Loading dose
When a drug is administered in a repeated or chronic dosing regimen (e.g. repeated oral doses, injections, or via an IV infusion), it is necessary to administer the drug for a period equal to approximately 5 half-lives of elimination in order for the drug to achieve an (average) steady state concentration. For a drug with a long half-life, this might mean that steady-state is not reached for 2 or more weeks, and related to this, the drug might not achieve a minimum effective concentration in the plasma for several days. This would be problematic if a rapid action of the drug is required – for example, if the drug is an antibiotic.
A loading dose is a large dose of drug administered as an initial bolus injection or infusion, or oral dose, that results in the drug reaching the desired steady state concentration immediately, or at least in a much shorter time than would otherwise be the case. The concept is quite straightforward; at steady state, the rate of drug elimination is equal to the rate of drug administration. Each dose of the drug distributes throughout the entire volume of distribution for that drug, so it is easy to determine how much drug is in the body at steady state. For example, if the drug of interest has a volume of distribution of 60 litres and the average plasma concentration at steady state (with a dosing regimen, let’s say, of 10 mg PO twice a day) is 1.2 mg/litre then there are (1.2 mg/l × 60 l) = 72 mg of drug in the body at steady state. So the loading dose would simply involve administering 72 mg to the patient over a short period of time, and thereafter administering 10 mg PO twice a day to maintain the steady state concentration at 1.2 mg/litre.
The use of a loading dose is typically recommended when a drug has a long half-life of elimination, when it is necessary to achieve an effective concentration rapidly, and when the target steady-state concentration is less than twice the minimum effective concentration (MEC). With respect to the last of these points, consider that for a drug with a half-life of elimination of 12 hours and a target Css of 8 mg/litre, it would take 5 hours to reach a MEC of 2 mg/litre (Css = 4 × MEC), 12 hours to reach a MEC of 4 mg/litre (Css = 2 × MEC), and 24 hours to reach a MEC of 6 mg/litre (Css = 1.33 × MEC).
When drugs distribute very slowly from the plasma to the tissue compartment, a loading dose administered over a very short time period may lead to dangerously-high drug concentrations in the plasma. For example, lidocaine distributes slowly to tissues, but distribution to brain is more rapid than to most other tissues (probably due to high vascularisation). As a result, a single large loading dose leads to elevated brain concentrations of lidocaine initially, which can lead to serious CNS side-effects. A lidocaine loading dose is therefore often split into an initial IV bolus dose of 1 mg/kg, followed by up to three subsequent IV bolus doses of 0.5 mg/kg at 8-10 minute intervals, and then a maintenance infusion of 2 mg/minute thereafter.
Barbiturate drugs such as phenobarbital have long half-lives of elimination (4 days, initially) and therefore may take 2-3 weeks to reach steady state. While a loading dose might seem appropriate for phenobarbital, tolerance to adverse effects builds up during the initial days of dosing with the drug such that by the time the patient reaches steady state, they have developed tolerance to potentially serious side effects. Administration of a loading dose would not allow the patient to develop tolerance and the consequences could be harmful, and possibly lethal.
