SCRIPT: hepatic dysfunction Flashcards
Liver function.
a) Assessed via which score?
b) What are the grades?
c) Which blood tests provide a good measure of liver ‘function’?
a) Child-Pugh score
- can and should be performed by the bedside
b) - A (mild) - life expectancy 15 - 20 years
- B (moderate) - 20% one-year mortality
- C (severe) - 50% one-year mortality
c) The 3 that are used in the Child-Pugh!! …
- Prothrombin time/ INR (raised in poor function)
- Albumin (low in poor function)
- Bilirubin (raised in poor function)
- Note: ALT, AST, Alk Phos and GGT are reflection of liver cell damage rather than liver ‘function’ (may not be deranged in advanced/ chronic disease)
LFTs.
a) Hepatocellular
b) Cholestatic
a) - ALT (liver-specific) - usually more markedly raised than AST
- AST (also found in heart and skeletal muscle) - may be raised in cardiac/muscle pathology; also AST 2-3x the ALT level indicates alcoholic liver disease
b) - Alk Phos -
- GGT - raised with Alk Phos = indicates cholestatic picture
Drugs contraindicated in acute/chronic liver disease.
a) Analgesics
b) Antihypertensives
c) Which drugs are known to worsen hepatic encephalopathy?
d) Other potentially dangerous drugs
a) - NSAIDs contraindicated in severe liver disease as can reduce renal blood flow and cause renal failure
- Paracetamol - stop?
- Opioids - lower dose probably needed
b) - ACE/ARBs contraindicated in Child-Pugh B and C as RAAS inhibition reduces renal blood flow and can precipitate renal failure
c) - Sedatives (e.g. benzodiazepines).
- Drugs causing agitation (e.g. antipsychotics).
- Constipating drugs (e.g. opioid analgesics).
- Drugs causing electrolyte disturbances (e.g. diuretics).
d) - Antiplatelets/ anticoagulants due to coagulopathy and risk of bleeding varices
- Any drug primarily metabolised by liver or excreted in bile (could be toxic - dose likely need reducing)
- Any drug/infusion with high sodium content (may worsen ascites)
Treatments for chronic liver disease.
a)
a) Diet
- Laxatives - lactulose commonly given (reduces absorption of nitrogenous products from GI tract)
b) - Propanolol for variceal bleeding prophylaxis
- Spironolactone for ascites
- Thiamine for Wernicke’s encephalopathy
Drug-induced liver injury.
a) Dose-dependent hepatitis
b) Idiosyncratic reactions (not dose-dependent)
c) Chronic liver cirrhosis
a) - Paracetamol
- NSAIDs, including aspirin
- Anti-TB drugs
- Statins (generally a mild trans-aminitis)
b) - Flucloxacillin (may occur up to 2 months later and is not dose-related)
- Co-amoxiclav (usually 1 - 6 weeks after course completed)
(often cholestatic picture with these drugs)
c) - Methotrexate
- Amiodarone
Paracetamol overdose.
a) Mechanism of liver injury
b) Patients at greater risk in overdose
c) How NAC works
d) Who should be given NAC?
e) King’s College Transplantation Criteria
f) Paracetamol max dose according to weight
a) - Paracetamol metabolite NAPQI accumulates
- Leads to depletion of glutathione reserves
- Leads to hepatocellular injury
b) Lower glutathione reserves:
- Malnourished/ anorexic/ cachexic
- HIV
- Alcoholics
- Pre-existing liver disease
- On enzyme inducing medications
c) Replace glutathione levels
d) - Patients whose paracetamol level lies above the nomogram treatment line >4 hours after ingestion
- Staggered overdose
- Patients presenting >8 hours post-ingestion after taking a potentially toxic amount (even if paracetamol level is unknown)
(note: no need to assess risk factors like anorexia or alcoholism when considering who to treat)
e) Presence of 1 or more of the following (CHIP):
- Creatinine > 300
- Hepatic encephalopathy grade 3 or 4
- INR > 6.5 (PT > 100)
- pH < 7.3
f) Adults > 50 kg:
- Oral - 0.5 - 1 g QDS (Max dose: 4 g per day)
- IV - 1 g over 15 mins, QDS (Max dose: 4 g per day)
Adults < 50 kg:
- Oral - 0.5 g QDS (Max dose: 2 g per day)
- IV - 15 mg/kg QDS (Max dose: 60 mg/kg/day)
Two-stage liver metabolism
- Phase 1 = cytochrome P450 metabolism (oxidation, reduction, methylation, etc.)
- Phase 2 = conjugation
Both phases are impaired in liver disease
Reasons why certain drugs need lower doses in liver disease
Reduced first-pass metabolism.
- this will be lower due to poor liver function leading to greater drug bioavailability (in severe cases, oral dosing will need to be similar to if given parenterally)
- in cirrhosis, portosystemic shunts develop, which bypass the liver
- so lower dose needed
Hepatically excreted (in bile)
- elimination will be slower due to poor liver function
- so lower dose needed
Lower albumin
- drugs which are highly protein bound may be affected by changes in albumin
Adverse effects
- certain drugs may exacerbate the consequences of liver disease (eg. NSAIDs further increase already high bleeding risk)
Hepatotoxic drugs
- worsen liver function further so should be avoided if at all possible
Cytochrome P450 inducers and inhibitors.
a) Drugs that use cytochrome P450 as substrate in its metabolism
b) Inducers - effects, examples
c) Inhibitors - effects, examples
a) Warfarin, COCP, ciclosporin
b) - Reduce concentration and efficacy of most drugs
- Increase concentration and efficacy of pro-drugs
Examples (PC BRAS)
- Phenytoin,
- Carbamazepine, topiramate
- Barbiturates
- Rifampicin
- Alcohol
- St John’s Wort
c) - Reduce concentration and efficacy of most drugs
- Increase concentration and efficacy of pro-drugs
Examples (AO DEVICES)
- Azole antifungals, allopurinol
- Omeprazole
- Disulfiram
- Ethanol
- Valproate
- Isoniazid
- Erythromycin, clarithromycin
- Sweet stuff - grapefruit and cranberry juice
Patient has undergone renal transplant and is on ciclosporin. Give the likely effect of the following drugs on the concentration of ciclosporin.
a) Carbamazepine
b) Allopurinol
c) Clarithromycin
d) Isoniazid
e) Grapefruit juice/ cranberry juice
f) Alcohol
g) Rifampicin
h) St John’s Wort
a) Carbamazepine:
- Enzyme inducer
- Reduce ciclosporin concentration
- ?transplant rejection
- higher ciclosporin dose needed
b) Allopurinol:
- Enzyme inhibitor
- Increase ciclosporin concentration
- ?over-immunosuppressed - ?severe infection
- lower ciclosporin dose needed
c) Clarithromycin
- Enzyme inhibitor
- Increase ciclosporin concentration
- ?over-immunosuppressed - ?severe infection
- lower ciclosporin dose needed
d) Isoniazid
- Enzyme inhibitor
- Increase ciclosporin concentration
- ?over-immunosuppressed - ?severe infection
- lower ciclosporin dose needed
e) Grapefruit juice/ cranberry juice
- Enzyme inhibitor
- Increase ciclosporin concentration
- ?over-immunosuppressed - ?severe infection
- lower ciclosporin dose needed
f) Alcohol
- Can inhibitor or induce CYPP450 enzymes
g) Rifampicin
- Enzyme inducer
- Reduce ciclosporin concentration
- ?transplant rejection
- higher ciclosporin dose needed
h) St John’s Wort
- Enzyme inducer
- Reduce ciclosporin concentration
- ?transplant rejection
- higher ciclosporin dose needed
Prescribing carefully in hepatic impairment.
a) Baseline
b) Monitoring
c) Drug choices
a) - Identify at risk patients.
- Baseline LFTs, albumin, PT and bilirubin
b) Monitor LFTs, albumin, PT and bilirubin at regular intervals throughout treatment with drug treatments known to cause hepatotoxicity.
- Monitor drug concentration where possible, to avoid toxicity which can cause liver injury.
c) - Avoid hepatotoxic drugs if possible
- Avoid drug-drug interactions which may increase the risk of liver injury.
- Drugs that are dependent on the liver for metabolism are likely to need dose reduction.
- Drugs that increase the risk of bleeding should be avoided, or used with caution in hepatic dysfunction.
- Be cautious with drugs that might exacerbate or precipitate the adverse effects of liver disease (eg. opioids and encephalopathy, sodium and ascites)
