Drug excretion Flashcards
Drug Excretion:
- The physical processes that lead to the irreversible removal of a drug and its metabolites from the body.
- Routes: Urine (kidneys), feces (bile), breast milk, expired air (lungs), hair, skin/sweat.
Drug Elimination:
- The removal of a drug from the body through metabolic and/or excretory processes.
- Components: Drug metabolism (~75%) and drug excretion.
Factors Affecting Drug Excretion:
- Molecular Size and Weight: Most drugs can pass into the filtrate.
- Drug Concentration in Plasma: Transporters are saturable.
- Urine pH: Affects drug ionization and reabsorption.
- Plasma Protein Binding: Affects glomerular filtration but not active secretion.
- Renal Blood Flow: Influences glomerular filtration rate (GFR).
- Impaired Renal Function: Due to aging, disease, or use of drugs (e.g., NSAIDs).
- Transporters: Involved in active secretion and reabsorption.
Fraction Unbound (fu):
The fraction of drug unbound in plasma, affecting renal clearance.
Routes of Drug Excretion:
- Urine (Kidneys): Main route for hydrophilic drugs and metabolites.
- Feces (Bile): Hepatobiliary excretion.
- Other Routes: Breast milk, expired air, hair, skin/sweat.
three processes involved in renal drug excretion
Glomerular Filtration:
Passive Reabsorption:
Active Tubular Secretion:
Glomerular Filtration:
- Small and free drugs pass through glomerular capillaries into the filtrate.
- Clinical Application: Measurement of blood creatinine levels to estimate GFR.
- Example: Impaired renal function leads to increased blood creatinine levels.
Passive Reabsorption:
- Most filtrate returns to circulation; small, lipophilic, and unionized drugs undergo passive diffusion back into the blood.
- Clinical Application: Alkalinizing urine with sodium bicarbonate to increase ionization and decrease reabsorption of salicylates in overdose cases.
- Example: Aspirin or methyl salicylate overdose.
Active Tubular Secretion:
- Transporters in the proximal tubules mediate drug secretion from peritubular capillaries to the tubular lumen.
- Clinical Application: Probenecid inhibits OAT1/3 to increase the concentration of co-administered drugs.
- Example: Cephalexin excreted via glomerular filtration and active tubular secretion; probenecid increases cephalexin concentration.
define Enterohepatic Recirculation:
Involves the circulation of drugs between the liver and intestines.
Enterohepatic Recirculation Process:
- Lipophilic drugs undergo hepatic metabolism.
- Conjugated metabolites are excreted into bile and stored in the gallbladder.
- Bile is released into the duodenum; conjugates are hydrolyzed by GI bacteria, generating unconjugated drugs.
- Unconjugated drugs are reabsorbed into the bloodstream.
Enterohepatic Recirculation drug example
Morphine: Undergoes hepatic metabolism and conjugation, excreted into bile, hydrolyzed by β-glucuronidase in the GI tract, and reabsorbed.
Describe individual variation in drug response
Differences in response to the same dose of a drug due to intrinsic and extrinsic factors. With Intrinsic Factors and Extrinsic Factors
Intrinsic Factors:
Genetics, age, sex, disease status, physiological conditions (e.g., pregnancy).
Extrinsic Factors:
Concomitant medications, diet, exposure to chemicals and environmental causes.
individual variation in drug response Impact on Treatment:
Variations can lead to treatment failures or toxicity, requiring dose adjustment or substitution with another drug.
CYP Single Nucleotide Polymorphism (SNP): Define
Genetic variations in CYP450 enzymes affect drug metabolism.
CYP Single Nucleotide Polymorphism (SNP): Phenotypes:
- Ultrarapid Metabolizer (UM): Increased enzyme activity.
- Extensive Metabolizer (EM): Normal enzyme activity.
- Intermediate Metabolizer (IM): Reduced enzyme activity.
- Poor Metabolizer (PM): Minimal or no enzyme activity.
Ultrarapid Metabolizer (UM):
Increased enzyme activity.
Extensive Metabolizer (EM):
Normal enzyme activity.
Intermediate Metabolizer (IM)
Reduced enzyme activity.
Poor Metabolizer (PM):
Minimal or no enzyme activity.
Impact on Drug Metabolism and Response: Pharmacologically Active Parent Drug:
UMs may require higher doses; PMs may require lower doses due to prolonged drug effects.
Impact on Drug Metabolism and Response:
Prodrug:
UMs convert prodrugs rapidly to active forms; PMs may have reduced therapeutic effects due to inadequate conversion.
Drug Clearance:
The efficiency of drug elimination, defined as the volume of plasma cleared of drug per unit time (e.g., L/hr).
Total Body Clearance:
Sum of hepatic clearance, renal clearance, and clearance by other routes.
Fraction Excreted (fe):
- The fraction of administered drug excreted unchanged in the urine.
Fraction Excreted (fe):
Hepatically Cleared Drugs:
Low fe, primarily metabolized in the liver.
Fraction Excreted (fe):
Renally Cleared Drugs:
High fe, excreted unchanged in the urine.
Determining Total Body Clearance (Non-Compartmental Analysis):
- Administer a single dose of drug (i.v. bolus or oral).
- Collect blood samples and measure drug plasma concentration at defined time points.
- Plot a plasma concentration-time curve and calculate the area under the curve (AUC).
Drug Bioavailability (F):
The fraction of administered dose of the parent drug that reaches the systemic circulation.
Drug Bioavailability (F):
For Intravenous Administration:
F = 1 (100% bioavailability).
Drug Bioavailability (F):
For Other Routes:
F is between 0 and 1.
Determining Bioavailability for Orally Administered Drug:
- Obtain plasma concentration-time curves for the drug administered via i.v. and oral routes.
- Calculate the respective AUCs.
