Obesity affecting the dosing & kinetics of the drugs.

The latest study published in Annual Review of Pharmacology & Toxicology has revealed that in many cases of prescribing and dispensing a drug, obesity is not completely considered and this specific kind of ignorance can cause adverse effects on the patients health.

Obesity: it is a world wide problem, in both developed as well as the developing countries. The correct dosing of medicines in obese patients is a time consuming and a critical work especially when the Narrow Therapeutic Index drugs are involved. The National Institute of Health and Care Excellence (NICE) recommends the use of body mass index (BMI) to evaluate overweight and obese persons. Obese individuals have a larger absolute lean body masses (LBM = Body weight – body fat) and fat masses than non obese people of the same age, gender and height. 

NICE classification of obesity: Ideal BMI ranges from 18.5 to 24.9 kilogram/metres squared. 

  • BMI 25-29.9 is overweight.
  • BMI 30-34.9 is obese Grade 1
  • BMI 35-39.9 is obese Grade 2
  • BMI >40 is obese Grade 3 or morbidity obese i.e. weight is a threat to health.

Deviations: 

  1. A very muscular person will have a greater weight in bones and muscles and may have a higher BMI with no excessive fat deposited in that person.
  2. In the elderly, the lowest morbidity is in the group with a BMI of 25-30 rather than 20-25.

Genes influence: an important link between obesity and genetic factors was determined by mapping of the human genome, evidence from certain animal cross breeding and single-gene mutations. Changes in the metabolism of the adipose tissues and pathways involved in these reactions can also play a role in obesity.

Effect of obesity on drug’s absorption: this belief prevailed that the absorption of drug remains unaffected by the changes brought about by obesity but now various questions are being raised on this very fact. It has been seen that obesity may lead to an increased absorption of oral medications, SC absorption of drug becomes compromised due to the low or poor supply of blood to subcutaneous tissues, IV administration becomes hard, IM administration with short needles becomes a problem.

Effect of obesity on drug’s distribution: factors responsible for altering the distribution of drug throughout the body are (proven in the latest study);

  • wider blood vessels
  • larger blood volume
  • cardiomegaly.

Other factors defining how the drug will distribute into the tissues include body composition, regional blood flow and the affinity of the drug for plasma proteins/tissues.

Distribution of lipophilic & hydrophilic drugs in obese: lipid soluble drugs shows increased volume of distribution (Vd) and consequently greater accumulation of such drugs in adipose tissues take place, lesser changes in Vd of water soluble drugs are seen. Drug’s peak serum concentrations or Cmax gets reduced due to obesity.

Example:

  1. pharmacokinetic studies conducted in obese patients depicted that the performance of weak or moderate lipophilic drugs like vecuronium & lithium is probable or can be foreseen due to their maximum distribution into the lean tissues.
  2. Benzodiazepines like midazolam or diazepam, highly lipophilic agents and their Vd has seen to be increased 10-folds in obese patients.
  3. Similarly, verapamil & lidocaine have more Vd in obese patients due to their lipophilic nature.

Effect on protein binding: plasma proteins like lipoproteins and a1 acid-glycoprotein highly concentrates in obese people but binding of drugs to albumin has not been seen to be significantly transmuted.

Effect on hepatic clearance: metabolism of many drug changes due to obesity but the obvious changes in this case are prominent  when the metabolizing potential of liver falls below >90%. Some studies indicate that obesity increases CYP 450 enzymes activity & enhances Phase 2 reactions. Reduced hepatic blood flow can also be a problem in drugs undergoing first pass metabolism.

Effect on drug’s excretion: Creatinine clearance (Clcr) is  a good estimation of the glomerular filtration rate (GFR). The CockCroft equation used in lean people to approximate GFR can work but its use in obese patients may not work the same due to the reasons like incongruity between body weight and muscle mass. Using serum creatinine, total body weight, height, age and gender as in Salazar-Corcoran equation can prove to be a better alternative for calculating Clcr in obese. Cockcroft, Salazar & modification of diet in renal disease (MDRD) equations are mostly used for clearance findings.

Limitations of these equations in obese people:

  1. Dependency of Cockcroft equation on total body weight overestimates GFR in obese.
  2. MDRD equation based on normalized body surface area (BSA) also aggrandizes GFR.

Half life of lipid soluble drugs increases due to accumulation. Obese patients with normal renal function have increased GFR and renal plasma flow leading to more increased clearance of drugs excreted by the kidneys.

Study: in Annual Reviews done by C. Knibbe, clinical pharmacologist of Leiden University, studied the effect of a cephalosporin , Cefazolin 2 grams for preventing wound infections in obese and non obese patients and the results showed no notable difference in the drug’s blood concentrations between two groups, whereas in the skin obese patients had >30% lower drug concentration, meaning that the stated dose of this antibiotic is not enough to show its optimal actions in obese patients.

According to Knibbe, obese patients are mostly given high doses of medications and such patients mostly suffer from sleep apnea and administering high doses of certain drugs like sedatives or morphine can prove very harmful than useful. 

 Pharmacokinetics changes & dosing modifications of aminoglycosides in critically ill obese patients: aminoglycoside appropriate dosing & proper use for correct indications is extensively described but the altered pharmacokinetics and proper dosing of these drugs in critically ill obese patients is not adequate. Sepsis along with obesity also changes the kinetics of these drugs. Aminoglycosides are usually used with other antimicrobial agents to combat infections but due to their distribution in the adipose, individual dosing modifications & TDM are the best options.

Conclusion: Obese patients need to be individually dosed as their altered pathophysiological  states affect all the steps in the pharmacokinetics of drugs and such changes due to obesity may necessitate the deviation from the commonly recommended doses in certain cases.

References: 

  • Annual Review of Pharmacology and Toxicology vol 55.
  • U.S. Pharmacist January 21, 2015.
  • Journal of Clinical Medical Research 2014.
  • PubMed.
 
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