Drug elimination refers to the process by which the body removes drugs and their metabolites. It mainly involves two steps: metabolism (chemical conversion of drugs) and excretion (removal from the body). Effective elimination ensures that drug levels do not accumulate to toxic levels and helps determine dosing intervals.
Components of Drug Elimination
Drug elimination has two major components:
- Metabolism (Biotransformation): conversion of drugs into more water-soluble compounds
- Excretion: removal of drugs and metabolites through kidneys, bile, lungs, or other routes
1. Drug Metabolism
The liver is the primary organ of metabolism, but other tissues such as the intestine, kidneys, lungs, and skin also participate.
Phases of Metabolism
Phase I Reactions (Functionalization)
These reactions introduce or expose functional groups on the drug molecule:
- Oxidation
- Reduction
- Hydrolysis
Most Phase I reactions are mediated by the cytochrome P450 (CYP450) enzyme system.
Phase II Reactions (Conjugation)
Drugs or Phase I metabolites are joined with endogenous molecules to increase solubility.
- Glucuronidation
- Sulfation
- Acetylation
- Glutathione conjugation
Factors Affecting Metabolism
- Genetics (fast or slow metabolizers)
- Age (reduced metabolism in elderly and infants)
- Liver diseases
- Drug interactions—enzyme induction or inhibition
2. Drug Excretion
Excretion removes parent drug and metabolites from the body. The major route is renal excretion, but other systems contribute.
Renal Excretion (Primary Route)
Occurs in three steps:
- Glomerular filtration – free (unbound) drugs pass into filtrate
- Tubular secretion – active transport of drugs into tubules
- Tubular reabsorption – lipid-soluble drugs can be reabsorbed
Biliary Excretion
Drugs enter bile and reach the intestines. Some undergo enterohepatic recycling, prolonging their effect.
Other Routes
- Lungs (volatile anesthetics)
- Skin (sweat)
- Saliva
- Breast milk
Clearance (Cl)
Clearance is the volume of plasma from which a drug is completely removed per unit time. It is an important indicator of elimination efficiency.
Total Body Clearance
Total clearance is the sum of clearance from all eliminating organs:
- Renal clearance
- Hepatic clearance
- Pulmonary clearance
Half-Life (t1/2)
Half-life is the time required for the plasma drug concentration to fall by 50%.
Importance of Half-Life
- Determines dosing interval
- Affects time to reach steady state
- Helps evaluate drug accumulation
First-Order vs Zero-Order Elimination
First-Order Kinetics
- Most drugs follow this
- Rate of elimination is proportional to drug concentration
- Constant fraction eliminated per unit time
Zero-Order Kinetics
- Elimination rate is constant and independent of concentration
- Seen in drugs like phenytoin, alcohol, aspirin (high doses)
Factors Affecting Drug Elimination
- Renal function (GFR, tubular function)
- Liver function
- Age (neonates and elderly have slower elimination)
- Drug interactions inhibiting or inducing enzymes
- Genetic variations
Clinical Significance
- Guides dosage adjustments in renal/hepatic impairment
- Helps prevent drug accumulation and toxicity
- Important in designing dosing regimens
- Assists in therapeutic drug monitoring
Detailed Notes:
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