Hepatotoxic Drugs Flashcards
Many drugs cause the asymptomatic elevation of hepatic enzymes, give an example of one of these drugs and hepatic enzymes:
Statins
- ALT
- AST
- GGT
- Alkaline phosphosphotase
Clinically significant liver injury is rare.
how does it present thouh?
Jaundice Abdominal pain Pruritis Impaired liver function resulting in deficient protein synthesis. Prolonged PT with hypoalbuminemia
What happens in phase 1 metabolic reactions
Drug is taken in and absorbed, broken down into metabolites which will either:
- Metabolite with modified activity
- Metabolite is inactivated
What happens in phase 2 of metabolic reactions?
Conjugation of drug metabolites
What are some consequences of drug metabolism?
- Product May become inactivated
- Product may become active
- Products May develop a new action
- Metabolites might become toxic
Name 5 mechanisms of injury in, drug induced liver injury:
- Covelant binding of drug to cellular proteins -> immune injury
- Inhibition of metabolic pathways
- Induction of apoptosis
- Blockage of cellular transport pumps
- Interference with mitochondrion function
What factors increase the risk of drug induced liver disease?
- Obesity
- Over the age of 18
- Pregnancy
- Concomitant with alcohol consumption
- Genetic polymorphism CYP2D6, CYP2C9
Name 3 drugs that pose as risk factors for DILI in old patients
Anti-TB drugs
Eruthromycine
Halothane
Flucloxacillin
Name 2 drugs that pose as risk factors for DILI in child patients:
Salicylate
Valproate
Name 2 drugs that pose as risk factors for DILI in obese patients:
Methotrexate
Halothane
Name a drug that pose as a risk factor for DILI in fasting/malnourished patients:
Acetaminophen
Name 3 drugs that pose as risk factors for DILI in female patients:
Doclofenac Erythromycin Isoniazid Flucloxacillin Halothane
Name 3 drugs that pose as risk factors for DILI in alcoholic patients:
Halothane
Methotrexate
Isoniazid
Acetominophen
Name 2 drugs that pose as risk factors for DILI in HIV patients:
Cotrimoxazole
Abacavir
Name 2 types of drugs that pose as risk factors for DILI in patients with HBV/HCV Co-infection :
Highly active ARV THERAPY
TB treatment
DILI can be classified into 2 types of reactions, what ar they?
Predictable reactions
Idiosyncratic reactions
Explain the 2 classifications of DILI reactions:
Predictable reactions
- Main example is paracetamol toxicity
- Reaction is dose dependent
- High incidence
- Results from direct toxicity of the drug or its metabolites
Idiosyncratic reactions:
- Variable latency: 1 week or 1 year ,after.
- Not dose related.
- Caused by major hepatotoxic drugs
- ALT levels are more than 3 times the normal levels
- ALP- Sign of liver toxicity
What are the 3 types of liver injury?
Hepatocellular - Elevated ALT Cholestatic - Elevated alkaline phosphatase (ALP) and total bilirubin Mixed - Elevated alkaline phosphatase ALP
How does hepatocellular damage maniafest.
Hepatocellular toxicity manifests as
- Malaise
- Right upper quadrant abdominal pain
- Marked relegation in ALT AST
- Hyperbilirubinaemia
In hepatocellular damage, what us hepatocellular jaundice known as?
Hyperbilirubinaemia
- Increases mortality rates by 50% if Bilirubin is 3X more than usual
- Without biliary obstruction or Gilbert’s syndrome
Drugs like paracetamol and isoniazid usually cause hepatocellular injury with a low chance of spontaneous recovery
(Liver transplant should be considered)
How does this kind of hepatocellular injury present?
Jaundice
Impaired hepatic synthesis
Name a few common drugs causing hepatocellular injury:
Rifampicin Purazinamide Statins Tetracycline Methotrexate NSAIDS Allupurinol Acarbose
How does cholestatic hepatotoxicty present?
Elevated ALP
Pruritis
Jaundice
Which 3 drugs are notorious for causing cholestatic hepatotoxicity?
Amoxicillin
Chlorpromazine
Clavulanate acid
Which of the 3 hepatotoxicity injuries leads to:
- Vanishing bile duct syndrome ( Progressive destruction of intrahepatic bile ducts)
- Cronic liver disease.
Cholestatic hepatotoxicity
Name a few drugs that cause cholestatic injury:
Amoxicillin Clavulanate acid Chloropromazine Estrogens Oral contraceptives Erythromycin Tricyclic anti-depressants
How does mixed type liver injury clinically present?
Neither ALP nor ALT elevations are clearly predominant in these syndromes.
Give a drug type that usually Caucasus mixed hepatic injury:
Phenytoin.
Give a few examples of drugs causing mixed hepatic injury:
Phenytoin Captopril Analopril Sulfonamide Veparamil
How is liver injury diagnosed?
Causality is assessed :
- Relationship between drug initiation and development of abn liver enzymes
- Individual susceptibility to DILI
- Exclude all other causes of liver disease I.e.
> Cirrhosis
> HBV/ HCV
> Auto-immune
> Metabolic causes
Name 2 things that improve the prognosis of liver injury:
- Early recognition.
- Identification of hepatotoxin and pattern of liver test abnormality.
What is the treatment for liver injury due to a hepatotoxic drug?
- Early withdrawal
- Antidotes if available I.e.
> N-acetylcysteine for paracetamol toxicity
> Silymarin or penicillin for Phalloides
- Antidotes if available I.e.
What drug is the antidote for hepatotoxic liver injury caused by Paracetemol?
N-acetylcysteine
What drug is the antidote for hepatotoxic liver injury caused by amanita phalloides?
Silymarin
Penicillin
What kind of drugs are considered hepatotoxic?
Herbs containing pyrrolizidine alkaloids.
- Chinese herbal formulations
- Kava Kava
- Germander
- Impala root
- Comfrey
What should be taken into consideration when prescribing medication for treating liver disease?
- The drug should be devoid of hepatotoxic effects
- Eliminated by the kidney
- Large therapeutic index
- No pharmacokinetic interactions
