Download Clinical Pharmacokinetics and Pharmacodynamics

CLINICAL PHARMACOKINETICS AND
PHARMACODYNAMICS
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

100
90
80
70
%
60
steady 50
state 40
30
20
10
0

1
2
3
Half-life
4
5
Half-life = time
required for serum
plasma
concentrations to
decrease by one-half
(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/eliminatio
n 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 = 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

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   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
 General
level
Cellular Level
PHARMACODYNAMICS
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
a drug
between the therapeutic and lethal doses of
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
 Altered
interaction
absorption
 Inhibition of metabolism
 Enhanced metabolism
 Protein binding competition
 Altered excretion
CLINICAL PRACTICE

Other factors (con’t)
 Drug-food
 NG
interaction
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
 Altered
affecting organ function
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

If plateau occurs, may need to add additional drug or choose
alternative agent
 Monitor

for efficacy
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
 Know

aspects of “target-concentration” therapy
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)
0.5
c)
0.5
d)
0.4
Bolus with 0.1 mg/kg and increase the infusion to
mg/kg/hr
Bolus with 0.4 mg/kg and increase the infusion to
mg/kg/hr
Bolus with 0.1 mg/kg and maintain the infusion at
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)
to
c)
a
d)
Increase his phenytoin dose to 12 mg/kg/day divided bid
Load him with phenytoin 5 mg/kg and increase his dose
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
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
c) Identify the drugs which require serum concentrations to
be monitored and project when you would obtain these
levels