2002A10 Outline the factors that determine recovery (offset of action) after ceasing a drug infusion.

Determinants

·   Final Ce at end of infusion

·   Rate of removal from effect site

·   Rate of elimination from central compartment

·   Threshold Ce for offset of effect

Compartment model

Infusion

·   ↓Duration

·   ↓Rate of admin

Drug

·   ↑Tissue:blood partition coefficients

·   ↑Clearance

Patient

·   ↑Cardiac output

·   ↑Tissue volumes

Fick’s law

↑Diffusion coefficient

(i.e. k_e0)

·   ↑Lipid solubility (e.g. fentanyl:morphine = 600:1)

·   ↓Molecular weight (e.g. propofol 178Da)

·   ↑%Unionised (e.g. propofol 98% at pH 7.4)

Short infusion

Offset during distribution phase

·   ↑Cardiac output

·   ↑Volume of distribution (e.g. fentanyl faster than alfentanil)

Long infusion

Offset during terminal elimination phase

·   ↓Cardiac output

·   ↓Volume of distribution (e.g. alfentanil faster than fentanyl)

·   ↑Metabolism (e.g. remifentanil faster than all)

·   ↑Excretion of drug or active metabolite

Opioid examples

Patient factors

·   Individual variability: e.g. ↑opioid sensitivity in elderly, neonate -> ↓Ce₅₀

·   Tolerance: e.g. chronic opioids -> receptor downregulation -> ↑Ce₅₀

Drug interactions

·   Synergistic: e.g. midazolam + propofol synergism -> ↓Ce₅₀ for both

·   Additive: e.g. propofol + sevoflurane -> ↓propofol Ce₅₀

Prolonged drug effect

·   Second messenger effects (e.g. NAd reuptake immediate, but offset 3-5 mins)

·   Genetic effect (e.g. ketamine -> ↓synaptic reinforcement -> ↓long term potentiation)

·   Irreversible binding (e.g. salicylic acid t_1/2β 3 hours, duration 7 days)

·   Prodrug (e.g. dabigatran -> dabigatran etexilate)

·   Active metabolites (e.g. desmethyldiazepam t_1/2β 100 hours -> long duration)