Extravascular administration dosing

With extravascular administration (e.g., per os [PO oral], intramuscular [IM], subcutaneous [SC], inhalation), less than 100% of a dose may reach the systemic circulation because of variations in bioavailability. 

Serial drug concentrations following single dose extravascular administration of different doses given as a solution (not as a formulated tablet, capsule, etc.) at amounts low enough so as to not precipitate in the gastrointestinal tract. 

The noncompartmental analysis of pharmacokinetic data after extravascular drug administration, when coupled with that of IV dosing, can yield additional relevant pharmacokinetic parameters, particularly regarding absorption processes. For example, the systemic availability F), which represents the net fraction of the drug dose reaching the systemic circulation after extravascular administration, is defined as ... 

Medications that exhibit a linear response or dose-independent response can have the therapy optimized by using a single blood level determination. If the drug is given by a constant-rate infusion or if it is an extravascular administration, the peak-trough fluctuations are minor, and the patient is at steady state, then a simple proportion can be used. 

This approach can be expanded to include other routes of administration such as IV infusion (of duration 7) and extravascular administrations such as oral, intramuscular, subcutaneous, or topical. Schemes and equations for these models are shown in Table 12.1. The integrated equations in Table 12.1 can be used to calculate drug concentrations after a single IV bolus, IV infusion, or oral dose as shown in Eigures 12.2 through 12.4. 

Figure 1.10 A typical semilogarithmic plot of plasma concentration (Cp) versus time following the extravascular administration of a dose of a drug that is rapidly distributed in the body.

Determine the absorbable amount of dmg remaining at the site of administration (Xa) and the amount of drug in the body and/or blood (X) at a time when the rate of absorption is equal to the rate of elimination for extravascularly administered dose of 500 mg via tablet. 

It will be very helpful to begin to compare Eq. 11.12 (for an intravenous bolus) and Eq. 12.13 (for extravascularly administered dose) for similarity and differences, if any, and identify the commonality between the two equations. It may he quickly apparent that the information obtained following the administration of a single dose of a drug, either intravenously or... 

This expression, which relies on fairly rapid absorption such that each subsequent dose is administered in the post-absorptive phase, can be readily employed to determine the extent of accumulation following extravascular administration of a drug as long as dosing interval and the elimination rate constant of the drug are available. Note the similarity between Eq. 12.27 for multiple oral dosing and Eqs 11.29,11.33 and 11.34 for multiple intravenous bolus administration. 

Figure 12.5 Plasma concentration (Cp) versus time following repetitive extravascular administration of a drug by either a series of maintenance doses (D (1 or an initial loading dose followed by a series of maintenance doses (D ) (2—4). 1, series of maintenance doses (i.e. no loading dose) 2, loading dose 1.5 times maintenance dose 3, loading dose twice maintenance dose 4, loading dose three times the maintenance dose, r, dosing interval t /2, drug half life.

Several factors - including the route of administration, the physicochemical properties, dosage form, and the physiological state of an individual - can affect the amount of the administered dose of a drug that reaches the systemic circulation after extravascular administration. The term bioavailability (F)... 

The relationship indicates that in the case of extravascular administration, the level of the drug in plasma first increases gradually, but when the rate of drug elimination becomes equal to that of absorption a maximum is finally achieved and afterwards only a decline is observed (Fig. 6). The time of occurrence of this r is independent from the dose, depending only on the rate constant for absorption and elimination as it is shown by the formula ... 

Methadone is a p receptor agonist with special properties that make it particularly useful as a maintenance agent. Rehably absorbed orally, it does not reach peak concentration until about 4 hours after administration and maintains a large extravascular reservoir (Kreek 1979). These properties minimize acute euphoric effects. The reservoir results in a plasma half-life of 1—2 days, so there are usually no rapid blood level drops that could lead to withdrawal syndromes between daily doses. Effective blood levels are in the range of 200-500 ng/mL. Trough levels of 400 ng/mL are considered optimal (Payte and Khouri 1993). There is wide variability among individuals in blood levels with identical doses (Kreek 1979), and some have inadequate levels even with doses as high as 200 mg/day (Tennant 1987 Tenore 2003). 

Fig. 39.7. (a) Two-compartment catenary model for extravascular (oral or parenteral) administration of a single dose D which is completely absorbed. The transfer constant of absorption is (b) Time courses of the amount in the extravascular compartment Xa, the concentration in the plasma compartment Cp and the content in the elimination pool X. ... 

Thus, amount of drug in the body following administration of an extravascular dose is a constant [(Dgka)/(ka — kei) multiplied by the difference between two exponential terms—one representing elimination [exp(—keit) and the other representing absorption [exp(—kat). ... 

Absolute bioavailability, which refers to the fraction of the extravascular (or PO) dose that reaches the systemic circulation unchanged (in reference to an IV dose). Absolute bioavailability is usually determined by calculating the respective AUC after PO and IV administration as... 

Systemic effects are more likely to occur with long-acting anesthetics if an excessive dose is used, if absorption into the blood stream is accelerated for some reason, or if the drug is accidentally injected into the systemic circulation rather than into extravascular tissues.17 40 Other factors that can predispose a patient to systemic effects include the type of local anesthetic administered, as well as the route and method of administration.3 Therapists and other health care professionals should always be alert for signs of the systemic effects of local anesthetics in patients. Early symptoms of CNS toxicity include ringing/buzzing... 

The pharmacokinetics of aminoglycosides ascribes to an interrelated two or three compartment model. The three compartment model comprises three phases, an a or distributive phase, and two elimination phases, P and Y- After administration of an intravenous dose in the three compartment model, the aminoglycoside first enters the a or distributive phase [33]. During this initial phase, the aminoglycoside is transported from the vascular to the extracellular compartment. The p or elimination phase represents the elimination of the aminoglycoside from the plasma and extravascular compartments [33]. The third or y phase corresponds to the protracted elimination of the aminoglycoside... 

The usual method for estimating systemic availability (F) of a drug after extravascular (p.o., i.m.) administration of the dose employs the method of corresponding areas ... 

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