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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