U01.05.007 Drug metabolism

Drug metabolism is divided into two primary phases that alter drugs to facilitate their elimination. Understanding these phases is crucial for assessing pharmacokinetics, especially in specific populations like geriatric patients or slow acetylators.

Phase I Metabolism

Characteristics:

Enzyme Dependence: Primarily involves the cytochrome P-450 enzyme system.
Reactions: Includes reduction, oxidation, and hydrolysis.
Metabolite Characteristics: Produces slightly polar, water-soluble metabolites that can be either active or inactive.

Impact on Geriatric Patients:

Geriatric patients experience a decline in Phase I metabolic activity, making them more dependent on Phase II for drug metabolism.
Reduced Phase I activity increases the risk of drug accumulation and potential toxicity.

Phase II Metabolism

Characteristics:

Enzyme Dependence: Does not depend on cytochrome P-450.
Reactions: Includes methylation, glucuronidation, acetylation, and sulfation.
Metabolite Characteristics: Produces very polar, water-soluble metabolites that are inactive and easily excreted by the kidneys.

Clinical Relevance:

Preservation in Ageing: Phase II metabolism remains largely intact in geriatric patients.
Drugs that rely on Phase II metabolism are often safer in older adults.

Slow Acetylators and Drug Metabolism

Definition: Individuals with a genetically determined slower acetylation process due to variations in N-acetyltransferase enzymes.
Clinical Implications: Slow acetylators exhibit reduced metabolism of certain drugs (e.g., isoniazid) during Phase II, leading to:
- Increased drug levels.
- Higher risk of side effects, such as hepatotoxicity or peripheral neuropathy.

Summary Table: Phase I vs Phase II Metabolism

Feature	Phase I	Phase II
Reactions	Reduction, oxidation, hydrolysis	Methylation, glucuronidation, acetylation, sulfation
Enzyme System	Cytochrome P-450 dependent	Non-cytochrome P-450 dependent
Metabolite	Slightly polar may be active or inactive	Very polar, inactive
Aging Impact	Declines in geriatric patients	Relatively preserved
Clinical Example	Warfarin metabolism	Isoniazid metabolism

Points to Remember

Phase I metabolism declines significantly in geriatric patients, making Phase II pathways more critical for drug elimination.
Drugs relying on Phase II metabolism are generally safer for older adults.
Slow acetylators are prone to increased side effects due to a reduced rate of Phase II acetylation (e.g., isoniazid toxicity).
Always adjust drug dosing based on metabolic capacity and patient age to avoid adverse effects.

Learning Tip for USMLE Step 1

Focus on how age and genetic variations impact drug metabolism phases. Understand specific drugs that are metabolized by Phase I (e.g., diazepam) versus Phase II (e.g., lorazepam) and their clinical implications.

USMLE Step 1 Review Series

Curriculum