Viva B(y)

This viva is relevant to the objectives of Section B of the 2017 CICM Primary Syllabus, which expects the exam candidate to understand "the fate of drugs in the body, including ...  how it is affected by extremes of age, obesity, pregnancy (including foetal) and disease (particularly critical illness)".

What are the effects of critical illness on drug absorption?
  • Delayed gastric empying = decreased drug absorption (paracetamol)
  • Gastric pH is higher = decreased drug absorption (clopidogrel)
  • Increased GIT permeability = increased drug absorption (electrolyte replacement)
  • Decreased mesenteric perfusion = decreased drug absorption (paracetamol)
  • Increased preabsorptive interactions = decreased drug absorption (NG feeds and phenytoin)
  • Decreased active efflux = increased drug absorption (tacrolimus)
  • Decreased skin/muscle perfusion tissue = decreased absorption from subcutaneous or intramuscular injectoins (heparin) 
What are the effects of critical illness on drug distribution?
  • Decreased protein = increased free drug levels of highly protein-bound drugs (phenytoin)
  • Altered protein binding due to changes in pH = altered free drug levels (calcium)
  • Increased volume of distribution = decreased elimination of drugs, decreased plasma concentration (aminoglycosides)
  • Microvascular haemodynamic dysfunction = decreased tissue penetration (piperacillin)
  • Impaired barrier functions = increased tissue penetration (benzylpenicillin into the CNS)
What are the effects of critical illness on drug metabolism?
  • Decreased hepatic blood flow = decreased clearance of high extraction ratio drugs (propofol)
  • Hypothermia = decreased hepatic clearance (midazolam)
  • Hyperthermia = increased clearance due to increased enzyme activity (suxamethonium)
  • Downregulation of hepatic enzymes = decreased clearance (theophylline)
  • Decreased hepatic syntheic function = decreased levels of soluble enzymes, decreased clearance of drugs in the plasma (suxamethonium)
What are the effects of critical illness on drug elimination?
  • Decreased renal blood flow and function = decreased clearance of unchanged drugs or metabolytes (everything! pick any example)
  • Increased glomerular filtration in hyperdynamic circulatory states = increased clearance of drugs (vancomycin)
What are the effects of obesity on drug absorption?
  • Increased gastric emptying rate =  higher oral peak dose (variable and drug-dependent)
  • Decreased gastric emptying rate due to bariatric surgery = lower oral peak dose (cyclosporine, thyroxine, phenytoin and rifampicin)
  • Poor subcutaneous fat circulation = decreased subcutaneous absorption (hCG)
  • Difficult intramuscular access = inadvertant subcutaneous injection
What are the effects of obesity on drug distribution?
  • Increased absolute and proportional amount of body fat = increased Vd for lipophilic drugs (benzodiazepines, lignocaine, thiopentone, verapamil)
  • Increased total body water = increased Vd for hydrophilic drugs (amikacin, gentamicin and tobramicin)
  • Increased α1-acid glycoprotein levels = decreased free fraction of some drugs (eg. propanolol) 
What are the effects of obesity on drug metabolism?
  • Increased hepatic blood flow due to increased cardiac output = increased clearance of high extraction ratio drugs (propofol)
  • Decreased hepatic blood flow due to fatty liver  = decreased hepatic clearance (clozapine, haloperidol)
  • Increased Phase II enzyme activity = increased hepatic clearance (lorazepam, oxazepam, paracetamol)
  • Increased soluble enzyme activity = increased substrate drug dose requirements (suxamethonium)
What are the effects of obesity on drug elimination?
  • Increased half-life due to increased volume of distribution for extremely lipophilic drugs (desmethyldiazepam, midazolam)
  • Increased cardiac output = increased GFR, increased renal clearance of hydrophilic drugs (vancomycin, aminoglycosides)
  • Increased tubular secretion = increased clearance out of proportion to increased GFR (ciprofloxacin, cimetidine and procainamide)
  • Decreased GFR due to diabetic nephropathy = reversal of the normal obesity-associated increase in clearance (vancomycin, aminoglycosides, ciprofoloxacin, etc)
What are the effects of old age on drug absorption?
  • Decreased gastric emptying rate = decreased oral absorption (digoxin, levodopa)
  • Increased gastric pH = decreased absorption of drugs which are dependent for pH for their dispersion (enteric-coated drugs); = increased absorption of weak based (methyldopa), decreased absorption of strong acids (amoxycillin)
  • Decreased intestinal absorptive surface = age-dependent decrease in drug absorption (indomethacin, prazosin and digoxin)
  • Decreased active transport = decreased transport of electrolytes and vitamins (zinc, calcium, folate and B12. )
  • Structural changes to stratum corneum = decreased transcutaneous absorption of hydrophilic substances (caffeine, aspirin)
  • Poor cutaneous circulation = decreased transcutaneous absorption (clonidine)
  • Unpredictable muscle circulation = erratic IM absorption (penicillin)
What are the effects of old age on drug distribution?
  • 10-15% decrease in total body water = decreased Vd for hydrophilic drugs (ethanol, lithium)
  • 10-15% increase in total body fat = increased Vd for lipophilic drugs (amiodarone, verapamil)
  • Decreased serum albumin = increased free fraction of albumin-bound drugs (phenytoin)
  • Increased serum α1-glycoprotein levels = decreased free fraction of alkaline drugs (metaclopromide, erythromycin)
  • P-glycoprotein efflux pump dysfunction = increased permeability of the BBB and this increased  effect-site concentration of CNS drugs (rifampicin, cyclosporin)
What are the effects of old age on drug metabolism?
  • Decreased hepatic tissue mass = decreased clearance by Phase I reactions (ibuprofen, propanolol, fentanyl) but not by Phase II reactions (aspirin, valproate, phenytoin)
  • Decreased hepatic blood flow = decreased clearance of high extraction ratio drugs (morphine, verapamil, lignocaine)
  • Decreased portal blood flow = increased oral bioavailability of high extraction ratio drugs (propanolol, labetalol)
What are the effects of old age on drug elimination?
  • Decreased glomerular filtration and decreased tubular function = decreased renal clearance of water-soluble drugs and metabolites (β-lactams, aminoglycosides)

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