2015A12 Describe the time course between an intravenous injection of a general
anaesthetic agent to loss of consciousness. Explain the delay using pharmacokinetic principles.

 

(note examiners expected discussion of pharmacodynamic concepts also)

 

List:

·      Intro

·      Kinetics

·      Biophasics

·      Dynamics

·      Induction kinetics

·      Special populations

 

Intro:

IV induction agent

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

Putative effect site

·   Brainstem (ascending reticular activating system)

·   Thalamus

·   (Frontal) cortex

Threshold

·   Critical effect site concentration exists for each drug

·   e.g. propofol 2-3mcg/mL

·   Varies between patients

·   Differs between induction and emergence within patients

Determinants: time to LOC

·   Pharmacokinetics: dose -> Cp

·   Pharmacobiophasics: Cp -> Ce

·   Pharmacodynamics: Ce -> effect

 

Kinetics: compartment model

Modelling

Cp = dose / volume of central compartment

·   Loading dose = Cpt x VDC (note: not VDSS)

·   At 70kg, VDC 0.45L/kg, Cpt 4mcg/mL, dose = 126mg

·   Note poor correlation with actual Cp

Representation

·   Tri-exponential decay curve

 

Biophasics:

Modelling

Peak Ce equilibration rate / distribution rate

-Equilibration

Rate

·   C1

o ↑Peak Ca (as above)

o % Cardiac output to brain

·   Diffusion coefficient (i.e. ke0)

o ↑Lipid solubility (e.g. ketamine 5-10x thiopentone)

o ↑%Unionised (e.g. propofol >99% unionized at pH 7.4)

o ↓Molecular weight

-Distribution

Rate

·   Cardiac output, compartment blood flow (e.g. ↑pregnant/neonate, ↓elderly/shock)

·   Compartment volume (e.g. ↑obesity/athlete, ↓cachexia)

·   Compartment solubility

Representation

Ce/dt = k1e x Cp – ke0 x Ce

Examples: t1/2ke0 (mins)

·   Ketamine 0.5

·   Methohexital 1

·   Thiopentone: 1.2

·   Etomidate 1.5

·   Propofol 2.6

·   Midazolam 5

 

Dynamics:

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 hypnotic dose of propofol by 20%

·   Additive: e.g. ↓Cp50 for propofol if co-induction

·   Infra-additive: e.g. ketamine + midazolam

·   Antagonistic: e.g. propofol + acute amphetamines

·   Tolerance: chronic barbiturate use -> ↑Cp50

Pharmacogenomic variation

·   e.g. propofol: Cp50 for immobility is 15mcg/mL with standard deviation of 5mcg/mL

·   Polymorphism of receptors, ion channels, ICF signalling

Representation

E = (E0 + Emax x Ceγ) / (EC50γ + Ceγ)

 

Induction-specific kinetics:

 

Time to LOC Peak Cp / (1/Time to peak Cp)

-Peak Cp

Concentration

·   Dose

·   Speed of injection (i.e. bolus cf. infusion)

·   1/Cardiac output

·   1/Central blood volume (Central blood volume total blood volume)

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

-Time to peak Cp

Time

·   1/Cardiac output (note bivalent effect)

·   1/Distance from injection site to heart

Representation

·   None yet!

 

Special populations:

 

Changes

TTPE

Peak Cp

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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