of 50
elimination is constant 45
40
regardless of amount of
35
drug present 30
• Dosage increases 25
saturate binding sites 20
15
and result in non-
10
proportional 5
increase/decrease in 0
drug levels
Michaelis-Menten Kinetics
• Follows linear kinetics 30

until enzymes become 25

saturated 20

• Enzymes responsible 15

for metabolism 10

/elimination become 5
saturated resulting in 0
non-proportional
increase in drug levels phenytoin
Special Patient Populations
• Renal Disease: same hepatic metabolism-
same/increased volume of distribution - prolonged
elimination = increase dosing interval
• Hepatic Disease: same renal elimination- same/increased
volume of distribution, slower rate of enzyme
metabolism= decrease dosage, increase dosing interval
• Cystic Fibrosis Patients: increase metabolism,
elimination, and larger volume of distribution= increase
dosage, decrease 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 Anagonist
– 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% (ED 50)
– 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
 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
• Increased Vd for drugs that typically are highly
protein bound if serum albumin and other protein
levels are low
– Have a higher concentration of free drug
– Substrate deficiencies
• Exhaustion of stores
• Metabolic stress
Effect of Disease on PD
• Upregulation of receptors
• Downregulation 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
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!!!