Diagnosis and Treatment of Adrenal Insufficiency in the Critically Ill Patient

Kwame Asare, Pharm.D.

Disclosures

Pharmacotherapy. 2007;27(11):1512-1528. 

In This Article

Pharmacokinetics

Approximately 90% of cortisol in plasma is reversibly bound to plasma protein under normal circumstances. Almost all of the steroid-binding capacity is accounted for by two proteins: cortisol-binding globulin (also known as transcortin) and, to a lesser extent, albumin. Cortisol-binding globulin has a high affinity for corticosteroids but relatively low binding capacity, whereas albumin has a low affinity but large binding capacity.[17] Only the fraction of corticosteroid that is unbound or free can produce an effect. Recent evidence suggests that in critically ill patients, there is a decrease in cortisol binding and an increase in free cortisol.[18,19] In patients with septic shock, adrenal insufficiency is believed to result from suppression of the HPA axis by cytokines and other inflammatory mediators.[2] Cytokines also cause resistance to glucocorticoids by decreasing the affinity of glucocorticoids for their receptors.[2] Reduction in global cortisol transport has also been reported in patients with septic shock.[18]

Cortisol, with its high degree of protein binding, is protected from hepatic clearance and therefore has slow elimination and a relatively long half-life (60-90 min). Aldosterone, with its lower protein binding (∼60%), has a relatively short half-life (20 min).[13] Binding of corticosteroids to plasma proteins may serve as a reservoir to decrease the fluctuations in freehormone concentrations, providing a uniform distribution of these hormones to the tissues.

The corticosteroids are metabolized by the liver to form glucuronic acid and sulfates. These metabolites are inactive and have no glucocorticoid or mineralocorticoid activity. They are primarily filtered by the kidneys and excreted in the urine (75%), whereas the remaining portion (25%) is eliminated by the bile and feces. Severe liver dysfunction markedly decreases the metabolism of these hormones, and renal dysfunction decreases their rate of elimination.[13] Elimination of glucocorticoids is enhanced by drugs that increase the hepatic metabolism of cortisol (e.g., phenobarbital, rifampin, phenytoin) and is decreased by drugs that inhibit the metabolism of cortisol (e.g., protease inhibitors). Therefore, patients receiving these drugs may need higher or lower doses of glucocorticoids, respectively.

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