A6. Drugs in liver disease Flashcards
Describe drug induced liver disease
-Some medicines can result in acute liver damage or cholestasis
-Monitoring of liver function is essential with these medicines
-Baseline LFTs should be taken & then further monitoring as required
-Schedule of this monitoring often listed in the BNF monograph
-Some medicines can result in hepatic enzyme induction OR inhibition
-Liver injury can be predictable & dose-dependent OR idiosyncratic
(unpredictable, occurs at a lower incidence)
-ALWAYS consider possible contribution of drugs in a patient with any type of liver damage
Drugs which can cause liver damage
one note
patient factors to consider in liver disease?
-Signs & symptoms
-LFTs
-Diagnosis
Drug factors to consider in liver disease
-Pharmacokinetics
-Pharmacodynamics
-Side effect profile
Describe drug handling in liver disease
-Liver is the main site of drug
metabolism
-Hepatic metabolism is most
important for lipid-soluble
drugs whereas water-
soluble drugs are readily
renally excreted
Many medications undergo what two stage metabolic process?
-Phase 1 involves metabolism (oxidation, reduction, hydrolysis)
e.g. cytochrome P450 enzymes (CYP450)
-Phase 2 includes biotransformation with conjugation of the drug or its
metabolites, examples of phase 2 pathways
e.g. glucuronidation and sulphation
Describe CYP-mediated reactions
-CYP-mediated reactions are affected more in liver disease
than phase 2 reactions
-Expression of CYP 1A, 2C19 and 3A are decreased in cirrhosis
Describe the inhibition and induction in alcoholic liver disease
one note
Changes in absorption in liver disease
-Decreased gut motility in cirrhosis means a delay in gastric emptying,
and a reduction in the rate, but not extent of absorption
-Reduced absorption & bioavailability of lipophilic drugs may occur with
cholestasis
-Drugs which have a low bioavailability due to high first pass metabolism may need dose reducing in liver disease due to an
increased bioavailability
Distribution changes in liver disease
-Ascites increases the volume of distribution for water
soluble drugs e.g. gentamicin, which leads to a
reduced drug concentration
-Ascites: build-up of fluid in the space between
lining of the abdomen and abdominal organs
-Low albumin levels may mean drugs which are
highly protein bound (phenytoin) usually are at a
higher concentration of free drug, potentially leading
to toxicity
-Excess bilirubin can displace highly protein bound
drugs from their binding sites → more free drug
metabolism changes in liver disease
-Impaired liver metabolism only occurs in severe disease (liver tissue has excellent
reserves)
-Reduced hepatic blood flow in cirrhosis due to portosystemic shunting (less
blood flows through liver, and moves to systemic circulation)
-Reduced hepatic clearance increases drug levels & toxicity → causes issues for
drugs with a narrow therapeutic window
-Prodrugs that need to be metabolise
elimination/ excretion changes in liver disease
-Renal excretion can be reduced in patients with severe liver
disease
-Hepatorenal syndrome
-CrCl may be overestimated in patients with cirrhosis
-Reduced serum creatinine if reduced muscle mass and
reduced conversion of creatine to creatinine in the liver
-If a drug is excreted in the bile, if the patient has cholestasis, this process will be reduced
Drug factors to think about in liver disease
-Hydrophilic or lipophilic?
-Protein bound?
-Does it displace bilirubin? Or is it displaced?
-Is it metabolised by the liver?
-Does it have a high extraction ratio?
-Is it potentially hepatotoxic?
Some common examples of medications you will need to be aware of reducing/avoiding in liver disease are:
-Constipating drugs
-Sedating drugs
-Drugs that lower seizure threshold
-Drugs which increase the risk of GI ulceration and bleeding
-Drugs which cause endocrine/metabolic changes
Describe constipating drugs in liver disease and example drugs?
-Medicines which can cause constipation (see Drugs in GI diseases lecture) can precipitate or worsen hepatic encephalopathy in patients with liver disease.
-Accumulation of toxic waste products can cross the blood-brain barrier
-HE is defined as a spectrum of neuropsychiatric abnormalities in patients with liver dysfunction
-Example drugs: loperamide, codeine, amitriptyline
How to treat constipation in liver disease?
Laxatives such as lactulose can be co-prescribed, this can also be used to prevent/treat encephalopathy
Sedating drugs in liver disease?
-Avoid in patients at risk of HE as the brain is more sensitive to sedating effects
-Sedation & confusion will increase risk or worsen HE
-Example drugs: opioids, sedating antihistamines, tricyclic antidepressants
Drugs which reduce seizure threshold in Liver disease? examples?
-Some drugs have an increased risk of convulsions
-Patients who struggle with excessive alcohol consumption are at an increased risk of seizures due to withdrawal
-Example drugs: tramadol, pethidine, sedating antihistamines, antipsychotics and antidepressants
Drugs which increase GI ulceration in Liver disease? examples?
-Risk in patients with portal hypertension, varices, low platelets & deranged
clotting
-Integrity of GI mucosa may already be compromised by excessive alcohol →
increased GI ulceration risk
-Vitamin K & clotting factor synthesis may be impaired
-Example drugs: clopidogrel, warfarin, corticosteroids, SSRIs
NSAIDs are C/I in patients with any degree of liver cirrhosis due to SEs:
-Fluid retention (patient already may have ascites)
-Electrolyte abnormalities
-Gastrointestinal ulceration & bleeding
-Inhibition of platelet aggregation
-Reduction in glomerular filtration
what are oesophageal varices?
-Varices are expanded blood vessels that develop most commonly in the oesophagus and stomach
-More common in people with cirrhosis
How do oesophageal varices develop?
Develop when blood flow through the liver is obstructed (blocked) by scarring, increasing the pressure inside the
portal vein, which carries blood from the intestines to the liver → portal hypertension
What can portal hypertension lead to?
-Portal hypertension leads to an increase in the blood pressure inside the veins
-Veins expand under higher pressure resulting in varices
-Managed pharmacologically with terlipressin, & reducing PV hypertension or surgically with banding
Drugs which can cause endocrine/metabolic changes?
-Diuretics can cause hyponatraemia & hypokalaemia → encephalopathy
-As discussed on previous slide NSAIDs can increase sodium & water retention → worsening ascites, precipitating renal
failure
-Medicines with a high sodium content e.g. antacids, soluble tablets can also precipitate/worsen ascites
