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Context-sensitive half-time, effect site and Keo

Get to grips with the basic nitty-gritty PK terminology required for a better understanding of the models.

Context-sensitive half-time (CSHT)

  • The time for the plasma concentration (and effect-site concentration) to decrease by 50% after stopping an infusion maintaining a constant plasma concentration
  • The “context” is the duration of that infusion for a drug fitting a multi-compartment model
  • CSHT almost always increases with time (remifentanil is a rare exception as it is metabolised rapidly by cholinesterases in the blood of which there is a ubiquitous supply)
  • Redistribution to the peripheral compartments contributes to the initial drop in the central compartment concentration
  • As peripheral compartments become full (saturated), the cessation of drug effect will depend more on metabolism and elimination from the central compartment. Fentanyl is a good example of this – with short infusions (up to an hour), it wears off quite quickly but this then becomes markedly prolonged.
  • Propofol has an elimination half-life of several hours but wears off quickly after stopping an infusion. This is because central compartments drop with redistribution, rather than metabolism.

Effect-site & keo

  • There is always a delay in effect after achieving a certain drug concentration in the central compartment
  • The effect site is the site of drug action e.g. if this was a beta blocker it would be the heart and the effect would be a decrease in heart rate. With anaesthetics and opioids this will be the CNS and the effect will be consciousness or analgesia
  • A blood-effect equilibrium constant, Keo, is used to describe the delay in clinical effect
  • Often the term “time to peak effect” is used to reflect how long it takes for a drug to act. This, of course, will depend on various factors including Keo
  • The effect compartment has an extremely small volume so it has no influence on the PK model
  • The time lag and the Keo can be estimated from measurement of clinical effects e.g. EEG or auditory evoked potentials for anaesthetics.
  • The Keo affects the speed at which the effect will be obtained
  • The smaller the Keo the longer the time lag between equilibrium being achieved between the plasma and effect-site compartments
  • Keo is critical in effect-site targeting which will be explained later this week. This is crucial and may have led to inaccuracies in effect site targeting with certain models e.g. Schnider
  • The Keo is drug-specific and different Keo may be applied in different models
    • Each drug and the PK models used to describe drug behaviour have their own Keo.
    • Keo may also vary between patients
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Introduction to Using Total Intravenous Anaesthesia (TIVA)

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