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 r**educed 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