• They are of mainly 2 types
Volatile anesthetics (diethyl ether, halothane,
enflurane, isoflurane, desflurane, sevoflurane)
• They have low vapor pressures and high boiling
• liquids at room temperature (20 deg C)
Gaseous anesthetics (nitrous oxide, xenon)
• They Have high vapor pressures and low boiling
• The use of nitrous oxide to relieve the pain of
surgery was suggested by Humphrey Davy in
• Crawford Long, a physician in rural Georgia,
first used ether anesthesia in 1842.
• In 1846 James Simpson, used chloroform to
relieve the pain of childbirth.
Mechanism of action
• Not properly understood.
• Primary focus (of research) has been on the
• Almost all anaesthetics (with the exceptions of
cyclopropane, ketamine and xenon) potentiate
the action of GABA at the GABAA receptor.
(GABAA receptors are ligand-gated Cl- channels
made up of five subunits (generally comprising
two α, two β and one γ or δ subunit).
• volatile anaesthetics (may) bind at the
interface between α and β subunits.
Two-pore domain K+ channels
(These belong to a family of 'background' K+
channels that modulate neuronal excitability.)
Channels made up of TREK1, TREK2, TASK1,
TASK3 or TRESK subunits (can be) directly
activated by low concentrations of volatile
and gaseous anaesthetics.
• Thus reducing membrane excitability.
• (Glutamate the major excitatory neurotransmitter
in the CNS, activates three main classes of
ionotropic receptor-AMPA, kainate and NMDA
• Nitrous oxide, xenon apppear to reduce NMDA
• Xenon appears to inhibit NMDA receptors by
competing with glycine.
• Other inhalation anaesthetics may also exert
effects on the NMDA receptor in addition to their
effects on other proteins such as the GABAA
• Inhaled anesthetics are taken up through gas
exchange in the alveoli.
Uptake & Distribution
A. Inspired Concentration and Ventilation
• The driving force for uptake is the alveolar
• Two determinants :
(controlled by the anesthesiologist)
(1) inspired concentration or partial pressure
(2) alveolar ventilation .
• Increases in the inspired partial pressure
increase the rate of rise in the alveoli and thus
• The increase of partial pressure in the alveoli
is expressed as
a ratio of alveolar concentration (F A ) over
inspired concentration (F 1 );
• The faster F A /F 1 approaches 1
(1 representing the equilibrium), the faster is
• The other parameter by which FA/F1
approaches to 1 is alveolar ventilation.
• However The magnitude of the effect varies
according to the blood:gas partition
Factors Controlling Uptake
2. Cardiac output
3. Alveolar-venous partial pressure difference
• The blood:gas partition coefficient is a useful
index of solubility.
• Defines the relative affinity of an anesthetic
for the blood compared with that of inspired
• The partition coefficients for desflurane and
nitrous oxide, which are relatively insoluble in
blood, are extremely low.
• When an anesthetic with low blood solubility
diffuses from the lung into the arterial blood,
relatively few molecules are required to raise
its partial pressure
• Therefore, the arterial tension of gas rises
• Conversely, for anesthetics with moderate to
high solubility ( halothane, isoflurane), more
molecules dissolve before partial pressure
changes significantly, and arterial tension of
the gas increases less rapidly.
• A blood: gas partition coefficient of 0.47 for
nitrous oxide means that - At equilibrium, the
concentration in blood is 0.47 times the
concentration in the alveolar space (gas).
• An increase in pulmonary blood flow (ie,
increased cardiac output) will increase the uptake
• But anesthetic taken up will be distributed in all
tissues, not just the CNS.
• Cerebral blood flow is well regulated and the
increased cardiac output will therefore increase
delivery of anesthetic to other tissues and not the
Alveolar-venous partial pressure difference—
• The anesthetic partial pressure difference
between alveolar and mixed venous blood is
dependent mainly on uptake of the anesthetic
by the tissues, including non-neural tissues.
• The greater this difference in anesthetic gas
tensions, the more time it will take to achieve
equilibrium with brain tissue.
• Recovery from inhalation anesthesia follows
some of the same principles in reverse that
are important during induction.
• One of the most important factors governing
rate of recovery is the
• Blood : gas partition coefficient of the
anesthetic agent. Lesser the value faster is the
• nitrous oxide, desflurane, and sevoflurane
occurs at a rapid rate.
• Recovery also depends on
1. Alveolar Ventilation (controlled by
2. Metabolism of anaesthetic.
• Modern inhaled anesthetics are eliminated
mainly by ventilation and are only metabolized
to a very small extent.
• However , metabolism have important
implications for their toxicity.
• In terms of the extent of hepatic metabolism,
the rank order for the inhaled anesthetics is
• halothane > enflurane > sevoflurane
>isoflurane > desflurane > nitrous oxide
A. Cerebral Effects
• Anesthetic potency is currently described by
the minimal alveolar concentration (MAC)
required to prevent a response to a surgical
• Inhaled anesthetics decreases the metabolic
activity of the brain.
• Decreased cerebral metabolic rate (CMR)
generally reduces blood flow within the brain.
• However, volatile anesthetics also cause
cerebral vasodilation, which can increase
cerebral blood flow.
• The net effect on cerebral blood flow
(increase, decrease, or no change) depends on
the concentration of anesthetic delivered.
• Clinical importance : An increase in cerebral
blood flow is undesirable in patients who have
increased intracranial pressure because of
brain tumor, intracranial hemorrhage, or head
• Anesthetic effects on the brain produce four
stages or levels of increasing depth of CNS
(Guedel’s signs, derived from observations of the
effects of inhaled diethyl ether):
• Stage I—analgesia: The patient initially
experiences analgesia without amnesia. Later in
stage I, both analgesia and amnesia are
• Stage II—excitement: During this stage, the
patient appears delirious, may vocalize but is
Respiration is rapid, and heart rate and blood
Stage III—surgical anesthesia:
• This stage begins with slowing of respiration
and heart rate and extends to complete
cessation of spontaneous respiration (apnea).
• Four planes of stage III are described based on
changes in ocular movements, eye reflexes,
and pupil size, indicating increasing depth of
Stage IV—medullary depression:
• Severe depression of the CNS, including the
vasomotor center and respiratory center in
• Without circulatory and respiratory support,
death would rapidly ensue.
B. Cardiovascular Effects
• All depress normal cardiac contractility
(halothane and enflurane more so than
isoflurane, desflurane, and sevoflurane).
• So they tend to decrease mean arterial
pressure in direct proportion to their alveolar
• In halothane and enflurane, the reduced
arterial pressure is caused primarily by
myocardial depression (reduced cardiac
output) and there is little change in systemic
• In contrast, isoflurane, desflurane, and
sevoflurane produce greater vasodilation with
minimal effect on cardiac output.
• Clinical importance : These differences may
have important implications for patients with
C. Respiratory Effects
• All volatile anesthetics possess varying
degrees of bronchodilating properties.
• The control of breathing is significantly
affected by inhaled anesthetics.
• With the exception of nitrous oxide, all
inhaled anesthetics cause a dose-dependent
decrease in tidal volume
increase in respiratory rate (rapid shallow
• All volatile anesthetics are respiratory
depressants (reduced ventilatory response to
increased levels of carbon dioxide in the
D. Renal Effects
• Inhaled anesthetics tend to decrease
glomerular filtration rate (GFR) and urine flow.
Effects on Uterine Smooth Muscle
• Nitrous oxide appears to have little effect on
• However, the halogenated anesthetics are
potent uterine muscle relaxants
• Toxicity of inhaled Anesthetics
A. Acute Toxicity
• Metabolism of enflurane and sevoflurane may
generate compounds that are potentially
nephrotoxic. (liberate fluoride ions)
• Prolonged exposure to nitrous oxide
decreases methionine synthase activity, which
could cause megaloblastic anemia
• All inhaled anesthetics can produce some
carbon monoxide (CO) from their interaction
with strong bases in dry carbon dioxide
3. Malignant hyperthermia—
is a heritable genetic disorder of skeletal
muscle that occurs in susceptible individuals
exposed to volatile anesthetics while
undergoing general anesthesia. ( Halothane)
4. Hepatotoxicity (halothane hepatitis)—
• a small subset of individuals previously
exposed to halothane has developed
fulminant hepatic failure.
• Cases of hepatitis of others have rarely been
B. Chronic Toxicity
• Under normal conditions, inhaled anesthetics
including nitrous oxide are neither mutagens
nor carcinogens in patients.
• Nitrous oxide can be directly teratogenic in
animals under conditions of extremely high
• Halogenated agents may be teratogenic in
• Nitrous oxide is completely eliminated by the
• Non toxic to liver , kidney and brain. No much
adverse effects on CVS , RS.
• Probably the safest with 30% oxygen
• N2O is a weak, low potency anesthetic agent.
• Action is quick and smooth .
• Recovery is rapid. Rarely exceeds 4 min.
• It is a poor muscle Relaxant.
• It has significant analgesic effects.
• Nitrous oxide is used primarily as an adjunct to
other inhalational or intravenous anesthetics
mainly during maitenance phase.
• 70% N2O +25-30% oxy + 0.2-2% potent
• Induction is relatively slow.
• Halothane is soluble in fat and other body tissues,
it will accumulate during prolonged
• Halothane can sensitize the myocardium to the
arrhythmogenic effects of Adrenaline.
Uses : Induction and maintenance anaesthesia
in pediatric age group.
Maintenance anaesthesia in adults
• Induction of anesthesia and recovery from
enflurane are relatively slow.
• It is primarily utilized for maintenance rather
than induction of anesthesia.
• Enflurane provokes seizure attacks in
• Enflurane produces significant skeletal muscle
• Induction with isoflurane and recovery from
isoflurane are faster than with halothane.
• It is typically used for maintenance of
anesthesia after induction with other agents
because of its pungent odor. Another e.g,
• Eventhough non-explosive in mixtures of air or
sevoflurane can undergo an exothermic
reaction with desiccated CO2 to produce airway
burns. So it should be used in open system airway
• Effects on CVS and RS is modest.
• It is well-suited for inhalation induction of
anesthesia (particularly in children)