PK

Question 1

Pharmacokinetics

Answer 1

What the body does to the drug
Absorption
Distribution
Metabolism
Excretion

Question 2

Factors Influencing PK

Answer 2

Ionization & lipid solubility
Ion trapping
Protein binding
Molecular size
Drug transporters

Question 3

Dissociation Constant

Answer 3

pKa
pH when drug 50% ionized & 50% non-ionized
Measures ionization extent

Question 4

Acid

Answer 4

Proton donors

Weak acid non-ionized when protonated HA

Question 5

Base

Answer 5

Proton acceptors

Weak base ionized when protonated BH+

Question 6

Non-Ionized

Answer 6

Neutral
Active form
Lipid soluble
Readily crosses membranes (blood-brain barrier, placenta, GI tract)
Undergoes tubular reabsorption
Hepatic metabolism
No renal excretion

Question 7

Ionization

Answer 7

Charged +/-
Inactive
No pharmacological effects
Water soluble
Renal excretion
Unable to cross membranes
No tubular reabsorption or hepatic metabolism

Question 8

Ion Trapping

Answer 8

Maternal-fetal drug transfer

Local anesthetic toxicity

Question 9

Protein Binding

Answer 9

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

Question 10

Absorption

Answer 10

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)

Question 11

First-Pass Effect

Answer 11

Enteral administration
GI tract to portal circulation
Decreases bioavailability

Question 12

Distribution

Answer 12

Two-compartment model
Central: Vasculature & vessel-rich tissues 10% body mass 75% CO
Peripheral: Muscle fat & bone 90% body mass 25% CO

Question 13

Vd

Answer 13

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

Question 14

Body Fluid Compartments

Answer 14

TOTAL:  42L
Intracellular 28L
Extracellular 14L 
- ISF 10L
- Plasma 4L

Question 15

Metabolism

Answer 15

Biotransformation
Enzyme-catalyzed change in chemical structure
Liver 1° metabolism organ
Goal: Convert lipid soluble agents into water soluble forms

Question 16

First-Order

Answer 16

Drug cleared at rate proportional to amount present in plasma
50%

Question 17

Zero-Order

Answer 17

Drug cleared at constant rate regardless plasma concentration
Alcohol

Question 18

Phase I

Answer 18

Increases polarity
Lipid to water-soluble
Oxidation 
Reduction
Hydrolysis

Question 19

Oxidation

Answer 19

Oxygen introduced into the molecule
Catalyzed by CYP-450 enzymes
Results in electron loss
↑ polarity

Question 20

Reduction

Answer 20

CYP-450 transfer enzymes directly to the substrate
Occurs when insufficient oxygen available to compete for electrons
Results in electron gain
↑ polarity

Question 21

Hydrolysis

Answer 21

Add H2O to ester or amide to break the bond into 2 smaller molecules

Question 22

Phase II

Answer 22

Conjugation
Synthetic reactions - forms new compound
Drug or metabolite conjugated w/ endogenous substance (glucuronic, sulfonic, or acetic acid)

Question 23

CYP-450 Enzymes

Answer 23

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

Question 24

Enzyme Induction

Answer 24

↑ activity by stimulating enzymes over time period
Chronic alcohol abuse induces enzymatic activity
Enzymes quickly break agents down → reduction in half-life

Question 25

Enzyme Inhibition

Answer 25

Exposure to certain drugs leading to agent accumulation ↑ plasma levels Potential for increased drug activity or toxicity

Question 26

Elimination

Answer 26

Drug removal from body Metabolism + excretion Impacting factors: Drug properties, organ function, concomitant medications, genetic variations

Question 27

Clearance

Answer 27

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

Question 28

Hepatic Clearance

Answer 28

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

Question 29

Elimination Half-Life

Answer 29

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

Question 30

Context Sensitive Half-Time

Answer 30

Continuous infusion Time required for infusion maintained at constant concentration to decrease by 50% Increases (accumulates) w/ longer infusions

Question 31

Renal Clearance

Answer 31

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

Question 32

Excretion

Answer 32

Passive glomerular filtration Water-soluble metabolites filtered & eliminated Active tubular secretion Lipid soluble molecules reabsorbed & placed back into circulation

Question 33

Elderly PK

Answer 33

``` Slow drug absorption ↑ adipose tissue percentage ↑ Vd ↓ plasma proteins ↓ hepatic blood flow & metabolism ↓ CO Prolonged circulation = slower onset ჻ remains in CNS longer ↓ renal function ```

Question 34

Chronic Kidney Disease

Answer 34

↓ clearance & elimination Protein binding impairment Metabolizing enzymes & J-drug transporters

Question 35

Chronic Liver Disease

Answer 35

Cirrhosis - all processes altered High portosystemic pressure impedes GI absorption Protein bound drugs Vd changes to hypoalbuminemia Ascites impacts Vd Phase I reactions affected

Question 36

Pharmacogenetics

Answer 36

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