Influence of morbid obesity on pharmacokinetics

In basic terms, all the problems arise from the difficulty of estimating the body fluid volume, and the tendency of the fatty tissue to accumulate lipophilic sedatives (and then release them gradually with disastrously prolonged effects).

Question 20 from the first paper of 2009 asks about the influence of morbid obesity on pharmacokinetics.  This seems to have extended into Part I material - Question 13 from the second Part I paper of 2012 also asked about pharmacokinetics and obesity, but this time omitting the descriptor morbid. With these two examples the only instances of this topic appearing in the exams, this chapter of revision notes was difficult to categorise. Ultimately a completely arbitrary decision was made to leave a summary "stub" here in the Fellowship reading section, and host the ponderous bulk of apocrypha and digressions in the Part I Pharmacokinetics section. 

As far as literature goes, The LITFL entry on this topic covers all the appropriate ground  If one were to read only one resource for this answer, it should be the article by Georges Cheymol (2000), which manages this issue with satisfactory brevity before digressing into a discussion of specific anaesthetic drugs and antibiotics.

Ideal body weight:

• The estimated optimum body mass of an individual:
• Ideal Body Mass = (height in cm - 100)

Significance to drug dosing:

• Generally drug dosing instructions are for total body weight, but this does not take into account obese individuals, or fluid-overloaded ICU patients
• Thus, in such patients, dosing should be tailored to ideal body weight (i.e. the weight they "should be" if they were not obese or fluid overloaded)
• lipid-soluble drugs should be dosed to total body mass rather than ideal body mass

Pharmacokinetic changes in obese patients

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 estimate 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.