Introduction to Pharmacokinetics

Question 1

What is Pharmacokinetics?

Answer 1

How a drug molecule moves through the body from administration to elimination

Question 2

What is Pharmacodynamics?

Answer 2

How a drug molecule affects its target to produce the desired physiological effect

Question 3

4 Steps of Pharmacodynamics

Answer 3

1. Absorption
2. Distribution
3. Metabolism
4. Elimination

Question 4

Absorption: how do drugs enter the body?

Answer 4

Must cross epithelial or endothelial layers

Question 5

Absorption: Surface Area? Speed of drug transit? pH?

Answer 5

Question 6

Absorption: Mechanisms for passing epithelial cell layers

Answer 6

Question 7

Absorption: Charge state of drug effect

Answer 7

Effects ability to diffuse across cell membrane; must be hydrophobic/uncharged

Weak acids: Protonated, pH < pKa

Weak bases: Deprotonated, pH > pKa

Question 8

Where are weak acids and bases absorbed?

Answer 8

Weak acids - stomach (low pH)

Weak bases - small intestine (higher pH)

Question 9

Henderson-Hasselbalch Equations: Weak acids/bases

Answer 9

Question 10

What is bioavailability?

Answer 10

The fraction of a drug dose that reaches the systemic circulation; IV drugs = 100%

Question 11

Area Under Curve (AUC)

Answer 11

Measure of total drug exposure

Question 12

“First pass effect”

Answer 12

Effect on oral drugs; picked up in mesenteric artery, into portal system, metabolized in liver; Bioavailability measured AFTER

Question 13

Intestinal bacteria role in absorption

Answer 13

Can degrade oral drugs, decrease absorption & bioavailability

Question 14

Body weight/body water breakdown

Answer 14

Question 15

Biochemical Equilibria that affect drug distribution

Answer 15

Protein binding, charge state/transporters, hydrophobicity, pH trapping, binding to tissue targets

Question 16

V_d Interpretation

Answer 16

V_d = 0.6 L/Kg –> all compartments

V_{d <} 0.6 L/Kg –> more in plasma (protein binding)

V_{d >} 0.6 L/Kg –> little in plasma (tissue binding/pH trapping)

Question 17

Total body water varies by:

Answer 17

Age: older, less water

Fat: more fat, less water

Question 18

Formula for Vd

Answer 18

V_d = Q/C_p

Question 19

Where are drugs metabolized?

Answer 19

Within cells of various organs

Question 20

Why are drugs metabolized?

Answer 20

Inactivation & faciliation of elimination by urine/feces

Question 21

What are the two phases of drug metabolism?

Answer 21

Phase I: Functionalization phase

Drug –> Phase I Metabolite (May be active or inactive)

Phase II: Conjugation phase

Phase I Metabolite –> Phase II Metabolite

Some drugs only undergo one or the other

Rxns increase size and polarity for clearance

Question 22

Acetominophen Metabolism Rxns & Other examples

Answer 22

Phase I: Reduction (Oxidation –most common– and Hydrolysis)

Phase II: Glutathionation (Glucuronidation –most common–, Glycine-conj., Sulfation, Acetylation, and Methylation)

Question 23

Metabolism Rxn Catalysts

Answer 23

Oxidation: Cytochrome p450 (15 families)

Glucuronidation: UDP-glucouronosyltransferase (22 enzymes)

Question 24

Metabolism Rxn enzymes for clinically relevant drugs

Answer 24

Phase I xenobiotics/most drugs: CYP families 1-3

Phase II most drugs: Various transferases

Question 25

Multiple Mechanisms of Metabolism

Answer 25

One drug can be metabolized by multiple mechanisms (acetominophen)

Question 26

Pro-drug metabolism

Answer 26

Phase I rxns sometimes needed to convert prodrug to active form; IE: Clopidogrel (Plavix) –> anticoagulant, using esterase

Question 27

Rate of drug metabolism

Answer 27

Dependent of concentration of drug vs enzyme:

Drug in excess = zero order kinetics (CR independent of [drug]); constant mg/hr, Non-constant T_1/2

Enzymes in excess = 1st order kinetics (CR dependent on [drug]); constant %/hr, constant T_1/2

Question 28

Enterohepatic Circulation

Answer 28

Allows metabolized drugs to be reabsorbed; GI bacteria may reverse phase I/II modifications allowing reabsorption; Antibiotics may block effect

EHC increases biological half-life of drugs

Question 29

Drug-drug interactions and individualized Tx (4 points)

Answer 29

1) One drug can alter another’s therapeutic and toxic effects by affecting its absorption, distribution, metabolism or clearance
2) Drug doses should generally be reduced for elderly patients due to reduced Vd, and reduced hepatic and renal function
3) “Beers Criteria for Potentially Inappropriate Medication Use in Older Adults” details recommended changes in the dosing of numerous drugs in elderly patients
4) Genetic polymorphisms affecting the activities of various proteins involved in PK account for a large part of the variability in drug response among individuals

Question 30

Drug-Drug interactions: Omeprazole & Cefpodoxime

Answer 30

Omeprazole prevents stomach acid from protonating Cefpodoxime, making it less absorbable

Question 31

Drug-Drug interactions: Digoxin & Antibiotics

Answer 31

Antibiotics prevent bacterial degradation of DIgoxin (anti-arrhythmic), causing drug overdose/toxicity

Question 32

Drug-Drug interactions: NSAIDS & Warfarin

Answer 32

NSAIDS bind to albumin, competing with Warfarin (anti-coagulant), increasing free warfarin and bleeding risk

Question 33

Drug-CYP enzyme interactions (Omeprazole and Clopidogrel)

Answer 33

Drugs can inhibit or induce a CYP enzyme, preventing inactivation (increased toxicities) or making another drug inactive (reducing efficacy)

Omeprazole inhibits CYP, preventing activation of Clopidogrel (anti-coagulant), reduing efficacy and increasing clotting risk

Question 34

Drug-Drug Interactions: Verapamil and Digoxin

Answer 34

Verapamil blocks clearance of Digoxin in nephrons, increasing Digoxin levels

Question 35

Patient-specific factors affecting PK of drugs (4)

Answer 35

1. Age
   a) absorption: reduced SI surface area/increased gastric pH
   b) distribution: reduced body water, increased body fat
   c) metabolism: reduced liver function
   d) clearance: reduced renal function
2. Body comp
3. Health Status
4. Genetic profile (variations/polymorphisms)
   a) absorption: transporters (p-glycoprotein ABCB1)
   b) distribution: serum proteins
   c) metabolism: phase I/II enzymes (CYPs)
   d) clearance: transporters (p-glycoprotein ABCB1)

Question 36

p-Glycoprotein/MDR1 polymorphisms

Answer 36

Transmembrane protein that pumps drugs out of cells; participates in absorption (GIT) and clearance (bile/urine) of many drugs.

Several genetic polymorphisms that alter activity

Question 37

CYP gene polymorphisms

Answer 37

1. CYP2D6 (20-25% of drugs), 75 variants, most common in caucasians; Metoprolol active –> inactive
2. CYP2C9 (15% of drugs), 3 variants, most common in caucasians/asians; Warfarin active –> inactive
3. CYP2C19 (5% of drugs), 5 variants, most common in asians; Omeprazone active –> inactive

All autosomal recessive

Most (type 1) or All (types 2 and 3) decrease activity