Serum pH, blood flow, protein binding, fat solubility, and degree of ionization influence the distribution of a medication (Buxton 2006). With the exception of lithium, methylphenidate, and venlafaxine, psychoactive drugs are 80%-95% bound to proteins, either albumin or a1-glycoprotein. Divalproex sodium and barbiturates tend to bind to albumin, whereas the tri-cyclic antidepressants (TCAs), amphetamines, and benzodiazepines bind to globulins. In general, only the unbound drug is pharmacologically active. Decreases in protein binding increase the availability of the drugs for therapeutic action and may increase medication side effects. Drugs with a narrow therapeutic range, such as divalproex sodium, may be more susceptible to alterations in protein binding.

Albumin binding is decreased in many physical illnesses including cirrhosis, pneumonia, malnutrition, acute pancreatitis, renal failure, and nephrotic syndrome. In these conditions, albumin-bound drugs with a low therapeutic index may increase in concentration, causing toxicity. In contrast, in hypo-thyroidism albumin binding may be increased. a1 Glycoprotein plasma concentrations may increase in patients with Crohn's disease, renal failure, rheumatoid arthritis, surgery, burns, and trauma. If protein binding is affected by disease, it may be necessary to make adjustments to medication dosages.

Distribution is also affected by body tissue composition and fluid shifts. Lipophilic drugs will have a more extensive volume of distribution in individuals with higher body mass percentages of adipose tissue. Changes in cardiac output and the intravascular to extravascular fluid shifts that are encountered in the context of burns or trauma have also been demonstrated to affect drug distribution (Han et al. 2007).

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