Intravenous infusion loading bolus

Compared to streptokinase, urokinase has been less extensively studied because of its high cost, ie, about 10 times that of a comparable treatment with streptokinase. In addition to the indications described for streptokinase, urokinase is indicated for use in patients with prior streptokinase treatment, or prior Streptococcal infection. Urokinase is commonly used at a loading dose of 4400 units /kg, with a maintenance intravenous infusion dose of 4400 units/kg/h for thromboses other than acute myocardial infarction. In the latter case, a much larger dose, ie, 0.5—2.0 million units/h or a bolus dose of 1.0 million units followed by a 60-min infusion with 1.0 million units, has been found optimal (106). An intracoronary dose of 2000 units/min for two hours was used in one comparative study with intracoronary streptokinase (107). In this study, urokinase exhibited efficacy equivalent to streptokinase with fewer side effects. Other studies with intracoronary urokinase have adrninistered doses ranging from 2,000 to 24,000 units/min with a reperfusion efficacy of 60—89% (108—112). In another urokinase trial, 2.0 million units were adrninistered intravenously, resulting in a thrombolytic efficacy of 60% (113). Effectiveness in terms of reduction in mortaUty rate has not been deterrnined because of the small number of patients studied. 

The loading dose is an intravenous bolus dose. However, in this instance, unlike the case of a single, isolated intravenous bolus dose considered in Ch. 3, the loading dose is immediately followed by the commencement of an intravenous infusion at constant rate. The intravenous bolus dose permits us to attain the desired plasma concentration at time = 0 and the concomitant constant infusion allows us to maintain this concentration. 

In a retrospective analysis of 36 patients who received intravenous levetiracetam for refractory status epilepticus [209 ] a median dose of 3000 mg/day (range 1000-9000) was used as a loading bolus or by continuous pump infusion. Status epilepticus was terminated in 69% of patients. None had cardiac dysrhythmias or significantly reduced blood pressure, or required an increase in the dose of catecholamines. Two patients had nausea and vomiting during levetiracetam loading, leading to aspiration pneumonia in one. 

Indications for treatment with streptokinase include acute occlusion of arteries, deep vein thrombosis, and pulmonary embolism. Streptokinase therapy in coronary thrombosis, which is the usual cause of myocardial infarction (54,71,72), has proved to be valuable. In this frequently fatal condition, the enzyme is adrninistered intravenously at a dose of 1.5 million units over 60 min, or given by intracoronary infusion at a 20,000- to 50,000-unit bolus dose followed by 2000 to 4000 units/min for 60 min therapy must be instituted as soon as practicable after the diagnosis of heart attack is made. For deep vein thrombosis, pulmonary embolism, or arterial occlusion, streptokinase is infused at a loading dose of 250,000 units given over 30 min, followed by a maintenance dose of 100,000 units over a 60-min period. 

Aprotinin is not effective after oral administration, but is administered intravenously as a loading dose followed by a continuous infusion. Its activity is expressed as kallikrein inactivation units (KIU). The conventional (Munich) dose regimen consists of an initial 2 x 10 KIU bolus, a similar initial dose to prime the bypass machine, and then 0.5 x 10 KIU/ hour by continuous infusion thereafter. The half-life of aprotinin is about 2 hours. Plasma concentrations of 125 KlU/ml are necessary to inhibit plasmin, but a... 

This is best accomplished by giving an intravenous bolus as a loading dose and then titrating the level using a continuous infusion. The rectal administration of aminophylline solution can also rapidly achieve therapeutic blood levels. Asthmatics who are prone to attacks of asthma can successfully utilize this route of administration instead of intravenous therapy. 

This may be accomplished by administering a loading intravenous bolus dose (Z>l) concomitant with the commencement of the infusion rate. 

Figures lO.lOand 10.11, respectively, showthe predicted and real plasma concentration versus time profiles following the administration of a drug as an intravenous bolus loading dose immediately followed by an infusion.

In Fig. 10.11, the plasma concentration versus time profile shows a trough. This might be attributed to an elapse in time between the completion of an intravenous bolus loading dose and the commencement of the infusion rate. The magnitude of the nadir observed in the plasma concentration versus time profile will be influenced by the elapsed time and the elimination half life of the drug. However, there is no bolus/infusion combination for a two-compartment drug that will produce a total plasma drug concentration that is constant over time the profile will have peaks and/or nadirs. This, therefore, could be an alternative explanation for the deviation from a horizontal line in Fig. 10.11. 

The conceptual understanding of Eq. 10.21 is vital not only for the understanding of the theory and rationale behind the use of two infusion rates to attain and then maintain the desired plasma concentration of a drug but also for the understanding of calculations of loading dose and maintenance dose Dm) when dmgs are administered as an intravenous bolus and extravascularly in multiple doses (discussed in Ch. 11). 

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