Drug Dosing in Hepatic Dysfunction Learning Objectives (Tran)

- The liver performs biotransformation (chemical alteration of drugs)

- Make drugs more easily excretable

- activates prodrugs

Liver's Role in Drug Metabolism

- oxidation

- reduction

- hydrolysis

Phase 1 modification

increases water solubility

Phase II conjugation

- decrease intrinsic clearance

- decrease hepatic clearance

- decrease albumin

- increase free drug fraction

- Leads to drug accumulation or altered activity

Hepatic dysfunction

- No single test accurately measures liver function

- Biomarkers

- AST,

- ALT

- Alk Phos

- GGT

- Bilirubin

- Albumin

- PT/INR

- Child-Pugh score

- MELD score

- CMP components (supportive labs)

- Goal: assess liver damage + functional capacity

Types of Assessments for Liver Function

Hepatic vs renal

Drug elimination

increase oral bioavailability due to decrease first-pass metabolism

Route of administration

decrease albumin which increases free drug

Protein binding

Affects high-extraction drugs

Hepatic blood flow

decrease metabolism in liver disease

Intrinsic clearance

decrease drug excretion

Biliary obstruction

Narrow index → higher risk

Therapeutic index

- Ascites

- Bilirubin

- Albumin

- INR/PT

- Encephalopathy

Child-Pugh Classification Parameters

- <7

- well compensated

Class A

- 7-9

- moderate impairment

Class B

- >10

- severe/decompensated

Class C

25% dose reduction

Score 8-9

50% dose reduction

Score ≥10

- High hepatic metabolism

- First-pass metabolism (oral drugs)

- High protein binding

- Narrow therapeutic index

Adjust doses when drugs have

- Azithromycin

- IV acetaminophen

- Oral acetaminophen >2 g/day

- NSAIDs

- Metformin

- Methotrexate

- ACE inhibitors (with ascites)

- Pioglitazone

Medications to Avoid in Severe Hepatic Dysfunction

- Warfarin

- Phenytoin

- Sirolimus

- Vancomycin

- Levothyroxine

- Carbamazepine

- Theophylline

- Digoxin

- Lithium

- Valproic Acid

- Tacrolimus

- Cyclosporin

Narrow Therapeutic Index Drugs

- Dabigatran

- Rivaroxaban

- Apixaban

- Endoxaban

Child Pugh A no dose adjustment needed

- Dabigatran

- Apixaban

Child Pugh B use with caution

- Rivaroxaban

- Endoxaban

Child Pugh B avoid

- Dabigatran

- Rivaroxaban

- Apixaban

- Endoxaban

Child Pugh C avoid

- A and B impairment can increase sensitivity

- C use caution

Warfarin