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The one-compartment model first-order absorption equations used by the program to compute doses indicates that a dose of 250 mg every 8 hours will produce a steady- state valproic acid concentration of 100 μg/mL. Estimate clearance and volume of distribution according to disease states and con- ditions present in the patient. The clearance rate for an pediatric patient that takes other drugs that induce hepatic drug metabolism is 20–30 mL/h/kg. A steady-state trough valproic acid serum concentration should be measured after steady state is attained in 3–5 half-lives. Valproic acid serum concen- trations should also be measured if the patient experiences an exacerbation of their seizures, or if the patient develops potential signs or symptoms of valproic acid toxicity. The suggested initial maintenance dosage rate for valproic acid in an adult patient not taking enzyme induc- ers is 20 mg/kg/d: 22 kg ⋅ 20 mg/kg/d = 440 mg/d, rounded to 400 mg or 200 mg every 12 hours. This dose would be titrated upward in 5–10 mg/kg/d increments every 1–2 weeks while monitoring for adverse and therapeutic effects. A steady-state trough total valproic acid serum concentration should be measured after steady state is attained in 1–2 weeks. Valproic acid serum concentrations should also be measured if the patient experiences an exacerbation of their epilepsy, or if the patient develops potential signs or symptoms of valproic acid toxicity. Use pseudolinear pharmacokinetics to predict new concentration for a dosage increase, then compute 10–20% factor to account for nonlinear, concentration- dependent plasma protein binding pharmacokinetics. Using pseudolinear pharmacokinetics, the resulting total steady-state valproic acid serum concentration would equal Dnew = (Cssnew/Cssold) Dold = (60 μg/mL / 40 μg/mL) 300 mg/d = 450 mg/d, 150 mg every 8 hours. Because of nonlinear, concentration- dependent protein binding pharmacokinetics, the total steady-state serum concentra- tion would be expected to be 10% less, or 0. Thus, a dosage rate of 450 mg/d would be expected to yield a total valproic acid steady-state serum concentration between 48–54 μg/mL.

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The dexamethasone suppression test is used for the diagnosis of Cushing’s syndrome and has also been used in the differential diagnosis of depressive psychiatric states. In normal individuals, the morning cortisol concentration is usually less than 3 mcg/dL, whereas in Cushing’s syndrome the level is usually greater than 5 mcg/dL. The results are not reliable in the patient with depression, anxiety, concurrent illness, and other stressful conditions or in the patient who is receiving a medication that enhances the catabolism of dexamethasone in the liver. To distinguish between hypercortisolism due to anxiety, depression, and alcoholism (pseudo-Cushing syndrome) and bona fide Cushing’s syndrome, a combined test is carried out, consisting of dexamethasone (0. In patients with Cushing’s disease, the suppressant effect of dexamethasone usually produces a 50% reduction in hormone levels. Corticosteroids and Stimulation of Lung Maturation in the Fetus Lung maturation in the fetus is regulated by the fetal secretion of cortisol. Treatment of the mother with large doses of glucocorticoid reduces the incidence of respiratory distress syndrome in infants delivered prematurely. When delivery is anticipated before 34 weeks of gestation, intramuscular betamethasone, 12 mg, followed by an additional dose of 12 mg 18–24 hours later, is commonly used. Betamethasone is chosen because maternal protein binding and placental metabolism of this corticosteroid is less than that of cortisol, allowing increased transfer across the placenta to the fetus. A study of over 10,000 infants born at 23 to 25 weeks of gestation indicated that exposure to exogenous corticosteroids before birth reduced the death rate and evidence of neurodevelopmental impairment. Corticosteroids and Nonadrenal Disorders The synthetic analogs of cortisol are useful in the treatment of a diverse group of diseases unrelated to any known disturbance of adrenal function (Table 39–2). The usefulness of corticosteroids in these disorders is a function of their ability to suppress inflammatory and immune responses and to alter leukocyte function, as previously described (see also Chapter 55). These agents are useful in disorders in which host response is the cause of the major manifestations of the disease. In instances in which the inflammatory or immune response is important in controlling the pathologic process, therapy with corticosteroids may be dangerous but justified to prevent irreparable damage from an inflammatory response —if used in conjunction with specific therapy for the disease process. Since corticosteroids are not usually curative, the pathologic process may progress while clinical manifestations are suppressed. Therefore, chronic therapy with these drugs should be undertaken with great care and only when the seriousness of the disorder warrants their use and when less hazardous measures have been exhausted. In general, attempts should be made to bring the disease process under control using medium- to intermediate-acting glucocorticoids such as prednisone and prednisolone (Table 39–1), as well as all ancillary measures possible to keep the dose low.

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