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

· Kinetics/dynamics

· Dynamics

· Special populations

Intro:

IV induction agent

· Induces LOC in one arm-brain circulation time (30sec in adult)

o Propofol: 1-2mg/kg

o Thiopentone: 3-7mg/kg

o Ketamine: 1-2mg/kg

o Etomidate: 0.3mg/kg

o Midazolam: 0.3mg/kg

Problems

· Three compartment model poorly describes induction kinetics

· Variable relationship between dose and concentration (= kinetics)

· Variable relationship between concentration and effect (= dynamics)

Implications

· Risk of overdose -> hypotension

· Risk of underdose -> risk of awareness

· Propofol TCI models are inaccurate at induction

Pharmacokinetics / pharmacobiophasics:

Time course

· Kinetics = administration -> plasma concentration (Cp)

o Three compartment model inaccurate

o Mostly patient-dependent delay

· Biophasics = plasma concentration -> effect site concentration (Ce)

o Represented by t_1/2ke0

o Inferred from lag between ∆Cp and ∆EEG pattern

o Mostly drug-dependent delay

Determinants

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

(A) Magnitude of peak effect ∝

· ↑Dose size

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

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

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

· ↑Speed and extent of recirculatory second peak (important if bolus is slow)

(B) Time to peak effect ∝

· ↑Rate of delivery to effect site

o ↑Cardiac output (note bivalent effects)

o ↓Distance from injection site to brain (e.g. CVC cf. lower limb PIVC)

· ↑Rate of effect site equilibration (↑k_e0 -> ↓t_1/2ke0)

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

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)

Dynamics:

Time course	· Dynamics = effect site concentration -> effect o Represented by dose response curve o Effect on brainstem, thalamus, cerebral cortex o Bind receptor -> activate receptor -> ion flux -> ↓membrane potential -> ↓electrical activity -> LOC o Minimal delay
Physiology	· Neonate: immature brain structures and pathways -> ↓Cp₅₀ · Elderly: ?↓ion channel function, ?↓ synaptic activity · Pregnancy: progesterone -> ↓Cp₅₀ · Obesity: inflammatory cytokines -> ↓Cp₅₀
Pathology	↓Cp₅₀ if: · ↓mAP (<40mmHg) · ↓pO₂ (<40mmHg) · ↑pCO₂ (>60mmHg sedation, >80mmHg anaesthesia if acute) · ↓Temp · ↓pH ↑Cp₅₀ if: · Anxiety, ↑SNS · ↑Temp
Drug interaction	· 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	↑	↑