Lecture 7 — Steady State, Loading Doses and Nonlinear Pharmacokinetics
Steady-state concentration
• With repeated doses, each new dose is given while some drug from earlier doses remains. Concentration peaks and troughs rise during accumulation.
• At steady state, drug input over a dosing interval equals drug elimination over that interval. Concentration still fluctuates between a recurring peak and trough; it does not become a perfectly flat line.
Eight-hour half-life example
• The hypothetical drug has an elimination half-life of 8 hours and is administered every 8 hours.
• During approximately the first 40 hours (five half-lives), concentrations accumulate. By around 40 hours, successive peaks and troughs become similar, indicating approximate steady state.
• Changing dose size changes the concentrations achieved, but does not ordinarily shorten the time needed to reach steady state.
Loading dose / IV bolus
• When waiting several half-lives is impractical, a larger initial loading dose may rapidly bring concentration toward the desired level.
• The lecture compares an IV bolus followed by continuous infusion with infusion alone: the bolus produces a much faster initial rise.
• A loading dose must be calculated using the drug’s pharmacokinetic properties and patient physiology; an excessive initial dose can produce toxicity.
Linear versus nonlinear pharmacokinetics
• In linear pharmacokinetics, exposure or concentration generally changes in proportion to dose under the conditions described in the lecture. Doubling the dose can approximately double the concentration.
• In nonlinear pharmacokinetics, dose and concentration are not proportional. As elimination mechanisms approach saturation, a small dose increase may cause a disproportionately large concentration increase.
Phenytoin: lecture example
• The lecture highlights phenytoin as an example of nonlinear pharmacokinetics, particularly at doses above approximately 300 mg/day.
• The slide discusses the therapeutic concentration range and illustrates that raising the dose from 300 mg to 400 mg may produce a much larger-than-proportional concentration increase.
• The lecture associates this behavior with capacity-limited or saturable elimination, discussed using maximum elimination velocity (Vmax).
How to interpret the source graphs
• Repeated-dose graph: each dose produces a peak followed by a decline; peaks and troughs accumulate, then repeat at steady state.
• Infusion comparison graph: an initial bolus produces a rapid high concentration, whereas infusion alone approaches its eventual level gradually.
• Nonlinear phenytoin graph: increasing dose can increase concentration disproportionately near saturable elimination. These are verbal explanations of the source graphs, not reconstructed datasets.
Prepared for Dear Study. Review alongside the original university PDF for figures and slide-specific details.
