Hepatotoxic Drugs &

Drug Administration In
Hepatic Impairment

BSc. Nursing 1st year

Dr. Rakesh Verma
Department of Clinical Pharmacology & Therapeutics
09/03/20 1
23
 Drugs and the Liver
The liver is the most important organ in which drugs
are structurally altered.

Drugs LIVER Drug Elimination

Drug Metabolites
(the good, the bad and the ugly)
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 Drug induced Hepatotoxicity
• Drug induced Hepatotoxicity is defined as injury to the
liver reflected by impaired liver function caused by
exposure to a drug.

• Drug Induced Liver Injury is also called DILI.

• Incidence is 1 in 10,000 to100,000 (under-reported)

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 Impaired Liver Function

• Hepatitis:ALT/AST> 2 ULN
• Cholestasis: ALP > 2 ULN
• Mixed disease: Both

Where,
• Alkaline phosphatase: ALP
• Alanine aminotransferase: ALT
• Aspartate aminotransferase: AST
• Upper Limit of Normal: ULN
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 What is the use of Bilirubin (jaundice)
& synthetic parameters then?

• ALT/AST + Bilirubin/PT raised or albumin lowered very

bad prognosis.

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 Based On Mechanism Of Hepatotoxicity
1. Predictable:
• Dose-dependent.
• Acetaminophen,carbon tetrachloride, phosphorus, and chloroform
• Often has temporal relationship

2. Unpredictable
• occur without warning
• unrelated to dose
• Phenytoin, Methydopa, Diclofenac
• have variable latency periods, ranging from a few days to 12 months.
• Often idiosyncratic or immunologically mediated or both
• Characterised by fever, rash, or eosinophilia. 09/03/2023 7
 Risk factors for drug-induced liver injury

• RACE: Blacks and Hispanics than whites and Asian.

• AGE: Elderly than children
• Sex: Females than males.
• Alcohol Alcoholics
• Liver disease: Patients with viral hepatitis, cirrhosis
• Genetic factors: Genetic differences in the P-450 enzymes(drug metabolising
enzymes) can result in abnormal reactions to same drugs, including
idiosyncratic(unpredictable) reactions.

• Similarly, persons who are malnourished, and persons who are fasting may be
susceptible 09/03/2023 8
 Dignosis
• Suspect:
• If after starting a drug one develops nonspecific anorexia, nausea,
and fatigue to obvious jaundice?? hepatocellular
jaundiceconfirm biochemically

• Nonspecific symtoms + pruritus ?? cholestatic liver

diseaseconfirm biochemically

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 CO KE

BO ZE
O
Burger B L OOD
HCV
HBV D R UG
Obesity/
diabetes

Abnormal
liver
tests
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Confirmed biochemically

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 Histological Diagnosis?
• Acetaminophen/ Halothane
• Centrilobular Necrosis
• α-Methyldopa/ Isoniazid 
• Diffuse Parenchymal Necrosis And Inflammation
• Valproic Acid or high-dose parenteral Tetracycline
• Microvesicular Steatosis

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 Management
• ALT rise 2- to 3-fold Enhanced Vigilance.

• ALT 4-5 times higher/Jaundice/encephalopathy Prompt discontinuation.

• Drug-induced cholestasis Cholestyramine/ Ursodeoxycholic acid for

alleviation of pruritus.

• In some cases there are antidotes,

• N-acetylcysteine for acetaminophen overdose
• Intravenous carnitine for valproate-induced mitochondrial injury. 09/03/2023 13
Drug Administration In Hepatic
Impairment

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 Bottom line
• If hepatic dysfuction is not very severe & liver is not involved in
metabolism eg; aminoglycoside, tetracycline other than doxycycline,
prescribing of most drugs is safe.

• When a drug undergoes significant hepatic metabolism, a reasonable

approach is to reduce the dose to 25-50% of normal and monitor the
response carefully.

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 CNS Drugs
• Sedatives, antidepressants and antiepilepsy drugs should
be avoided or used with extreme caution.

• In treatment of alcohol withdrawal, drugs that are

metabolized out side the liver eg; oxazepam,
tremazepam & Lorazepam should be used.

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 Gastrointestinal system
Aluminium and calcium based preparations
cause constipation and may thereby
precipitate hepatic encephalopathy, as can
antimotility drugs.

Sodium containing drugs can exacerbate

fluid retention. 09/03/2023 17
Albumin Binding Drugs & Anticoagulants

• Less albumin, less bound drug, more unbound active drug fraction.

• The effect of oral anticoagulants is increased because synthesis of

coagulation factors is impaired.

• In case of highly protein bound drug (Phenytoin),oral anti-

coagulants(warfarin) and drug with high hepatic extraction ratio
(propanolol), dosing, if feasible, should be guided by plasma
concentration monitoring.
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 We deal with body as a whole
not with system.

• However, Patients with severe decompensated liver disease usually

have associated renal impairment, with obvious consequences for
drugs eliminated predominantly by the kidney.

• Aspirin and other NSAIDs may exacerbate impaired renal function

and fluid retention by inhibiting prostaglandin synthesis

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4 Golden rules in Significant Liver
Dysfunction

1. Reduce oral doses of high extraction drugs such as

propranolol.
2. Monitor the biologic effect of the drug(heart rate).
3. Monitor blood levels (if possible).
4. Start with low dose and titrate up to biologic effect or
blood level.

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