This document discusses general anesthetics used for inducing and maintaining anesthesia. It describes the ideal properties of anesthetic drugs and the physiologic effects they produce, including analgesia, amnesia and loss of consciousness. Two main types of general anesthetics are intravenous and inhalational agents. Common intravenous agents include propofol, opioids and benzodiazepines. Inhaled agents include desflurane, sevoflurane and nitrous oxide. The document outlines the stages of anesthesia and factors influencing the uptake and distribution of inhaled anesthetics in the body.

2.  An ideal anesthetic drug would induce a
smooth and rapid loss of consciousness,
while allowing for a prompt recovery after its
administration is discontinued. The drug
would also possess a wide margin of safety
and be devoid of adverse effects.

3. The physiologic state induced by general
anesthetics typically includes
 Analgesia
 Amnesia
 Loss of consciousness
 Inhibition of sensory and autonomic reflexes
 Skeletal muscle relaxation.

4. General anesthetics are typically of two types
1. Intravenous anesthetics
2. Inhalation anesthetics
Recently, intravenous anesthesia has become a
more widely used technique around the world.

5.  Several different classes of intravenous drugs
are used, alone or in combination with other
anesthetic and analgesic drugs, to achieve
the desired anesthetic state.

6. These drugs include the following:
 Barbiturates (eg, thiopental, methohexital)
 Benzodiazepines (eg, midazolam, diazepam)
 Propofol
 Ketamine
 Opioid analgesics (morphine, fentanyl,
sufentanil, alfentanil, remifentanil)
 Miscellaneous sedative-hypnotics (eg,
etomidate, dexmedetomidine).

7. The most commonly used inhaled anesthetics are
 Halothane
 Enflurane
 Mthoxyflurane
 Isoflurane
 Desflurane
 Sevoflurane.
The above compounds are volatile liquids that are
aerosolized in specialized vaporizer delivery
systems.
 Nitrous oxide, a gas at ambient temperature and
pressure, continues to be an important adjuvant
to the volatile agents.

8.  Modern anesthesia typically involves a
combination of intravenous (eg, for induction
of anesthesia) and inhaled (eg, for
maintenance of anesthesia) drugs.
 However, volatile anesthetics (eg,
sevoflurane) can also be used for induction of
anesthesia, and intravenous anesthetics (eg,
propofol) can be infused for maintenance of
anesthesia

9.  The traditional description of the various
stages of anesthesia (the so-called Guedel's
signs) were derived from observations of the
effects of inhaled diethyl ether, which has a
slow onset of central action owing to its high
solubility in blood. Using these signs,
anesthetic effects on the brain can be divided
into four stages of increasing depth of central
nervous system (CNS) depression

10.  Stage of analgesia: The patient initially
experiences analgesia without amnesia. Later
in stage I, both analgesia and amnesia are
produced.

11.  Stage of excitement: During this stage, the
patient often appears to be delirious and may
vocalize but is definitely amnesic.
 Respiration is irregular both in volume and
rate, and retching and vomiting may occur if
the patient is stimulated. For these reasons,
efforts are made to limit the duration and
severity of this light stage of anesthesia by
rapidly increasing the concentration of the
agent. This stage ends with the
reestablishment of regular breathing.

12.  Stage of surgical anesthesia: This stage
begins with the recurrence of regular
respiration and extends to complete
cessation of spontaneous respiration (apnea).
Four planes of stage III have been described
in terms of changes in ocular movements, eye
reflexes, and pupil size, which may represent
signs of increasing depth of anesthesia.

13.  This stage is divided into four planes
 Plane 1: the eye balls rotate ventrally, swallowing
reflexes are depressed, respiration is normal
 Plane 2: pupils are slightly dilated, respiration is
regular but shallow, heart rate and B.P mildly
decreased, suitable for most surgrey
 Plane 3: Deeply anesthesized, pulpils dilated,
light reflex weak or absent, respiratory rate less
than 12 breaths/ min.
 Plane 4: pupil is severely dilated with absent light
reflex, loss muscle tone, severe drops in heart
rate and blood pressure.

14.  Stage of medullary depression: This deep
stage of anesthesia includes severe
depression of the CNS, including the
vasomotor center in the medulla, as well as
the respiratory center in the brain stem.
Without circulatory and respiratory support,
death rapidly ensues.

15.  A general anesthetic is rarely given as the
sole agent. Anesthetic adjuncts usually are
used to augment specific components of
anesthesia, permitting lower doses of general
anesthetics with fewer side effects.

16.  While benzodiazepines can produce
anesthesia similar to that of barbiturates,
they are more commonly used for sedation
rather than general anesthesia because
prolonged amnesia and sedation may result
from anesthetizing doses. As adjuncts,
benzodiazepines are used for anxiolysis,
amnesia, and sedation prior to induction of
anesthesia or for sedation during procedures
not requiring general anesthesia.

17.  The benzodiazepine most frequently used in the
perioperative period is MIDAZOLAM followed
distantly by diazepam (VALIUM, others), and
lorazepam (ATIVAN, others).
 Benzodiazepines reduce both cerebral blood flow
and metabolism .
 They are effective anticonvulsants.
 Benzodiazepines modestly decrease blood
pressure and respiratory drive, occasionally
resulting in apnea. Thus, blood pressure and
respiratory rate should be monitored in patients
sedated with intravenous benzodiazepines.

18.  MIDAZOLAM is water soluble and typically is
administered intravenously but also can be
given orally, intramuscularly, or rectally; oral
midazolam is particularly useful for sedation
of young children.
 Midazolam produces minimal venous
irritation as opposed to diazepam and
lorazepam. These drugs also sometime cause
thrombophlebitis.

19.  Midazolam has more rapid onset and shorter
in duration of effect.
 Sedative doses of midazolam (0.01-0.05
mg/kg intravenously) reach peak effect in ~2
minutes and provide sedation for ~30
minutes.

20.  Dexmedetomidine (PRECEDEX) is an imidazole
derivative that is a highly selective α 2
adrenergic receptor agonist.
 Dexmedetomidine is a sedative-hypnotic that
provides analgesia with little respiratory
depression and, in most patients, a tolerable
decrease in blood pressure and heart rate.
The drug is likely to be increasingly used for
sedation and as an anesthetic adjunct.

21.  Dexmedetomidine has the very useful
property of producing sedation and analgesia
with minimal respiratory depression thus, it is
particularly valuable in sedation of patients
who are not endotracheally intubated and
mechanically ventilated. The sedation
produced resembles more to natural sleep,
making patient to easily arouse.

22.  The most common side effects of
dexmedetomidine include hypotension and
bradycardia, both of which are attributed to
decreased catecholamine release by
activation peripherally and in the CNS of the
alpha 2A receptor.
 The recommended loading dose is 1 g/kg
given over 10 minutes, followed by infusion
at a rate of 0.2-0.7 g/kg per hour.

23.  With the exception of ketamine, neither
parenteral nor currently available inhalational
anesthetics are effective analgesics. Thus,
analgesics typically are administered with
general anesthetics to reduce anesthetic
requirement and minimize hemodynamic
changes produced by painful stimuli.

24.  During the perioperative period, opioids often
are given at induction to prevent responses to
predictable painful stimuli (e.g., endotracheal
intubation and surgical incision).

25.  Nonsteroidal anti-inflammatory drugs, COX-
2 inhibitors, and acetaminophen sometimes
provide adequate analgesia for minor surgical
procedures. However, opioids are the primary
analgesics used during the perioperative
period because of the rapid and profound
analgesia they produce.

26.  Fentanyl , sufentanil, alfentanil , remifentanil,
meperidine, and morphine are the major
parenteral opioids used in the perioperative
period. The primary analgesic activity of each of
these drugs is produced by agonist activity at mu
opioid receptors.
 Remifentanil has an ultrashort duration of action
(~10 minutes) and accumulates minimally with
repeated doses or infusion; it is particularly well
suited for procedures that are briefly painful, but
for which little analgesia is required
postoperatively.

27.  Single doses of fentanyl, alfentanil, and
sufentanil all have similar intermediate
durations of action (30, 20, and 15 minutes,
respectively), but recovery after prolonged
administration varies considerably. Fentanyl's
duration of action lengthens the most with
infusion, sufentanil's much less so, and
alfentanil's the least.

28.  Marked decreases in respiratory rate and
heart rate with much smaller reductions in
blood pressure are seen to varying degrees
with all opioids.
 Muscle rigidity that can impair ventilation
sometimes accompanies larger doses of
opioids.
 The incidence of sphincter of Oddi spasm is
increased with all opioids, although morphine
appears to be more potent in this regard

29.  The frequency and severity of nausea, vomiting,
and pruritus after emergence from anesthesia are
increased by all opioids to about the same
degree.
 A useful side effect of meperidine is its capacity
to reduce shivering, a common problem during
emergence from anesthesia other opioids are not
as efficacious against shivering, perhaps due to
less kappa receptor agonism.
 Opioids often are administered intrathecally and
epidurally for management of acute and chronic
pain

30.  Depolarizing (e.g., succinylcholine) and non-
depolarizing muscle relaxants (e.g.,
vecuronium) often are administered during
the induction of anesthesia to relax muscles
of the jaw, neck, and airway and thereby
facilitate laryngoscopy and endotracheal
intubation.
 Barbiturates will precipitate when mixed with
muscle relaxants and should be allowed to
clear from the intravenous line prior to
injection of a muscle relaxant.

31.  Muscle relaxants are not by themselves
anesthetics and should not be used for the
purpose of adequate anesthetic depth.
 The action of non-depolarizing muscle relaxants
usually is antagonized, once muscle paralysis is
no longer desired, with an acetylcholinesterase
inhibitor such as neostigmine or edrophonium
combined with a muscarinic receptor antagonist
(e.g., glycopyrrolate or atropine) to offset the
muscarinic activation resulting from esterase
inhibition

32.  Muscle relaxants used in anesthesia have few
side effects. However, succinylcholine has
multiple serious side effects (bradycardia,
hyperkalemia, and severe myalgia) including
induction of malignant hyperthermia in
susceptible individuals.

33.  Oxygen (O2) is essential to life. Hypoxia is a
life-threatening condition in which oxygen
delivery is inadequate to meet the metabolic
demands of the tissues. Since oxygen delivery
is the product of blood flow and oxygen
content, hypoxia may result from alterations
in tissue perfusion, decreased oxygen tension
in the blood, or decreased oxygen-carrying
capacity

34.  Under ideal conditions, when ventilation and
perfusion are well matched, the alveolar PO2
will be ~14.6 kPa (110 mm Hg). The
corresponding alveolar partial pressures of
water and CO2 are 6.2 kPa (47 mm Hg) and
5.3 kPa (40 mm Hg), respectively. Under
normal conditions, there is complete
equilibration of alveolar gas and capillary
blood, and the PO2 in end-capillary blood is
typically within a fraction of a kPa of that in
the alveoli.

35.  (6) Anticholinergic drugs (eg, atropine and
glycopyrrolate) may be used to decrease oral and
airway secretions and to treat bradycardia;
however, they can also dilate the pupils.
 (7) Although vital sign monitoring remains the
most common method of assessing depth of
anesthesia during surgery, newer techniques
often involve computer-assisted monitoring of
cerebral function using indices of EEG activity.
These automated cerebral monitoring techniques
use indices derived from EEG signals.

36.  A wide variety of gases and volatile liquids
can produce anesthesia. One of the
troublesome properties of the inhalational
anesthetics is their low safety margin. The
inhalational anesthetics have therapeutic
indices (LD50/ED50) that range from 2 to 4,
making these among the most dangerous
drugs in clinical use.

37.  It is essential to understand that inhalational
anesthetics distribute between tissues (or
between blood and gas) such that equilibrium
is achieved when the partial pressure of
anesthetic gas is equal in the two tissues.
When a person has breathed an inhalational
anesthetic for a sufficiently long time that all
tissues are equilibrated with the anesthetic,
the partial pressure of the anesthetic in all
tissues will be equal to the partial pressure of
the anesthetic in inspired gas.

38. Uptake & Distribution of Inhaled Anesthetics
 The concentration of an inhaled anesthetic in
a mixture of gases is proportional to its
partial pressure (or tension).
 Achievement of a brain concentration of an
inhaled anesthetic necessary to provide an
adequate depth of anesthesia requires
transfer of the anesthetic from the alveolar air
to the blood and from the blood to the brain.

39.  The rate at which a therapeutic concentration
of the anesthetic is achieved in the brain
depends primarily on
1. Solubility of anesthetic
2. Concentration of anesthetic in the inspired
air
3. Volume of pulmonary ventilation
4. Pulmonary blood flow
5. Partial pressure gradient between arterial
and mixed venous blood anesthetic
concentrations.

40. Solubility
 The blood:gas partition coefficient is a useful
index of solubility and defines the relative affinity
of an anesthetic for the blood compared with that
of inspired gas. 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, and therefore the arterial tension rises
rapidly

41.  Anesthetics with moderate-to-high solubility
(eg, halothane, isoflurane), more molecules
dissolve before partial pressure changes
significantly, and arterial tension of the gas
increases less rapidly

42.  For example, For a given concentration or
partial pressure of the two anesthetic gases
in the inspired air, it will take much longer for
the blood partial pressure of the more soluble
gas (halothane) to rise to the same partial
pressure as in the alveoli. Since the
concentration of the anesthetic agent in the
brain can rise no faster than the
concentration in the blood, the onset of
anesthesia will be slower with halothane than
with nitrous oxide.

44.  Anesthetic Concentration in the Inspired Air
 Increases in the inspired anesthetic
concentration increase the rate of induction
of anesthesia by increasing the rate of
transfer into the blood according to Fick's
law.

45.  Advantage is taken of this effect in anesthetic
practice with inhaled anesthetics that possess
moderate blood solubility (eg, enflurane,
isoflurane, and halothane). For example, a
1.5% concentration of isoflurane may be
administered initially to increase the rate of
rise in the brain concentration; the inspired
concentration is subsequently reduced to
0.75–1% when an adequate depth of
anesthesia is achieved.

46.  In addition, these moderately soluble
anesthetics are often administered in
combination with a less soluble agent (eg,
nitrous oxide) to reduce the time required for
loss of consciousness and achievement of a
surgical depth of anesthesia.

47.  Pulmonary Ventilation
 The rate of rise of anesthetic gas tension in
arterial blood is directly dependent on both
the rate and depth of ventilation.

48.  For example, a fourfold increase in ventilation
rate almost doubles the arterial tension of
halothane during the first 10 minutes of
administration but increases the arterial tension
of nitrous oxide by only 15%. Therefore,
hyperventilation increases the speed of induction
of anesthesia with inhaled anesthetics that would
normally have a slow onset. Depression of
respiration by opioid analgesics slows the onset
of anesthesia of inhaled anesthetics unless
ventilation is manually or mechanically assisted.

49.  Pulmonary Blood Flow
 An increase in pulmonary blood flow (ie,
increased cardiac output) slows the rate of rise in
arterial tension, particularly for those anesthetics
with moderate-to-high blood solubility.
Increased pulmonary blood flow exposes a larger
volume of blood to the anesthetic agent in the
alveoli, thereby increasing the blood carrying
capacity and decreasing the rate of rise in the
anesthetic tension in the blood (and brain).

50.  In patients with circulatory shock, the
combined effects of decreased cardiac output
(resulting in decreased pulmonary flow) and
increased ventilation will accelerate induction
of anesthesia with halothane and isoflurane.
However, this effect is much less important
with the less soluble agents sevoflurane,
nitrous oxide, and desflurane

51.  Arteriovenous Concentration Gradient
 The anesthetic concentration gradient between
arterial and mixed venous blood is dependent
mainly on uptake of the anesthetic by the tissues,
including nonneural tissues. Depending on the
rate and extent of tissue uptake, venous blood
returning to the lungs may contain significantly
less anesthetic than arterial blood. The greater
this difference in anesthetic gas tensions, the
more time it will take to achieve equilibrium with
brain tissue.

52.  During the induction phase of anesthesia (and
the initial phase of the maintenance period), the
tissues that exert greatest influence on the
arteriovenous anesthetic concentration gradient
are those that are highly perfused (eg, brain,
heart, liver, kidneys, and splanchnic bed). These
tissues receive over 75% of the resting cardiac
output. In the case of volatile anesthetics with
relatively high solubility in highly perfused
tissues, venous blood concentration will initially
be very low, and equilibrium with the arterial
blood is achieved slowly.

53.  Muscle and skin constitute 50% of the total body
mass, anesthetics accumulate more slowly in
these tissues than in highly perfused tissues (eg,
brain) because they receive only one-fifth of the
resting cardiac output. Although most anesthetic
agents are highly soluble in adipose (fatty)
tissues, the relatively low blood perfusion to
these tissues delays accumulation, and
equilibrium is unlikely to occur with most
anesthetics during a typical 1- to 3-hour
operation.

54. Measurement of Anesthetic Potency
 The potency of general anesthetic agents usually
is measured by determining the concentration of
general anesthetic that prevents movement in
response to surgical stimulation. For inhalational
anesthetics, anesthetic potency is measured in
MAC units, with 1 MAC defined as the minimum
alveolar concentration that prevents movement in
response to surgical stimulation in 50% of
subjects.

55. Elimination
 The time to recovery from inhalation
anesthesia depends on the rate of elimination
of the anesthetic from the brain. Many of the
processes responsible for transfer of the
anesthetic during the recovery phase are
simply the reverse of those that occur during
the introduction of the anesthetic agent.

56.  One of the most important factors governing
rate of recovery is the blood:gas partition
coefficient of the anesthetic agent.
 Other factors controlling rate of recovery
include the pulmonary blood flow, the
magnitude of ventilation, and the tissue
solubility of the anesthetic.

57.  Two features of the recovery phase are
different from induction of anesthesia.
 First, transfer of an anesthetic from the lungs
to blood can be enhanced by increasing its
concentration in inspired air, while the
reverse transfer process cannot be enhanced
because the concentration in the lungs
cannot be reduced below zero.

58.  Second, at the beginning of the recovery phase, the
anesthetic gas tension in different tissues may be
quite variable, depending on the specific agent and
the duration of anesthesia.
 Inhaled anesthetics that are relatively insoluble in
blood (ie, possess low blood:gas partition
coefficients) and brain are eliminated at faster rates
than the more soluble anesthetics. The washout of
nitrous oxide, desflurane, and sevoflurane occurs at a
rapid rate, leading to a more rapid recovery from
their anesthetic effects compared with halothane and
isoflurane.

59.  Halothane is approximately twice as soluble
in brain tissue and five times more soluble in
blood than nitrous oxide and desflurane; its
elimination therefore takes place more slowly,
and recovery from halothane- and isoflurane-
based anesthesia is predictably less rapid.

60.  Clearance of inhaled anesthetics via the lungs is the major
route of elimination from the body. However, hepatic
metabolism may also contribute to the elimination of some
volatile anesthetics.
 Over 40% of inspired halothane is metabolized during an
average anesthetic procedure, whereas less than 10% of
enflurane is metabolized over the same period. Oxidative
metabolism of halothane results in the formation of
trifluoroacetic acid and release of bromide and chloride
ions. Under conditions of low oxygen tension, halothane is
metabolized to the chlorotrifluoroethyl free radical, which
is capable of reacting with hepatic membrane components
and on rare occasion has resulted in halothane-induced
hepatitis.

61.  The inhalational anesthetics inhibit excitatory
synapses and enhance inhibitory synapses in
various preparations. These effects likely are
produced by both pre- and postsynaptic actions
of the inhalational anesthetics. The inhalational
anesthetic isoflurane clearly can inhibit
neurotransmitter release, while the small
reduction in presynaptic action potential
amplitude produced by isoflurane (3% reduction
at MAC concentration) substantially inhibits
neurotransmitter release

62.  Chloride channels gated by the inhibitory GABAA
receptors are sensitive to clinical concentrations
of a wide variety of anesthetics, including the
halogenated inhalational agents.
 Clinical concentrations of inhalational anesthetics
enhance the capacity of glycine to activate
glycine-gated chloride channels (glycine
receptors), which play an important role in
inhibitory neurotransmission in the spinal cord
and brainstem.

63.  NMDA receptors are glutamate-gated cation
channels that are somewhat selective for calcium
and are involved in long-term modulation of
synaptic responses (long-term potentiation) and
glutamate-mediated neurotoxicity.
 Nitrous oxide, cyclopropane and xenon are
potent and selective inhibitors of NMDA-
activated currents, suggesting that these agents
also may produce unconsciousness by means of
actions on NMDA receptors.

64.  Halogenated inhalational anesthetics activate some
members of a class of K+ channels known as two-
pore domain channels; other two-pore domain
channel family members are activated by xenon,
nitrous oxide, and cyclopropane. These channels are
located in both pre-synaptic and post-synaptic sites.
The post-synaptic channels are important in setting
the resting membrane potential of neurons and may
be the molecular locus through which these agents
hyperpolarize neurons. Activation of pre-synaptic
channels can lead to hyperpolarization of the pre-
synaptic terminal, thereby reducing neurotransmitter
release.

65.  In principle, general anesthetics could
interrupt nervous system function, including
peripheral sensory neurons, the spinal cord,
the brainstem, and the cerebral cortex.

66. Effects on the Cardiovascular System
 Inhaled anesthetics change heart rate either directly
by altering the rate of sinus node depolarization or
indirectly by shifting the balance of autonomic
nervous system activity. Bradycardia can be seen with
halothane, probably because of direct vagal
stimulation. In contrast, enflurane, and sevoflurane
have little effect, and both desflurane and isoflurane
increase heart rate. In the case of desflurane,
transient sympathetic activation with elevations in
catecholamine levels can lead to marked increases in
heart rate and blood pressure when high inspired gas
concentrations are administered.

67.  Effects on the Respiratory System
 With the exception of nitrous oxide, all inhaled anesthetics
in current use cause a dose-dependent decrease in tidal
volume and an increase in respiratory rate. However, the
increase in respiratory rate is insufficient to compensate
for the decrease in volume, resulting in a decrease in
minute ventilation. All volatile anesthetics are respiratory
depressants, as indicated by a reduced response to
increased levels of carbon dioxide. The degree of
ventilatory depression varies among the volatile agents,
with isoflurane and enflurane being the most depressant.
All volatile anesthetics in current use increase the resting
level of PaCO2

68.  The bronchodilating action of halothane and
sevoflurane makes them the induction agents of
choice in patients with underlying airway
problems (eg, asthma, bronchitis, chronic
obstructive pulmonary disease). Airway irritation,
which may provoke coughing or breath-holding,
is rarely a problem with halothane and
sevoflurane. However, the pungency of
desflurane makes this agent less suitable for
induction of anesthesia despite its low blood:gas
partition coefficient.

69.  Effects on the Brain
 Inhaled anesthetics decrease the metabolic rate of the
brain. Nevertheless, the more soluble volatile agents
increase cerebral blood flow because they decrease
cerebral vascular resistance. The increase in cerebral
blood flow is clinically undesirable in patients who
have increased intracranial pressure because of a
brain tumor or head injury. Volatile anesthetic-
induced increases in cerebral blood flow increase
cerebral blood volume and further increase
intracranial pressure. Of the inhaled anesthetics,
nitrous oxide is the least likely to increase cerebral
blood flow.

70. Effects on the Kidney
 Depending on the concentration, volatile
anesthetics decrease the glomerular filtration
rate and renal blood flow, and increase the
filtration fraction.
Effects on the Liver
 Volatile anesthetics cause a concentration-
dependent decrease in hepatic blood flow

71. Effects on Uterine Smooth Muscle
 Nitrous oxide appears to have little effect on
uterine musculature. However, the
halogenated anesthetics are potent uterine
muscle relaxants and produce this effect in a
concentration-dependent fashion.

72. Hepatotoxicity
 Postoperative hepatic dysfunction is typically
associated with factors such as blood transfusions,
hypovolemic shock, and other surgical stresses rather
than volatile anesthetic toxicity.
 Serum from patients with halothane hepatitis
contains a variety of autoantibodies against hepatic
proteins. Trifluoroacetylated (TFA) proteins in the
liver could be formed in the hepatocyte during the
biotransformation of halothane by liver drug-
metabolizing enzymes.

73. Nephrotoxicity
 Metabolism of methoxyflurane, enflurane, and
sevoflurane leads to the formation of fluoride
ions, and this has raised questions concerning
the potential nephrotoxicity of these three
volatile anesthetics. Changes in renal
concentrating ability have been observed with
prolonged exposure to both methoxyflurane and
enflurane but not sevoflurane

74. Malignant Hyperthermia
 Malignant hyperthermia is an autosomal dominant
genetic disorder of skeletal muscle that occurs in
susceptible individuals undergoing general
anesthesia with volatile agents and muscle relaxants
(eg, succinylcholine). The malignant hyperthermia
syndrome consists of the rapid onset of tachycardia
and hypertension, severe muscle rigidity,
hyperthermia, hyperkalemia, and acid-base
imbalance with acidosis that follows exposure to one
or more of the triggering agents

75.  Treatment includes administration of
dantrolene (to reduce calcium release from
the sarcoplasmic reticulum) and appropriate
measures to reduce body temperature and
restore electrolyte and acid-base balance

76. Chronic Toxicity
 Under normal conditions, inhaled anesthetics
(including nitrous oxide) are neither mutagens
nor carcinogens in patients.
 Prolonged exposure to nitrous oxide decreases
methionine synthase activity and theoretically can
cause megaloblastic anemia, a potential
occupational hazard for staff working in
inadequately ventilated dental operating suites.

77.  Halothane:
◦ no longer widely used
◦ potent, non-irritant
◦ blood: gas partition coefficient is 2.4 and oil: gas
coefficient is 220
◦ Minimum alveolar concentration is 0.8 % v/v
◦ may cause hypotension and dysrhythmias; about
30% metabolised

78. ◦ can be useful when slow recovery is desirable but
otherwise the 'hangover' due to high lipid solubility
is unwanted
◦ because of its potential for inducing hepatotoxicity,
halothane has largely been replaced by newer
volatile anaesthetics.

79.  Enflurane:
◦ halogenated anaesthetic similar to halothane
◦ less metabolism than halothane, therefore less risk
of toxicity
◦ faster induction and recovery than halothane (less
accumulation in fat)
◦ risk of epilepsy-like seizures.
◦ blood: gas partition coefficient is 1.9 and oil: gas
coefficient is 98
◦ Minimum alveolar concentration is 0.7 % v/v

80.  Isoflurane:
◦ similar to enflurane but lacks epileptogenic property
◦ may precipitate myocardial ischaemia in patients with
coronary disease
◦ irritant to respiratory tract.
◦ It is typically used for maintenance of anesthesia after
induction with other agents because of its pungent odor,
but induction of anesthesia can be achieved in < 10
minutes with an inhaled concentration of 3% isoflurane
in O2,

81. ◦ blood: gas partition coefficient is 1.4 and oil: gas
coefficient is 91
◦ Minimum alveolar concentration is 1.2 % v/v
 Sevoflurane:
◦ Sevoflurane is widely used, particularly for
outpatient anesthesia, because of its rapid recovery
profile
◦ similar to desflurane, with lack of respiratory
irritation.

82. ◦ Well suited for inhalation induction especially in
children
◦ Hepatic metabolism of sevoflurane also produces
inorganic fluoride. Serum fluoride concentrations
peak shortly after surgery and decline rapidly.
◦ blood: gas partition coefficient is 0.6 and oil: gas
coefficient is 53
◦ Minimum alveolar concentration is 2.1 % v/v

83.  Nitrous oxide:
◦ low potency, therefore must be combined with other
agents
◦ It is combined with oxygen to avoid hypoxia
◦ rapid induction and recovery
◦ good analgesic properties
◦ risk of bone marrow depression with prolonged
administration
◦ accumulates in gaseous cavities.
◦ N2O is frequently used in concentrations of about 50% to
provide analgesia and mild sedation in outpatient
dentistry.

84. Xenon
 Xenon is an inert gas that first was identified as
an anesthetic agent in 1951. It is unlikely to
enjoy widespread use because it is a rare gas that
cannot be manufactured and must be extracted
from air. This limits the quantities of available
xenon gas and renders xenon very expensive.
 Xenon exerts its analgesic and anesthetic effects
at a number of receptor systems in the CNS.

85.  Xenon is extremely insoluble in blood and
other tissues, providing for rapid induction
and emergence from anesthesia.
 It is sufficiently potent to produce surgical
anesthesia when administered with 30%
oxygen.

86.  Barbiturates
 The three barbiturates most commonly used
in clinical anesthesia are sodium thiopental,
thiamylal, and methohexital. Sodium
thiopental has been used most frequently for
inducing anesthesia. Thiamylal (SURITAL) is
licensed in the U.S. only for veterinary use.

87.  Thiopental has very high lipid solubility, and this
accounts for the speed of onset and transience of its
effect when it is injected intravenously.
 The free acid is insoluble in water, so thiopental is
given as the sodium salt. On intravenous injection,
thiopental causes unconsciousness within about 20 s,
lasting for 5-10 min.
 The anaesthetic effect closely parallels the
concentration of thiopental in the blood reaching the
brain, because its high lipid solubility allows it to
cross the blood-brain barrier without noticeable
delay.

88.  The typical induction dose (3-4 mg/kg) of thiopental
produces unconsciousness in 10-30 seconds with a
peak effect in 1 minute and duration of anesthesia of
5-8 minutes.
 Recovery from the anaesthetic effect of a bolus dose
occurs within about 5 min, governed entirely by
redistribution of the drug to well-perfused tissues;
very little is metabolised in this time. After the initial
rapid decline, the blood concentration drops more
slowly, over several hours, as the drug is taken up by
body fat and metabolised. Consequently, thiopental
produces a long-lasting hangover.

89.  Repeated intravenous doses cause progressively
longer periods of anaesthesia, because blood
concentration becomes progressively more
elevated as more drug accumulates in the body.
For this reason, thiopental is not used to
maintain surgical anaesthesia but only as an
induction agent.
 Thiopental binds to plasma albumin (roughly 85%
of the blood content normally being bound)

90.  Accidental injection of intravenous thiopental-a
strongly alkaline solution-around rather than
into the vein, or into an artery, can cause pain,
local tissue necrosis and ulceration or severe
arterial spasm that can result in gangrene. If the
injection is into an artery then immediate
injection of procaine, through the same needle, is
the recommended procedure to encourage
vasodilatation.
 Thiopental has little analgesic property and
causes profound respiratory depression.

91.  Because intracranial pressure and blood
volume are not increased (in contrast to the
volatile anesthetics), thiopental is a desirable
drug for patients with cerebral swelling (eg,
head trauma, brain tumors).

92.  Methohexital has been useful for
neurosurgical procedures involving surgical
removal of seizure foci. However, it also has
antiseizure activity and is the drug of choice
for providing anesthesia in patients
undergoing electroconvulsive therapy (ECT).
Given its more rapid elimination,
methohexital is also preferred over thiopental
for short ambulatory procedures.

93.  Propofol (2,6-diisopropylphenol) has become
the most popular intravenous anesthetic.
 Its rate of onset of action is similar to that of
the intravenous barbiturates but recovery is
more rapid.
 Patients feel better in the immediate
postoperative period because of the
reduction in postoperative nausea and
vomiting and a sense of well-being.

94.  Propofol is used for both induction and
maintenance of anesthesia as part of total
intravenous or balanced anesthesia techniques,
and is the agent of choice for ambulatory
surgery.
 Propofol has become increasingly popular for
intravenous sedation in the operating room as
part of a monitored anesthesia care technique
and in diagnostic suites for procedural sedation.

95.  The drug is also effective in producing prolonged
sedation in patients in critical care settings.
 Prolonged administration of conventional
emulsion formulations can elevate serum lipid
levels.
 Prolonged use of high-dose propofol infusions
for the sedation of critically ill young children has
led to severe acidosis in the presence of
respiratory infections and to possible neurologic
sequelae upon withdrawal.

96.  After intravenous administration of propofol,
the distribution half-life is 2–8 minutes, and
the redistribution half-life is approximately
30–60 minutes. The drug is rapidly
metabolized in the liver at a rate ten times
faster than that of thiopental. Propofol is
excreted in the urine as glucuronide and
sulfate conjugates.

97.  At the usual anesthetic doses, propofol
produces dose-related depression of
respiratory system.
 It also causes marked decrease in blood
pressure during induction
 Pain at the site of injection is the most
common adverse effect of bolus
administration.

98.  Etomidate is a carboxylated imidazole that can be
used for induction of anesthesia in patients with
limited cardiovascular reserve. Its major
advantage over other intravenous anesthetics is
that it causes minimal cardiovascular and
respiratory depression. Etomidate produces a
rapid loss of consciousness, with minimal
hypotension even in elderly patients with poor
cardiovascular reserve. The heart rate is usually
unchanged, and the incidence of apnea is low

99.  The drug has no analgesic effects, and
coadministration of opioid analgesics is
required to decrease cardiac responses
during tracheal intubation and to lessen
spontaneous muscle movements. Following
an induction dose, initial recovery from
etomidate is less rapid (< 10 minutes)
compared with recovery from propofol.

100.  Distribution of etomidate is rapid, with a biphasic
plasma concentration curve showing initial and
intermediate distribution half-lives of 3 and 29
minutes, respectively. Redistribution of the drug
from brain to highly perfused tissues appears to
be responsible for the relatively short duration of
its anesthetic effects. Etomidate is extensively
metabolized in the liver and plasma to inactive
metabolites, with only 2% of the drug excreted
unchanged in the urine.

101.  Etomidate causes a high incidence of pain on
injection, myoclonic activity, and postoperative
nausea and vomiting.
 It causes involuntary muscle movements during
induction.
 Etomidate may also cause adrenocortical
suppression with decreased plasma levels of
cortisol after a single dose. Prolonged infusion of
etomidate in critically ill patients may result in
hypotension, electrolyte imbalance, and oliguria
because of its adrenal suppressive effects.

102.  Ketamine closely resembles, both chemically
and pharmacologically, phencyclidine, which
is a 'street drug' with a pronounced effect on
sensory perception.
 The mechanism of action of ketamine may
involve blockade of the membrane effects of
the excitatory neurotransmitter glutamic acid
at the NMDA receptor subtype

103.  Ketamine is a highly lipophilic drug and is
rapidly distributed into well-perfused organs,
including the brain, liver, and kidney.
Subsequently ketamine is redistributed to
less well perfused tissues with concurrent
hepatic metabolism followed by both urinary
and biliary excretion.

104.  Given intravenously, ketamine takes effect
more slowly (1-2 min) than thiopental, and
produces a different effect, known as
'dissociative anaesthesia', in which there is a
marked sensory loss and analgesia, as well as
amnesia, without complete loss of
consciousness. During induction and
recovery, involuntary movements and peculiar
sensory experiences often occur.

105.  Ketamine produces its cardiovascular effects
by stimulating the central sympathetic
nervous system and, to a lesser extent, by
inhibiting the reuptake of norepinephrine at
sympathetic nerve terminals. Increases in
plasma epinephrine and norepinephrine
levels occur as early as 2 minutes after an
intravenous bolus of ketamine and return to
baseline levels in less than 15 minutes.

106.  Ketamine markedly increases cerebral blood flow,
oxygen consumption, and intracranial pressure.
 Respiration is unaffected by effective anaesthetic
doses. This makes it relatively safe to use in low-
technology healthcare situations or in
emergencies in the field.
 Ketamine is very useful for poor-risk geriatric
patients and high-risk patients in cardiogenic or
septic shock because of its cardiostimulatory
properties.

107.  The main drawback of ketamine is that
hallucinations, and sometimes delirium and irrational
behaviour, are common during recovery.
 In an effort to enhance ketamine's efficacy and
reduce its side-effect profile, investigators separated
the isomers and demonstrated that the S(+) ketamine
possessed greater anesthetic and analgesic potency.
However, even the S(+) isomer of ketamine possesses
psychotomimetic side effects. Ketamine has also
been compounded for topical use and this
preparation is purportedly useful for some types of
arthritic pain.

108.  Midazolam, a benzodiazepine, is slower in onset
and offset than the other intravenous
anesthetics, like ketamine, causes less
respiratory or cardiovascular depression.
Midazolam (or diazepam) is often used as a
preoperative sedative and during procedures
such as endoscopy, where full anaesthesia is not
required. It can be administered in combination
with an analgesic such as alfentanyl. In the event
of overdose it can be reversed by flumazenil

109.  The combined use of a sedative (e.g. the dopamine
antagonist droperidol) related to antipsychotic drugs
and an opiate analgesic such as fentanyl can produce
a state of deep sedation and analgesia (known as
neuroleptanalgesia) in which the patient remains
responsive to simple commands and questions, but
does not respond to painful stimuli or retain any
memory of the procedure. This can be used for minor
procedures such as endoscopy but is less used since
the advent of midazolam which has a shorter
duration of action. Use of neuroleptanalgesics is
more common in veterinary medicine.