Anaes · Applied cardiovascular & respiratory physiology
Pharmacokinetics: compartment models
Also known as Pharmacokinetics · Compartment model · Volume of distribution · Clearance · Half-life · Redistribution
Pharmacokinetics describes what the body does to the drug — absorption, distribution, metabolism and excretion — and the compartment model is the mathematical framework that predicts drug concentration over time. The framework rests on five exam-critical ideas: the body is modelled as connected compartments (the central compartment of plasma and well-perfused tissues, a fast peripheral compartment of muscle, and a slow peripheral compartment of fat) between which the drug distributes and redistributes; the volume of distribution (Vd) is the apparent volume that would contain the total drug at the plasma concentration — a large Vd means the drug has left the plasma for the tissues (lipophilic drugs); clearance (CL) is the volume of plasma cleared of drug per unit time, and is the main determinant of the maintenance infusion rate; the elimination half-life (t1/2) is the time for the plasma concentration to fall by 50 percent, determined by Vd and CL (t1/2 equals 0.693 times Vd over CL); and redistribution from the peripheral compartments back to the central compartment is the mechanism by which a single IV bolus of thiopental or propofol wears off — the drug has not been metabolised, it has redistributed to muscle and fat, dropping the brain concentration below the effect threshold. Built on the Marsh-Schnider PK-PD comparison study (Ye 2026), the four-model propofol comparison study (Introna 2026), the paediatric melatonin PK study (de Barros Garioud 2026), the remimazolam PK review (Dong 2025), the LC-MS/MS propofol assay study (Ng 2026), and the body-size PK virtual trial (Marques 2026).
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- The three-compartment model is the standard for IV anaesthetic agents: the central compartment (V1, plasma and vessel-rich tissues), a fast peripheral compartment (V2, muscle) and a slow peripheral compartment (V3, fat). Redistribution from V2 and V3 back to V1 is the mechanism of recovery from a single IV bolus of thiopental or propofol — the drug has NOT been metabolised, it has redistributed.
- Volume of distribution (Vd) is an APPARENT volume — a Vd larger than total body water means the drug has accumulated in tissue (lipophilic drugs like propofol, thiopental, fentanyl). A Vd near the plasma volume means the drug stays in the blood (polar, protein-bound drugs).
- Clearance (CL) is the volume of plasma cleared per unit time (mL per min); the maintenance infusion rate equals the target plasma concentration times CL. Half-life (t1/2) equals 0.693 times Vd divided by CL — so a large Vd (fat-soluble drug) or a small CL (slow metabolism) both lengthen the half-life.
- Context-sensitive half-time (CSHT) is the time for the plasma concentration to fall by 50 percent AFTER stopping an infusion of a given duration — it is NOT the same as the terminal half-life. For drugs with large Vd (fentanyl, thiopental), the CSHT increases dramatically with infusion duration (accumulation in peripheral compartments).
- Target-controlled infusion (TCI) uses a pharmacokinetic model (Marsh, Schnider, Eleveld) to compute the infusion rate that achieves and maintains a target effect-site concentration — the model is a PREDICTION, not a measurement; individual variability means the actual concentration may differ.
Meet the patient
A 78-year-old, 110 kg man arrives for an emergency laparotomy. You induce with propofol and run a propofol-remifentanil total intravenous anaesthesia infusion for four hours. The processed EEG shows a deeper trace than the displayed effect-site concentration predicted, and emergence is slow. The pump showed plausible numbers throughout — so why is the patient still asleep?[1]
The two questions that decide every TIVA case are the two this topic answers: where did the drug go? (the compartments and Vd), and how fast does it leave? (clearance and the context-sensitive half-time). The pump is a model, not a measurement — and the model assumes a typical patient this one is not.[1]
References6ShowHide
- [1]Ye J, et al. A Prospective Study of Marsh PK-PD Model and Schnider PK-PD Model During Anesthesia Induction for Obese Patients Undergoing Elective Heart Surgery Pharmacol Res Perspect, 2026.PMID 42286797
- [2]Introna M, et al. Target concentrations of propofol predicted by four different pharmacokinetic/pharmacodynamic models to induce loss of consciousness in neurosurgical patients J Anesth Analg Crit Care, 2026.PMID 42231496
- [3]Garioud ALB, Afshari A, Halgreen LR, et al. Pharmacokinetics of Intravenous Melatonin in Preschool-Aged Pediatric Surgical Patients Paediatr Anaesth, 2026.PMID 42325096
- [4]Dong Y. Remimazolam in anesthesia and sedation: A narrative review J Anesth Transl Med, 2025.PMID 41929379
- [5]Ng MKL, et al. Development and Application of an LC-MS/MS Assay for Plasma Propofol Quantification in Major Noncardiac Surgical Patients to Evaluate Target-Controlled Infusion Algorithms Ther Drug Monit, 2026.PMID 42214089
- [6]Marques L, et al. Model-Based Virtual Clinical Trial Reveals Renal Impairment and Body Size as Key Determinants of Pharmacokinetic Variability and Drug-Drug Interaction Risk in Propranolol Therapy Pharmaceutics, 2026.PMID 42357253