Plasma drug concentration intravenous dose interval

Again we will take blood samples at intervals after dosing, measure plasma drug concentrations, and plot the results on a linear graph (Fig. 11). The first and obvious thing to note is that the plasma concentrations rise to a maximum at around 1 h, whereas, of course, the early plasma concentrations taken soon after the intravenous bolus were the highest. The time to reach the peak plasma concentration after an oral dose is often abbreviated to Tmax, and the concentration itself to Cmax - the maximum concentration achieved after that dose. 

Because the area under the plasma drug concentration-time curve during a dosage interval at steady-state is equal to the total area under the curve after administering a single intravenous dose, the average plasma concentration at steady-state can be estimated from... 

Figure 11.6 Plasma drug concentration (Cp) versus time profile following the intravenous bolus administration of many equal doses at an identical dosing interval (t). In this representation, the dosing regimen has been designed so that the plasma drug concentrations will fall within the therapeutic range at steady state.

Figure 11.11 A plot of plasma concentration (Cp) versus time following repetitive intravenous bolus administration of a drug. The figure demonstrates the plasma level resulting from either a series of maintenance doses (dashed line) or an initial loading dose followed by a series of maintenance doses (continuous line), min, minimum max, maximum MTC, minimum toxic concentration MEC, minimum effective concentration t, dosing interval.

Opioids maybe administered in a variety of routes including oral (tablet and liquid), sublingual, rectal, transdermal, transmucosal, intravenous, subcutaneous, and intraspinal. While the oral and transdermal routes are most common, the method of administration is based on patient needs (severity of pain) and characteristics (swallowing difficulty and preference). Oral opioids have an onset of effect of 45 minutes, so intravenous or subcutaneous administration maybe preferred if more rapid relief is desired. Intramuscular injections are not recommended because of pain at the injection site and wide fluctuations in drug absorption and peak plasma concentrations achieved. More invasive routes of administration such as PCA and intraspinal (epidural and intrathecal) are primarily used postoperatively, but may also be used in refractory chronic pain situations. PCA delivers a self-administered dose via an infusion pump with a preprogrammed dose, minimum dosing interval, and maximum hourly dose. Morphine, fentanyl, and hydromorphone are commonly administered via PCA pumps by the intravenous route, but less frequently by the subcutaneous or epidural route. 

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). 

FIGURE 3-4 Relationship between dosing interval and plasma concentrations of the antiasthmatic drug theophylline. A constant intravenous infusion [shown by the smoothly rising line] yields a desired plasma level of 10 mg/L. The same average plasma concentration is achieved when a dose of 224 mg is taken every 8 hours, or a dose of 672 mg every 24 hours. However, note the fluctuations in plasma concentration seen when doses are taken at specific hourly intervals. 

Figure 10 Plasma concentrations of a drug following a multiple-dosing regimen, of fixed dose and interval, intravenously (top) and orally (bottom). Note that in both cases the area under the plasma concentration-time curve within a dosing interval at plateau is equal to the total area following a single dose. Source From Ref. 1.

Fig. 9.35. A typical plasma concentration versus time profile for a drug administered intravenously as a fixed dose (Xq) at a fixed dosing interval (t).

Figure 11.3 Plasma concentration (Cp) versus time profile following the administration by intravenous bolus of identical doses of a drug (1-4) at identical dosing intervals (t). Please note that peak plasma concentration or, for that matter, the plasma concentration at any given time for the second, the third and subsequent doses are higher than for the first dose (because of drug accumulation), min, minimum max, maximum.

Figure 11,5 Maximum (max peak) and minimum (min "trough") plasma concentrations (Cp) following the administration of an identical intravenous bolus dose of a drug at an identical dosing interval. MTC, minimum toxic concentration MEC, minimum effective concentration.

Figure 39.4a represents schematically the intravenous administration of a dose D into a central compartment from which the amount of drug Xp is eliminated with a transfer constant kp. (The subscript p refers to plasma, which is most often used as the central compartment and which exchanges a substance with all other compartments.) We assume that mixing with blood of the dose D, which is rapidly injected into a vein, is almost instantaneous. By taking blood samples at regular time intervals one can determine the time course of the plasma concentration Cp in the central compartment. This is also illustrated in Fig. 39.4b. The initial concentration Cp(0) at the time of injection can be determined by extrapolation (as will be indicated below). The elimination pool is a hypothetical compartment in which the excreted drug is collected. At any time the amount excreted must be equal to the initial dose D minus the content of the plasma compartment Xp, hence ...

Most drugs that are administered on an outpatient basis are taken orally on a fixed-dose fixed-time interval regimen, for example, a specific dose, taken one, two or three times daily. In contrast to intravenous injection, orally administered drugs may be absorbed slowly, and the plasma concentration of the drug is influenced by both the rate of absorption and the rate of drug elimination (Figure 2.6). 

Items 16-18 A new drug was studied in 20 healthy volunteers to determine basic pharmacokinetic parameters. A dose of 100 mg was administered as an intravenous bolus to each volunteer and blood samples were analyzed at intervals as shown in the graph below. The average plasma concentrations at each time are shown by the solid circles at 10 and 30 minutes and at 1,2, 3, 4, 6, and 8 hours after administration. 

Figure 11.2 Plasma concentration (Cp) versus time profile following the administration of dose of a drug as an intravenous bolus (n = 1). Please note that the second identical dose (n = 2) was administered after a long interval. (It is assumed that the interval is > 10 half lives of drug and, therefore, there is an insignificant amount of drug left in the blood from the first dose.)...

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