Pharmacokinetics 1

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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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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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

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Pharmacokinetics 1