Introduction to Pharmacokinetics Flashcards
What is Pharmacokinetics?
How a drug molecule moves through the body from administration to elimination
What is Pharmacodynamics?
How a drug molecule affects its target to produce the desired physiological effect
4 Steps of Pharmacodynamics
- Absorption
- Distribution
- Metabolism
- Elimination
Absorption: how do drugs enter the body?
Must cross epithelial or endothelial layers
Absorption: Surface Area? Speed of drug transit? pH?
Absorption: Mechanisms for passing epithelial cell layers
Absorption: Charge state of drug effect
Effects ability to diffuse across cell membrane; must be hydrophobic/uncharged
Weak acids: Protonated, pH < pKa
Weak bases: Deprotonated, pH > pKa
Where are weak acids and bases absorbed?
Weak acids - stomach (low pH)
Weak bases - small intestine (higher pH)
Henderson-Hasselbalch Equations: Weak acids/bases
What is bioavailability?
The fraction of a drug dose that reaches the systemic circulation; IV drugs = 100%
Area Under Curve (AUC)
Measure of total drug exposure
“First pass effect”
Effect on oral drugs; picked up in mesenteric artery, into portal system, metabolized in liver; Bioavailability measured AFTER
Intestinal bacteria role in absorption
Can degrade oral drugs, decrease absorption & bioavailability
Body weight/body water breakdown
Biochemical Equilibria that affect drug distribution
Protein binding, charge state/transporters, hydrophobicity, pH trapping, binding to tissue targets
Vd Interpretation
Vd = 0.6 L/Kg –> all compartments
Vd < 0.6 L/Kg –> more in plasma (protein binding)
Vd > 0.6 L/Kg –> little in plasma (tissue binding/pH trapping)
Total body water varies by:
Age: older, less water
Fat: more fat, less water
Formula for Vd
Vd = Q/Cp
Where are drugs metabolized?
Within cells of various organs
Why are drugs metabolized?
Inactivation & faciliation of elimination by urine/feces
What are the two phases of drug metabolism?
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
Acetominophen Metabolism Rxns & Other examples
Phase I: Reduction (Oxidation –most common– and Hydrolysis)
Phase II: Glutathionation (Glucuronidation –most common–, Glycine-conj., Sulfation, Acetylation, and Methylation)
Metabolism Rxn Catalysts
Oxidation: Cytochrome p450 (15 families)
Glucuronidation: UDP-glucouronosyltransferase (22 enzymes)
Metabolism Rxn enzymes for clinically relevant drugs
Phase I xenobiotics/most drugs: CYP families 1-3
Phase II most drugs: Various transferases
Multiple Mechanisms of Metabolism
One drug can be metabolized by multiple mechanisms (acetominophen)
Pro-drug metabolism
Phase I rxns sometimes needed to convert prodrug to active form; IE: Clopidogrel (Plavix) –> anticoagulant, using esterase
Rate of drug metabolism
Dependent of concentration of drug vs enzyme:
Drug in excess = zero order kinetics (CR independent of [drug]); constant mg/hr, Non-constant T1/2
Enzymes in excess = 1st order kinetics (CR dependent on [drug]); constant %/hr, constant T1/2
Enterohepatic Circulation
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
Drug-drug interactions and individualized Tx (4 points)
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
Drug-Drug interactions: Omeprazole & Cefpodoxime
Omeprazole prevents stomach acid from protonating Cefpodoxime, making it less absorbable
Drug-Drug interactions: Digoxin & Antibiotics
Antibiotics prevent bacterial degradation of DIgoxin (anti-arrhythmic), causing drug overdose/toxicity
Drug-Drug interactions: NSAIDS & Warfarin
NSAIDS bind to albumin, competing with Warfarin (anti-coagulant), increasing free warfarin and bleeding risk
Drug-CYP enzyme interactions (Omeprazole and Clopidogrel)
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
Drug-Drug Interactions: Verapamil and Digoxin
Verapamil blocks clearance of Digoxin in nephrons, increasing Digoxin levels
Patient-specific factors affecting PK of drugs (4)
- 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 - Body comp
- Health Status
- 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)
p-Glycoprotein/MDR1 polymorphisms
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
CYP gene polymorphisms
- CYP2D6 (20-25% of drugs), 75 variants, most common in caucasians; Metoprolol active –> inactive
- CYP2C9 (15% of drugs), 3 variants, most common in caucasians/asians; Warfarin active –> inactive
- 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
