PK in Hepatic Impairment

## The Challenge of Hepatic Dose Adjustment

Unlike renal impairment, where GFR provides a quantitative measure for dose adjustment, no single test reliably predicts hepatic drug clearance. Liver function tests (ALT, AST, bilirubin) reflect hepatocyte damage but do not correlate well with metabolic capacity. This makes hepatic dose adjustment inherently less precise.

## Types of Liver Disease and Their PK Effects

### Cirrhosis

The most predictable PK effects occur in cirrhosis:

- **Reduced hepatocyte mass**: fewer functional hepatocytes means lower intrinsic clearance
- **Portal-systemic shunting**: blood bypasses the liver through collateral vessels, drastically reducing first-pass metabolism. Oral bioavailability of propranolol increases from ~25% to ~65%.
- **Hypoalbuminemia**: hepatic synthesis of albumin falls, increasing free drug fractions
- **Reduced hepatic blood flow**: portal hypertension redistributes blood flow away from the liver

### Acute Hepatitis

Inflammatory liver disease may transiently reduce CYP activity. The effect is variable and unpredictable. Phase II pathways are generally better preserved than Phase I.

### Cholestasis

Impaired biliary excretion affects drugs eliminated through bile (rifampin, some statins). Obstructive jaundice can also reduce CYP activity through bile acid-mediated effects.

## Child-Pugh Score

The Child-Pugh classification (A, B, or C) is the most commonly used tool for hepatic dose adjustment, though it was designed for surgical risk assessment, not pharmacokinetics:

| Class | Points | Typical Approach |
|-------|--------|-----------------|
| A (mild) | 5-6 | Usually no adjustment needed |
| B (moderate) | 7-9 | Reduce dose 25-50%; avoid hepatotoxic drugs |
| C (severe) | 10-15 | Reduce dose 50-75% or avoid drug entirely |

Components: bilirubin, albumin, INR, ascites, encephalopathy.

## Specific PK Alterations

### High-Extraction Drugs

For drugs like lidocaine, morphine, and propranolol (extraction ratio > 0.7), clearance depends on hepatic blood flow. In cirrhosis, both reduced flow and portal shunting dramatically increase oral bioavailability and reduce systemic clearance.

### Low-Extraction Drugs

For drugs like warfarin, diazepam, and theophylline (extraction ratio < 0.3), clearance depends on intrinsic metabolic capacity and protein binding. Reduced hepatocyte function directly impairs clearance, while hypoalbuminemia increases free drug.

### Phase I vs Phase II

Phase I (CYP) reactions are more impaired in liver disease than Phase II (conjugation). Prefer drugs cleared by glucuronidation (lorazepam, oxazepam, temazepam) over those requiring CYP oxidation (diazepam, midazolam) in liver disease.

## Practical Dosing Guidelines

1. **Use Child-Pugh score** as a starting framework for dose adjustment
2. **Prefer Phase II-metabolized drugs** when therapeutic alternatives exist
3. **Monitor free drug levels** when protein binding changes are expected
4. **Avoid hepatotoxic drugs** (acetaminophen in high doses, methotrexate, isoniazid) when possible
5. **Start at lower doses** and titrate cautiously with close monitoring

## Key Takeaways

- No single liver test predicts drug metabolic capacity accurately
- Child-Pugh score provides rough guidance for dose adjustment
- Portal shunting dramatically increases oral bioavailability of high-extraction drugs
- Phase I metabolism is impaired more than Phase II in liver disease
- Hypoalbuminemia increases free drug fractions, complicating interpretation of drug levels