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
0
10
20
30
40
50
60
70
80
90
100
0 5 10 20 30 60 120 180
minutes
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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,
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
0
10
20
30
40
50
60
70
80
90
100
%
steady
state
1 2 3 4 5
Half-life
Loading Doses
Loading doses allow
rapid achievement of
therapeutic serum
levels
Same loading dose used
regardless of
metabolism/elimination
dysfunction
0
5
10
15
20
25
30
35
40
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
0
20
40
60
80
100
120
dose
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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
0
5
10
15
20
25
30
35
40
45
50
dose
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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
0
5
10
15
20
25
30
dose
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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 (K
D
)
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% (ED
50
)
Concentration of the drug which induces a
specified clinical effect in 50% of subjects
Lethal Dose 50% (LD
50
)
Concentration of the drug which induces death
in 50% of subjects
Definitions
Therapeutic Index
Measure of the safety of a drug
Calculation: LD
50
/ED
50
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 V
d
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) 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
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
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
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
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
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
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