PK Flashcards
Pharmacokinetics
What the body does to the drug Absorption Distribution Metabolism Excretion
Factors Influencing PK
Ionization & lipid solubility Ion trapping Protein binding Molecular size Drug transporters
Dissociation Constant
pKa
pH when drug 50% ionized & 50% non-ionized
Measures ionization extent
Acid
Proton donors
Weak acid non-ionized when protonated HA
Base
Proton acceptors
Weak base ionized when protonated BH+
Non-Ionized
Neutral Active form Lipid soluble Readily crosses membranes (blood-brain barrier, placenta, GI tract) Undergoes tubular reabsorption Hepatic metabolism No renal excretion
Ionization
Charged +/- Inactive No pharmacological effects Water soluble Renal excretion Unable to cross membranes No tubular reabsorption or hepatic metabolism
Ion Trapping
Maternal-fetal drug transfer
Local anesthetic toxicity
Protein Binding
Liver or kidney disease, poor nutrition, 3rd trimester ↓ protein availability
Albumin - most prominent protein; preferentially bonds w/ acids
Alpha 1 acid protein preferentially bonds w/ bases
Extensive binding slow drug elimination
Absorption
Bioavailability Amount drug able to produce effect after entering the body - Drug & patient factors - First-pass effect (prodrugs) Plasma distribution curve - Alpha 1st phase (distribution) - Beta 2nd phase (elimination)
First-Pass Effect
Enteral administration
GI tract to portal circulation
Decreases bioavailability
Distribution
Two-compartment model
Central: Vasculature & vessel-rich tissues 10% body mass 75% CO
Peripheral: Muscle fat & bone 90% body mass 25% CO
Vd
Volume of distribution
Drug distribution & redistribution before elimination
Affected by drug properties
Amount drug in body / serum concentration
Normal Vd = 0.6L/kg
Large > 0.6L/kg
Small < 0.4L/kg
Body Fluid Compartments
TOTAL: 42L Intracellular 28L Extracellular 14L - ISF 10L - Plasma 4L
Metabolism
Biotransformation
Enzyme-catalyzed change in chemical structure
Liver 1° metabolism organ
Goal: Convert lipid soluble agents into water soluble forms
First-Order
Drug cleared at rate proportional to amount present in plasma
50%
Zero-Order
Drug cleared at constant rate regardless plasma concentration
Alcohol
Phase I
Increases polarity Lipid to water-soluble Oxidation Reduction Hydrolysis
Oxidation
Oxygen introduced into the molecule
Catalyzed by CYP-450 enzymes
Results in electron loss
↑ polarity
Reduction
CYP-450 transfer enzymes directly to the substrate
Occurs when insufficient oxygen available to compete for electrons
Results in electron gain
↑ polarity
Hydrolysis
Add H2O to ester or amide to break the bond into 2 smaller molecules
Phase II
Conjugation
Synthetic reactions - forms new compound
Drug or metabolite conjugated w/ endogenous substance (glucuronic, sulfonic, or acetic acid)
CYP-450 Enzymes
Cytochrome (CY) P-450 microsomal enzymes found in smooth ER
Iron-containing hemoprotein
Peak absorption 450nm when reacting w/ carbon monoxide
Mixed function oxidase system
Enzyme Induction
↑ activity by stimulating enzymes over time period
Chronic alcohol abuse induces enzymatic activity
Enzymes quickly break agents down → reduction in half-life
Enzyme Inhibition
Exposure to certain drugs leading to agent accumulation
↑ plasma levels
Potential for increased drug activity or toxicity
Elimination
Drug removal from body
Metabolism + excretion
Impacting factors: Drug properties, organ function, concomitant medications, genetic variations
Clearance
Volume plasma drug completed cleared via metabolism & excretion
Impacted by drug properties & body ability to clear
Directly proportional to dose
Inversely r/t half-life
Clearance organs - liver & kidney
Determined by blood flow & organ ability to extract drug from blood
Hepatic Clearance
Perfusion dependent elimination > 0.7L/kg
High extraction ratio
↓ perfusion ↓ clearance
Capacity dependent elimination - small drug amount removed per unit time
Low extraction ratio < 0.3L/kg
Hepatic perfusion does not have significant effect on clearance
Dependent on hepatic enzymes & protein binding
↓ protein binding ↑ clearance
Elimination Half-Life
Time necessary for plasma concentration drug to decrease by half
1° first-order kinetics (drug removed at constant rate)
Drug eliminated after 4-5 half-lives
Frequent dosing = accumulation
Context Sensitive Half-Time
Continuous infusion
Time required for infusion maintained at constant concentration to decrease by 50%
Increases (accumulates) w/ longer infusions
Renal Clearance
Kidney efficient at removing water-soluble molecules
Actively secreted substances include: Morphine, meperidine, furosemide, penicillin, quaternary ammonium
Urine pH influences drug elimination
Weak acids better excreted in alkaline urine
Weak bases better excreted in acidic urine
Excretion
Passive glomerular filtration
Water-soluble metabolites filtered & eliminated
Active tubular secretion
Lipid soluble molecules reabsorbed & placed back into circulation
Elderly PK
Slow drug absorption ↑ adipose tissue percentage ↑ Vd ↓ plasma proteins ↓ hepatic blood flow & metabolism ↓ CO Prolonged circulation = slower onset ჻ remains in CNS longer ↓ renal function
Chronic Kidney Disease
↓ clearance & elimination
Protein binding impairment
Metabolizing enzymes & J-drug transporters
Chronic Liver Disease
Cirrhosis - all processes altered
High portosystemic pressure impedes GI absorption
Protein bound drugs Vd changes to hypoalbuminemia
Ascites impacts Vd
Phase I reactions affected
Pharmacogenetics
Variation in human genes responsible for different responses to drug therapy
Involves identifying drug response markers at disease level, metabolism, or target
Polymorphisms - variations in DNA sequences that occur in at least 1% population
