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8/8/2019 Pharmacokinetics 1
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Clinical Pharmacokinetics and
Pharmacodynamics
Janice E. Sullivan, M.D.
Brian Yarberry, Pharm.D.
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Why Study Pharmacokinetics (PK)
and Pharmacodynamics (PD)?
Individualize patient drug therapy
Monitor medications with a narrowtherapeutic 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
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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
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Absorption in the Pediatric Patient
Gastrointestinal pH changes
Gastric emptying
Gastric enzymes
Bile acids & biliary function
Gastrointestinal flora
Formula/food interaction
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Time to Peak Concentration
0
10
20
30
40
50
60
70
80
90
100
0 5 10 20 30 60 120 180
min te
concentration
IV
Ora
Recta
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Distrib
ution 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 Distrib
ution Body Composition
total body water & extracellular fluid
adipose tissue & skeletal muscle
Protein Binding
albumin, bilirubin, E1-acid glycoprotein
Tissue Binding
compositional changes
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Metab
olism 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
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Metab
olism 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
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Phase 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 reactions types Hydrolysis
Oxidation
Reduction
Demethylation
Methylation
Alcohol dehydrogenase metabolism
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Phase 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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PediatricE
limination 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
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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 staterapidly; drugs with long half-life take days
to weeks to reach steady state
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Steady State Pharmacokinetics Half-life = time
required for serum
plasma concentrationsto decrease by one-
half (50%)
4-5 half-lives to reach
steady state
%
steady
state
Ha f- ife
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Loading Doses
Loading doses allow
rapid achievement of
therapeutic serumlevels
Same loading dose used
regardless of
metabolism/eliminationdysfunction
w/ bo s
w/o
bo s
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Linear Pharmacokinetics
Linear = rate of
elimination is
proportional to amountof drug present
Dosage increases
result in proportional
increase in plasmadrug levels
ose
concentration
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Nonlinear Pharmacokinetics
Nonlinear = rate of
elimination is constant
regardless of amountof drug present
Dosage increases
saturate binding sites
and result in non-proportional
increase/decrease in
drug levels
ose
concentration
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Michaelis-
Menten Kinetics
Follows linear kinetics
until enzymes become
saturated Enzymes responsible
for metabolism
/elimination become
saturated resulting innon-proportional
increase in drug levels
se
c
ncenta
ti
n
hen t in
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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
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Pharmacogenetics Science of assessing genetically determined
variations in patients and the resulting affect
on drug pharmacokinetics andpharmacodynamics
Useful to identify therapeutic failures and
unanticipated toxicity
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Pharmacodynamics Study of the biochemical and physiologic
processes underlying drug action
Mechanism of drug action Drug-receptor interaction
Efficacy
Safety profile
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Pharmacodynamics What the drug does to the body
Cellular level
General
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Pharmacodynamics
Cellular Level
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DrugA
ctions 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
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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
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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 reactionsNormal cellular function is physically inhibited
Cellular function is turned on
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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
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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
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Drug Receptors Agonist
Drugs which alter the physiology of a cell by
binding to plasma membrane or intracellularreceptors
Partial agonist
A drug which does not produce maximal effecteven 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
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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 longerrecognizes the
agonist binding site.
High doses of an agonist do not overcome the
antagonist in this situation
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Drug Receptors Irreversible Antagonist
Bind permanently to the receptor binding site
therefore they can not be overcome withagonist
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Pharmacodynamics
Definitions
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De initions 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 ofinducing
Used to compare compounds within classes of
drugs
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De initions 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
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De initions 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
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Dose-Response Relationship Drug induced responses are not an all or
none phenomenon
Increase in dose may:
Increase therapeutic response
Increase risk of toxicity
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Clinical PracticeWhat must one consider when one is
prescribing drugs to a critically ill infant or
child???
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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 maturationalchanges in organ systems and the subsequent
effect on PK and PD
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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
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Clinical Practice Other factors
Drug-drug interaction
Altered absorption
Inhibition of metabolism
Enhanced metabolism
Protein binding competition
Altered excretion
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Clinical Practice Other factors (cont)
Drug-food interaction
NG orNJ feeds
Continuous vs. intermittent
Site of optimal drug absorption in GI tract must be
considered
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Effect ofDisease 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)
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Effect ofDisease 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
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Effect ofDisease on Drug
DispositionAlterations in protein synthesis
If serum albumin and other protein levels are low,
there is altered Vd of free fraction of drugs thattypically are highly protein bound therefore a higher
free concentration of drug
Substrate deficiencies
Exhaustion of stores Metabolic stress
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Effect o
fDisease 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
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Effect o
fDisease on PD
Altered response due to:
Acid-base status
Electrolyte abnormalities
Altered intravascular volume
Tolerance
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Management of DrugT
herapy 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
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Management ofDrug 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 bemeasured?
Zero-order or first-order kinetics?
Does it change with increasing serum concentrations?
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Management ofDrug Therapy Critical aspects oftarget-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
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REMEMBER
No drug produces a
single effect!!!
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Case #JB is a y.o. male ith pneumonia. He has a
history ofrenal insufficiency and is follo ed by the
nephrology service. His sputum gram stain from
anETT
sho s gram negative rods. He needs tob
estarted on an aminoglycoside. Currently, his
BUN/SCr are /1. mg/dL ith a urine output of
. cc/kg/hr. You should:
a) Start with a normal dose and interval for ageb) 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
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Case #MJ is a y.o. female ith a history of
congenital heart disease. She is maintained on
digoxin 10 mcg/kg/day divided bid. She has adysrhythmia 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
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Case #A
C is a y.o male on a midazolam infusion
for
sedation in the P CU. He is currently
maintained on 0. 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 0.5mg/kg/hr
d) Bolus with 0.1 mg/kg and maintain the infusion at 0.4
mg/kg/hr
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Case #JD is a 10 y.o. child on phenytoin NGbid (10
mg/kg/day) for post-traumatic seizures but
continues to have seizures. He is on continuous NG
feeds. His phenytoin level is 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 of10 mg/kg,
continue his current dose of10 mg/kg/day and recheck a
level in 2 days (sooner if seizures persist).
d) Add another anticonvulsant
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Case #LF is a 12 y.o. ith sepsis and a serum albumin
of1.2 mg/dL. She has a seizure disorder hich
has been ell controlled ith phenytoin (serum
concentration on admission as19
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
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Case #
KD is a12
y.o. child admitted ith status asthmaticusho is treated by her primary physician ith
theophylline (serum concentration is 18 mcg/ml). Based
on her CXR and clinical findings, you treat her ith
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
concentrationsc) Increase her dose of theophylline by 10% and monitor daily
serum concentration
d) Continue her current dose of theophylline and monitor daily
serum concentrations
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Case #BJ is a 13 y.o. S/P BMTfor ALL. She is admitted to
the P CU in septic shock. She has renal
insufficiency ith a BUN/SCr of /2.1 mg/dL and
is onfluconazole, 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 toher renal dysfunction
c) Identify the drugs which require serum concentrations to be
monitored and project when you would obtain these levels