Liver Disease - 3

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  • Created by: LBCW0502
  • Created on: 30-11-19 14:23
Describe features of drug handling in liver disease (1)
Liver disease - broad spectrum of conditions. Limited information available to help guide drug dosing (e.g. creatinine clearance of renal impairment, no formula for hepatic impairment)
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Describe features of drug handling in liver disease (2)
Child-Pugh scoring system - not developed to predict drug handling but disease severity/outcome. BNF/SPC recommendations - most drugs cautioned/CI (overly cautious)
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Which patient factors are considered when safely prescribing in liver disease?
Underlying diagnosis, overall severity (Child-Pugh/MELD), signs and symptoms, trends in LFTs/disease progression, overall goals for care
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Which drug factors are considered when safely prescribing in liver disease? (1)
PK properties (F, Vd, Cl). PD properties. S/E profile. Therapeutic index. Route of administration (e.g is the patient able to swallow tablets?).
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Which drug factors are considered when safely prescribing in liver disease? (2)
MR preparations not used – patients have an extended duration of action due to lack of metabolism from condition. Drug interactions e.g. phenytoin, aspirin (protein binding, albumin, bilirubin) etc.
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What is the general approach when using drugs to treat liver disease?
Avoid hepatotoxic drugs. Ideally use drugs with a shorter half life. If raised INR/PT and bilirubin or low albumin consider dose reduction. Start with small dose and increase slowly or dose as required. Monitor patient closely with regular review
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What is the general approach when using LFTs to investigate liver disease?
Trends not in isolation. Abnormal LFTs may not be due to liver dysfunction. Review metabolic and synthetic functions of the liver
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Describe features of bilirubin
Drug absorption for highly lipophilic drugs - reduced absorption. Biliary clearance - reduced clearance. Enterohepatic recirculation - reduced exposure, clinical effect. Competition for protein binding sites - displace drug, enhance clinical effect
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Describe features of tranaminases (1)
AST and ALT (no link between AST/ALT and AUC). False normal in cirrhosis. Patients could have normal LFT but have chronic liver disease, change in metabolism – fake normal. Drug induced, ALP and GGT. Cholestasis may reduce drug absorption
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Describe features of tranaminases (2)
Some drugs can be enzyme inducers and cause elevations in GGT
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Describe features of albumin
Can indicate synthetic function. Decreased albumin - decreased protein binding, increased free drug, increased clinical effect. Lower doses with close monitoring may be required. Misinterpretation of TDM. Drugs include phenytoin
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What is PK?
The branch of pharmacology concerned with the movement of drugs within the body. Liver disease will influence pharmacokinetic parameters. But extensive decompensation before effects on drug handling become clinically significant
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Describe features of absorption
Absorption may be altered e.g. ascites results in decreased absorption, cholestasis (decreased absorption of lipophilic drugs)
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Describe features of distribution (1)
Alteration due to reduced protein binding (low albumin levels or increased bilirubin). Increased unbound drug and increased clinical effect. Ascites. Cachectic
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Describe features of distribution (2)
Increased unbound drug due to ascites and cachectic, use ideal/adjusted body weight (or dry weight – prior to fluid build-up) for dosing (avoid overdose due to unrealistic weight/fluid build-up)
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Describe features of metabolism (1)
Complex/not fully understood. Liver will carry out drug metabolism even in cirrhotic patients. Factors which affect hepatic metabolism are functioning cell mass and liver blood flow
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Describe features of metabolism (2)
Main function - make drugs water soluble and easier to excrete (via kidneys) but for some drugs pharmacologically active compounds may be formed in the process. Consider accumulation, excretion (form – unchanged or not)
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Describe features of metabolism (3)
Reduction in functioning cell mass (accumulation of active drug, lower metabolism), enhanced response (increased F), increased S/E (prolonged t1/2 of drugs and increased toxicity of repeated doses). Low extraction ratio drugs
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Describe features of metabolism (4)
Hepatic blood flow reduced, bioavailability not affected except for drugs that are highly protein bound. Metabolism dependent on functional capacity of liver. Reduced functional capacity - delayed elimination from systemic circulation, prolonged t1/2
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Describe features of metabolism (5)
May need to adjust dose interval. E.g. citalopram, theophylline. Hepatic blood flow may be reduced in high extraction ratio drugs (highly first pass effect). Hepatic clearance depends on blood flow to liver, hepatic blood flow reduced, F increased
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Describe features of metabolism (6)
May need to adjust dose and interval e.g. propranolol, morphine, sertaline, sumatriptan. Cirrhosis, portal vein thrombosis, cardiac failure, shock (very low BP), portal systemic shunting
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Describe the effect of cholestasis on metabolism
Bile fails to flow from hepatocytes to duodenum and is diverted to blood. Bile salts compete for protein binding sites. Reduced protein binding of drugs. Reduced absorption of lipid soluble drugs. Drugs eliminated by biliary route may accumulate
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Describe features of elimination (1)
Enterohepatic circulation - if cholestasis then reduction in recirculation and drugs may be less effective (eg. MMF). Extensive biliary clearance – drugs may accumulate e.g. vinca alkaloids, doxorubicin, mycophenolate
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Describe features of elimination (2)
Renal excretion affected, hepatorenal syndrome, eGFR overstimated in cirrhotic patients
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What is PD?
The branch of pharmacology concerned with the effects of drugs and the mechanism of their action. Patients may be at risk of exaggerated response, increased toxicity, reduced response
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Describe features of the exaggerated response (1)
Cerebral sensitivity and tissue responsiveness to sedative and hypnotic drugs can be increased e.g. opioid analgesics, BDZs. Patients with encephalopathy have altered blood- brain permeability
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Describe features of the exaggerated response (2)
Cerebral blood flow and receptor sensitivity - brain more sensitive to sedating effects
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Describe features of the exaggerated response (3)
Increased central action, drugs cross BBB, start with low doses (consider stopping if reduced response, patient is confused)
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What are the side effects of the drugs? (1)
Cause sedation - can precipitate or worsen encephalopathy e.g. opioid analgesics, benzodiazepines, hypnotics. Cause GI ulceration – increased risk GI mucosal damage and bleeding e.g. NSAIDs, aspirin, bisphoshonates.
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What are the side effects of the drugs? (2)
Cause constipation – can precipitate or worsen encephalopathy e.g. opioid analgesics, sedating antihistamines, antimuscarinics
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What are the side effects of the drugs? (3)
S/E – sedation, GI ulceration (catastrophic bleed – no clotting factors being produced, NSAIDs not used due to risk of bleeding, use paracetamol instead), constipation (opiate) – unable to excrete ammonia, worsening symptoms of HE (start lactulose)
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What are the cautions with the drugs? (1)
Interfere or have an adverse effects on clotting – increased risk of bleeding e.g. warfarin, aspirin, clopidogrel, NSAIDs. Cause fluid retention and electrolyte imbalance – can precipitate or worsen HE (e.g. diuretics)
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What are the cautions with the drugs? (2)
High Na content in drugs (precipitates/worsens ascites) e.g. soluble tablets, some IV preparations, antacids. Narrow therapeutic index/hepatotoxic/nephrotoxic
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Describe the routes of administration
Oral – generally preferred. Avoid modified release and long-acting preparations. Avoid IM if deranged clotting. Topical preparations – consider transdermal absorption. May cause irritation. Rectal – consider presence varices/bleeding
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Which factors need to be considered when investigating and treating liver disease? (1)
No single method for determining liver function. Think about the underlying cause of the liver disease. Is the cirrhosis compensated or decompensated? • Prevent precipitation of decompensated cirrhosis, difficult to get them compensated again
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Which factors need to be considered when investigating and treating liver disease? (2)
Always look at trends in LFTs. Albumin, INR, PT and bilirubin are considered the best predictors (synthetic and excretory function)
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Which factors are considered when choosing a drug treatment for liver disease?
Is drug highly metabolised in liver? What is it side-effect profile? Be aware of potential renal impairment. Think about route of administration. Titrate to patient response
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Describe features of drug-induced liver disease
Increase in incidence. Lots of drugs are hepatotoxic (e.g. high doses of herbal medicines). Drugs can cause wide spectrum of damage (acute/chronic liver damage). Generally discontinuation of the drug results in resolution – not always the case though
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Describe features of hepatotoxicity (1)
Generally accepted patients with pre-existing liver disease do not have an increased susceptibility to developing hepatotoxicity. Effects can be more severe due to reduced hepatic reserve
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Describe features of hepatotoxicity (2)
Exceptions - methotrexate, certain cytotoxics, sodium valporate. E.g. sodium valproate (hepatotoxic) and co-amoxiclav – drug induced liver damage
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What are the risk factors for DILD?
Gender (more common in females). Age. Genetics. Concurrent diseases e.g. obesity, diabetes, co-infection with HIV. Polypharmacy
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Describe features of intrinsic reactions
Predictable, reproducible, dose dependent, occur rapidly (hours), cause necrosis, acute liver failure e.g. paracetamol overdose
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Describe features of idiosyncratic reactions
Not predictable, not reproducible, not dose dependent, take longer to occur (weeks/months), can result in metabolic idiosyncrasy or immunoallergic reaction. Can cause any type of liver injury e.g. increased LFTs, jaundice, fever, rash, eosinophilia
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Give examples of idiosyncratic reactions and causative agents (1)
Cholestasis – OCP, warfarin, azathioprine, flucloxacillin. ALF – allopurinol, cyclophosphamide, NSAIDS, MDMA. Steatosis – amiodarone, corticosteroids, TPN. Fibrosis and cirrhosis – methotrexate. Vascular disorders – OCP, azathioprine
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Give examples of idiosyncratic reactions and causative agents (2)
Acute hepatitis – phenytoin, isoniazid. Chronic hepatitis - isoniazid
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