2009B02 What are the potential side effects of propofol and its formulations?

 

(a.k.a. non-ideal features)

 

List:

·     Intro

·     Pharmaceutics

·     Pharmacokinetics

·     Pharmacodynamics: CNS, CVS, resp, other

 

Pharmaceutics: adverse effects

Ingredient

mg/mL

Function

Side effect

Soybean oil

100

Solvent: oil in water emulsion

·  Bacterial contamination:

o Discard if open >6 hours

o Finish infusion by 12 hours

·  Lipotoxicity

·  Propofol infusion syndrome

o Mitochondrial dysfunction

o Lactic acidosis, bradycardia arrest

o Rare

o Mainly in unwell children)

 

(Alternative solvents: liposomes, medium chain TAG, cyclodextrins)

Glycerol

22.5

Tonicity

 

Egg lecithin

12

Emulsifier

·  Very low risk anaphylaxis (protein deplete)

Disodium edetate

0.5

Antimicrobial

 

NaOH

Tiny

Adjust pH

 

Unknown

 

 

·  Pain on injection: ? cause

 

Pharmacokinetics:

Absorption

·  IV cf inhaled: risk of indefinite accumulation

Distribution

·  Large VDSS -> slow offset after long infusion

·  Small, lipid soluble, unionized -> rapid placental transfer

Metabolism / excretion

·  Quinol metabolite -> green hair and urine

Modelling

·  Unable to measure plasma concentration clinically

·  Unable to measure effect site concentration

 

Central nervous system:

Narrow therapeutic index

i.e. sedation <-> general anaesthesia

·  Risk of airway obstruction, apnoea

·  Inappropriate for untrained staff to administer propofol sedation

Excitatory phenomena

·  Myoclonus/hiccough occurs in 10%

o ? Differential effect on excitatory and inhibitory neurons

o ? Loss of cortical inhibition

o ? Disrupted dopaminergic/cholinergic signalling in subcortex

·  Note: no EEG evidence of seizure

·  Note: propofol is intrinsically anticonvulsant

Cerebral hypoperfusion

CPP = mAP – (CVP or ICP)

·  ↓mAP may be greater than ↓ICP or ↓CVP

·  Problem partly offset by ↓CMRO2

Euphoria

·  ↑Dopamine discharge at subanaesthetic dose

·  Risk of addiction, dependence

Delirium

·  Higher risk in the elderly

·  ? Cause

Other

·  No antidote available

 

Cardiovascular:

Mechanisms

·  Inhibit L-Ca2+ channel (↓L-Ca2+)

·  ↑Nitric oxide release (↑NO)

·  ↓SNS output from medulla due to ↑GABA activity (↓SNS)

Clinical effects

·  ↓Venous tone, ↓venous return, ↓preload (major effect)

·  ↓Heart rate, ↓contractility

·  ↓SVR, ↓afterload (most important effect)

·  ↓Cardiac output

·  ↓mAP

·  ↓Organ perfusion (e.g. oliguria)

At risk organs:

·  Below autoregulatory threshold mAP (e.g. <70mmHg for kidney)

·  Pressure-passive organ (e.g. placenta)

·  Poorly tolerates ischaemia (e.g. brain)

At risk patients:

·  Poor autoregulation

o Elderly

o Atherosclerosis

·  Minimal reserve

o Shock

o LV failure

 

Respiratory:

Respiratory depression: mechanism

·  ↑GABA -> suppress medulla resp centre and spinal motor neurons

Respiratory depression: clinical effects

·  ↓RR, ↓VT

·  Risk apnoea at induction

·  ↓Response to ↑PaCO2 and ↓PaO2

·  Synergistic resp depression with BDZ and opioids

↓Airway reflexes

·  ↑Risk aspiration if unprotected airway

↓Pharyngeal dilator tone

·  ↑Risk obstruction

·  Very common if OSA

↓HPV

·  Vasodilatation -> universal ↓PVR -> worse V/Q matching

·  Relatively preserved cf. volatile anaesthetics