PHARMACOLOGY OF THE LIVER

Talk about drugs treating hyperlipidaemias (topic 7.3)

Conditions caused by drugs:

Halothane is used for general anaesthesia; a side effect of halothanes is Halothane hepatitis
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Symptoms: fever, marked jaundice, dark urine, tachycardia, weakness

Patient has history of many surgeries, with fevers after each
Lab results: leukocytosis, eosinophilia, hypoglycemia, very elevated AST & ALT, alkaline
phosphate, and bilirubin
massive centrilobular hepatic necrosis may occur 6 weeks after insult
treat with support

Isoniazid (INH) is used to treat TB, a side effect of INH is INH hepatotoxicity
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history of tuberculosis and isoniazid treatment (the DOC for TB)

Symptoms: jaundice, peripheral neuropathy (foot drop, etc), hepatomegaly, SLE
labs may show increased AST, ALT, GGT, alkaline phosphate, DHL
treat with support and Vitamin B6
INH competes with Vitamin B6 Vit. B6 deficiency

Acetaminophen, better known as Paracetamol, is used as a pain killer. Acetominophen overdose

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Symptoms: stupor, vomiting, icterus, asterixis, dehydration

Lab results: very elevated AST & ALT, bilirubin, prolonged PT, elevated creatinine, BUN,
hypoglycemia, metabolic acidosis, elevated serum acetaminophen
may have coagulative centrilobular necrosis and fulminant hepatic failure
treat with N-acetylcysteine to replace depleted glutathione
Acetominophen is metabolized by in the liver by CytP450 (2El,3A4) which depletes
glutathione

Reyes syndrome
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Occurs when aspirin is given to a child with chicken pox or influenza B

child may present in a coma with papulovesicular rash, papilledema, asterixis,
labs may show hypoglycemia, increased blood ammonia, elevated ALT & AST, prolonged PT
may have acute hepatic necrosis and CT scan may show cerebral edema
(hepatoencephalopathy)
liver biopsy may show microvesicular steatosis and abnormal mitochondria
treat with support, consider transfusion or dialysis

Alcohol
Metabolism

ethanol is converted to acetaldehyde by alcohol dehydrogenase (ADH)

o acetaldehyde is highly toxic and makes you sick
acetaldehyde is converted to acetate by aldehyde dehydrogenase (ALDH)
o ALDH comes in several forms, ALDH2 is in the liver
o ALDH2 in turn has 2 alleles (one, two) and ALDH2two is dominant but inactive and
has high incidence in Asians
o the inactivity of ALDH2 two allows accumulation of the toxic acetaldehyde and is a
possible explanation for low rates of alcoholism in Asia

- disulfiram inhibits ALDH to accumulate acetaldehyde and is used to curb alcoholics from drinking
- naloxone is sometimes also used in alcoholics

Mellanby effect intoxication (the feeling of drunkenness) is greater as blood alcohol concentration
is rising than when it is decreasing, thus acute tolerance
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inhibits hypothalamic temperature regulation

inhibits ADH (vasopressin), resulting in increased diuresis
inhibits LH and other pituitary hormones
cross reacts with other drugs via P450-2El induction

Chronic effects of alcohol

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physical dependence is heritable in 50% of alcoholics

inhibits GI motility, may lead to gastritis, peptic ulcers
myopathy and cardiomyopathy, fatty liver, cirrhosis, neural structural damage (Korsakoffs)
panceatitis due to stimulation of secretin causing hypersecretion of pancreatic enzymes
which plug pancreatic ducts leading to pancreatic insufficiency and malabsorption syndrome
Vitamin deficiencies
o thiamine deficiency beriberi
o riboflavin deficiency mouth angular stomatitis and glossitis
o niacin deficiency pellagra
o pyridoxine deficiency not well defined
o Vitamin C deficiency scurvy
o folic acid deficiency birth defects and fetal alcohol syndrome in pregnancy