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)

References

Roberts, Derek J., and Richard I. Hall. "Drug absorption, distribution, metabolism and excretion considerations in critically ill adults." Expert opinion on drug metabolism & toxicology 9.9 (2013): 1067-1084.

Smith, Brian S., et al. "Introduction to drug pharmacokinetics in the critically ill patient." CHEST Journal 141.5 (2012): 1327-1336.

Heyland, D. K., et al. "Impaired gastric emptying in mechanically ventilated, critically ill patients." Intensive care medicine 22.12 (1996): 1339-1344.

Johnston, John D., et al. "Gastrointestinal permeability and absorptive capacity in sepsis." Critical care medicine 24.7 (1996): 1144-1149.

DeCarolis, Douglas D., et al. "Comparative dose response using the intravenous versus enteral route of administration for potassium replenishment." Intensive and Critical Care Nursing36 (2016): 17-23

Barquist, Erik S., et al.  Journal of Trauma and Acute Care Surgery 63.1 (2007): 159-163.

Lahner, E., B. Annibale, and G. Delle Fave. "Systematic review: impaired drug absorption related to the co‐administration of antisecretory therapy." Alimentary pharmacology & therapeutics 29.12 (2009): 1219-1229.

Yeung, Sam CS Au, and Mary HH Ensom. "Phenytoin and enteral feedings: does evidence support an interaction?." Annals of Pharmacotherapy 34.7-8 (2000): 896-905.

Bonnet, F., et al. "Changes in hepatic flow induced by continuous positive pressure ventilation in critically ill patients." Critical care medicine 10.11 (1982): 703-705.

Jochberger, Stefan, et al. "Antifactor Xa activity in critically ill patients receiving antithrombotic prophylaxis with standard dosages of certoparin: a prospective, clinical study." Critical Care 9.5 (2005): R541.

Lemahieu, Wim, et al. "Cytochrome P450 3A4 and P‐glycoprotein Activity and Assimilation of Tacrolimus in Transplant Patients with Persistent Diarrhea." American journal of transplantation 5.6 (2005): 1383-1391.

Btaiche, Imad F., et al. "Critical illness, gastrointestinal complications, and medication therapy during enteral feeding in critically ill adult patients." Nutrition in Clinical Practice 25.1 (2010): 32-49.

De Paepe, Peter, Frans M. Belpaire, and Walter A. Buylaert. "Pharmacokinetic and pharmacodynamic considerations when treating patients with sepsis and septic shock." Clinical pharmacokinetics 41.14 (2002): 1135-1151.

Roberts, Jason A., and Jeffrey Lipman. "Pharmacokinetic issues for antibiotics in the critically ill patient." Critical care medicine 37.3 (2009): 840-851.

Boucher, Bradley A., et al. "Phenytoin pharmacokinetics in critically ill trauma patients." Clinical Pharmacology & Therapeutics 44.6 (1988): 675-683.

Gonzalez, Daniel, et al. "The effect of critical illness on drug distribution." Current pharmaceutical biotechnology 12.12 (2011): 2030-2036.

Joukhadar, Christian, et al. "Plasma and tissue pharmacokinetics of cefpirome in patients with sepsis." Critical care medicine 30.7 (2002): 1478-1482.

Joukhadar, Christian, et al. "Impaired target site penetration of ß-lactams may account for therapeutic failure in patients with septic shock." Critical care medicine 29.2 (2001): 385-391.

Roberts, Derek J., et al. "Effect of acute inflammatory brain injury on accumulation of morphine and morphine 3-and 6-glucuronide in the human brain." Critical care medicine 37.10 (2009): 2767-2774.

Vaja, Rakesh, Larry McNicol, and Imogen Sisley. "Anaesthesia for patients with liver disease." Continuing Education in Anaesthesia, Critical Care & Pain 10.1 (2009): 15-19.

Shedlofsky, Steven I., et al. "Endotoxin administration to humans inhibits hepatic cytochrome P450-mediated drug metabolism." Journal of Clinical Investigation 94.6 (1994): 2209.

Roh, Mark S., et al. "Stimulatory effect of interleukin-1 upon hepatic metabolism." Metabolism 35.5 (1986): 419-424.

Ballard, Berton E. "Pharmacokinetics and temperature." Journal of pharmaceutical sciences 63.9 (1974): 1345-1358.

Udy, Andrew A., Jason A. Roberts, and Jeffrey Lipman. "Implications of augmented renal clearance in critically ill patients." Nature Reviews Nephrology 7.9 (2011): 539-543.

Boucher, Bradley A., G. Christopher Wood, and Joseph M. Swanson. "Pharmacokinetic changes in critical illness." Critical care clinics 22.2 (2006): 255-271.

Blouin, Robert A., and Graham W. Warren. "Pharmacokinetic considerations in obesity." Journal of pharmaceutical sciences88.1 (1999): 1-7.

De Baerdemaeker, Luc EC, Eric P. Mortier, and Michel MRF Struys. "Pharmacokinetics in obese patients." Continuing Education in Anaesthesia, Critical Care & Pain 4.5 (2004): 152-155.

Cheymol, Georges. "Effects of obesity on pharmacokinetics." Clinical pharmacokinetics 39.3 (2000): 215-231.

Hanley, Michael J., Darrell R. Abernethy, and David J. Greenblatt. "Effect of obesity on the pharmacokinetics of drugs in humans." Clinical pharmacokinetics 49.2 (2010): 71-87.

Lemmens, Hendrikus JM. "Perioperative pharmacology in morbid obesity." Current Opinion in Anesthesiology 23.4 (2010): 485-491.

Sankaralingam, Sowndramalingam, Richard B. Kim, and Raj S. Padwal. "The impact of obesity on the pharmacology of medications used for cardiovascular risk factor control." Canadian Journal of Cardiology 31.2 (2015): 167-176.

Weinstein, Jeffrey A., et al. "Pharmacodynamics of vecuronium and atracurium in the obese surgical patient." Anesthesia & Analgesia 67.12 (1988): 1149-1153.

Dunn, Terry E., et al. "Pharmacokinetics and pharmacodynamics of methylprednisolone in obesity." Clinical Pharmacology & Therapeutics 49.5 (1991): 536-549.

Wang, Ellen Q., and Ho-Leung Fung. "Effects of obesity on the pharmacodynamics of nitroglycerin in conscious rats." The AAPS Journal 4.4 (2002): 80-88.

Robinson, Jennifer A., and Anne E. Burke. "Obesity and hormonal contraceptive efficacy." Women’s health 9.5 (2013): 453-466.

Padwal, R., D. Brocks, and A. M. Sharma. "A systematic review of drug absorption following bariatric surgery and its theoretical implications." Obesity reviews 11.1 (2010): 41-50.

Hanley, Michael J., Darrell R. Abernethy, and David J. Greenblatt. "Effect of obesity on the pharmacokinetics of drugs in humans." Clinical pharmacokinetics 49.2 (2010): 71-87.

Sanderink, Ger‐Jan, et al. "The pharmacokinetics and pharmacodynamics of enoxaparin in obese volunteers." Clinical Pharmacology & Therapeutics 72.3 (2002): 308-318.

Verdich, C., et al. "Effect of obesity and major weight reduction on gastric emptying." International journal of obesity 24.7 (2000):

Wright, Richard A., et al. "Gastric emptying and obesity." Gastroenterology 84.4 (1983): 747-751.

Chan, Carina CW, et al. "Bioavailability of hCG after intramuscular or subcutaneous injection in obese and non‐obese women." Human Reproduction 18.11 (2003): 2294-2297.

Abernethy, Darrell R., and David J. Greenblatt. "Drug disposition in obese humans." Clinical pharmacokinetics 11.3 (1986): 199-213.

Cheymol, Georges. "Clinical pharmacokinetics of drugs in obesity." Clinical pharmacokinetics 25.2 (1993): 103-114.

Bauer, LA al, et al. "Influence of weight on aminoglycoside pharmacokinetics in normal weight and morbidly obese patients." European journal of clinical pharmacology 24.5 (1983): 643-647.

Benedek, I. H., et al. "Serum alpha 1‐acid glycoprotein and the binding of drugs in obesity." British journal of clinical pharmacology 16.6 (1983): 751-754.

Abernethy, Darrell R., et al. "Enhanced glucuronide conjugation of drugs in obesity: studies of lorazepam, oxazepam, and acetaminophen." Translational Research101.6 (1983): 873-880.

Ijaz, Samia, et al. "Impairment of hepatic microcirculation in fatty liver." Microcirculation 10.6 (2003): 447-456.

Merrell, Matthew D., and Nathan J. Cherrington. "Drug metabolism alterations in nonalcoholic fatty liver disease." Drug metabolism reviews 43.3 (2011): 317-334.

Bentley, John B., et al. "Weight, pseudocholinesterase activity, and succinylcholine requirement." Anesthesiology 57.1 (1982): 48-49.

Janmahasatian, Sarayut, et al. "Lean body mass normalizes the effect of obesity on renal function." British journal of clinical pharmacology 65.6 (2008): 964-965.

Abernethy, Darrell R., et al. "Prolongation of drug half‐life due to obesity: studies of desmethyldiazepam (clorazepate)." Journal of pharmaceutical sciences 71.8 (1982): 942-944.

Greenblatt, David J., et al. "Effect of age, gender, and obesity on midazolam kinetics." Anesthesiology 61.1 (1984): 27-35.

Bauer, L. A., D. J. Black, and J. S. Lill. "Vancomycin dosing in morbidly obese patients." European journal of clinical pharmacology 54.8 (1998): 621-625.

Bauer, LA al, et al. "Influence of weight on aminoglycoside pharmacokinetics in normal weight and morbidly obese patients." European journal of clinical pharmacology 24.5 (1983): 643-647.

Rafecas Jorba, Immaculada, et al. "Insulin degradation by adipose tissue is increased in human obesity." Journal of Clinical Endocrinology and Metabolism, 1995, vol. 80, p. 693-695 (1995).

Allard, Sylvie, et al. "Intravenous ciprofloxacin disposition in obesity." Clinical Pharmacology & Therapeutics 54.4 (1993): 368-373.

Derry, Christine L., et al. "Pharmacokinetics and pharmacodynamics of triazolam after two intermittent doses in obese and normal-weight men." Journal of clinical psychopharmacology 15.3 (1995): 197-205.

Varin, France, et al. "Influence of extreme obesity on the body disposition and neuromuscular blocking effect of atracurium." Clinical Pharmacology & Therapeutics 48.1 (1990): 18-25.

Abernethy, Darrell R., and Janice B. Schwartz. "Verapamil pharmacodynamics and disposition in obese hypertensive patients." Journal of cardiovascular pharmacology 11.2 (1988): 209-215.

Bonadonna, Riccardo C., et al. "Obesity and insulin resistance in humans: a dose-response study." Metabolism 39.5 (1990): 452-459.

Jansen, Paul AF, and Jacobus RBJ Brouwers. "Clinical pharmacology in old persons." Scientifica 2012 (2012).

Turnheim, Klaus. "When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly." Experimental gerontology 38.8 (2003): 843-853.

Turnheim, Klaus. "Drug dosage in the elderly." Drugs & aging13.5 (1998): 357-379.

EVANS, MARK A., et al. "Gastric emptying rate in the elderly: implications for drug therapy." Journal of the American Geriatrics Society 29.5 (1

Russell, Tanya L., et al. "Upper gastrointestinal pH in seventy-nine healthy, elderly, North American men and women." Pharmaceutical research 10.2 (1993): 187-196.

Merfeld, A. E., et al. "The effect of pH and concentration on α‐methyldopa absorption in man." Journal of pharmacy and pharmacology 38.11 (1986): 815-822.

Holt, Peter R. "Intestinal malabsorption in the elderly." Digestive Diseases 25.2 (2007): 144-150.

Bender, A. Douglas. "Effect of age on intestinal absorption: implications for drug absorption in the elderly." Journal of the American Geriatrics Society 16.12 (1968): 1331-1339.

Kaestli, Laure-Zoé, et al. "Use of transdermal drug formulations in the elderly." Drugs & aging 25.4 (2008): 269-280.

Holdsworth, Mark T., et al. "Transdermal fentanyl disposition in elderly subjects." Gerontology 40.1 (1994): 32-37.

Roskos, Kathleen V., Howard I. Maibach, and Richard H. Guy. "The effect of aging on percutaneous absorption in man." Journal of Pharmacokinetics and Pharmacodynamics 17.6 (1989): 617-630.

Klein, C., et al. "Transdermal clonidine therapy in elderly mild hypertensives: effects on blood pressure, plasma norepinephrine and fasting plasma glucose." Journal of hypertension. Supplement: official journal of the International Society of Hypertension 3.4 (1985): S81-4.

Kentala, Erkki, Timo Kaila, and Jussi Kanto. "Intramuscular atropine in elderly people: pharmacokinetic studies using the radioreceptor assay and some pharmacodynamic responses." Basic & Clinical Pharmacology & Toxicology 65.2 (1989): 110-112.

Divoll, Marcia, et al. "Absolute bioavailability of oral and intramuscular diazepam: effects of age and sex." Anesthesia & Analgesia 62.1 (1983): 1-8.

Collart, P., et al. "Kinetic study of serum penicillin concentrations after single doses of benzathine and benethamine penicillins in young and old people." Sexually Transmitted Infections 56.6 (1980): 355-362.

Dube, A. H. "A comparison of serum concentrations produced by phenethicillin, penicillin V, and penicillin G after oral and intramuscular administration in geriatric patients." Antibiotics & Chemotherapy 11.10 (1961): 625-9.

GREENBLATT, DAVID J. "Reduced serum albumin concentration in the elderly: a report from the Boston Collaborative Drug Surveillance Program." Journal of the American Geriatrics Society 27.1 (1979): 20-22.

Routledge, PhA. "The plasma protein binding of basic drugs." British journal of clinical pharmacology 22.5 (1986): 499-506.

Le Couteur, David G., and Allan J. McLean. "The aging liver." Clinical pharmacokinetics 34.5 (1998): 359-373.

Mangoni, Arduino A., and Stephen HD Jackson. "Age‐related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications." British journal of clinical pharmacology 57.1 (2004): 6-14.

Toornvliet, Rolf, et al. "Effect of age on functional P‐glycoprotein in the blood‐brain barrier measured by use of (R)‐[11C] verapamil and positron emission tomography." Clinical Pharmacology & Therapeutics 79.6 (2006): 540-548.

Sun, Haiying, et al. "Drug efflux transporters in the CNS." Advanced drug delivery reviews 55.1 (2003): 83-105.

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