Injection extravascular

Fig. 39.8. (a) Semilogarithmic plot of plasma concentration Cp (pg I" ) versus time t. The straight line is fitted to the later part of the curve (slow 3-phase), with the exception of points that fall below the quantitation limit. TTte intercept B of the fitted line is the extrapolated plasma concentration that would have been obtained at time 0 with an intravenous injection. The slope sp is proportional to the transfer constant of elimination k. (b) Semilogarithmic plot of the residual plasma concentration C (pg r ) versus time t, on an expanded time scale t. The straight line is fitted to the first part of the residual curve (fast a-phase), with the exception of points whose residuals fall below the quantitation limit. The intercept B of the fitted line, is the same as that in panel a. The slope is proportional to the transfer constant of absorption from the extravascular compartment. 

The effect of incomplete absorption is that only a fraction of a single-dose D is made available to the central plasma compartment. The solution of the previous model needs, therefore, to be modified by replacing the term D by F D. Consequently the area under the curve AUCg under incomplete extravascular absorption will be smaller than the maximal AUC that results from complete absorption. The latter, as we have seen is equal to the AUC obtained from a single intravenous injection, which we denote by AUC,. These considerations can be summarized as follows ... 

Whenever a drug is administered by an extra-vascular route, there is a danger that part of the dose may not reach the blood (i.e., absorption may not be complete). When the intravenous route is used, the drug is placed directly in the blood therefore an IV injection is, by definition, 100% absorbed. The absolute bioavailability of an extravascular dosage form is defined relative to an IV injection. If IV data are not available, the relative bioavailability may be defined relative to a standard dosage form. For example, the bioavailability of a tablet may be defined relative to an oral solution of the drug. 

For this calculation, it is unnecessary to assume that Vd and/or kei are the same for the two studies. It is only necessary that fe be the same in both studies. This is usually a valid assumption unless the drug undergoes a significant amount of first-pass metabolism in the gut wall or liver following oral administration or a significant amount of decomposition at an intra muscular (IM) injection site. When this occurs, the availability of the extravascular dosage form may appear to be low, but the fault will not lie with the formulation. The bioavailability will be a true reflection of the therapeutic efficacy of the drug product, and reformulation may not increase bioavailability. 

Because of their low molecular weight (<2000 Da), the standard NS-CA are extravasated to a massive extent on first pass in noncerebral areas. Thus, Canty et al. reported that first-pass extraction of a conventional nonionic CA averaged 33 % in normally perfused myocardial areas and 50% in stenotic areas (where coronary blood flow was reduced by 50%) [15]. These data may even have underestimated first-pass myocardial extraction of CA because of back diffusion of the molecule. In another model, approximately 80% of the myocardial content of I-iothalamate was found in the extravascular space 1 minute after intravenous injection in rats [16]. 

Absorption is the critical factor that determines entry of an antimicrobial agent into the blood stream when an extravascular route of administration, i.e. oral, intramuscular (IM), or subcutaneous (SC) injection is used. Absorption, the extent of which depends mainly on the physicochemical properties of the antimicrobial agent, is associated with intra-mammary or intra-uterine therapy. 

The IM and SC routes are by far the most frequently used extravascular parenteral routes of drug administration in farm animals. The less frequently used parenteral routes have limited application, in that they aim at directly placing high concentrations of antimicrobial agent close to the site of infection. These routes of administration include intra-articular or subconjuctival injection and intra-mammary or intra-uterine infusion. These local routes differ from the major parenteral routes in that absorption into the systemic circulation is not a prerequisite for delivery of drug to the site of action. The combined use of systemic and local delivery of drug to the site of infection represents the optimum approach to... 

Concentrated sodium chloride injection Inadvertent direct injection or absorption of concentrated sodium chloride injection may give rise to sudden hypernatremia and such complications as cardiovascular shock, CNS disorders, extensive hemolysis, cortical necrosis of the kidneys, and severe local tissue necrosis (if administered extravascularly). Do not use unless solution is clear. When administered peripherally, slowly infuse through a small bore needle placed well within the lumen... 

Crook et al.57 reported that the plasma concentration of 111 after its injection into a dog at 10 mg/kg followed essentially the same Course as that of 2-PAM I injected Intravenously at 30 mg/kg. Inasmuch as the plasma concentrations at approximately the same times after injection of the two oximes were almost Identical, despite the difference between the doses, one must assume that III has a much smaller volume of distribution than 2-PAM I and that either the kinetics of removal of 2-PAM I from its larger volume of distribution were correspondingly greater than those of III or the 2-PAM I in extravascular components of its volume of distribution was held there tenaciously. The fairly rapid changes in the 2-PAM I concentrations found by Kalser l in various organs and tissues of the mouse argue against the validity of the latter possibility. 

The most frequent adverse reactions associated with the administration of proleukin include fever, chills, fatigue, malaise, nausea and vomiting. It has also been associated with capillary leak syndrome (CLS). CLS is defined as a loss of vascular tone and effusion of plasma proteins and fluids into the extravascular space. This leads to hypotension and decreased organ perfusion, which may cause sudden death. Other side effects include anaphylaxis, injection site necrosis and possible autoimmune and inflammatory disorders. 

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... 

Primary routes of entry of toxicants to the human body are dermal, gastrointestinal, and respiratory. Methods for studying these different routes are numerous, but they are perhaps best developed for the study of dermal absorption because this route is subject to more direct methodology, whereas methods for studying respiratory or gastrointestinal absorption require more highly specialized instrumentation. Additional routes encountered in experimental studies include intraperitoneal, intramuscular, and subcutaneous routes. When direct entry into the circulatory system is desired, intravenous (IV) or intra-arterial injections can be used to bypass the absorption phase. Information from this more direct route of entry (e.g., IV) should, however, be used in addition to data from the extravascular route of interest to adequately assess the true extent of absorption of a toxicant. 

Immunogenicity may be affected by the route of administration. Extravascular injection has been shown to stimulate antibody formation more than IV application, but this is most likely due to the increased immunogenicity of protein aggregates and precipitates formed at the injection site [44]. A recent study investigated the effect of the route of administration of INF-P preparations on inducing anti-INF-P antibodies in multiple sclerosis patients. The results indicate that IM injections appear less immunogenic compared to SC injections, resulting in both a lower serum level of anti-INF-P antibodies as well as a delay in their appearance [45]. 

Because it is not absorbed on oral administration, sodium stibogluconate must be administered parenterally. It is distributed in the extravascular compartment. Metabolism is minimal and the drug is excreted into the urine. Adverse effects include pain at the injection site, gastrointestinal upsets, and cardiac arrhythmias. Renal and hepatic function should be periodically monitored. 

Injection into the left ventricle or the proximal aorta is likely to produce more marked effects. Cardiac rate, stroke volume, and cardiac output increase. There is a rise in right and left atrial pressures and left ventricular end-diastolic pressure. The pulmonary arterial pressure is also increased. The blood volume expands and peripheral blood flow increases and then decreases as systemic resistance falls. The hematocrit falls and venous pressure gradually rises. As the systemic arterial pressure falls, the heart rate increases. These responses are largely due to the injection of strongly hypertonic solutions, which promote a rapid expansion of the plasma volume water shifts from the extravascular fluid spaces to the blood and moves out of the erythrocytes, which shrink and become crenated. Blood viscosity rises, but plasma viscosity does not increase significantly. The erythrocytes give up potassium to the plasma and this might contribute to the observed reduction in peripheral vascular resistance. 

Inadvertent injection into extravascular tissues causes pain, swelling, and possibly tissue necrosis. Pain on intravenous injection has been noted in 10% of patients (14). Intra-arterial injection causes vascular spasm and can cause gangrene of a distal extremity. 

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