Anaes · Physiology

Distribution, clearance and half-life

Also known as Volume of distribution · Clearance · Elimination half-life · Elimination rate constant · Loading dose · Maintenance infusion · Steady state · Context-sensitive half-time · Bioavailability

Distribution, clearance and half-life are the three pharmacokinetic parameters that govern how much drug to give, how often to give it, how long it takes to reach steady state, and how quickly it wears off. The framework rests on eight exam-critical ideas. First, the body can be modelled as a single compartment in which the drug distributes instantaneously and is eliminated by first-order kinetics (a constant FRACTION, not a constant amount, removed per unit time), giving an exponential concentration-time decline and a half-life of 0.693 divided by the elimination rate constant. Second, intravenous anaesthetic drugs behave as TWO or more compartments: a central (vessel-rich, blood and well-perfused tissues) compartment into which the drug is injected and from which it is sampled, and a peripheral compartment into which it distributes; the concentration-time curve therefore shows a steep distribution phase (alpha) followed by a slower elimination phase (beta), described by the transfer rate constants k12, k21 and k10. Third, the volume of distribution Vd equals dose divided by the initial concentration and is an apparent, not a real, volume: lipid-soluble tissue-bound drugs (thiopental, propofol, fentanyl) have Vd of many litres per kilogram, whereas polar muscle relaxants stay in extracellular fluid with Vd around 0.1 to 0.3 L per kg. Fourth, clearance CL is the volume of blood plasma completely cleared of drug per unit time, equals the rate of elimination divided by the concentration, and equals Vd times the elimination rate constant; hepatic clearance is liver blood flow times the extraction ratio, separating drugs into flow-dependent (high extraction: morphine, lignocaine, propranolol) and capacity-dependent (low extraction: diazepam, warfarin, theophylline) classes. Fifth, the elimination half-life equals 0.693 times Vd divided by CL, steady state is reached in about five half-lives, and the loading dose equals Vd times the target concentration while the maintenance rate equals CL times the target concentration. Sixth, the context-sensitive half-time (Hughes 1992) is the time for the plasma concentration to fall by 50 per cent AFTER stopping an infusion designed to hold a constant concentration; it rises with infusion duration for fentanyl and thiopental as the peripheral compartment fills and redistribution slows, but stays essentially flat at about three minutes for remifentanil because non-specific esterases metabolise it independently of organ blood flow. Seventh, bioavailability F is the fraction of the administered dose reaching the systemic circulation unchanged: it is one for intravenous drugs and less than one for oral drugs because of first-pass hepatic and gut-wall metabolism. Eighth, the clinical relevance is direct: target-controlled infusion of propofol and remifentanil is built on compartment models, and the context-sensitive half-time explains why remifentanil allows rapid, predictable recovery regardless of infusion duration. Built on the foundational clearance papers (Rowland, Benet and Graham 1973; Wilkinson and Shand 1975; Pang and Rowland 1977; Benet 2010), the opioid pharmacokinetic analysis (Shafer and Varvel 1991), the context-sensitive half-time paper (Hughes, Glass and Jacobs 1992), the remifentanil pharmacokinetic study (Egan 1993), the measured context-sensitive half-times of remifentanil and alfentanil (Kapila 1995), and the propofol pharmacokinetic models used in target-controlled infusion (Marsh 1991; Schnider 1999).