Pk2
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Clinical Pharmacokinetics
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 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
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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
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
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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
0102030405060708090
100
0 5 10 20 30 60 120 180
minutes
con
cen
trat
ion
IVOralRectal
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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
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Pediatric Distribution
• Body Composition total body water & extracellular fluid adipose tissue & skeletal muscle
• Protein Binding– albumin, bilirubin, 1-acid glycoprotein
• Tissue Binding– compositional changes
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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
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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
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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
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Phase I reactions types
• Hydrolysis
• Oxidation
• Reduction
• Demethylation
• Methylation
• Alcohol dehydrogenase metabolism
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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
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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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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
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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 state rapidly; 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 concentrations to decrease by one-half (50%)
• 4-5 half-lives to reach steady state0
102030405060708090
100
% steady state
1 2 3 4 5
Half-life
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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/obolus
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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
conc
entr
atio
n
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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
05
101520253035404550
dose
conc
entr
atio
n
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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
conc
entr
atio
nphenytoin
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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
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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