Ep 2 – Propofol for the FRCA Primary

Contents

• Propofol is the most commonly used anaesthetic induction agent in UK healthcare
• What is Propofol?
• Propofol Pharmacology
  • Pharmacodynamics of Propofol
  • Pharmacokinetics of Propofol
• What is Propofol Infusion Syndrome?
• Core Concept
• Application clinically.
• References

Propofol is the most commonly used anaesthetic induction agent in UK healthcare

Its Utility is endless, used for induction of anaesthesia (where it massively reduces laryngeal reflexes), maintenance of anaesthesia, procedural sedation in theatre and in other hospital areas (ED/ cardioversion etc) and also to maintain sedation on critical care, it can solve laryngospasm, emergence delirium and possibly even ‘status migranosus’ although it does cause a spot of unconsciousness….

You will already be or will soon be very familiar with 2,6 diisopropyl phenol!

What is Propofol?

Propofol is a short-acting intravenous anesthetic agent used for the induction and maintenance of general anesthesia. It acts by enhancing GABAergic inhibition in the central nervous system, leading to sedation and hypnosis.

Propofol Pharmacology

• Name – Propofol
• Class – Phenol Derivative
• Chemical name – 2,6 di-isopropyl phenol
• Colour / appearance – White Opaque Liquid
• Additives – Egg Phosphatide and Soy Bean Oil
• Presented in 20 ml, 50ml or 100ml ampoule/bottle – Concentration 1 or 2 %
• Dose & route : Intravenous 1 – 2 mg/kg – Plasma conc. of 4-8 mcg/ml maintains anaesthesia
• History – Brough to market in 1986!

Pharmacodynamics of Propofol

• Mechanism: Potentiates endogenous GABA, although true mechanism not fully clear
• Actions: Hypnosis that is dose dependent – Will terminate epileptic seizure activity.
• Onset and Offset times: Onset is greater than one arm brain circulation – Offset is dependent on infusion time, a bolus dose will redistribute and offset within 10 minutes, clearance dependent on cardiac output, chiefly hepatic, but some renal too.

Side effects of Propofol

• CVS: Sympathetic inhibition – dropped venous tone – less pre load, dropped arterial lone, less SVR.
  • Cardiac output remains somewhat unaltered as these changes facilitate forward flow. But perfusion pressure across the system drops. It causes some myocardial negative inotropy but barely.
  • Arterial Vasodilation , myocardial depression, very rarely bradycardia
• RESP: Apnoea, laryngeal reflex obtundation, some bronchodilation
• CNS: coma, reduced cerebral o2 demand, reduced ICP/IOP Up to 10% can have paradoxical excitatory movements.
•  Due to inhibition of inhibitory structures, I think of it like, the drug doesn’t get to all the bits of the brain at the same rate, and parts are probably more susceptible than other parts.
• Metabolic : Infusion syndrome. High triglycerides, metabolic acidosis, arrythmias, renal failure, rhabdomyolysis
• Others: Pain on injection

Pharmacokinetics of Propofol

Absorption Not relevant as IV, note arterial injection is not a disaster – just onset time prolonged.

Propofol Distribution

• VOD 4 L/KG (highest of any induction agent) 
• Protein binding 98%   
• pKa 11 – 98% unionised at pH7.4
• Rapid redistribution occurs due to its lipid solubility, (it quickly gets into the brain) but as plasma levels drop it will begin to equilibrate across multiple tissues and organ systems and the CNS concentration will decline to sub clinical levels.

Propofol Metabolism

• Half-life 9.3 – 60 mins
• Liver metabolism to non active metabolites that are really cleared 40% conjugated to glucuronide and 60% metabolised to quinol which gets sulphated and excreted in urine
• Clearance exceeds hepatic blood flow suggesting some extra hepatic metabolic effects.

Elimination – Clearance 18.8 – 40.3 ml/kg/min

Noteables

• Long infusions exhibit progressively lengthening context sensitive half times – think, if you have managed to fill their fat stores which takes time to get in and time to get out.
• In kiddies – it appears that they are more prone to propofol infusion syndrome and its considered somewhat contraindicated in sub 16 year olds for PICU sedation
• Intra arterial injection leads to slower onset times, but no particular sequelae.

What is Propofol Infusion Syndrome?

Aka PRIS, an over zealous and prolonged infusion of propofol can lead to a state of significant metabolic derangement, where the electron transport chain in the mitochondria struggles to function,( at least this is demonstrated in animal models on all 4 elements of the electron transport chain I, II, III and IV) There are a few suggested mechanisms, but it appears that the propofol impersonates co-enzyme Q and this is critical for mitochondrial function.

It results in a developing metabolic acidosis, hyperkalaemia, rhabdomyolysis, and subsequent renal failure.

Can get Brugada like ECG changes (Coved T-wave with STE)

It is notably a cause of green urine (quinol, the metabolic product of propofol metabolism is has a green hue???

Blood tests should check creatinine kinase alongside plasma triglycerides

The state can be predicted based on the dosing to body weight that occurs, and monitoring plasma triglycerides can go some way to act as a warning sign of excess.

Prolonged infusion should not exceed 4mg/kg/hour

Historic fatality appears to be around 35% (earlier in time was very high, on negative trend)

This happens with propofol, and not with equivalent intralipid dosages (but remember high lipids can trigger a acute pancreatitis)

Treatment = stop the drug, supportive treatment

Core Concept

Ionisation has relevance across many different drugs. check out the PKA episode for the full low down!

The core of it, an ionised drug is unable to cross the fatty membranes that encapsulate cells, of the CNS / PNS

Therefore the degree of ionisation relates to how prompt to act a drug might be, the greater the unionised fatty soluble fraction the quicker it diffuses to where it needs to go.

There is an intrinsic balance of the molecule between these two states that is dictated by the environment within which it exists, the main factor that influences this is the pH. (The negative log of the concentration of hydrogen ions in a system/solution.)

And the way this ratio / balance is described in pharmacology is the pKa of the drug.

In a hypothetical system a drug with a pKa of 7.35 will, have a 50:50 mix of ionised to unionised molecule if the system is at pH 7.35

If you imagine a membrane that has a different pH environment on one side vs the other,

And have a drug that becomes unionised in acidic environments, it can cross the membrane, become ionised again and loose its ability to escape back across the membrane. (some drugs exhibit ion trapping on the fetal side of the placenta which is a more acidic realm)

Application clinically.

Starting out – work out a dose and see if it works…. Can always give more and in big ‘rugby’ lads, alcoholics who are not drunk or those with other alternative life styles, always worth having a second syringe drawn up.

Is synergistic with other sedating agents – midazolam, fentanyl clonidine/dexomedetomidine

And is often given alongside ketamine to stop a patient ‘having their eyes open when they shouldn’t when you’ve GA’d with ketamine…… ‘

TCI and TIVA is the future!

In resus once a patient is intubated, often starting at 10ml an hour of propofol and ramping it up as able into the 20s, as it takes a fair while to reach steady state if there is not a loading bolus. This approach does carry an increased risk of awareness, and in non-obtunded poorly patients you would run the risk of this. Remember depth of anaesthesia depends on the level of patient consciousness and the level of drug administered. Someone who was GCS 3 from an opiate overdose, will need initially fairly sparse amounts of propofol, but as the agent wears off you must escalate propofol. you do not want someone waking up 2 hours later and self-extubating on ITU whilst you are busy elsewhere!

What is that Propofol TCI formula??

TIVA protocol when you’ve not got a PK Pump with Schneider/Marsh/Eleveld

• 10 mg kg/h for 10 min,
• 8 mg kg/h for a further 10 min
• Then Continuous infusion of 4-6 mg kg/h

In Neuro head injured type patients, get them deep (30ml/hour propofol) and expect to be starting a metaraminol infusion alongside – the goal is to turn off their brain, and if you put a BIS on, you might be surprised at how not deep a fit young person is! Watch how much propofol you get through using Marsh Tiva on a 30 year old ! (although the counter point here is, a sedated extra dural patient who is being transferred, is yet to have a surgeon operating on them)

Great Drug, excellent obliteration of laryngeal reflexes, makes LMA/SGA/Auragain insertion very manageable (if you tried it with thiopentone, it would not go so well), if you’re interested Check out the Thiopentone Episode too!

References

Krajčová, A., Waldauf, P., Anděl, M. et al. Propofol infusion syndrome: a structured review of experimental studies and 153 published case reports. Crit Care 19, 398 (2015). https://doi.org/10.1186/s13054-015-1112-5