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

 

List:

·      Intro

·      Intravenous induction agents

·      Pharmacokinetics: ADME

·      Pharmacodynamics: global↓, tolerance, polymorph, drug interactions, physiology, pathology

 

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

·  Variable relationship between dose and concentration

·  Variable relationship between concentration and effect, particularly mobility

·  Variable duration of effect from induction bolus

Implication

·  Risk of overdose -> hypotension

·  Risk of underdose -> risk of awareness

 

Induction kinetics:

Onset time

Time to LOC peak Cp / time to peak Cp

 

(A) Peak Cp

·   Dose size

·   Speed of injection (bolus cf. TCI injection)

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

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

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

 

(B) Time to peak Cp

·   Cardiac output (note bivalent effect)

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

Offset time

Time to offset of bolus: distribution rate x metabolism rate x excretion rate

 

(A) Rate of distribution

·   Cardiac output / compartment blood flow (as above)

·   Compartment volume (e.g. obesity ↑)

·   Compartment: blood partition coefficient

(B) Metabolism rate: rarely important

·   e.g. ↓phase 1 reactions -> metabolism-limited clearance (e.g. thiopentone)

·   e.g. cirrhosis/shock -> ↓flow-limited clearance (e.g. propofol)

·   Polymorphism of CYP450 enzymes: varied drug metabolism rate

·   Enzyme induction (e.g. cimetidine) -> ↑metabolism (e.g. barbiturates)

·   Enzyme inhibition (e.g. amiodarone) -> ↓metabolism

(C) Excretion rate: rarely important

·   Renal failure -> accumulate small/hydrophilic substances (e.g. norketamine, α-OH-midazolam)

·   Liver failure -> ↓bile secretion -> accumulate large/hydrophobic substances

 

Biophasics:

Peak Ce

equilibration rate / distribution rate

-Equilibration rate

Rate

·   C1

o ↑Peak Cp (as above)

o % Cardiac output to brain (↑: neonate, elderly, shock)

·   Diffusion coefficient (i.e. ke0) – examiner seemed interested in drug differences

o ↑Lipid solubility

o ↑%Unionised

§ ↓[Plasma proteins] e.g. neonate, elderly, pregnant, obese

§ ↓pH if acidic (thiopentone high risk ): e.g. neonate, shock

§ ↑pH if basic

o ↓Molecular weight

-Distribution rate

Rate

·   Cardiac output, compartment blood flow (see above)

·   Compartment volume (see above)

Compartment solubility

Representation

Ce/dt = k1e x Cp – ke0 x Ce

Examples: t1/2ke0

·   Ketamine 0.5 mins

·   Thiopentone 1 min

·   Etomidate 1.5 mins

·   Propofol 2.6 mins

·   Midazolam 4 mins

 

Dynamics:

Physiology

·   Neonate: immature brain structures and pathways -> ↓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 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 amphetamine

·   Tolerance: e.g. chronic barbiturate use -> ↑Cp50 hypnosis

Pharmacogenomic variation

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

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

Idiosyncratic effects

·   Propofol: myoclonus in 10%

·   Thiopentone:  acute intermittent porphyria rarely

·   Etomidate: severe PONV common

·   Ketamine: post-op delirium in 30%

 

 

 

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