Hepatic Clearance Flashcards
Determinants of hepatic clearance
Hepatic blood flow - Q
Intrinsic clearance - CLint
Fraction unbound in the plasma - fu
Changes in liver blood flow: effect on hepatic clearance
High E drug: decreased CL
Low E drug: no change
Changes in intrincsic clearance: effect on hepatic clearance
Enzyme Induction
- CLint increased b/c Vmax increased
Liver Disease
- CLint decreased b/c Vmax decreased
Enzyme Inhibition: competitive inhibition
- CLint decreased b/c Km increased
Changes in protein binding: effect on hepatic clearance
Low E drug
- Decreased protein binding : increased CLh
High E drug
- Doesn’t matter. No one is safe.
Restrictive clearance
Clearance “restricted” to free unbound drug
- Affected by changes in protein binding
- Low E drugs.
- Protein binding “protects” the drug
Non-restrictive clearance
Clearance of free drug, and the bound drug that becomes free to take it’s place.
- Unaffected by changes in protein binding
- High E drugs.
- Protein binding does not “protect” the drug
Determine if a drug is high or low E
- Determine total body clearance:
- Look it up
- CL / F - Determine percent excreted renally unchanged
- Look it up - Determine hepatic clearance
- CLh = (100% - renal%) * total body clearance - Determine extraction ratio
- E = CLh / Q
Reasons for altered hepatic blood flow (Q)
CHF - decrease Cirrhosis - decrease Shock - decrease Sepsis - decrease Food intake Mechanical ventilation - decrease Positive end-expiratory pressure - decrease Drugs - Vasopressors - INCREASE
Km
Affinity: concentration of dug in the liver at which the rate of metabolism if half maximal
Low, intermediate, and high E values
Low: E /< 0.3
Intermediate: E = 0.3 - 0.7
High: E >/ 0.7
Low, intermediate, and high E values
Low: E /< 0.3
Intermediate: E = 0.3 - 0.7
High: E >/ 0.7
What factors effect a low E drug?
Drug or disease induced changes in:
- CLint (liver disease)
- Fu (protein or protein binding changes)
What factors affect a low E drug?
Drug or disease induced changes in:
- CLint (liver disease)
- Fu (protein or protein binding changes)
ffp in low E drug
Approaches 1
Almost everything makes it through
No first-pass effect
Notable Low E drug
Phenytoin
