Bolus Administration

Because a change in current causes a change in the rate of delivery across the skin, bolus drug delivery can be obtained by increasing the current for a short period of time. For example, Heit et al. (1993) have been able to stimulate secretion of follicle-stimulating hormone (FSH) in swine by short-term iontophoresis of luteinizing hormone-releasing hormone (LHRH). 

Such changes in the strength of the current can be preprogrammed to occur at selected times of the day or can be provided on demand by pressing a button on the patch. 

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Insulin pump therapy consists of a programmable infusion device that allows for basal infusion of insulin 24 hours daily, as well as bolus administration following meals. As seen in Fig. 40-3, an insulin pump consists of a programmable infusion device with an insulin reservoir. This pump is attached to an infusion set with a small needle that is inserted in subcutaneous tissue in the patient s abdomen, thigh, or arm. Most patients prefer insertion in abdominal tissue because this site provides optimal insulin absorption. Patients should avoid insertion sites along belt lines or in other areas where clothing may cause undue irritation. Infusion sets should be changed every 2 to 3 days to reduce the possibility of infection. 

Fluorouracil Inhibition of the enzyme thymidylate synthase, the rate-limiting step in thymidine formation. Dose-limiting Myelosuppression and mucositis with bolus administration Diarrhea and hand-foot syndrome with continuous infusion Additional toxicities Skin discoloration, nail changes, photosensitivity, and neurologic toxicity... 

The preparation of salts of organic compounds is one of the most important tools available to the for-mulator. Compounds for both IM and IV solutions may require high solubility in order for the drug to be incorporated into acceptable volumes for bolus administration (see Table 1). Sodium and potassium salts of weak acids and hydrochloride and sulfate salts of weak bases are widely used in parenterals requiring highly soluble compounds, based on their overall safety and history of clinical acceptance. 

Equation (9) is most often associated with intravenous bolus administration, although proper definition of A, allows this equation to apply to extravascular and intravenous infusion administrations. 

Bolus administration is usually characterized by a normalized injection function that effectively inputs the dose in a bell-shaped curve manner. Since bolus administration is not instantaneous, this approach is considered more realistic. I(t) for bolus administration is... 

Following intravenous bolus administration, the partition coefficients for a noneliminating blood flow-limited compartment is... 

Epidural anesthesia is administered by injecting local anesthetic into the epidural space. Located outside the spinal cord on its dorsal surface, the epidural space contains fat and is highly vascular. Therefore, this form of anesthesia can be performed safely at any level of the spinal cord. Furthermore, a catheter may be placed into the epidural space, allowing for continuous infusions or repeated bolus administrations of anesthetic. 

Continuous IV infusion of 5-FU is generally well tolerated but is associated with palmar-plantar erythrodysesthesia or hand-foot syndrome. This distinct skin toxicity can be acutely disabling, but it is reversible and not life threatening. IV bolus administration is associated with leukopenia, which is dose limiting and can be life threatening. Both methods are associated with a similar incidence of mucositis, diarrhea, nausea and vomiting, and alopecia. 

The most sensitive technique for measuring brain uptake is the intravenous bolus administration or infusion and subsequent measurement of brain concentrations (Figure 2.4). Depending on the pharmacokinetics of the test compound in plasma, brain sampling may be performed after suitable circulation times ranging from minutes to hours or days. 

Laying-hens eliminate sulfadimidine rapidly by metabolic pathways including hydroxylation and acetylation. Following intravenous SDM administration, a biphasic elimination-time curve was noticed 10.2 + 3.3 H). Figure 8 shows the plasma disposition of SDM and its metabolites following an oral SDM bolus administration once daily of 100 mg/kg to a chicken. The percentage of N -SDM in plasma is the highest (Table I). Within 3 days of termination of the SDM therapy, plasma concentrations of SDM and its metabolites falls rapidly below the detection limit of the HPLC method (0.02 /ig/ml). 

BASIC PULSE-CHASE KINETICS. For the case of a single pool of A that becomes promptly labeled with tracer A, bolus administration of tracer will initially increase the tracer/tracee ratio (indicated by the initial isotopic enrichment Eo), which will subsequently suffer exponential decay As is the case for all first-order processes, the rate law is ... 

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. 

Continuous iV infusion For continued reduction of the heart rate (up to 24 hours) in patients with atrial fibrillation or atrial flutter, an IV infusion may be administered. Immediately following bolus administration of 20 mg (0.25 mg/kg) or 25 mg (0.35 mg/kg) and reduction of heart rate, begin an IV infusion. The recommended initial infusion rate is 10 mg/h. Some patients may maintain response to an initial rate of 5 mg/h. The infusion rate may be increased in 5 mg/h increments up to 15 mg/h as needed, if further reduction in heart rate is required. The infusion may be maintained for up to 24 hours. Therefore, infusion duration more than 24 hours and infusion rates more than 15 mg/h are not recommended. 

Hypotension Rapid bolus administration may be associated with exaggerated hypotension, including shock, and rarely, cardiac arrest. To avoid hypotension, administer in a dilute solution over 60 minutes or more. Stopping the infusion usually results in prompt cessation of these reactions. Frequently monitor blood pressure and heart rate. 

Meta-Analysis Group in Cancer. Efficacy of intravenous continuous infusion of fluorouracil compared with bolus administration in advanced colorectal cancer. J Clin Oncol 1998 16( 1 ) 301—308. 

The toxicities of 5-fluorouracil vary with the schedule and mode of administration. Nausea is usually mild if it occurs at all. Myelosuppression is most severe after intravenous bolus administration, with leukopenia and thrombocytopenia appearing 7 to 14 days after an injection. Daily injection or continuous infusion is most likely to produce oral mucositis, pharyngitis, diarrhea, and alopecia. Skin rashes and nail discoloration have been reported, as have photosensitivity and increased skin pigmentation on sun exposure. Neurological toxicity is manifested as acute cerebellar ataxia that may occur within a few days of beginning treatment. 

Route of administration NovoSeven is intended for intravenous bolus administration only, after reconstitution with the appropriate volume of sterile water for injection. 

Ronte of administration Ontak is intended for intravenous use only and should be infused over at least 15 minutes. It is not intended for bolus administration. 

F. Role in therapy Reteplase is a novel thrombolytic agent. It has a longer half-life than alteplase, which allows bolus administration. Its administration technique is much simpler than that of alteplase. In addition reteplase has achieved more rapid, complete, and sustained thrombolysis of the infarct-related artery compared to standard doses of alteplase with comparable safety. Reteplase is at least as effective as streptokinase and alteplase in AMI. 

In view of the short plasma half-life of 5-FU, most authors believe that continuous administration of 5-FU (CIFU) is the superior 5-FU schedule compared to bolus regimens. Continuous infusion of 5-FU seems to inhibit predominantly DNA s mthesis, whereas bolus administration of 5-FU inhibits RNA splicing and DNA synthesis, resulting in different toxicity and efficacy profiles (24,25). 

Clearance can be calculated from the area under the concentration-time curve (AUC area under the curve) following bolus administration C/=Dose/AUC. This can be used for any form of intravenous administration and does not rely on compartmental analysis. 

Vecuronium can be given by repeated bolus administration or by a continuous infusion for maintenance of block. A general rule of thumb for administration by infusion is to use 0.1 mg-kg-l h-l following some recovery from a bolus dose of 0.1 mg-kg-1. The dose requirements diminish with time as peripheral storage sites become saturated. It is strongly advocated that neuromuscular block be routinely monitored during prolonged administration. 

Redistribution of thiopental after an intravenous bolus administration. Note that the time axis is not linear. 

The amide local anesthetics are widely distributed after intravenous bolus administration. There is also evidence that sequestration can occur in lipophilic storage sites (eg, fat). After an initial rapid distribution phase, which consists of uptake into highly perfused organs such as the brain, liver, kidney, and heart, a slower distribution phase occurs with uptake into moderately well-perfused tissues, such as muscle and the gastrointestinal tract. As a result of the extremely short plasma half-lives of the ester type agents, their tissue distribution has not been extensively studied. 

Nephrotoxicity in the form of proteinuria and glomerular calcification following intravenous (bolus) administration at 284 and 408mg/kg/day for 14 days. These findings were not seen at 1 and 28 mg/kg/day... 

Both somatostatin and octreotide cause transient increases in mean arterial pressure and mean pulmonary pressure when given intravenously to patients with cirrhosis, more marked with bolus administration than with continuous infusion (5). This may be either direct or mediated by inhibition of gut vasodilatory peptides (SEDA-24, 505 6) and is not usually associated with significant clinical effects. 

Effects on respiration are similar to those of thiopental at usual anesthetic doses. However, propofol causes a marked decrease in systemic blood pressure during induction of anesthesia, primarily through decreased peripheral resistance. In addition, propofol has greater negative inotropic effects on the heart than etomidate and thiopental. Apnea and pain at the site of injection are common adverse effects of bolus administration. Muscle movements, hypotonus, and (rarely) tremors have also been reported following its use. Clinical infections due to bacterial contamination of the propofol emulsion have led to the addition of antimicrobial adjuvants (eg, ethylenediaminetetraacetic acid and metabisulfite). 

The early discussion on IV bolus administration was completely based on the one-compartment model. The discussion somewhat avoided covering exactly what was happening to the drug immediately after the injection. Most Cp-time data is not recorded until 15 minutes after injection of the drug. Why Because interpreting data for the first 15 minutes requires the two-compartment model. 

Fig. 4.4 Tissue distribution of total radioactivity at 24 h after single IV bolus administration of5 mg/kg [3H]-labeled ISIS 104838 or ISIS 113715 to rats. Concentration values represent total radioactivity concentration in microgram equivalent/g (pg eq/g).

This value indicates that the IV bolus administration gives a significantly better bioavailability than oral administration. 

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