Plasma drug concentration intravenous infusion rate

In Fig. 10.11, the plasma concentration versus time profile shows a trough. This might be attributed to an elapse in time between the completion of an intravenous bolus loading dose and the commencement of the infusion rate. The magnitude of the nadir observed in the plasma concentration versus time profile will be influenced by the elapsed time and the elimination half life of the drug. However, there is no bolus/infusion combination for a two-compartment drug that will produce a total plasma drug concentration that is constant over time the profile will have peaks and/or nadirs. This, therefore, could be an alternative explanation for the deviation from a horizontal line in Fig. 10.11. 

Figure 10.13 Setup for the rate of elimination of drug from plasma and the plasma drug concentration following the discontinuation of a constant rate intravenous infusion.

As shown above, early/late sampling will require the use of equations to adjust observed high and low concentrations to achieve more accurate estimates of the "peak" and trough concentrations. Early/late sampling will also have ramifications for the equations used to for solve for the apparent volume of distribution and the elimination rate constant by using two steady-state plasma drug concentrations sampled after a multiple intravenous infusion. Table 14.4 summarizes these equations. 

True steady state is usually only achieved for a prolonged period with intravenous infusion. If we assume that we wish for a similar steady value after oral administration, then we need to balance our dosing frequency with the rate of decline of drug concentration and the rule of thumb referred to earlier (dosing interval equal to drug half-life) can be applied. Unbound clearance and free drug are particularly applicable to drugs delivered by the oral route. For a well-absorbed compound the free plasma concentrations directly relate to Cli (intrinsic unbound clearance). 

By setting the input function, I(t), in the differential equations on p. 28 to a constant rather than zero the equations can be solved to yield the disposition function for an intravenous infusion. With a fixed rate infusion, the plasma concentration will gradually increase towards a steady state concentration, CSS. Since CSS is constant, the amount of drug entering the body via the infusion at steady state must equal that being eliminated, (i.e. the clearance). Thus the infusion rate, R, e.g. mg min-1, needed to reach CSS is R=CSS.CI. It will take approximately 4 to 5 terminal half-lives to reach 95% CSS. Note that if the infusion rate is doubled CSS will also double, but the time taken to reach CSS remains the same, i.e. it is independent of the infusion rate (Figure 2.6). 

A patient is being treated with morphine by intravenous infusion. The steady state plasma concentration of the drug is to be maintained at 0.04 fig cm 3. Calculate the rate of infusion necessary assuming a first order elimination process (for morphine Vd is 4.0 dm3 and tU2 is 2.5 hours). 

With continuous intravenous infusion, the rate of drug entry into the body is constant. In the majority of cases, the elimination of a drug is first-order, that is, a constant fraction of the agent is cleared per unit time. Therefore, the rate of drug exit from the body increases proportionately as the plasma concentration increases and at every point in time is proportional to the plasma concentration of the drug. 

When a drug is administered by continuous intravenous infusion, the infusion rate (Ro) required to provide a desired steady-state plasma concentration is... 

Equation 9.98 permits one to calculate the infusion rate necessary to attain and then maintain the desired steady-state plasma concentration of a drug if the systemic clearance of the drug is available. Equation 9.98 also provides a convenient way to determine the apparent volume of distribution of a drug by means of intravenous infusion experiment if the infusion rate (Q), the elimination rate constant (K), and the steady-state plasma concentration (C )gg are known. 

The conceptual understanding of Eq. 10.21 is vital not only for the understanding of the theory and rationale behind the use of two infusion rates to attain and then maintain the desired plasma concentration of a drug but also for the understanding of calculations of loading dose and maintenance dose Dm) when dmgs are administered as an intravenous bolus and extravascularly in multiple doses (discussed in Ch. 11). 

Figure 10.10 Predicted or theoretical plasma concentration (Cp) versus time profile following the administration of a drug as an intravenous bolus loading dose (DJ immediately followed by an infusion at rate Q. MTC, minimum toxic concentration MEC, minimum effective concentration ss, steady state.

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