4. Inhalational Agents: Sevoflurane Flashcards
The Pharmacology of Sevoflurane
Physicochemical characteristics:
highly fluorinated hydrocarbon with the simple formula C4H3F7O.
boiling point 59 °C;
blood–gas partition coefficient 0.68;
minimum alveolar concentration (MAC50) 2.0%;
metabolism 3–5%.
Central nervous system effects:
sevoflurane is a hypnotic agent that can be used for
the induction and maintenance of general anaesthesia.
Theories about its mechanism
of action are detailed in the following.
Central nervous system effects:
sevoflurane is a vasodilator which increases cerebral blood flow
and may thereby affect intracranial pressure
it also decreases the cerebral metabolic rate and oxygen consumption (CMRO2).
t uncouples the relationship between cerebral blood flow and PaCO2
reduction in cerebral perfusion pressure
secondary to its cardiodepressant effects
degree of neuroprotection via
a process analogous to ischaemic preconditioning.
Effects on the electroencephalogram (EEG):
the changes are dose-dependent.
At low concentrations (at MAC less than 1.0),
sevoflurane (and the other volatile agents)
reduce power in the alpha range (waves of frequency 8–15)
increase it in the beta range (16–30 Hz).
There is thus a shift overall to greater frequencies
As anaesthesia deepens, however, the activity in these frequencies
decreases towards
the theta (4–7 Hz)
delta (<3 Hz) ranges.
At MAC greater than 2.0, all the volatile agents induce EEG burst suppression.
Respiratory effects
reduces alveolar ventilation by reducing tidal volume
accompanied by an increase in respiratory frequency
rise in respiratory rate and resultant increase in dead-space ventilation
leads to an increase in PaCO2,
->respiratory centres become less sensitive
reduces bronchial tone
not an airways irritant and is a forgiving agent inhalation induction
because even
high inspired concentrations rarely
provoke coughing, laryngospasm or breath-holding
Cardiovascular effects
acts both as a vasodilator which decreases systemic vascular resistance
as a myocardial depressant which reduces cardiac output
mean arterial pressure
minimally arrythmogenic but may prolong the
QT interval and so is best avoided in patients with +
congenital or acquired long QT syndrome.
Hepatic effects
: sevoflurane undergoes minimal metabolism (3–5%)
and is not degraded to antigenic trifluroacetic acid-protein complexes
(as happens with the metabolism of halothane).
It leads to a dose-dependent reduction in hepatic blood
flow secondary to its cardiovascular depressant actions.
Renal effects
negligible effects on renal physiology,
but because it is a fluorinated hydrocarbon,
it does produce inorganic fluoride ions sufficient to raise
serum fluoride levels in some subjects to more than 50 μmol l−1.
Although this is a level at which fluoride has been shown to cause polyuric renal failure (following
prolonged anaesthesia with methoxyflurane, for example),
it does not appear to be clinically significant when associated with sevoflurane administration, and the agent is not considered to cause renal toxicity.
Effects on the uterus
MH?
: sevoflurane causes a dose-dependent reduction in uterine tone.
Malignant hyperpyrexia: sevoflurane is a trigger agent
Compounds A and B
Compounds A and B:
sevoflurane reacts with strong monovalent hydroxide bases,
such as those which are used in soda lime and barium lime CO2 absorbers,
to produce a number of substances,
including compounds A (trifluoromethyl vinyl ether), B, D, E and G.
Only compound A has been shown to have any toxicity,
as it is degraded into a nephrotoxic metabolite.
(The reaction with barium lime is about five times more rapid than with soda lime.)
The dose-dependent renal damage noted in rats has never been seen in humans
despite many millions of administrations,
probably because of marked quantitative
differences in rodent enzyme systems.
Mechanisms of action:
the volatile agents act at the central neuraxial level
(brain as well as spinal cord); at axons and synapses;
and at the molecular level,
on pre- and post-synaptic membranes.
As a generalization about their overall mechanism of action,
however,
it appears that these agents acts as potent agonists at the GABAA and glycine
receptors and thereby inhibit the function of their post-synaptic ligand-gated ion
channels of the GABAA receptor
Mechanisms of action other
agents also act pre-synaptically
as antagonists to inhibit ion channel activity
mediated by serotoninergic, glutaminergic
and particularly the nicotinic acetylcholine receptors
They act at spinal cord level by diminishing nociceptive afferents
ascending to thalamo-cortical tracts. Hypnosis is
mediated at supraspinal level,
with the areas particularly influenced being the thalamus
and the reticular formation in the midbrain.
Cardioprotection: ischaemic and anaesthetic preconditioning
Ischaemic preconditioning describes the protective evolutionary process whereby tissues that are exposed to recurrent ischaemic, hypoxic or metabolic insults that injure, but do not kill,
the cells, are better able to tolerate a subsequent and much more severe event.
The cascade results in the modulation of myocardial mitochondrial
activity via activation of the ATP-sensitive potassium
channels, which are found on the nuclear, mitochondrial and sarcolemmal membranes
of cardiac myocytes,
activation of the mitochondrial permeability transition pore
leads finally to a reduction in
intracellular calcium and a fall in myocardial contractility
number of agents, particularly halogenated
inhalation anaesthetics, but also opioids, appear to trigger an analogous process, now
described as ‘anaesthetic preconditioning’.
The effect is initiated at MAC values as low
as 0.25 but is maximal at MAC 1.0–1.5.
Sophisticated studies have confirmed that
volatile agents prime some of these signalling pathways and initiate a cascade of
reactions with alterations in cardiac gene and protein expression
