2020A13 Describe the time course between an intravenous injection of a general
anaesthetic agent to loss of consciousness. Explain the delay using pharmacokinetic principles.

List:

� Intro

� Summary

� Kinetics/dynamics

� Dynamics

� Special populations

Intro:

IV induction

� Agent induces unconsciousness in one arm-brain circulation time

� Unconsciousness occurs upon reaching a threshold concentration at the effect site, usually well before the peak

Problems

� Three compartment model poorly describes induction kinetics

� Variable relationship between dose and concentration

� Variable relationship between concentration and effect

Implications

� Risk of overdose -> hypotension

� Risk of underdose -> risk of awareness

� Propofol TCI models are inaccurate at induction

Summary:

Kinetics

� Delay = administration -> plasma concentration (Cp)

� Not well represented by the three compartment model

� Mostly patient-dependent delay

Biophasics

� Delay = plasma concentration -> effect site concentration (Ce)

� Represented by t1/2ke0

� Inferred by lag between ∆Cp and ∆EEG pattern

� Mostly drug-dependent delay

Dynamics

� Delay = effect site concentration -> effect

� Represented by dose response curve

� Effects on ionotropic receptors brainstem, thalamus, cerebral cortex

� Effects are virtually immediate

� Mostly threshold-dependent delay

Kinetic/biophasic determinants:

Graph

Speed of LOC ∝ (magnitude of peak effect) / (time to peak effect)

Magnitude of peak

Peak∝

� ↑Dose size

� ↑Speed of injection (bolus cf. TCI injection)

� ↓Cardiac output (↑pregnant/neonate/obese, ↓elderly/shock)

� ↓Central blood volume (↑pregnant/obese/neonate, ↓elderly/shock)

� ↑Recirculatory second peak (important if bolus is slow)

Time to peak

Speed ∝

� ↑Rate of delivery to effect site

o ↑Cardiac output (note bivalent)

o ↓Distance from injection site (e.g. jugular cf. foot)

� ↑Rate of distribution

o ↑Cardiac output (note bivalent)

o ↑Compartment uptake (e.g. ↑lipid solubility)

� ↑Rate of effect site equilibration

o ↑Lipid solubility (e.g. thiopentone: t1/2_ke0 1 min -> clear endpoint)

o ↑% Unionized (e.g. propofol >99%: t1/2_ke0 2.6 mins)

o ↓Thickness (e.g. immature BBB in neonate)

Pharmacodynamic determinants:

Physiological	� Neonate: immature brain structures and pathways -> ↓Cp₅₀ � Elderly: ?↓ion channel function, ?↓ synaptic activity � Pregnancy: progesterone -> ↓Cp₅₀ � Obesity: inflammatory cytokines -> ↓Cp₅₀
Pathological	↓Cp₅₀ if: � ↓mAP (<40mmHg) � ↓pO₂ (<40mmHg) � ↑pCO₂ (>60mmHg sedation, >80mmHg anaesthesia if acute) � ↓Temp � ↓pH ↑Cp₅₀ if: � Anxiety, ↑SNS � ↑Temp
Drug interactions	� Synergistic: e.g. fentanyl 1mcg/kg reduces dose of propofol by 20% � Additive: e.g. ↓propofol Cp₅₀ if co-induction with volatile agent � Infra-additive: e.g. ketamine + midazolam � Antagonistic: e.g. propofol + acute amphetamines � Tolerance: chronic barbiturate use -> ↑Cp₅₀
Pharmacogenomics	� e.g. propofol Cp₅₀ for immobility is 15mcg/mL with std dev 5mcg/mL � Polymorphism of receptors, ion channels, ICF signalling

Special populations:

	Changes	Time to peak	Magnitude of peak
Neonate	↑CO +100% ↑%CO to brain ↓Arm-brain distance	↓	↓
Pregnant	↑CO +25% ↓%CO to brain ↑BV 50%	↓	↓
Elderly	↓CO variable ↓BV variable ↑%CO to brain variable	↑	↑
Shocked	↓CO ↓BV ↑%CO to brain	↑	↑

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