adverse effects of drugs on the liver

Which drugs are hepatotoxic

Bilirubin metabolism and excretion

Steroids, androgens, oestrogen, contraceptives, Rifampicin

Centrilobular necrosis

Paracetamol, carbon tetrachloride

Hepatocellular necrosis

Salicylates

Fatty change and liver failure

Tetracycline

Type B (‘Bizarre’)

Acute hepatocellular necrosis

Methyldopa

Antidepressants (MAOI)

Ibuprofen

Antiepileptics

Choleostatic hepatitis

Chloromazine

Type C (`Chronic treatment effects’)

Benign liver tumour

Anabolic steroids

Contraceptives

Chronic active hepatitis

Isoniazid

Dantrolene

Hepatic fibrosis / cirrhosis

Methotrexate

Amiodarone

Idiosyncratic drug induced liver injury

•Drug Induced Liver Injury (DILI) is a rare side effect of some medicines

•(DILI) is an unpredictable type of liver injury following exposure to medication within the recommended dose which is distinctive from liver injury caused by drug overdosage, commonly caused by paracetamol overdose (POD)

•DILI usually occurs after a latency period ranges from few days to months post-exposure compared to a period from hours to days in liver injury due to overdose.

•Drug induced liver injury symptoms range from nothing (asymptomatic) to very severe and are like the symptoms of other liver conditions

•Drug induced liver injury is usually diagnosed by ruling out other types of liver disease

•Most people recover from drug induced liver injury, but it can take some time and may involve changing or stopping medication

Pathophysiological of paracetamol liver injury

•Paracetamol overdose 

•>>remaining nontherapeutic doses of paracetamol 

•>> metabolized by CYP2E1 and CYP1A2

•>> reactive intermediate toxic metabolite, NAPQI

•NAPQI forms mitochondrial protein adducts which drive oxidative stress-induced hepatoxicity through rapid conjugation with GSH 

>>initiate programmed cell death

Risk factor

•Dosage

•Drug-drug interactions

  - polypharmacy

•Patient

  - age

  - sex

  - ?liver conditions

  - weight

  - diabetes

  - genes

  - pregnancy

  - smoking and alcohol

Common symptoms

Some of the most common symptoms of drug induced liver injury are:

⁻Tiredness or fatigue

⁻Loss of appetite

⁻Developing a yellow colour to your skin or eyes (jaundice)

⁻Itching

⁻Pain on the right-hand side of your body under your ribs (right upper quadrant or RUQ pain)

⁻Feeling sick (nausea)

⁻A skin rash

How do hepatic diseases change the pharmacology of drugs

•Change PK of drugs – ADME

Extent of alteration depends upon M and E of drug, and disease severity

Absorption

•Changes in bioavailability?

•Bioavailability refers to the extent and rate at which the active moiety (drug or metabolite) enters the systemic circulation, thereby accessing the site of action

•i.e. iv = 100% availability

Change dosage to accommodate, decrease liver functions

•If liver function is reduced

>> there is a ↓ in potential for 1st pass metabolism

>> in healthy subject dosage is set to allow for high 1st pass metabolism therefore need to ↓ oral dose as bioavailability will be higher

-when might this not be the case?

•

Need to know if drug is lipophilic (micelles) if so, it may be that bioavailability of lipophilic drugs will be ↓ due to ↓ lipoproteins 

Drug distribution in reduced liver function

•May be affected due to a reduction in

-Plasma binding proteins

  e.g. ↓ albumin thus free fraction of drug is ↑ thus more effective(?)

-Tissue binding

Lipid solubility

•In cirrhosis CYP levels can be decreased

Evidence of a correlation between ↓CYPs and ↑severity of disease

Drug elimination

•Depends on route of elimination

•If in urine this largely depends on kidney function – need to test

•If in stool need to check function of Biliary system

•

•Check hepatic clearance (extraction ratio)

Check renal clearance

Assess damage to liver

• alanine amino transferase

• Aspirate aminotransferase

• Total bilirubin

• Conjugate bilirubin

• Alkaline phosphatase

• Albumin

• Total protein

ALT

•Alanine aminotransferase (ALT) – an enzyme mainly found in the liver; the best test for detecting hepatitis

AST

an enzyme found in the liver and a few other places, particularly the heart and other muscles in the body

Total bilirubin

measures all the yellow bilirubin pigment in the blood

Conjugated bilirubin

measures the form made only in the liver and is often requested with total bilirubin in infants with jaundice

Alkaline phosphate

an enzyme related to the bile ducts; often increased when they are blocked, either inside or outside the liver

Albumin

measures the main protein made by the liver and tells how well the liver is making this protein

Total protein

measures albumin and all other proteins in blood, including antibodies made to help fight off infections