Question 13

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

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

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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.


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


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