Drug administration intravenous infusion

Fig. 9.34. Typical plasma concentration versus time profile following administration of a drug by intravenous infusion.

Rapid intravenous infusion of torsades-inducing drugs Concomitant administration of more than one agent known to cause QT interval prolongation/torsades de pointes Possible genetic predisposition Previous history of drug-induced torsades de pointes... 

The short plasma half-life of dobutamine (1-2 minutes) was found by Murphy et al. (4) to be due to the rapid redistribution of the drug from the plasma to the tissue. However, plasma half-life of radioactivity following the administration of 14C-dobutamine was 1.9 hours. The major circulating metabolite is the glucuronide conjugate of 3-0-methyldobutamine. During a continuous intravenous infusion of dobutamine, the plasma level of the parent drug reach a maximum within 8 to 10 minutes, while those of the metabolites peak be-... 

Just as new drugs must be tested in animals by the route to be used in humans, so must they be tested in volunteers using the intended route for patients. But there are clear benefits in testing all drugs when going into humans for the first time using intravenous infusions, even if systemic exposure in patients will be achieved by another route. These benefits relate primarily to the fact that intravenous infusion allows for precise control of drug administration. 

The following data was obtained after the administration of a single 500-mg dose of a drug by slow intravenous infusion. Calculate the AUC, elimination rate constant, and the biological half-life of the drug. 

In the case of drug administration by an intravenous infusion, the average steady state concentration (Css) is obtained by the equation,... 

The same relationship to k i and half-life also apply, so that as with intravenous infusion 87.5 % of the final steady state concentration is achieved following administration of the drug for three half-lives. 

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). 

Lability can be used to advantage to create drugs that are designed for topical or intravenous infusion administration. For topical administration compounds may benefit from rapid systemic clearance to overcome possible side-effects. Thus the compound is stable at its topical site of action (skin, eye etc.) but rapidly degraded by the esterases present in blood, liver and kidneys to its inactive metabolites. This approach renders the compound selective. 

Injection Slow infusion of injection is preferable to bolus administration. Rapid infusion of digitalis glycosides has been shown to cause systemic and coronary arteriolar constriction, which may be clinically undesirable. Caution is thus advised and injection probably should be administered over a period of 5 minutes or more. Mixing injection with other drugs in the same container or simultaneous administration in the same intravenous line is not recommended. 

The highly polar ionic character of EDTA limits its oral absorption. Moreover, oral administration may increase lead absorption from the gut. Consequently, EDTA should be administered by intravenous infusion. In patients with normal renal function, EDTA is rapidly excreted by glomerular filtration, with 50% of an injected dose appearing in the urine within 1 hour. EDTA mobilizes lead from soft tissues, causing a marked increase in urinary lead excretion and a corresponding decline in blood lead concentration. In patients with renal insufficiency, excretion of the drug—and its metal-mobilizing effects—may be delayed. 

Transdermal delivery is a noninvasive intravenous infusion of drug to maintain efficacious drug levels in the body for predictable and extended duration of activity. Diffusion-controlled transdermal systems are designed to deliver the therapeutic agent at a controlled rate from the device to and through the skin into the systemic circulation. This route of administration avoids unwanted presystemic metabolism (first-pass effect) in the GI tract and the liver. Patient satisfaction has been realized through decreased... 

Nitroprusside rapidly lowers blood pressure, and its effects disappear within 1-10 minutes after discontinuation. The drug is given by intravenous infusion. Sodium nitroprusside in aqueous solution is sensitive to light and must therefore be made up fresh before each administration and covered with opaque foil. Infusion solutions should be changed after several hours. Dosage typically begins at 0.5 g/kg/min and may be increased up to 10 g/kg/min as necessary to control... 

Administration of BNP as nesiritide (see Chapter 13 Drugs Used in Heart Failure) in patients with severe heart failure increases sodium excretion and improves hemodynamics. However, the peptide has to be given by constant intravenous infusion. A more promising approach may be the use of drugs that inhibit the neutral endopeptidase responsible for the breakdown of ANP. This is discussed below under Vasopeptidase Inhibitors. 

---