Block 8

• The functions of gut microbiota include ................, ................., ................., ................ and ..................

  control of inflammatory response and immune response.

  drug metabolism.

  bile acids metabolism.

  vitamins and proteins production.

  intestinal barrier integrity.
• Biotransformation is a .............................

  It renders ................ and ................ to ................. and ................... so that they are .....................

  process that involves converting a drug into product or inert substances after or before reaching at the sight of action.

  lipid soluble; non-polar compounds; water soluble; polar compounds; excreted via various processes in the body.
• What are xenobiotics?
• Phase 1 of biotransformation involves the ...........................

  It is mediated by ........................

  It is often .................... and occurs in .......................

  It may ................... or ....................

  It is ...................... (genetic polymorphisms, inhibitable, inducible).

  direct modification of the primary structure.

  cytochromes P450.

  rate-limiting; endoplasmic reticulum.

  eliminate toxic molecules; generate toxic molecules.

  highly variable.
• Phase 2 of biotransformation is known as the ..................... stage.

  It ................................. (what does it do?)

  It increases ....................

  The ....................... are generally found in the .................... but some are .................

  conjugation.

  catalyzes covalent binding of drugs to polar ligands (transferases) such as glutathione, glucuronic acid, sulfate, and amino acids.

  water solubility.

  enzymes; endoplasmic reticulum; cytosolic.
• Once drugs have been altered by Phase I and Phase II enzymes, they may be excreted through ................... and ....................

  biliary excretion

  renal excretion
• Mechanisms of drug interactions include ................, ..............., ..............., ................, .................. and .................

  GI absorption

  protein binding displacement

  modified drug excretion

  transporter-mediated interactions

  enzyme induction

  enzyme inhibition
• The general principles of drug interactions during absorption include .............., ................ and the ...........................

  dissolution

  site of absorption

  rate vs extent of absorption
• Mechanisms of GI absorption drug interactions - Drug binding in the GI Tract:

  Drugs with .................... adsorb other drugs onto ................ e.g., ............... and .................

  Drugs capable of forming insoluble complexes or chelates with other drugs include ..............., ................ and ............... collectively known as ............, ................. and ............... (................), ................ such as ............... e.g., ............, ............. and .............., .............. and ..................

  Interactions are avoided by ..................

  large surface areas; their surfaces; activated charcoal; antacids.

  methyldopa; tetracycline; levodopa; iron salts; antacids; sucralfate; quinolones; binding resins; cholestyramine; thyroxine; thiazides; warfarin; phenytoin; enteral feeds.

  give drug >2 hours before binding agent.
• Mechanisms of GI absorption drug interactions - Alteration in GI motility:

  ......................... is an important determinant.

  ....................... agents slow gastric emptying.

  .................... and ................ increase gastric emptying.

  Increased motility ............................. and therefore .......................

  Interactions are avoided by .....................

  gastric emptying.

  anticholinergic.

  metoclopromide; erythromycin.

  decreases dissolution time; decreases absorption.

  separation does not help.
• Mechanisms of GI absorption drug interactions - Alteration in GI pH:

  Absorption of .................... is better in acidic medium.

  ..................... requires acidic medium to dissolve and .................., ................ and ................. reduce bioavailability.

  Interactions are avoided by .....................

  weak acids.

  ketoconazole; H2-antagonists; PPIs; antacids.

  adjusting the dosing times.
• Mechanisms of GI absorption drug interactions - Alteration in intestinal flora:

  Antimicrobials ...................... and ...........................

  Interactions are avoided by .....................

  increase digoxin concentrations

  decrease oral contraceptive effectiveness.

  different dosing time does not help.
• Mechanisms of GI absorption drug interactions - Alteration in drug metabolism within the wall of the intestine:

  ........................ is a selective inhibitor of intestinal metabolism (CYP3A4) as it interacts with .................., ..............., .............., ............, .............., ............... and ................... [CFATMAT].

  Interactions are avoided by .....................

  grapefruit juice.

  cyclosporin; felodipine; astemizole; terfenadine; midazolam; alprazolam; triazolam.

  avoiding the combination.
• Protein binding displacement mechanism of drug interaction:

  ................. is negatively charged and interacts with acidic drugs such as .............., .............. and ..............

  .................. interacts with basic compounds such as ................, ..............., and ...............


  albumin; warfarin; NSAIDs; phenytoin.

  alpha1-acid glycoprotein; propranolol; disopyramide; lidocaine.
• Modified drug excretion mechanism of drug interactions:

  Glomerular filtration - ............. plus ................. induced renal failure.

  Active tubular secretion - .............. and .............., ................ and .................

  Passive tubular reabsorption.

  ................. and .............. cause a 312% increase in ddl AUC as ............... cause an increase of ............... levels due to unknown mechanism.


  digoxin; aminoglycosides.

  penicillin; probenecid; sodium; lithium.

  didanosine; allopurinol; allopurinol; didanosine.
• Four strong enzyme inducers include .............., .............., ................ and ...............

  The effect of enzyme induction is ............................

  barbiturates; carbamazepine; rifampicin; phenytoin.

  increasing the amount of P450 present thus speeding up the oxidation and clearance of a drug.
• After a long day of lectures and a GPS test, Leanne Mkhize decides they are going to drink a pint of strong lager. The total volume of the pint is 576 ml and the ABV is 7.8%. How much units of alcohol will they ingest?

  4.49 units of alcohol.
• Low risk drinking includes .............. units/week for males and .............. units/week for females.

  High risk drinking includes ............... g/day for males and ............... g/day for females.

  21; 14.

  60; 40.
• Alcohol is metabolized mainly by the ...................

  The .............., ............... and ............... also metabolize alcohol.

  Within the liver 3 enzymes oxidize ethanol viz. .................., ............... and ................

  The product of all three enzymes is ....................., which is further metabolized into ......................

  liver.

  brain; pancreas; stomach.

  alcohol dehydrogenase; CYP2E1; catalase.

  acetaldehyde; acetate.
• Acetaldehydes may be the ..................... of alcoholic liver injury and their effect include .............................., .............................., .......................... and ...................................... and these are ..................... and can ..................., ..................... and ........................


  principal mediator; impairment of the mitochondrial oxidation of fatty acids leading to the accumulation of FA and TG; formation of oxygen-derived free radicals; depletion of mitochondrial glutathione; bind to hepatic macromolecules such as amines and thiols to form adducts; immunogenic; trigger autoimmune liver damage; stimulate hepatic cell to produce collagen; impair intracellular transport.
• The risk factors of alcohol liver disease include ..................., ..................., .............., ..............., ................. and ..................

  amount and duration of drinking; genetics; gender; pattern of drinking; co-existent chronic viral hepatitis; nutrition.
• The spectrum of alcohol liver disease includes .................. which is ................, ................. which is ................., and ................. which is .................

  steatosis; reversible

  steatohepatitis; reversible

  cirrhosis; irreversible
• Steatosis i.e., ............... is the most .................

  Patients are usually .................

  Occasional symptoms include ............., .............. and .................

  ..................... are usually normal.

  ................. is required for definite diagnosis.

  It disappears over ................... with ....................

  alcoholic fatty liver; frequent abnormality found in alcoholics.

  anorexia; nausea; RUQ pain.

  liver function tests.

  biopsy.

  4-6 weeks; complete abstinence.
• Diagnostic criteria for steatohepatitis includes ......................., .............................., ................., ..............., ................. and ..................


  jaundice onset less within previous 8 weeks; long term consumption of alcohol with <60 days of abstinence before jaundice onset; AST>50 U per L; AST/ALT ratio >1.5; both AST and ALT >400 U per L; total bilirubin >3mg per dL.
• Prognosis:

  The Maddrey Index - .................

  MELD score - ..................

  GAHS - .................

  The Lille score is used to ............................

  >32

  >-21

  >-9

  assess response to corticosteroids.
• Contraindications for steroids include ................, ................, ................, ............. and .................


  active GI bleeding

  severe pancreatitis

  uncontrolled diabetes

  active infection

  renal failure
• The treatment of alcohol hepatitis is ...................................

  If Lille score is ............... then continue for .....................

  prednisolone 40mg orally for one week.

  <0.45; another 3 weeks.
• Alcohol cirrhosis clinical features include ..............., .................., ................ and ...............

  bilateral parotid enlargement; palmar erythema; dupuytren's contracture; spider angiomatosis.
• Pathogenesis of ascites:

  Portal hypertension - ..................... - ..................... - ...................... - ...................... - .................. - .................... OR ................. - .....................


  splanchnic vasodilation

  decreased effective circulatory volume

  activation of RAAS

  renal sodium avidity

  ascites

  renal vasoconstriction

  hepatorenal syndrome
• The various grades of ascites include ................ which is .............., .............. which ..............., and ................ with .................

  grade 1; only detectable by ultrasound.

  grade 2; causes moderate symmetrical distension of abdomen.

  grade 3; causing marked abdominal distension.
• Conventionally ascites is classified as .................... or .................. The purpose of this subdivision is to .................... Thus ''malignancy classically causes an .................... ascites and cirrhosis causes a ...................... ascites''.


  exudate (ascitic fluid protein >25g/l); transudate (<25g/l); help identify the cause of ascites; exudative; transudative.
• Essential tests for ascites include .............., .............., ............. and ..............

  ................. should only be requested when there is suspicion for malignancy.

  ...................... is very accurate in detecting PHT-caused ascites.

  A ...................... is diagnostic of spontaneous bacterial peritonitis.

  ................... is indicative of pancreatitis.

  cell count and type; ascitic fluid albumin; ascitic fluid culture; ascitic fluid amylase.

  ascitic fluid cytology.

  SAAG >1.1 g/dL.

  neutrophil count of more than 250 cells/mm3.

  high ascitic amylase.
• A high SAAG is caused by .............., ............ and ...............

  cirrhosis

  cardiac failure

  nephrotic syndrome
• A low SAAG is caused by ..............., ............. and ...............

  malignancy

  pancreatitis

  TB
• Management of ascites in cirrhosis:

  ................... should be restricted to a .........................

  There is no role for ..................... in patients with uncomplicated ascites. ....................... is the drug of choice in the initial treatment of ascites due to cirrhosis. It is started at a daily dose ............................

  ....................... is added if ................... fails to resolve ascites. The initial dose of .................. is ................. and it is generally increased every .................. up to a dose not exceeding ...................

  ........................... is the first line treatment for patients with large or uncomfortable ascites.

  Dietary salt; no-added salt diet of 5.2 g/day of salt.

  water restriction.

  spironolactone; 100mg which is increased every 3-5 days until 400mg.

  furosemide; spironolactone at 400 mg; furosemide; 40mg/day; 3-5 days; 160mg/day.

  therapeutic paracentesis.
• What is the target weight loss in cirrhotic ascites?


  in patients with severe oedema there is no need to slow down the rate of daily weight loss. Once the oedema has resolved but ascites persists, weight loss should not exceed 0.5 kg/day.
• How do you assess compliance with salt restriction in a patient with ascites?

  urinary sodium excretion
• Refractory ascites refers to ascites that .........................

  It includes two sub-groups viz., ................ and ................

  ................. is the first line of treatment in patients with refractory ascites.

  .................... is the definitive treatment option.

  cannot be satisfactorily prevented by medical intervention.

  diuretic resistant ascites; diuretic intractable ascites.

  therapeutic paracentesis.

  liver transplant.
• Hepatorenal syndrome is a .................. that occurs in patients with .............., ..............., and ................, as well as in patients with .................. or ...............

  It is caused by ................ which occurs in patients with ................. and ...............

  HRS may occur spontaneously with ..................., or secondary to a precipitating event such as................. or .................... without ...................

  potentially reversible syndrome.

  cirrhosis.

  ascites.

  liver failure.

  acute live failure.

  alcoholic hepatitis.

  intra-renal vasoconstriction.

  end-stage liver disease.

  circulatory dysfunction.

  worsening liver function.

  bacterial infection.

  large volume paracentesis.

  albumin administration.
• Diagnosis of hepatorenal syndrome:

  1. Cirrhosis with ............ or ..............

  2. Serum creatinine ..................

  3. No improvement of .................. after at least .............. with ................ and ............... with ................

  4. Absence of ....................

  5. No current/recent treatment with .................. drugs.

  6. Absence of ....................... as indicated by ................... of ................., ................. of ................. and/or ...................

  ascites; acute liver failure.

  >1.5mg/dL.

  serum creatinine; 2 days; diuretic withdrawal; volume expansion; albumin.

  shock.

  nephrotoxic drugs.

  parenchymal kidney disease; proteinuria; >500mg/day; microhaematuria; >50 RBC/high power field; abnormal renal USS.