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
concentration
Time to Peak Concentration
100
90
80
70
60
50
40
30
20
10
0
IV
Oral
Rectal
0
5
10
20
30
minutes
60
120
180
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 onehalf (50%)
• 4-5 half-lives to reach
steady state
100
90
80
70
%
60
steady 50
state 40
30
20
10
0
1
2
3
Half-life
4
5
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
120
100
concentration
• Linear = rate of
elimination is
proportional to amount
of drug present
• Dosage increases
result in proportional
increase in plasma
drug levels
80
60
40
20
0
dose
• 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
concentration
Nonlinear Pharmacokinetics
50
45
40
35
30
25
20
15
10
5
0
dose
Michaelis-Menten Kinetics
30
concentration
• Follows linear kinetics
until enzymes become
saturated
• Enzymes responsible
for metabolism
/elimination become
saturated resulting in
non-proportional
increase in drug levels
25
20
15
10
5
0
dose
phenytoin
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
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)
Continue digoxin at the current dose
b)
c)
d)
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)
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
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
c)
d)
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)
d)
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
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)
c)
d)
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)
Identify the drugs which may worsen her renal function
b)
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
c)