Steady-state plasma concentration practical

In practice, one will seek to obtain an estimate of the elimination constant kp and the plasma volume of distribution Vp by means of a single intravenous injection. These pharmacokinetic parameters are then used in the determination of the required dose D in the reservoir and the input rate constant k (i.e. the drip rate or the pump flow) in order to obtain an optimal steady state plasma concentration... 

The plasma concentration will continue to rise until it reaches a plateau, or steady state. At this time, the plasma concentration will fluctuate between a maximum (Cmav) and a minimum (CrnLn) level, but, more important, the amount of drug eliminated per dose interval will equal the amount of drug absorbed per dose. When a drug is given at a dosing interval that is equal to its elimination half-life, it will reach 50% of its steady-state plasma concentration after one half-life, 75% after two half-lives, 87.5% after three, 93.75% after four, and 96.87% after five. Thus, from a practical viewpoint,... 

The "practical" steady-state condition, the "practical steady-state plasma concentration, and the time required for attaining this condition. 

A "practical steady-state concentration has been reached when plasma concentration of a drug in the blood is within 5% of tme steady-state plasma concentration. Alternatively, we may say that a "practical steady-state concentration has been reached when the plasma concentration of a drug in the blood represents 95% or greater of the true steady-state plasma concentration. 

Please note that the time required to reach "practical" steady-state condition is always equal to 4.32ti/2 of that drug. For example, let us assume we wish to attain a plasma concentration of 10 pg mL at true steady state that is, the chosen infusion rate yields a true steady-state plasma concentration of 10pgmL . Therefore, lOpgmL X 0.95 = 9.5 pgmL is the "practical" steady-state concentration and it will occur at 4.32fi/2. 

Show the profile (rectilinear coordinates) of practical and true steady-state plasma concentrations against the infusion rate. 

The practical steady-state plasma concentration occurs at 2.16 h (half life is 0.5 h therefore, 4.32 X 0.5 h = 2.16h). Note that the number of elimination half lives required to attain the practical steady-state concentration will remain tmaffected by the chosen in fusion rate, f. The loading dose required to reach tme steady-state plasma concentration of 74.99 pgmL" instantaneously can be determined by employing either of two equations ... 

By definition, the practical steady-state concentration represents 95% of the tme state plasma concentration 8(igmL x0.95 = 7.6 xgmL . Please note that this concentration is 1.333 times the corresponding plasma concentration for the infusion rate of 3.186 mg kg h of procainamide HCl. 

Using convenient, practical values for infusion rate (Q) and dosing interval (t), what exact peak and trough steady-state plasma drug concentrations will be achieved ... 

Blood concentrations were measured in two trials in general practice (3). On both regimens (single and divided doses), a steady state was reached after 1 week, but there was considerable individual variability (up to ten-fold) in plasma concentrations. In a multicenter study of over 2000 records from more than 500 general practitioners (4) the onset of action usually occurred within the first week of treatment and the effect was complete after 3M weeks roughly half of the total improvement occurred by the end of the first week. 

Since enzyme inhibition involves reversible mechanisms, CLi , (ij may vary with regard to the type and concentration of inhibitor. The concentrations of an inhibitor (or drug) that are relevant to clinical application can be approached for the prediction in the in vivo situation. In practice, a ratio in AUC, hepatic clearance (CLhept), plasma concentration at steady state (Css), or intrinsic clearance (CLjnt) caused by metabolism-based DDIs is commonly used to assess the degree of metabolism inhibition in vivo (Eq. 16.7). If a drug is eliminated due to both metabolism and renal excretion, the fraction of the drug metabolized by the inhibited enzyme (fj ) should be introduced to the prediction. With inclusion of fj, the ratio change in AUC in the presence and absence of an inhibitor can be expressed for competitive and noncompetitive (Eq. 16.8). 

It is necessary to administer procainamide, as an intravenous infusion, to control arrhythmias in a patient (100 kg) admitted into a hospital. The desired practical and true steady-state procainamide plasma concentrations are determined to be 5.7 and 6.0pgmL , respectively. 

Determine the practical steady-state procainamide plasma concentration, (Cp)ss, for the calculated infusion rate. 

The infusion rate of 318.62 mg h (3.186 mgh kg ) of procainamide hydrochloride will provide a practical steady-state procainamide plasma concentration of 5.7pgmL at... 

Since the right side of Eq. 12.9 is always positive, it is apparent that the maximum plasma concentration at steady state occurs at an earlier time than that following the administration of a single dose. Furthermore, the time at which the maximum plasma concentration is observed following the first dose (i.e. t ax) is often the time at which the plasma is sampled after the administration of subsequent doses to assess peak plasma concentration. Mathematical principles clearly suggest that this would not be a sound practice since the time at which a maximum plasma concentration occurs is not constant until steady state is attained. 

Volume of distribution at steady state V ). This is a proportionality constant that relates the plasma concentration and the amount of drug remaining in the body at a time, following the attainment of practical steady state (virtual elimination equilibrium, which is reached at a time greater by at least 4.32 elimination half lives of the dmg). This volume of distribution is independent of elimination parameters such as fCio or drug clearance. 

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