CLINICAL PHARMACOLOGY 2003 (PART 9B)

If a drug is administered by constant-rate i.v. infusion it is important to know when steady state has been reached, for maintaining the same dosing schedule will then ensure a constant amount of drug in the body and the patient will experience neither acute toxicity nor decline of effect. The t1/2 provides the answer: with the passage of each t1/2 period of time, the plasma concentration rises by half the difference between the current concentration and the ultimate steady-state (100%) concentration. ...
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CLINICAL PHARMACOLOGY 2003 (PART 9B) 7 GENERAL PHARMACOLOGYTime to reach steady state Decline in plasma concentrationIf a drug is administered by constant-rate i.v. Since t1/2 is the time taken for any plasma con-infusion it is important to know when steady state centration to decline by one-half, starting at anyhas been reached, for maintaining the same dosing steady-state (100%) plasma concentration, in 1 x t1/2schedule will then ensure a constant amount of the plasma concentration will fall to 50%, in 2 x t1/2drug in the body and the patient will experience to 25%, in 3 xt1/2to 12.5%, in 4 xt1/2to 6.25% and inneither acute toxicity nor decline of effect. The t1/2 5 x t1/2 to 3.125% of the original steady-stateprovides the answer: with the passage of each t1/2 concentration.period of time, the plasma concentration rises by Hence the il/2 can predict the rate and extent ofhalf the difference between the current concentration decline in plasma concentration after dosing isand the ultimate steady-state (100%) concentration. discontinued. The relation between t/£ and time toThus: reach steady-state plasma concentration applies to all drugs that obey first-order kinetics, as much to in 1 x t1/2, the concentration will reach (100/2) dobutamine (t/£ 2 min) when it is useful to know50%, that an alteration of infusion rate will reach a in 2 x t1/2 (50 + 50/2) 75%, plateau within 10 min, as to digoxin (il/2 36 h) when in 3 x i (75 + 25/2) 87.5%, a constant (repeated) dose will give a steady-state in 4 x ty2 (87.5 + 12.5/2) 93.75% plasma concentration only after 7.5 days. Plasma t1/2 in 5 x i (93.75 + 6.25/2) 96.875% of the ultimate values are given in the text where they seemsteady state. particularly relevant. Inevitably, natural variation within the population produces a range in tl/2 values When a drug is given at a constant rate (continuous or for any drug. For clarity only, single average t1/2 intermittent) the time to reach steady state depends only values are given while recognising that the population on the t/2 and, for all practical purposes, after 5 x t/2 the amount of drug in the body will be constant and the range may be as much as 50% from the stated figure plasma concentration will be at a plateau. in either direction. A few t1/2 values are listed in Table 7.1 so that they can be pondered upon in relation to dosing in clinical practice.Changes in plasma concentration Biological effect t^ is the time in which theThe same principle holds for change from any biological effect of a drug declines by one half. Withsteady-state plasma concentration to a new steady drugs that act competitively on receptors (a- and (3-state brought about by increase or decrease in the adrenoceptor agonists and antagonists) the biologicalrate of drug administration, provided the kinetics effect t1/2 can be provided with reasonable accuracy.remain first-order. Thus when the rate of admin-istration is altered to cause either a rise or a fall inplasma concentration, a new steady-state concen-tration will eventually be reached and it will take TABLE 7.1 Plasma t/2 of some drugsa time equal to 5 x tl/2 to reach the new steady Drug t/2state. ...