Liver Disease = Drug selection/dosing Flashcards
What does the liver do?
Production of plasma proteins
synthesis of clotting factors
Production of bile = req for absorption of fat, fat soluble vitamins, lipophilic drugs
Enterohepatic (re)circulation of bile salts and some drugs
Conjugation and excretion of bilirubin
Hormone inactivation
Metabolism and excretion
Do LFTs always indicate liver disease?
No, some liver disease can present in the presence or absence of abnormal LFT
What is Alanine transferase used to measure?
ALT = Cell death
What is aspartate transferase used to measure?
AST = cell death
What is alkaline phosphatase used to measure?
Alk phos or ALP = biliary problems
What is gamma GT/GGT used to measure?
Biliary problems
Helps clarify if raised alk phos is from liver
What do altered liver aminotransferase levels indicate about liver health?
(GENERALLY)
Indicate inflammation and necrosis (hepatocyte damage and death)
NOT RELIABLE MEASURE OF DYSFUNCTION
Explain the De Ritis Ratio
Ratio of AST:ALT
> 1 = damage is probably alcohol related
<1 = probably non alcoholic liver disease
What do altered liver ALT levels indicate?
Inc = hepatocellular damage
Also = muscle damage, acute MI, renal infarction
Haemolysis = falsely elevated levels
What do altered liver AST levels indicate?
Found in: liver, heart, kidney, pancreas
Raised = hepatocellular damage, acute MI, musculoskeletal disease, intestinal injury, haemolysis, hypothyroidism, pulmonary embolism, necrotic tumours
Dec = Vit B6 def, preg
What do altered liver Alk phos levels indicate?
Found in: liver, bone, placenta, biliary tract
Raised = hepatobiliary obstruction (+ other liver disease, associated w/ cholestasis), bone disease, children, preg, over 50
Dec = Vit D tox, milk-alkali syndrome, scurvy, hypophosphatasemia, hypothyroidism
What do altered liver GGT/gammaGT levels indicate?
One of the only LIVER SPECIFIC LFT!
Clarify if inc ALT is liver origin
Raised in = Cholestasis, diabetes, alcohol abuse, enz inducing meds
What do altered bilirubin levels indicate?
Raised = intravascular haemolysis, failure of conjugation in hepatocytes, biliary obstruction
- direct hyperbilirubinemia = biliary obstruction, cholestasis, hepatocellular injury - indirect hyperbilirubinemia = inc bilirubin production --> haemolysis
What is total bilirubin?
Conjugates + unconjugated + delta
What is direct bilirubin?
conjugated + delta
Explain the movement/breakdown of bilirubin in the liver
Bilirubin is bound to albumin in blood, taken up by hepatocytes
In hepatocytes = bilirubin conjugated with glucuronic acid
Conjugated (direct) bilirubin = secreted into bile (allows plasma albumin to stay low)
Cumulatively, what does bilirubin, ALP, and aminotransferases indicate?
Whether jaundice is pre-hepatic due to:
- intrahepatic damage
- intrahepatic cholestasis
- post-hepatic
What do altered serum albumin levels indicate?
Dec (due to dec synth) = chronic hepatitis, severe acute hepatitis, cirrhosis, malnutrition
Dec (due to inc loss of albumin) = burns, crohn’s disease, nephrotic syndrome
Dec (Due to inc catabolism) = infection, trauma, thyrotoxicosis
What are signs of severely low serum albumin?
Ascites (inc volume of dist, reduces absorption of water soluble meds)
Peripheral oedema
Pulmonary oedema
Reduced protein binding of drugs
In what liver conditions can you seen jaundice in?
cholestasis
severe cirrhosis
end stage liver failure
What are some clinical signs of compensated cirrhosis?
Xanthelasmas
Parotid enlargement
Spider naevi
Gynecomastia
Small/large liver
Splenomegaly
What are some clinical signs of general cirrhosis?
Jaundice
Fever
Loss of body hair
What are some clinical neurological signs of decompensated cirrhosis?
(neurological)
Disorientated
Drowsy
Hepatic flap
fetor hepaticus
Generally, what is the appearance of someone with liver disease?
Jaundice
Thin/skinny
Muscle wasting
Ascites =portal HTN, low plasma albumin, enhanced renal retention of Na
Gynaecomastia
Spider naevi
easily bruised/bruising
What are the general rules for drug choice in liver disease?
Avoid herbal medicines
Avoid medicines previously linked to liver ADRs (raised LFT)
Avoid hepatotoxic drugs
Use potentially hepatotoxic drugs w/ caution
List some potentially hepatotoxic drugs
Abx = Amoxicillin/clavulanate, flucloxacillin
Analgesics = NSAIDs, paracetamol
Anticonvulsants = sodium valproate, phenytoin
Herbal/dietary supps = black cohos, echinacea, body-building, weight loss supplements
Outline steatotic liver disease (diagnosis, risk factor, association, what is)
Diagnosis = histology or imaging, slightly abnormal LFTs
Accumulation of fat in the liver
Risk factors = over nutrition, insulin resistance, complicated by alcohol use
Associated w/ obesity, high chol/TG, T2DM
What are some LFT characteristics of SLD/Fatty liver/mild disease?
ASL/ALT = 2x ULN
Some ongoing damage, no other LFT/clotting/albumin/cirrhosis/cholestasis
No change in drug characteristics
What are some LFT/other characteristics of cholestasis?
Jaundice
Raised bilirubin, alk phos, GGT = 3x ULN
ALT, AST normal unless cirrhosis
Can be due to med
How is ADME influenced in cholestasis?
Reduced absorption = lipid soluble drugs (inc vit K)
Impaired elimination = biliary excreted drugs
Protein bound drugs = high bilirubin displace protein bound drug –> inc free [serum]
metabolic function unchanged
What drug types should be changed (dose, administration, avoided, etc.) in cholestasis?
Lipid soluble meds = will have reduce absorption
Medicines excreted in bile = impaired secretion
Protein bound medicines = high bilirubin can displace meds bound to plasma
Entero-hepatically recycled meds = dec/no excretion in bile
What drugs should you be cautious of in cholestasis?
Co-amoxiclav, fluclox
oestrogen, NSAID, carbamazepine
What is portal HTN and varices? (causes, effects)
Hepatocytes die, liver becomes scarred/fibroses –> blood cannot flow freely —> portal HTN
Reduces 1st pass metabolism –> blood from gut bypasses the liver
Minor bleed –> vomit blood or pass tarry stool
What are general rules for drug choice in cirrhosis and acute liver failure?
Avoid pro-drug and drugs w/ active metabolites = conversion is unpredictable
Prefer with shorter half-life
No hepato-renal syndrome, prefer drugs that are renally excreted
Drug with high first pass effect = reduce dose
Drug only available in hepatically metabolised forms = dose intervals may/will need to be inc depending on degree of impairment
Varices = drug w/ high first-pass effect, reduce dose
Discuss the symptoms of compensated cirrhosis?
portal hypertension
splenomegaly
Varices
spider naevi
Discuss some LFT changes seen in compensated cirrhosis?
ALT/AST = normal or 3*ULN
Albumin, clotting = normal
Bilirubin = may be normal, may inc (restrictions associated w/ cholestasis apply
Metabolic function may be normal, can deteriorate to decompensated cirrhosis, reduced first pass metabolism
Portal HTN = reduce blood flow through liver and therefore reduced metabolism
Discuss decompensated cirrhosis in drug treatment
Dose and freq adjustment of liver metabolised drugs
Varices dec 1st pass effect
Will need to dec drug freq/inc time between doses and avoid pro-drugs
What are the LFT symptoms/signs of decompensated cirrhosis?
Bilirubin usually raised, therefore restrictions associated with cholestasis also apply
Reduced albumin, inc clotting time = avoid highly bound protein medicines
Ascites inc vol of dist, reduces the absorption of water soluble meds
What are some drugs with high extraction/poor bioavailability?
Atorvastatin
Fluvastatin
Morphine
Pravastatin
Rosuvastatin
Simvastatin
What drugs should be avoided in cirrhosis?
Sedating, constipating drugs = encephalopathy
- opiates, TCAs, antihistamines, benzos, barbiturates, hypnotics, antipsychotics
- CCB, antispasmodics (hyoscine), loperamide (constipation)
Antiplatelet/anticoagulant = bleeding
- NSAIDs, aspirin, clopidogrel, dipyridamole, warfarin, heparin
Nephrotoxic = hepatorenal
- NSAIDs, COX-2 inhibitors, aminoglycosides, ACE inhibitors
sodium = ascites
gastric ulcerations = bleeding
- NSAIDs, aspirin, corticosteroids, bisphosphonates
Seizures = risk of seizures
- tramadol, varenicline/buproprion
- phebothiazines, sedating antihistamines
What are some LFT changes with acute liver failure?
Raised AST/ALT, bilirubin, clotting, encephalopathy
Albumin = normal, take time for it to be affected
Blood flow unaffected = no cirrhosis, portal HTN/varices –> take time to develop
Metabolism = severely affected
