Question 13

Created on Wed, 07/12/2017 - 03:03
Last updated on Mon, 12/25/2017 - 02:55
Pass rate: 36.4%
Highest mark:

Other SAQs on this topic

Describe the effects of obesity on drug pharmacology (70% of marks).

Give examples of drugs that illustrate those effects (30% of marks).

[Click here to toggle visibility of the answers]

College Answer

This question could be approached by describing the effects of obesity on drug distribution, binding and elimination. Candidates that took this approach generally did better than those with a less structured approach. With obesity, fat body mass increases relative to the increase in lean body mass leading to an increased volume of distribution particularly for 
highly lipid soluble drugs, e.g. midazolam. However, the dosing of non-lipid soluble drugs,e.g. non-depolarising muscle relaxants,should be based on ideal body weight. An increase in blood volume and cardiac output associated with obesity may require an increased loading dose to achieve a therapeutic effect, e.g.thiopentone. Plasma protein binding of drugs may 
be decreased due to an increased binding of lipids to plasma proteins, resulting in an increased free fraction of drug. A reduction in plasma protein concentration due to an increase in acute phase proteins may also result in decreased plasma protein drug binding and increased free fraction of drug. Pseudocholinesterase levels are increased in obesity and therefore the dose of suxamethonium should be based on total body weight. Plasma and tissue esterase levels are increased resulting in the increased clearance of drugs by these enzymes e.g. remifentanil. Hepatic clearance is usually normal but may be impaired in liver 
disease caused by obesity. Renal clearance is usually increased due to increased body weight, increased renal blood flow and increased glomerular filtration rate. Renal clearance may be impaired in renal disease caused by obesity related diseases, e.g. diabetes. Insulin doses may be increased due to peripheral insulin resistance in type 2 diabetes caused by obesity. Most answers were deficient in examples of drugs to illustrate the effects of obesity on drug pharmacology.

Discussion

Even though the college answer focused on pharmacokinetics almost exclusively, the college question actually asked about pharmacology as a broad category. Thus, one needs to bring some pharmacodynamics into it as well. The college answer attempts this by mentioning the changes in insulin sensitivity associated with Type II diabetes (which, strictly speaking, is not related to obesity, even thoug obesity and diabetes are strongly associated). 

  • 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
  • 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) 
  • 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)
  • 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)
  • Decreased dose response
    • Resistance to haemodynamic effects of nitroglycerine 
    • Resistance to the effects of oral contraceptives (Robinson et al, 2013)
    • Resistance to the effects of atracurium (Varin et al, 1990), which the authors blamed on the desensitisation of acetylcholine receptors associated with an inactive sedentary lifestyle. 
    • Resistance to the effects of insulin
  • Exaggerated dose response

References

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.