A Textbook of Clinical Pharmacology and Therapeutics

DRUG-INDUCED LIVER DISEASE

After oral administration, the entire absorbed dose of a drug is
exposed to the liver during the first pass through the body. The
drug itself or its metabolites may affect liver function. Metabolic
pathways may become saturated at high concentrations and
drug or metabolites may accumulate, leading to toxicity. The
drugs shown in Table 34.6 predictably cause hepatotoxicity at
excessive doses. Although hepatotoxicity is traditionally
divided into dose-dependent and dose-independent hepato-
toxicity, the relationship is not always clear-cut. For example,
even with predictable hepatotoxins, there is considerable inter-
individual variation in susceptibility to hepatic damage. This
can sometimes be attributed to genetic polymorphism or to
environmental stimuli affecting hepatic microsomal enzymes,
or to previous liver disease. Although dose-independent
hepatotoxicity is used to classify those reactions that are ‘idio-
syncratic’ and usually unpredictable (Table 34.7), the severity of
the resulting liver disease may be related to dose or to duration
of therapy. Particular drugs tend to produce distinctive patterns
of liver injury, but this is not invariable (see also Chapter 12).

INVESTIGATION AND MANAGEMENT OF HEPATIC

DRUG REACTIONS

Depending on the clinical presentation the most important dif-
ferential diagnoses are hepatic dysfunction due to viral infection
(which may be asymptomatic), malignant disease, alcohol and
congestive cardiac failure. The aetiology of a minor elevation of
transaminases is often undetermined. If the patient is being
treated for a disease associated with hepatic dysfunction, partic-
ularly with multiple drugs, identification of the responsible
agent is particularly difficult. Minor elevations of transaminase

activity are often picked up on routine biochemical profiles. If

they are considered to be drug related, but further treatment is

indicated, it is reasonable to continue the drug with regular

monitoring of liver enzymes if a better alternative therapy is not

available. If the transaminases reach more than twice, and/or

the bilirubin rises to 1.5the upper limit of the normal range,

it is prudent to stop the drug if the clinical situation permits.

DRUGS THAT MODIFY APPETITE

APPETITE-SUPPRESSING (ANORECTIC) DRUGS

The most common form of malnutrition in the UK is obesity.

Obesity is a major risk factor for cardiovascular disease, stroke

and type 2 diabetes mellitus. It is preventable, since obese

patients are fat because they eat too many calories for their

energy needs. Naturally, a calorie-controlled diet and adequate

but sensible amounts of exercise are the essentials of treatment.

Unfortunately, the results of treating patients at weight-reduc-

tion clinics are disappointing and only a few individuals

achieve permanent weight loss. There has accordingly been a

great deal of interest in the possibility of altering appetite phar-

macologically in order to help the patient to reduce his or her

calorie intake. Unfortunately, the causes of obesity are only

currently being more comprehensively studied.

In 1994, the gene for obesity (OB) in the mouse was identi-

fied. The OB gene encodes the protein leptin, which is pro-

duced only in fat cells and is secreted into the blood. The

human homologue of the OB gene has now been identified.

Leptin is thought to be a blood-borne signal from the adipose

tissue that informs the brain about the size of an individual’s

fat mass. Much more research is required to determine its

exact role in neuroendocrine, reproductive, haematopoietic

262 ALIMENTARY SYSTEM ANDLIVER

Table 34.6:Dose-dependent hepatotoxicity

Drug Mechanism Comment/predisposing factors

Paracetamol Hepatitis See Chapter 54

Salicylates Focal hepatocellular necrosis Autoimmune disease (especially systemic lupus

erythematosus)

Reye’s sydrome In children with viral infection (contraindicated in

children 16 years)

Tetracycline Central and mid-zonal necrosis with fat droplets –

Azathioprine Cholestasis and hepatitis Underlying liver disease

Methotrexate Hepatic fibrosis –

Fusidic acid Cholestasis, conjugated hyperbilirubinaemia Rare

Rifampicin Cholestasis, conjugated and unconjugated Transient

hyperbilirubinaemia

Synthetic oestrogens Cholestasis, may precipitate gallstone disease Underlying liver disease, rare now that low-dose

oestrogens are generally given

HMG CoA reductase Unknown Usually mild and asymptomatic (statins)

inhibitors