Question 20

College Answer

°     Ideal body weight is usually estimated from formulae or approximately:

IBW (kg) males =height cm -100, IBW (kg) females height cm -110

°     Dosing weight is best worked out from ideal body weight.

Lean body weight or dosing weight = ideal body weight + (ABW-IBW) x 0.4

Pharmacokinetics

Distribution

°     markedly affected by ratio of adipose tissue to lean body mass

°     Increased volume of distribution for lipid soluble drugs

°     Accumulation of lipophilic drugs in fat stores

°     May increase dose needed to gain effect

°     Vd of hydrophilic drugs less affected but blood, extracellular fluid, body organ, and connective tissue volume are also increased.

°     Total body water may be increased by resuscitation volume etc

°     Cmax reduced and T1/2 increased

°     Lipid soluble drugs usually dosed on ABW, water soluble drugs dosed on ideal or lean body weight

Metabolism

°     Variable effects. More likely to be affected by critical illness with drug interactions, reduced hepatic blood flow, altered protein binding

Excretion

°     Obese patients with normal renal function have an increased glomerular filtration rate and thus an increased clearance of drugs excreted by the kidney. Co existing disease processes eg diabetes may change this

°     Calculated and measured creatinine clearance correlate poorly in obesity and in critically ill

Thus morbidly obese predisposed to inadequate dosing and increased toxicity. Need to measure serum levels of drugs with low therapeutic index.

Discussion

Ideal body weight:

• Who says its "ideal"? Well. The definition is "the ideal weight associated with maximum life-expectancy for a given height". 
• There are numerous equations, all of which tend to agree (or, close enough for government work). One such equation is:
   
  
     Ideal body weight (kg) = height (cm) - 100
   
  
  (100 for males, and 105 or 110 for females.)
  Ideally, this technique should tell you what weight a person should  be, and therefore help you estimate their lean body mass so as to dose their drugs appropriately.
• The bizarre assumption made in this calculation is that inside every morbidly obese person there is a mass of lean tissue which is ideal for their maximal life expectancy, and which is directly proportional to their height. All patients of the same height would end up receiving the same dose if you use this metric, no matter how much they weigh.
• This is clearly incorrect, as obese individuals tend to have more lean body mass than normal people (as more muscle is required to carry all the extra weight).

Effect on absorption:

• Gastric emptying may be increased OR decreased (and it is unpredictable).
• Absorption from the subcutaneous compartment will be slowed due to poor blood flow to subcutaneous fat
• Intramuscular injection (or intrathecal, or even intravenous for that matter) is made difficult by poor access.

Effect on distribution:

• Increased volume of distribution for lipid-soluble drugs
• Increased accumulation of drugs in the fat compartment
• Blood flow in fat is poor in people of normal weight: it is only about 5% of the total cardiac output.
• In obese individuals, blood flow to fat is even poorer.
• Obese individuals are also likely to have a degree of heart failure which further decreases blood flow.
• This makes their fat a large compartment of potential distribution for lipophilic drugs which fills gradually, and then becomes a slowly emptying reservoir.
• Body fluid volume is also increased, increasing the volume of distribution of water-soluble drugs
• Protein binding may be altered (but this is far from clear: most papers seem to say that albumin binding is unchanged)

Effect on metabolism:

• Hepatic clearance is slowed not only by decreased cardiac output but also by fatty infiltration. But, you never actually know whether metabolic activity is going to be mre or less rapid. remember that lean tissue (and potentially metabolic organ mass) may be increased.
• However, increased CYP450 (2E1) activity has been observed
• Increased Phase II conjugation activity may be present

Effect on clearance:

• Diabetes which co-exists with obesity tends to damage kidneys, slowing the renal clearance. However, glomerular filtration rate may be increased in healthy obese individuals.
• Biliary clearance may be slowed by bile stasis or existing bile duct disease

Effect on pragmatic drug dosing and monitoring:

• Obese people have a larger absolute lean body mass (LBM), as well as fat mass. Lean components account for 20-40% of the absolute body weight ( it is purely the support muscle required to drag all that fat around). Exactly how much muscle is hidden in any given obese individual is difficult to est accurately with the aid of standard equations.
• The net effect of this is that both under-dosing and over-dosing is more likely than with individuals of normal weight, and monitoring of therapeutic levels is important.
• Pharmacokinetic data in obesity does not exist for most drugs. Generally drug dosing instructions are for total body weight, but this does not take into account obese individuals, or fluid-overloaded ICU patients.

• In obese individuals, the ideal body weight is likely to underestimate their lead body mass, leading to under-dosing.
• The total body weight is likely to over-estimate the dose and lead to overdosing.
• Thus, in such patients, most drug dosing should be tailored to lean body weight (LBW).
• In the case of most nonlipophilic drugs, IBW is sufficient because V_d does not change.
• In the case of  strongly hydrophilic drugs, instead of calculating LBW, 20% can be added to the IBW to account for the increase in lean body tissue content.
• In the case of strongly lipophilic drugs, and in the case of many anaesthetic agents, LBW is the ideal metric.

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.