Pharmacology of inhalational anesthetics
History
The discovery of the anesthetic properties of nitrous oxide, diethyl ether, and
chloroform in the 1840s was followed by a hiatus of about 80 years before other
inhaled anesthetics were introduced. In 1950, all available inhaled anesthetics were
either flammable or potentially toxic to the liver. Halothane was synthesized in 1951
and introduced for clinical use in 1956. However, the tendency for alkane derivatives,
such as halothane, to enhance the arrhythmogenic effects of epinephrine led to the
search for new inhaled anesthetics derived from ethers. Methoxyflurane, a methyl
ethyl ether, was the first such derivative, being introduced for clinical use in 1960.
Although this drug does not enhance the arrhythmogenic effects of epinephrine, its
extreme solubility in blood and lipids results in a prolonged induction and slow
recovery from anesthesia. More important, however, is the extensive hepatic
metabolism of methoxyflurane that results in elevations in plasma fluoride
concentrations sufficient to produce nephrotoxicity in some patients, especially if the
duration of administration exceeds 2.5 MAC hours. Enflurane, the next methyl ethyl
ether derivative, was introduced for clinical use in 1973. This anesthetic does not
enhance the arrhythmogenic effects of epinephrine and, unlike halothane and
methoxyflurane, is resistant to metabolism, thus minimizing the likelihood of
hepatotoxicity or nephrotoxicity. Isoflurane, the isomer of enflurane, was introduced
for clinical use in 1981. This drug is the most resistant to metabolism of all the
clinically available inhaled anesthetics, emphasizing the unlikely occurrence of organ
toxicity, following its administration.
Figure 1: inhaled anesthetics
Physical & chemical properties of inhalational agents (table 1 & figure
1)
Nitrous Oxide
Nitrous oxide is a low-molecular-weight, odorless to sweet-smelling, nonflammable
gas of low potency and poor blood solubility (0.46) that is most commonly
administered in combination with opioids or volatile anesthetics to produce general
anesthesia. Although nitrous oxide is nonflammable, it will support combustion. Its
poor blood solubility permits rapid achievement of an alveolar and brain partial
pressure of the drug. Analgesic effects of nitrous oxide are prominent, but skeletal
muscle relaxation is minimal. Increasing awareness of the possible adverse effects
related to the high-volume absorption of nitrous oxide and appreciation of potential
toxic effects on organ function, may lead to a decline in the use of this anesthetic.
Halothane
Halothane is a halogenated alkane derivative that exists as a clear, nonflammable
liquid at room temperature. The vapor of this liquid has a sweet nonpungent odor. An
intermediate solubility in blood, combined with a high potency, permits rapid onset
and recovery from anesthesia using halothane alone or in combination with nitrous
oxide or injected drugs such as opioids.
Despite its chemical stability, halothane is susceptible to decomposition to
hydrochloric acid, hydrobromic acid, chloride, bromide, and phosgene. For this
reason, halothane is stored in amber-colored bottles, and thymol is added as a
preservative to prevent spontaneous oxidative decomposition. Thymol that remains in
vaporizers following vaporization of halothane can cause vaporizer turnstiles or
temperature-compensating devices to malfunction.
Enflurane
Enflurane is a halogenated methyl ethyl ether that exists as a clear, nonflammable
volatile liquid at room temperature and has a pungent, ethereal odor. Its intermediate
solubility in blood combined with a high potency permits rapid onset and recovery
from anesthesia using enflurane alone or in combination with nitrous oxide or injected
drugs such as opioids.
Isoflurane
Isoflurane is a halogenated methyl ethyl ether that exists as a clear, nonflammable,
volatile liquid at room temperature and has a pungent, ethereal odor. Its intermediate
solubility in blood combined with a high potency permits rapid onset and recovery
from anesthesia using isoflurane alone or in combination with nitrous oxide or
injected drugs such as opioids.
Isoflurane is characterized by extreme physical stability, undergoing no detectable
deterioration during 5 years of storage or on exposure to soda lime or sunlight. The
stability of isoflurane negates the need to add preservatives such as thymol to the
commercial preparation.
Desflurane
Desflurane is a fluorinated methyl ethyl ether that differs from isoflurane only by
substitution of a fluorine atom for the chlorine found on the alpha-ethyl component of
isoflurane. Solubility characteristics (blood:gas partition coefficient 0.42 and oil:gas
partition coefficient 18.7) and potency (MAC 4.58%) permit rapid achievement of an
alveolar partial pressure necessary for anesthesia followed by prompt awakening
when desflurane is discontinued. The vapor pressure of desflurane at 20 C is 669
mmHg. The ratio of the fatal anesthetic concentration to that preventing movement to
a painful stimulation (MAC) for desflurane in animals is 2.45 compared with 3.02 for
isoflurane. Desflurane produces dose-related decreases in blood pressure and cardiac
output that range from similar to somewhat greater than those evoked by equivalent
doses of isoflurane. Infusions of epinephrine that provoke cardiac dysrhythmias
during administration of desflurane and isoflurane are similar. Metabolism of
desflurane is less than isoflurane, and the likelihood of organ damage from toxic
metabolites seems remote. Indeed, plasma fluoride concentrations and renal or hepatic
function tests do not change following inhalation of desflurane for about 90 minutes.
Sevoflurane
Sevoflurane is a fluorinated methyl ethyl ether with a vapor pressure of 170 mmHg at
20 C. Solubility characteristics (blood:gas partition coefficient 0.59 and oil:gas
partition coefficient 55) and potency (MAC 1.71) permit rapid achievement of an
alveolar partial pressure necessary for anesthesia followed by a prompt awakening
when sevoflurane is discontinued. Inhalation of sevoflurane is not irritating to the
airways, and there is a high degree of patient acceptance. Cardiovascular effects of
sevoflurane appear to be similar to those of other volatile anesthetics. Defluorination
of sevoflurane manifests as plasma fluoride concentrations that average 22 uM L -1
after 1 hour of administration. This peak level declines rapidly, often to near normal
values in less than 1 hour, reflecting the poor overall lipid solubility of this drug.
Table 1: physical & chemical properties of inhalational agents
Molecular
Weight (g)
N2O
44.4
Halothane
197.4
Enflurane 184.5
Isoflurane
184.5
Desflurane
168
Sevoflurane
200
*Supports combustion.
Boiling
Point (C)
-88
50.2
56.5
48.5
23.5
58.5
Vapor Pressure
(mm Hg, 20C)
244
172
240
669
170
Chemical
Stabilizer
Yes
No
No
No
No
Flammability
Limits
No*
No
No
No
20.8% in O2
11% in O2
PHARMACOKINETICS OF INHALED ANESTHETICS:
Pharmacokinetics of inhaled anesthetics describes their (1) absorption (uptake) from
alveoli into pulmonary capillary blood, (2) distribution in the body, (3) metabolism,
and (4) elimination, principally via the lungs. A series of partial pressure gradients
beginning at the anesthetic machine serve to propel the inhaled anesthetic across
various barriers (alveoli, capillaries, cell membranes) to their sites of action in the
central nervous system. The principal objective of inhalation anesthesia is to achieve a
constant and optimal brain partial pressure of the inhaled anesthetic.
The brain and all other tissues equilibrate with the partial pressures of inhaled
anesthetics delivered to them by arterial blood (Pa). Likewise, arterial blood
equilibrates with the alveolar partial pressures (PA) of anesthetics. This emphasizes
that the PA of inhaled anesthetics mirrors the brain partial pressure (Pbr). This is the
reason that PA is used as an index of (1) depth of anesthesia, (2) recovery from
anesthesia, and (3) anesthetic equal potency (MAC). It is important to recognize that
equilibration between two phases means the same partial pressure exists in both
phases. Equilibration does not mean equality of concentrations in two phases.
Understanding those factors that determine the PA and thus the Pbr permits control of
the doses of inhaled anesthetics delivered to the brain so as to maintain a constant and
optimal depth of anesthesia.
1.
2.
Induction of anesthesia occurs when an anesthetizing partial pressure has been
achieved in the brain (Pbr). The brain can be considered as the final site for a series of
concentration gradients in anesthetic partial pressures that begins with the
concentration of anesthetic delivered from the anesthesia machine (Table 15- 2).
The goal of inhalation anesthesia is to maintain an optimal and unchanging Pbr as
reflected by the alveolar partial pressure (PA). The ability to clinically measure the Pa
in the exhaled gases from the patient’s lungs permits the anesthesiologist to control
the depth of anesthesia (Pbr).
3.
The rate of induction of anesthesia is determined by the rate of rise of the Pa.
 During induction of anesthesia, blood returning to the lungs from tissues has a
lower partial pressure (tissue uptake) than that in the alveoli.
 As a result, uptake of anesthetic occurs from alveoli and creates an inspired-toalveolar partial pressure difference.
4.
Solubility (partition coefficients) of anesthetics in blood and tissues determines the
time necessary for equilibration between two phases to occur (Table 15-3).
 Blood:gas solubility determines uptake from the alveoli into the blood and thus
the rate of induction of anesthesia.
 Brain:blood solubility determines the time necessary for equilibration of partial
pressures between the blood and brain.
Concentration effect states that the higher the inspired partial pressure (Pi) the more
rapid the increase in Pa.
Second gas effect states that administration of high concentrations of N2O accelerates
the rate of uptake of concomitantly inhaled gases (isoflurane, oxygen).
5.
6.
7.
Recovery from anesthesia reflects reversal of the concentration gradients established
during induction of anesthesia.
 In contrast to induction of anesthesia, the rate of recovery from anesthesia may be
influenced by the duration of prior administration and the metabolism of the
inhaled anesthetic.

Recovery is most rapid following the short-duration administration of inhaled
anesthetics that are poorly soluble in blood and tissues.
Minimum Alveolar Concentration (MAC)
Potency is commonly expressed as the MAC of the inhalational anesthetic. This is the
alveolar concentration of anesthetic at 1 atmosphere (atm) that prevents movement in
50% of subjects in response to a painful stimulus. Various noxious stimuli have been
used to provoke the response, including skin incision or electrical current.
 MAC reflects Pbr because the PA is in equilibrium with the brain.
 Clinically, it is necessary to administer 1.2–1.3 times MAC to prevent movement
in at least 95% of patients.
 Combinations of inhaled anesthetics have additive effects on MAC (as a guide,
1% N2O usually decreases MAC for the volatile anesthetic by about 1% [may be
less in children and with poorly soluble volatile anesthetics]).
 Comparison of effects of inhaled anesthetics on various organ systems is based on
evaluation of equally potent MAC values for each drug (Table 2).

The relative effects for anesthetics can be defined by calculating the anesthetic or
therapeutic index, which is the dose producing a given effect divided by the MAC.
For example, the dose of an anesthetic producing apnea when divided by the
MAC defines its respiratory anesthetic index; an indication of the anesthetic’s
margin of safety with respect to breathing. The MAC has also been useful in
quantifying the effect of other drugs or pathophysiologic states on anesthetic
requirement.
TABLE 2. Anesthetic Requirements (MAC) for Inhaled Anesthetics
MAC
MAC
(30 to 60 years
(% with 60%
old, 37C PB760,%)
to 70% N2O)
N2O
104
Halothane
0.74
0.29
Enflurane
1.68
0.60
Isoflurane
1.15
0.50
Desflurane 6.3
2.83
Sevoflurane 2.0
0.66
Factors That Influence MAC:


Decrease MAC
o Increasing age
o Hypothermia
o Other CNS depressants (opioids, benzodiazepines)
o Decreased CNS concentrations of neurotransmitters
(antihypertensives)
o Acute alcohol ingestion
o Alpha-2 agonists (clonidine)
o Pregnancy
Increase MAC
o Hyperthermia

o Chronic alcohol abuse (?)
o Increased CNS concentrations of neurotransmitters (monoamine
oxidase inhibitors)
No Change in MAC
o Gender
o Anesthetic metabolism
o Paco2 21 to 95 mm Hg
EFFECTS OF INHALED ANESTHETICS ON ORGANS AND
SYSTEMS
A.
1.


2.


3.


4.
5.
Central Nervous System
Volatile anesthetics produce drug-specific and dose-dependent increases in
cerebral blood flow (CBF) by virtue of their cerebral vasodilating effects
(halothane > enflurane > isoflurane = desflurane = sevoflurane).
N2O is a cerebral vasodilator but, because of its limited potency, it is
associated with only modest increases in CBF.
Increases in CBF produced by volatile anesthetics tend to normalize with time
(CBF normalizes after 2 hours of halothane administration).
Volatile anesthetics decrease cerebral metabolic oxygen requirements
(CMRo2), with the largest decrease produced by isoflurane (flat
electroencephalogram [EEG] at about 2 MAC).
The CBF at which EEG evidence of ischemia occurs is lower with isoflurane
than with halothane suggesting a possible cerebral protecting effect of
isoflurane.
Isoflurane is associated with better maintenance of the relationship between
CMRO2 requirements and CBF, perhaps explaining the lower increase in CBF
produced by this drug (theoretically the administration of isoflurane in the
presence of pre-existing suppression of CMRO2 could result in exaggerated
increases in CBF).
In patients with decreased intracranial compliance, drug-induced increases in
CBF produce parallel increases in cerebral blood volume and intracranial
pressure (ICP).
Volatile anesthetics can alter production and reabsorption of cerebrospinal
fluid but, as with CBF, these effects normalize with time.
In the presence of modest hypocapnia, isoflurane (probably also desflurane)
appears less likely to produce potentially undesirable increases in ICP in
patients with decreased intracranial compliance than enflurane or halothane.
Enflurane is unique in producing dose-dependent spike-wave activity on the
EEG, which is exaggerated by hypocapnia.
Volatile anesthetics and N2O produce decreased amplitude and increased
latency in the cortical components of somatosensory evoked potentials.
B.
Respiratory System
1. Ventilatory volumes and frequency of breathing. Volatile anesthetics produce
drug-specific and dose-dependent depression of ventilation, as evidenced by
increases in PaCO2
 Decreases in tidal volume are incompletely offset by increases in rate of
breathing (rapid, shallow breathing characteristic of the general anesthetic
state) such that alveolar ventilation is decreased.

2.
3.
4.
5.
C.
Substitution of N2O for a portion of the volatile anesthetic results in less of an
increase in the Paco2 at the same total MAC as with the volatile anesthetic
alone.
Effects of the intercostal muscles and diaphragm. Loss of intercostal muscle
function with increasing doses of volatile anesthetics results in the characteristic
rocking boat appearance of ventilation (chest collapses and abdomen protrudes as
the diaphragm descends during inspiration) during general anesthesia.
Chemical control of breathing
 Volatile anesthetics produce dose-dependent decreases in the ventilatory
response to carbon dioxide, whereas even subanesthetic concentrations (0.1
MAC) of these drugs block the ventilatory response to hypoxemia.
 The absence of hyperpnea during arterial hypoxemia means that a useful
clinical sign of hypoxia cannot be relied on during anesthesia.
 Assisted ventilation of the lungs to offset anesthetic-induced increases in
Paco2 is of limited value because apnea occurs when Paco2 is lowered by
about 5 mm Hg (apneic threshold).
 Surgical stimulation increases ventilation so as to decrease Paco2 by about 5
mm Hg.
Airway caliber
 Volatile anesthetics are equally effective in decreasing airway resistance by
causing bronchodilatation.
 Volatile anesthetics are equally effective for patients with asthma, although
halothane and sevoflurane may be preferable to the other volatile anesthetics
that have a more pungent odor that can cause airway irritation.
Hypoxic pulmonary vasoconstriction. Volatile anesthetics in doses administered
clinically do not seem to interfere with diversion of blood flow away from poorly
ventilated or unventilated alveoli.
Circulatory System
1. Comparative Circulatory Effects
 Decreased blood pressure
D=H=I=E=S
 Increased heart rate
D=E=I>H=S
 Decreased cardiac output
H=E>D=I=S
 Decreased systemic vascular resistance
S=D=I>E>H
 Cardiac sensitization
H>D=I=E=S
(H = halothane; E = enflurane; I = isoflurane; D = desflurane; S = sevoflurane.)
o Increased heart rate during administration of isoflurane (also
desflurane but at a higher dose) may reflect maintenance of
baroreceptor activity in response to decreases in blood pressure.
Minimal to absent changes in heart rate during administration of
halothane- and sevoflurane- induced decreases in blood pressure
suggest impairment of baroreceptor activity.
o Abrupt increases in the alveolar concentration of desflurane and
isoflurane (but not sevoflurane), produce transient increases in blood
pressure and heart rate (magnitude less with isoflurane), which may
reflect stimulation of irritant receptors in the airway leading to
o
o
o
2.
o
o
o
o
3.
o
o
increased sympathetic nervous system activity (blocked by prior
administration of fentanyl or esmolol)
Distribution of cardiac output is altered by anesthetics, with increased
flow to the brain (halothane), skeletal muscles (isoflurane), and skin
and decreased blood flow to the kidneys, liver, and gastrointestinal
tract.
Substitution of N2O for a portion of the volatile anesthetic results in
less decrease in blood pressure at the same total MAC as with the
volatile anesthetic alone.
N2O produces a mild sympathomimetic effect manifesting as increases
in systemic vascular resistance. When administered in the presence of
opioids, N2O can decrease blood pressure and cardiac output.
Cardiac dysrhythmias, conduction, and drug interactions
Volatile anesthetics with an ether linkage are less likely than halothane
to produce cardiac dysrhythmias in the presence of exogenous
epinephrine injection.
Children are less likely than adults to develop epinephrine-induced
cardiac dysrhythmias.
Volatile anesthetics exert a direct depressant effect on the sinoatrial
node. Conduction of cardiac impulses is preserved through normal
pathways better by isoflurane than by halothane.
Myocardial depression produced by volatile anesthetics may be
enhanced by calcium entry blockers and b antagonists.
Coronary circulation
Isoflurane, but not the other volatile anesthetics, may uncouple the
generally close relationship between coronary blood flow and
myocardial oxygen requirements.
Isoflurane-induced dilation of intramyocardial arterioles, particularly
in the presence of decreased coronary perfusion pressure and critical
anatomic location of coronary artery stenosis, could divert blood flow
away from areas of myocardium supplied by pressure dependent
collateral blood vessels (coronary artery “steal”).
D.
Renal effects of volatile anesthetics are mainly a reflection of changes in
blood flow to the kidneys. Anesthesia is typically associated with decreases in renal
blood flow, glomerular filtration rate, and urine output.
E.
Volatile anesthetics have inherent skeletal muscle relaxant properties and
potentiate the effects of nondepolarizing muscle relaxants.
 The mechanism of potentiation may involve desensitization of the
postjunctional membrane or changes in skeletal muscle blood flow.
 Potentiation of nondepolarizing muscle relaxants is greatest with isoflurane,
enflurane, desflurane, and sevoflurane, intermediate with halothane, and least
with N2O.
F.
Metabolism and Toxicity
 Organ toxicity produced by volatile anesthetics reflects the production of
metabolites and not the effects of the intact anesthetic molecule.
 Metabolism is largely dependent on tissue solubility of the anesthetic
(determines reservoir available for exposure to the liver after the drug is
discontinued) and the vulnerability of the drug to metabolism:
 Methoxyflurane
4% to 50%





Halothane
Sevoflurane
Enflurane
Isoflurane
Desflurane
15% to 20%
3%
2.4%
0.2%
0.02%
o Desflurane is the most resistant of the volatile anesthetics to
metabolism.
o Sevoflurane is metabolized to fluoride (nephrotoxicity does not appear
to be a clinical problem) and degraded by soda lime and baralyme in a
temperature dependent manner to an olefin (compound A, which in
high concentrations in animals may be nephrotoxic and hepatotoxic)
(Fig. 2).
Fig. 2: rate of degradation by soda lime in relation to temperature.
Sevoflurane is the least & desflurane is the most resistant to degradation.

o In genetically susceptible patients, an oxidative trifluoroacetyl
metabolite of halothane (also a potential metabolite of other fluorinated
volatile anesthetics) may evoke the production of neoantigens directed
against hepatocytes.
Hematopoiesis
o Prolonged exposure to N2O may produce anemia similar to pernicious
anemia because of anesthetic-induced inhibition of methionine
synthetase, which is involved in the metabolism of vitamin B12.
o Volatile anesthetics, even with prolonged administration, do not appear
to alter hematopoiesis.
G.
Surgical stress and endocrine response reflects the effects of the anesthetic
and surgery (most important) and can be quantitated by measurement of plasma
concentrations of cortisol and catecholamines.
H.
Uterine relaxation accompanies administration of all volatile anesthetics and
can contribute to uterine blood loss when gravid patients are anesthetized. Inhaled
drugs delivered to the parturient also cross the placenta and similarly affect the fetus.