A. Time course of drug concentration in blood during regular intake
B. Time course of drug concentration with irregular intake

Accumulation: Dose, Dose Interval, and Plasma Level Fluctuation

Successful drug therapy in many illnesses is accomplished only if drug concentration is maintained at a steady high level. This requirement necessitates regular drug intake and a dosage schedule that ensures that the plasma concentration neither falls below the therapeutically effective range nor exceeds the minimal toxic concentration. A constant plasma level would, however, be undesirable if it accelerated a loss of effectiveness (development of tolerance), or if the drug were required to be present at specified times only.

A steady plasma level can be achieved by giving the drug in a constant intravenous infusion, the steady-state plasma level being determined by the infusion rate, dose D per unit of time x, and the clearance, according to the equation: C - D

This procedure is routinely used in intensive care hospital settings, but is otherwise impracticable. With oral administration, dividing the total daily dose into several individual ones, e.g., four, three, or two, offers a practical compromise.

When the daily dose is given in several divided doses, the mean plasma level shows little fluctuation. In practice, it is found that a regimen of frequent regular drug ingestion is not well adhered to by patients. The degree of fluctuation in plasma level over a given dosing interval can be reduced by use of a dosage form permitting slow (sustained) release (p. 10).

The time required to reach steady-state accumulation during multiple constant dosing depends on the rate of elimination. As a rule of thumb, a plateau is reached after approximately three elimination half-lives (t1/2).

For slowly eliminated drugs, which tend to accumulate extensively (phen-procoumon, digitoxin, methadone), the optimal plasma level is attained only after a long period. Here, increasing the initial doses (loading dose) will speed up the attainment of equilibrium, which is subsequently maintained with a lower dose (maintenance dose).

Change in Elimination Characteristics During Drug Therapy (B)

With any drug taken regularly and accumulating to the desired plasma level, it is important to consider that conditions for biotransformation and excretion do not necessarily remain constant. Elimination may be hastened due to enzyme induction (p. 32) or to a change in urinary pH (p. 40). Consequently, the steady-state plasma level declines to a new value corresponding to the new rate of elimination. The drug effect may diminish or disappear. Conversely, when elimination is impaired (e.g., in progressive renal insufficiency), the mean plasma level of renally eliminated drugs rises and may enter a toxic concentration range.

A. Accumulation: dose, dose interval, and fluctuation of plasma level
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