The liver plays a central role in drug metabolism, biotransformation, biliary excretion, and protein synthesis. Hepatic disease—whether due to hepatitis, alcoholic liver disease, fatty liver, or cirrhosis—significantly alters pharmacokinetics. These changes influence how the body absorbs, distributes, metabolizes, and eliminates drugs, making dose adjustment essential to avoid toxicity. Understanding these alterations is crucial for safe and effective drug therapy in patients with compromised liver function.
Overview of Hepatic Disease and its Impact
Hepatic disease affects essential physiological functions such as:
- Drug metabolism (Phase I and II reactions)
- Synthesis of albumin and clotting factors
- Bile production and flow
- Portal blood flow
- Detoxification of endogenous and exogenous compounds
When liver function is impaired, drugs may accumulate, prolong their half-life, and cause toxicity, especially for medications extensively metabolized hepatically.
Pharmacokinetic Changes in Hepatic Disease
Hepatic impairment influences all components of pharmacokinetics: absorption, distribution, metabolism, and excretion (ADME).
1. Absorption
- Portal hypertension causes gastrointestinal edema, reducing absorption.
- Delayed gastric emptying slows drug delivery to the intestine.
- Altered first-pass metabolism increases bioavailability of high-extraction drugs.
- Cholestasis reduces absorption of fat-soluble vitamins and drugs.
Impact: Many oral drugs show increased bioavailability in cirrhosis due to reduced first-pass extraction.
2. Distribution
- Hypoalbuminemia reduces protein binding, increasing free drug concentration (e.g., phenytoin, warfarin).
- Ascites increases the volume of distribution for hydrophilic drugs.
- Portal hypertension and fluid retention alter drug distribution patterns.
Impact: Drugs with high protein binding must be dosed cautiously as free drug levels rise significantly.
3. Metabolism
Drug metabolism is the most affected pharmacokinetic process in hepatic disease.
- Phase I reactions (oxidation, reduction, hydrolysis) are significantly impaired.
- Phase II reactions (conjugation) are less affected but may still be reduced in advanced disease.
- Reduced cytochrome P450 activity slows clearance of many drugs.
- Shunting of blood around hepatocytes reduces metabolism of high-extraction drugs.
High-extraction ratio drugs affected:
- Propranolol
- Morphine
- Verapamil
- Lidocaine
Low-extraction ratio drugs affected:
- Warfarin
- Theophylline
- Diazepam
Impact: Reduced metabolism increases half-life and risk of adverse effects.
4. Excretion
- Cholestasis impairs biliary excretion of drugs.
- Reduced bile flow affects drugs excreted via bile (e.g., rifampicin).
- Enterohepatic circulation is disrupted.
Impact: Poor elimination leads to drug accumulation and toxicity.
Pharmacodynamic Changes in Hepatic Disease
In addition to pharmacokinetics, hepatic disease affects the body’s sensitivity to drugs:
- Increased sensitivity to CNS depressants (benzodiazepines, opioids)
- Altered receptor function
- Electrolyte imbalances affecting drug responses
Hepatic encephalopathy increases susceptibility to sedative toxicity.
Effect on Specific Drug Classes
1. Sedatives and Hypnotics
Benzodiazepines and barbiturates may cause prolonged CNS depression due to impaired metabolism.
2. Opioids
Morphine, codeine, and oxycodone have reduced clearance and increased half-life.
3. Beta-blockers
High first-pass metabolism causes increased bioavailability in cirrhotic patients.
4. Anticoagulants
Warfarin effects are enhanced due to reduced protein binding and impaired synthesis of clotting factors.
Clinical Implications of Hepatic Impairment
1. Increased Risk of Drug Toxicity
- Accumulation due to impaired metabolism
- Higher free drug concentration
- Enhanced pharmacologic effects
2. Reduced Drug Efficacy
Some prodrugs requiring hepatic activation may have reduced efficacy.
3. Prolonged Drug Action
Half-life increases significantly in liver disease, requiring careful dose reduction.
Approach to Drug Dosing in Hepatic Disease
Key principles for adjusting drug doses include:
- Start low and titrate slowly
- Avoid high first-pass drugs when possible
- Use drugs with renal elimination instead of hepatic clearance
- Monitor for signs of toxicity regularly
- Prefer short-acting drugs to avoid accumulation
Use of Child-Pugh Score
The Child–Pugh classification helps determine severity of liver disease and predict drug clearance.
- A (mild): minimal dose adjustment
- B (moderate): dose reduction required
- C (severe): avoid hepatically metabolized drugs
Examples of Dosing Recommendations
- Acetaminophen: avoid doses > 2 g/day
- Morphine: use lower doses; active metabolites accumulate
- Diazepam: use shorter-acting alternatives (lorazepam)
- Beta-blockers: start at small doses
Detailed Notes:
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PATH: PHARMD/ PHARMD NOTES/ PHARMD FIFTH YEAR NOTES/ CLINICAL PHARMACOKINETICS AND PHARMACOTHERAPEUTIC DRUG MONITORING (TDM)/ EFFECT OF HEPATIC DISEASE ON PHARMACOKINETICS.