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home - Liver - Liver Failure - Drug Toxicity Written by Dr Sebastian Zeki
Knowledge


Assesses the severity of liver dysfunction and its prognostic
significance following haemorrhage

Knows importance of correcting hypovolaemia preventing
complications of GI bleeding and deterioration of liver function and
stopping bleeding

Knows the potential use of blood & clotting factors the role of
antibiotics the use of vasoconstrictors therapeutic endoscopy the
indication for transjugular intra-hepatic portosystemic shunt (TIPS) or
surgical shunt surgery

Aware of the specific complications of bleeding in cirrhotic patients –
including hepatic encephalopathy need for airway protection
nutrition identification of alcohol withdrawal

Skills
Shows proficiency in endoscopy – including emergency endoscopic
techniques of variceal band ligation endoscopic sclerotherapy
injection of cyanoacrylate glues for gastric varices

Can place safely and manage a Sengstaken tube in refractory
variceal bleeding

Can prevent and treat complications including hepatorenal failure
ascites spontaneous bacterial peritonitis and hepatic encephalopathy

Behaviours
Appreciates criteria for referral to specialist centre when appropriate –
such as with bleeding gastric or ectopic varices or consideration of
TIPS

Appreciates need to treat patients using a multi–disciplinary approach
Shows understanding of an empathic approach which may involve


Also....

Knowledge
Knows risks and prognosis of recurrent variceal bleeding in cirrhotic
patients

Aware of role of secondary prophylaxis with either non–selective ?-
blockers endoscopic ligation or both

Skills
Can select suitable endoscopic therapy and perform the appropriate
procedure competently

Behaviours
Appreciates the potential role of other specialists e g interventional
radiologists and nurse specialists

Also...

Knowledge


Understands the mechanisms of biliary metabolism the various
abnormalities that lead to hyperbilirubinaemia and knows and
recognises the causes of the various forms of jaundice

Skills
Selects and interprets appropriate investigations and formulate
management plans

Behaviours
Approaches patients presenting with jaundice in a logical and
methodical manner

Also...
Knowledge


Can define the different types (I and II) of hepatorenal
syndrome(HRS)

Knows the differential diagnosis of different types of renal
failure/impairment in liver disease

Understands the major and minor criteria in diagnosis of HRS and be
able to differentiate between HRS and acute kidney injury

Appreciates the prognostic significance of renal impairment in
patients with chronic liver disease

Knows the options for management and treatment of HRS the role of
colloids and vasoconstrictors as well as renal supportive treatment by
dialysis

Skills
Uses and interprets result of sometimes complex investigations
appropriately

Behaviours
Can judge when to involve other specialists especially nephrologists
radiologists and intensivists

Also...

Knowledge


Understands the pathogenesis of hepatic encephalopathy (HE)
Knows the differential diagnosis of HE including the existence of risk
factors for its causation including metabolic disorders and intracranial
structural disorders (such as subdural haematomas)

Knows factors that may precipitate HE including bleeding electrolyte
disturbance drugs or other organ failure

Knows the various treatment options appropriate for grade of severity

Skills
Can grade the mental state (Glasgow coma score and West Haven
Criteria)

Shows ability to differentiate between acute and acute on chronic liver
injury

Can identify the patient at risk of raised intracranial pressure and
cerebral oedema

Selects and use investigations appropriately and determine timing of
airway protection

Behaviours
Appreciates the role of other specialists and interacts in a
professional manner with intensivists neurologists
neurophysiologists radiologists and other specialists

Makes referral where appropriate to specialist centre for liver
transplantation

Also...

Knowledge


Understands the causes of acute hepatitis including viral druginduced alcohol-induced and auto-immune liver disease

Knows the appropriate plan of investigation and management of
specific diseases including the role of serological investigations and
liver biopsy

Skills
Takes an accurate history from patients with acute liver disease and
performs detailed clinical examination

Utilises investigation in a structured manner
Behaviours
Considers all therapeutic modalities and preparedness to refer to
specialist centre where diagnosis remains in doubt or appropriate
management cannot be performed

Also...

Knowledge
Assessment
Methods GMP
Recognises and knows how to diagnose acute and chronic drug
induced liver injury and dysfunction
SCE 1,2
Aware of methods of diagnosis, role of liver biopsy and therapy
including role of steroids in treatment in selected cases
SCE, CbD 1
Skills
Understands the role of both prescription and recreational drugs and
the aetiology of a wide variety of liver disease and dysfunction often
requiring prompt intervention or involvement of specialist services
SCE, CbD 1,2,3
Has awareness of the range of iatrogenic liver dysfunction SCE, CbD 1,2,3
Behaviours
Able to interact with specialist pharmacy services. Can use yellow
card reporting system of potential adverse effects of drugs.

Also....

Knowledge


Understands the causes and pathophysiology of acute liver failure
Can plan appropriate investigation evaluate prognosis and construct
a detailed management plan

Identifies those potentially suitable for emergency liver transplantation
Skills
Develops ability to make accurate evaluation of patients with liver
failure at the stage of initial presentation

Can deliver management plan appropriately evaluate changes in
patient’s condition and react accordingly

Utilises the range of medical interventions necessary to support
critically ill patients

Behaviours
Demonstrates ability to identify patients at risk of developing acute
liver failure and understand the criteria for referral to specialist centres

Works collaboratively with nurses and all ITU staff as well as
colleagues in other clinical disciplines to deliver the highest standard
of clinical care

Communicates effectively and relates with empathy to family and
close friends of patients

Drug Toxicity

Written by Dr Sebastian Zeki Hepatocyte Injury/Death Underlying liver disease —Liver disease affects Phase I>IIIntra and Extrahepatic Cholestasis leads to decreased secretion (phase III) of both endogenous and exogenous substances. Genetics —Many have CYP polymorphismsExample: alcohol-metabolizing CYP2E1 subfamily and in the CYP2D6 subfamily, which is responsible for the metabolism of drugs such as metopro-lol, quinidine, and desipramine.Genetic polymorphisms in the phase II and IIIExample: glutathione s-transferases and the hepatotoxicity seen with certain chemical carcinogens (eg, benzo(a)pyrene). Age —Phase I activity is reduced with agePhase II activity is unaffected by ageInfants may have immature CYP enzymes. Drugs-Phase IInduction and inhibition of CYP is an important problemPhase IIUsually not a problem- but reduced phase II reactions have been described with chlorpromazine and valproate.Phase IIIInhibition (eg, atorvastatin, carvedilol, clarithromycin, sertraline) and induction (eg, amiodarone, diltiazem, erythromycin, St.John's wort can occur. Diet —-Can induce CYP with Brussels sprouts, cabbage, cruciferous vegetables (such as broccoli), and charcoal-broiled beef.-Grapefruit juice inhibits CYP3A activity,-Chronic alcohol ingestion increases CYP2E1 x2 and lasts 10 days after abstinence.Alcohol also inhibits GSH synthesis with faster GSH turnover and impairs mitochondrial transport of GSH (with sequestra-tion within the mitochondria).Drugs with increased hepatotoxicity when associated with alcohol intake are paracetamol, isoniazid, cocaine, methotrex-ate, and vitamin A.CYP activity is increased by high protein diets and reduced by low protein diets and severe malnutrition.Thus, states of severe malnutrition or chronic alcoholism with poor nutrition may influence certain detoxifying cofactors such as glutathione. Factors affecting phase I, II, and III reactions Mechanisms Of Drug Induced Toxicity . DRUG Phase 1 (Polar groups are added to lipophilic molecules by oxidation, reduction, or hydrolysis to render them water soluble ) Phase II This makes drug more hydrophilic) Cytochrome P450 super-family of mixed function oxidases (CYP). Reactive metabolite Conjugated drug(= readily excretable, nontoxic substances. Occasionally result in toxic Excretory transporters Excretion Transferases GlucoronideSulfateGlutathioneMethyl NADPH NADP Phase III reactions —These result in excretion into bile-mediated by ATP-dependent transporters (members of the adenosine triphosphate (ATP)-binding cassette (ABC) superfamily) in bile canaliculi.The predominant role of the excretor-transporters is that of regulation of bile formation and the excretion of xenobiotics.Altered activity of these excretor-transporters can lead to hepatotoxicity. Phase I reactions — Carried out by the CYP family: 50 proteins in 18 families (eg, CYP2) and 43 subfamilies (eg, CYP2E1).Reactions are localized to the cytoplasmic membrane of endoplasmic reticulum (microsomal-type- responsible for phase I drug metabolism) or mitochondria (mitochondrial type).Most drugs and toxins metabolized by CYP1, CYP2, and CYP3 (esp CYP3A4 which metabolises 50% of all drugs) families- smaller contribution from CYP4. Large water-soluble polar groupsGlucuronic acidSulfateAcetateGlycineGlutathioneMethyl group. Occurs within the hepatocyte cytoplasm via the UDP-glucuronyl transferases (UGT1 and UGT2), sulfotransferases, and glutathione S-transferases. -Metabolite covalent binding-Cell stress-Immune mediated injury Innate immune system Adaptive immune system

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