Obesity related alterations in pharmacokinetics and pharmacodynamics of drugs: emerging clinical implications in obese patients - part I

Obesity is escalating among children and adults all over the world. This non-communicable disorder contributes heavily to se­vere morbidity and mortality in humans due to the occurrence of diabetes mellitus, cardiovascular diseases, osteoarthritis, and some cancers. Excess deposition of white adipose tissue in obese patients produces hormone like bioactive substances that pro­duce inflammatory cytokines, atherosclerosis and cardiovascular diseases, to name a few. Obesity can also cause pathophysiolo­gal changes in liver, kidney, and GI tract that can affect drug disposition, resulting in therapeutic failure or toxic drug reactions. Alterations in drug absorption, distribution, metabolism and excretion (ADME), ie. pharmacokinetics (PK) and pharmacodynam­ics (PD) have been observed in lean and obese patients. A limited number of studies have shown significant differences in the PK parameters such as Vd, CL, t1/2, Tmax, Cmax, and AUC of drugs (e.g., antimicrobials, chemotherapeutics, anesthetics, CNS agents) in obese and lean patients. In view of these observations, clinical responses to medications can markedly differ between non-obese and obese patients, and this phenomenon can lead to improper dosing, often leaving obese patients mistreated for their ailments. Morbidly obese patients are more likely to wake up during surgical interventions done under general anesthesia, es­pecially propofol. It is therefore imparative that the loading and maintinance dose of drugs, especially anesthetics and lipophilic agents, should be adjusted in obese patients. Further, obese men, women and children should be enrolled in clinical trials to determine the safety and efficacy of pharmaceuticals. The focus of this review is to highlight the relationship of obesity-related alterations in drug ADME and to provide an updated overview about the PK and PD changes observed for a wide spectrum of drugs in obese and non-obese patients. Literature-based recommendations for rational therapeutic dose-modifications are also provided in the publication.Keywords: absorption, distribution, metabolism, excretion (ADME), overweight, obesity, pharmacokinetics, pharmacodynam­ics, drug dose adjustment, obese patient