4. Propofol Flashcards
Chemistry
Propofol is a substituted stable phenolic compound:
2,6-di-isopropylphenol.
It is highly lipid-soluble and water-insoluble and
is presented as either a 1% or 2% emulsion in soya bean oil.
Other constituents include egg lecithin (which is a phospholipid - Egg albumen
is antigenic, whereas egg lecithin is not.)
and glycerol
EDTA) reduces the risk of bacterial contamination.
weak organic acid with a
pKa of 11.
Mechanisms of action
enhances inhibitory synaptic transmission by activation of the Cl− channel
on the β1 subunit of the GABAA receptor
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inhibits acetylcholine release in areas such as the prefrontal cortex and parts of the limbic system.
inhibits the NMDA subtype of the glutamate receptor
Clinical uses
These include induction and maintenance of anaesthesia in adults and
children, sedation in intensive care and sedation during procedures
under local or regional anaesthesia.
Its anti-emetic effects can benefit chemotherapy patients when
given by low-dose infusion
Dose and routes of administration:
The drug is used only intravenously.
A dose of 1–2 mg kg−1 will usually induce anaesthesia in adults.
Children may require twice this dose.
TIVA infusion rates vary greatly,
but would typically range between 4 and 12 mg kg−1 h−1
(or 4–8 μg ml–1 effective site concentrations).
Propofol is an effective anti-emetic when given at a rate of 0.5–1.0 mg kg−1 hr–1
Onset and duration of action:
an induction dose of propofol will lead to rapid loss of consciousness
(within a minute).
Rapid redistribution to peripheral tissues (distribution
half-life is 1–2 minutes) leads to rapid awakening
Pharmacokinetics
Propofol is highly protein-bound (98%) and has a large volume of distribution (2–10 l kg−1).
As is frequently the case given the heterogeneity of human subjects,
the reported pharmacokinetic data vary considerably with its distribution
half-life quoted at between 1 and 8 minutes and the elimination half-life at
4–12 hours.
It has a relatively short context-sensitive half-life which is quoted as
being 40 minutes after infusions of duration up to 8 hours,
which therefore makes it a suitable drug for total intravenous anaesthesia.
Its metabolism is mainly, although not exclusively, hepatic,
with the production of sulphate and glucuronide conjugates
and other inactive metabolites which are excreted in urine.
Main Effects and Side Effects
CNS: propofol causes CNS depression and hypnosis.
CMRO2 is decreased, as are cerebral blood flow and intracranial pressure.
It may be associated with excitatory effects and dystonic movements,
particularly in children.
Hiccups are common after rapid injection.
higher doses it is an effective anti-convulsant, so most
anaesthetists ignore the data sheet assertion that it is contraindicated in patients with
epilepsy.
Cardiovascular system:
Systemic vascular resistance and preload fall,
yet it is relatively unusual to see compensatory tachycardia.
Relative bradycardia is more common.
Propofol is a myocardial depressant, partly via the inhibition of calcium
channels, so the reduction in contractility also reduces oxygen demand.
Respiratory system:
Propofol is a respiratory depressant which also suppresses laryngeal reflexes.
(Without this attribute it is unlikely that the use of the laryngeal
mask airway would have become so well established. According to the inventor of the
device, Dr Archie Brain, his early demonstrations using thiopental for induction did
not go at all well.)
Gastrointestinal system
: when given by infusion (at a rate of 0.5–1.0 mg kg hr–1) the
drug attenuates chemotherapy-induced emesis.
Other side effects:
propofol causes pain on injection.
Preparations which include medium-chain triglycerides in the formulation have reduced this problem.
Longterm infusion, particularly in children but also in adult critical care patients, has been
associated with ‘propofol infusion syndrome’.
The data sheet for propofol states that it should not be used in pregnancy, but this increasingly is ignored, and many maternity units routinely use propofol for general anaesthesia for caesarean section.
PRIS
In severe cases this is characterized by
hyperlipidaemia,
profound metabolic acidosis and
rhabdomyolysis which can lead to
renal and cardiac failure.
The syndrome may be due to effects on mitochondria,
either by direct inhibition of the respiratory chain of oxidative phosphorylation or by
compromising mitochondrial metabolism of free fatty acids.
This remains unproven.
It is recommended that infusions should be limited to no more than a rate of 4 mg
kg–1 h–1, although this does not eliminate the risk of the syndrome.
Miscellaneous
: propofol is not a trigger for malignant hyperpyrexia, and it may also
be used safely in patients with porphyria.
It does not release histamine, and adverse reactions are very rare.
It does not have any marked modulating effects on the
immune system. (This is in contrast to volatile anaesthetics).
Target-controlled infusion (TCI) and total intravenous anaesthesia (TIVA)
+
good recovery characteristics,
avoidance of inhalational agents and their pollution,
less nausea
cardiostability.
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risk of awareness,
linked to the wide variability between subjects,
the complexity and cost of equipment and
the importance of secure intravenous access
Suitability of Propofol as an Agent for TCI
It is a highly lipophilic hypnotic that distributes rapidly from blood to the effector
site. It then undergoes further rapid redistribution to muscle and fat before being
metabolized.
The initial distribution half-life, α, of propofol is short (2–3 minutes), whereas
intermediate distribution, β1, takes 30–60 minutes. The terminal phase decline, β2,
is less steep and takes 3–8 hours. The immediate volume of distribution is 228
ml kg−1, but the steady state volume of distribution in healthy young adults is around
800 litres.
CSH
Clearance: the whole body clearance of propofol is 2,500 ml min−1.
