2006B03 Describe the factors which contribute to the inter-individual variability in drug
response seen with intravenous induction agents.

 

List:

·     Intro

·     Kinetics/biophasics

·     Dynamics

 

Intro:

IV induction drugs

·     Propofol: 1-2mg/kg

·     Thiopentone: 3-7mg/kg

·     Ketamine: 1-2mg/kg

·     Etomidate: 0.3mg/kg

·     Midazolam: 0.3mg/kg

Problems

·      The 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   Modelled by t1/2ke0

o   Mostly drug-dependent delay

Onset

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 (↑ke0 -> ↓t1/2ke0)

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

o  ↑Lipid solubility (e.g. thiopentone – t1/2ke0 1 min – hence clear endpoint)

o  ↑% Unionized (e.g. propofol >99% - t1/2ke0 2.6 mins)

Offset

Speed of offset ∝ distribution x metabolism x excretion

 

(A) Distribution ∝

·      ↑Cardiac output / compartment blood flow (as above)

·      ↑Compartment volume (↑obesity/bodybuilders, ↓cachexia)

·      ↑Compartment-to-blood partition coefficient

 

(B) Metabolism: rarely important after induction bolus

·      e.g. thiopentone: zero order kinetics -> hang-over effect

 

(C) Excretion rate: unimportant after induction bolus

·      e.g. ketamine: accumulation of norketamine metabolite in renal failure

 

Dynamics:

Time course

·      Dynamics = effect site concentration -> effect

o   Represented by dose response curve

o   Effect on brainstem, thalamus, cerebral cortex

o   Minimal delay

Physiology

·      Neonate: immature brain structures -> ↓Cp50

·      Elderly: ?↓ion channel function, ?↓ synaptic activity -> ↓Cp50

·      Pregnancy: progesterone -> ↓Cp50

·      Obesity: inflammatory cytokines -> ↓Cp50

·      Anxiety -> ↑SNS -> ↑Cp50

Pathology

↓Cp50 if:

·      ↓mAP (<40mmHg)

·      ↓pO2 (<40mmHg)

·      ↑pCO2 (>60mmHg sedation, >80mmHg anaesthesia if acute)

·      ↓Temp

·      ↓pH

↑Cp50 if:

·      ↑Temp

Drug interaction

·      Synergistic: e.g. fentanyl 1mcg/kg reduces dose of propofol by 20%

·      Additive: e.g. ↓propofol Cp50 co-induction with volatile agent

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

·      Antagonistic: e.g. propofol + acute amphetamine

·      Tolerance: e.g. chronic barbiturate use

Pharmacogenomic

·      e.g. propofol Cp50 for immobility is 15mcg/mL with std dev 5mcg/mL

·      Polymorphism of receptor structure and number, ion channels, ICF signalling

Idiosyncratic

·      Propofol: myoclonus in 10%

·      Thiopentone:  acute intermittent porphyria rarely

·      Etomidate: severe PONV common

·      Ketamine: post-op delirium in 30%

 

 

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