Drugs pharmacology in liver disease

Drugs pharmacology in Liver disease

By

M.H.Farjoo M.D. , Ph.D.Shahid Beheshti University of Medical Science

M.H.FarjooM.H.Farjoo

Drugs pharmacology in Liver disease

Introduction General guidelines Absorption and Liver Metabolism in Liver Drug Effect on Liver Liver Blood Flow Protein Binding Age Effect Specific Drugs


Introduction

Acute liver impairment interferes with drug metabolism and elimination.

Chronic liver impairment affects all parameters of pharmacokinetic.

Because most drugs are metabolized by the liver, it is susceptible to drug toxicity.

Impaired liver function greatly increases the risks of adverse drug effects.


Introduction Cont’d

Many drugs change liver function tests without clinical signs of liver dysfunction.

Hepatotoxicity is potentially life threatening.

Liver is able to function with as little as 10% of undamaged hepatic cells.

With severe hepatic impairment, extrahepatic metabolism becomes more important.


Introduction Cont’d

Clients at risk for impaired liver function include: Primary liver disease (eg, hepatitis, cirrhosis). Diseases that impair blood flow to the liver (heart

failure, shock, major surgery, or trauma). Hepatotoxic drugs. Malnourished people or those on low-protein diets.


General guidelines

General guidelines when using drugs include: Clinical signs for hepatotixicity should be sought

(nausea, vomiting, jaundice, hepatomegaly). Hepatotoxic drugs should be avoided if possible:

(acetaminophen, INH, statins, methotrexate, phenytoin, aspirin and alcohol).


Monitoring liver tests: Serum bilirubin levels above 4 to 5 mg/dl Prothrombin time greater than 1.5 times control Serum albumin below 2.0 g/dl Elevated alanine and aspartate aminotransferases

(ALT & AST).

General guidelines Cont’d

Location of hepatocellular enzymes. The major diagnostic hepatocellular enzymes are located at various sites in the hepatocyte, giving rise to different patterns of enzyme release with different causes of injury. Alanine aminotransferase (ALT) and the cytoplasmic isoenzyme of aspartate aminotransferase (ASTc) are found primarily in the cytosol. With membrane injury as in viral or chemically-induced hepatitis, these enzymes are released and enter the sinusoids, raising plasma AST and ALT activities. Mitochondrial aspartate aminotransferase (ASTm) is released primarily with mitochondrial injury, as caused by ethanol as in alcoholic hepatitis. Alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT) are found primarily on the canalicular surface of the hepatocyte. Bile acids accumulate in cholestasis and dissolve membrane fragments, releasing bound enzymes into plasma. GGT is also found in the microsomes, represented as rings in the figure; microsomal enzyme-inducing drugs, like phenobarbital and dilantin, can also increase GGT synthesis and raise plasma GGT activity.


Absorption and Liver

Some oral drugs are extensively metabolized in the liver.

This process is called the first-pass effect or presystemic metabolism.

With cirrhosis, oral drugs are distributed directly into the systemic circulation.

This means that oral drugs metabolized in the liver must be given in reduced doses.

presystemic clearance

Mechanism of presystemic clearance. After drug enters the enterocyte, it can undergo metabolism, excretion into the intestinal lumen, or transport into the portal vein. Similarly, the hepatocyte may accomplish metabolism and biliary excretion prior to the entry of

drug and metabolites to the systemic circulation .


Metabolism in Liver Most drugs are metabolized by enzymes in the liver They are called the cytochrome P450 [CYP] or the

microsomal enzymes. CYP system consists of 12 groups:

Nine of them metabolize endogenous substances. Three of them metabolize drugs.

The three groups that metabolize drugs are: CYP1 to CYP3.


Metabolism in Liver Cont’d

The CYP3 metabolizes 50% of drugs, the CYP2 45%, and the CYP1 group 5%.

They catalyze oxidation, reduction, hydrolysis, and conjugation with glucuronic acid or sulfate.

Excretion decreases when the liver cannot metabolize lipid-soluble drugs into water-soluble ones to be excreted by the kidneys.

An impaired liver cannot synthesize adequate amounts of metabolizing enzymes.

Conjugation Pic.

Elimination of drugs


Metabolism in Liver Cont’d

Dosage should be reduced for drugs that are extensively metabolized in the liver including: Cimetidine and Ranitidine Diazepam and Lorazepam Morphine and Meperidine (Pethidine) Phenytoin Propranolol Verapamil.


Drug Effect on Liver

With chronic administration, some drugs increase metabolizing enzymes in the liver: enzyme induction.

Enzyme induction accelerates drug metabolism and larger doses is required.

Rapid metabolism also increases the production of toxic metabolites.

Enzyme induction does not occur for 1-3 weeks because new enzymes must be synthesized.


Drug Effect on Liver Cont’d

Enzyme inducers consist of: phenytoin, rifampin, phenobarbital, ethanol, and cigarette smoking.

Tolerance and cross-tolerance are attributed to activation of liver metabolizing enzymes.

They also are attributed to decreased sensitivity or numbers of receptor sites.



Metabolism can be decreased in a process called enzyme inhibition.

It occurs with co-administration of drugs that compete for the same metabolizing enzymes.

In this case, smaller doses of the slowly metabolized drug is needed to avoid toxicity.

Enzyme inhibition occurs within hours or days of starting an inhibiting agent.

Enzyme inhibitors consist of: Cimetidine, fluoxetine, and ketoconazole.

enzyme induction and inhibition Pic.



Some drugs indirectly affect liver function: Epinephrine decreases blood flow by constricting

hepatic artery and portal vein. β blockers decrease blood flow by decreasing

cardiac output.


Liver Blood Flow

Hepatic metabolism also depends on hepatic blood flow.

Hepatic blood flow ↓ => delivery of drug to hepatocytes ↓ => drug metabolism ↓ => drug toxicity ↑


Protein Binding

Protein binding affects distribution.

The impaired liver is unable to synthesize plasma proteins (albumin) adequately.

Liver impairment causes accumulation of substances (bilirubin) that displace drugs from protein-binding sites.


When protein binding ↓ => free drug ↑ => drug distribution to sites of action & elimination ↑ => onset of drug action ↑ => duration of action ↓

When protein binding ↓ => peak blood levels and adverse effects ↑

Protein Binding Cont’d

Protein binding Pic.

Protein binding Pic.


Age Effect Pharmacokinetics differs in neonates, especially

prematures, because their organs are not fully developed.

Until 1 year, liver function is still immature. Children of 1 to 12 years have increased activity

of metabolizing enzymes. After 12 years of age, children handle drugs

similarly to adults.


Age Effect Cont’d

In elderly, physiologic changes alters all pharmacokinetic processes in the liver.

Many drugs are metabolized more slowly and accumulate with chronic administration.


Potentially hepatotoxic drugs include: Acetaminophen Halothane Isoniazid Sodium Valproate Phenytoin Amiodarone Erythromycin Oral Contraceptives Trimethoprim-Sulfamethoxazole

Specific Drugs


Acetaminophen

A single dose of 10–15 g, produces liver injury and 25 g is fatal.

Maximal hepatic failure occurs 4–6 days after ingestion, and aminotransferase levels may approach 10,000 units.

Treatment is gastric lavage, supportive measures, and oral activated charcoal or cholestyramine.

Neither of these agents is effective if given >30 min after acetaminophen ingestion.


Acetaminophen Cont’d

Administration of cysteine, or N-acetylcysteine reduces the severity of hepatic necrosis.

Therapy should begin within 8 h of ingestion but may be effective after 24–36 h.

If hepatic failure occurs despite N-acetylcysteine therapy, liver transplantation is the only option.

Acetaminophen metabolism

Metabolism of acetaminophen (top center) to hepatotoxic metabolites. (GSH, glutathione; SG, glutathione moiety).


Halothane

It is an idiosyncratic hepatotoxicity.

It causes severe hepatic necrosis in a small number of individuals, many of whom had previous exposure.

Halothane is not a direct hepatotoxin but rather a sensitizing agent.

Adults, obese people and women have higher risk.


Halothane Cont’d

The case-fatality rate of halothane hepatitis is 20–40%.

Patients with delayed spiking fever or jaundice after halothane should not receive it again.

Cross-reactions between halothane and methoxyflurane is reported.

So the latter agent should not be used after halothane reactions.


Isoniazid

In ~10% of adults elevated serum aminotransferase levels develop during the first few weeks.

In ~1% of treated patients, an illness similar to viral hepatitis develops .

The case-fatality rate may be 10%.

Isoniazid hepatotoxicity is enhanced by alcohol, rifampin, and pyrazinamide.


Sodium Valproate It is associated with severe hepatic toxicity and rarely,

fatalities, predominantly in children.

Elevations of serum aminotransferase levels occurs in 45% of patients but have no clinical importance.

Its metabolite, 4-pentenoic acid, is responsible for hepatic injury.

Hepatotoxicity is more common in persons with mitochondrial enzyme deficiencies

It may be ameliorated by IV carnitine, which valproate therapy depletes.


Phenytoin

Phenytoin rarely causes severe hepatitis leading to fulminant hepatic failure.

Hepatic injury is usually manifested within the first 2 months after phenytoin therapy.

Aminotransferase and ALP levels is increased and represent the potent enzyme–inducing properties of phenytoin.


Amiodarone

Clinically important liver disease develops in <5% of patients.

It has a half-life of up to 107 days so liver injury may persist for months after stopping the drug.


Erythromycin

The important adverse effect is a cholestatic reaction.

It is more common in children than adults.

Most of these reactions have been associated with the estolate salt.

The reaction usually begins during the first 2 or 3 weeks of therapy.


Oral Contraceptives

Combination pills of estrogenic and progestational steroids lead to intrahepatic cholestasis.

It occurs in a small number of patients weeks to months after taking these agents.

The lesion is reversible on withdrawal of the agent.

The two steroid components act synergistically on hepatic function but the estrogen is more responsible.

OCPs are contraindicated in patients with a history of recurrent jaundice of pregnancy.


Trimethoprim-Sulfamethoxazole

In most cases, liver injury is self-limited.

The hepatotoxicity is attributable to the sulfamethoxazole component of the drug.

Some Features of Toxic and Drug-Induced Hepatic Injury

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Drugs pharmacology in liver disease