INHALATIONAL

ANAESTHETIC AGENTS
Presented by:
Dr Hafiz Abdul Hannan
1st Year Resident
Department Of Anesthesia
Services Hospital Lahore

CONTENTs :
Introduction
Brief

history
Properties of Ideal inhalational agent
Pharmacokinetics
Pharmacodynamics
Individual inhalational agents
Comparative pharmacology

Inhalation anesthetics
The term inhalation anesthetic refers to anesthetics
administered in a gaseous form.
These include nitrous oxide (N2O), a gas at room
temperature, and the volatile anesthetics, which are
nonflammable liquids at room temperature.
Inhalation anesthetics are the most common drugs
used for maintenance of general anesthesia
because of their

ease of administration and

the ability to reliably monitor their effects with clinical
signs and end-tidal concentration.

BRIEF HISTORY:
Diethyl ether first used by William T.G. Morton
in the USA in 1846

a.

b.

Chloroform was the next agent to receive

attention, by James Simpson in 1847.
it was discontinued due to:severe cardiovascular depression (sudden death ?
VF).
dose dependent hepatotoxicity.
Cyclopropane was discovered accidentally in 1929
and was very popular for almost 30 yrs.
the increasing use of electronic equipment
necessitated the discontinuation of this

Halothane, synthesized in 1951 by prominent

British chemist, Charles Walter Suckling, while
working at the Imperial Chemical Industries (ICI).
Later in 1956, M. Johnstone used it clinically
first time.

Enflurane has been in use since 1970.

Isoflurane- since 1981
Sevoflurane- since 1990
Desflurane- since1996

1)

2)

3)

variety of other agents were investigated but

discarded for various reasons including..
Explosive mixtures with oxygen
-diethyl ether
- ethyl chloride
- divinyl ether
- cyclopropane
Postoperative liver necrosis / sudden death
chloroform
Postoperative renal failure - methoxyflurane

Evolution of inhaled anesthetics

INHALED AGENTS:
Previous - Chloroform, Cyclopropane, Methoxyflurane, Trichloroethylene, Fluroxene, Diethylether
Current - Nitrous Oxide, Halothane, Enflurane, Isoflurane, Sevoflurane, Desflurane
Others - Xenon, Argon, Nitrogen, Compound 485, Thiomethoxyflurane, n-Pentane, Hydrogen.

THE IDEAL ANESTHETIC AGENTS

PHYSICAL PROPERTIES
BIOLOGICAL PROPERTIES
The agents in use today demonstrate many
favorable characteristics, no single agent has all
the desirable properties mentioned.

PHYSICAL PROPERTIES
NONFLAMMABLE, NON-EXPLOSIVE AT ROOM TEMPERATURES
STABLE IN LIGHT
LIQUID AND VAPORISABLE AT ROOM TEMPERATURE (I.E LOW
LATENT HEAT OF VAPORISATION)

STABLE AT ROOM TEMPERATURE, WITH A LONG SHELF LIFE

STABLE WITH SODA LIME, AS WELL AS PLASTICS AND METALS
ENVIRONMENTALLY FRIENDLY, NO OZONE DEPLETION
CHEAP AND EASY TO MANUFACTURE

BIOLOGICAL PROPERTIES
PLEASANT TO INHALE, NON-IRRITANT, INDUCE
BRONCHODILATATION
LOW BLOOD : GAS SOLUBILITY,
HIGH OIL : WATER SOLUBILITY

I.E FAST ONSET

I.E HIGH POTENCY

MINIMAL EFFECTS ON OTHER SYSTEMS,

I.E CVS, RESP, HEPATIC, RENAL OR

ENDOCRINE

NO BIOTRANSFORMATION, SHOULD BE EXCRETED IDEALLY VIA THE

LUNGS, UNCHANGED
NON-TOXIC TO OPERATING THEATRE PERSONNEL

THE GOAL OF DELIVERING INHALED

ANESTHETICS
The goal of delivering inhaled anesthetics is to produce the
anesthetic state by establishing a specific concentration (partial
pressure) in the central nervous system (CNS).
This is achieved by establishing the desired partial pressure in
the lungs that ultimately equilibrates with the brain and spinal
cord.
At equilibrium, the CNS partial pressure (P B ) equals the blood
partial pressure (Pa), which equal alveolar partial pressure (P A).

PB = P a = P A
( at equilibrium)

PHARMAKOKINETICS
(what the body does to a drug)

Include four phases:

uptake, distribution, metabolism, and
elimination.

Uptake and distribution of inhaled anesthetics

Inhalation anesthetic agents must pass through many

barriers between the anesthesia machine and the brain.
Including machine vaporizer, breathing circuit, lungs
alveoli, blood and then brain.

1. Factors affecting THE

inspiratory concentration (FI):
The fresh gas leaving the anesthesia machine mixes with
gases in the breathing circuit before being inspired by the
patient.
Therefore the patient is not necessarily receiving the
concentration set on the vaporizer.
The actual composition of the inspired gas mixture
depends mainly on these three factors
1. Fresh gas flow rate, (FGF)
2. The volume of the breathing system, and
3. Any absorption by the machine or breathing
circuit
The higher the fresh gas flow rate, the smaller the
breathing system volume, and the lower the circuit
absorption, the closer the inspired gas concentration will
be to the fresh gas concentration. i.e., FI = FGF

FACTORS AFFECTING
ALVEOLAR CONCENTRATION
FA :
These factors include
UPTAKE
Which is determined by
Solubility of anesthetic in the blood. i.e., blood: gas
partition coefficient
alveolar blood flow i.e., Cardiac output
Partial pressure diff. between alveolar gas and venous
blood (PA-v ).

VENTILATION
Increasing ventilatory rate can raise FA/FI for soluble
anesthetics as they are more subject to uptake.

CONCENTRATION AND SECOND GAS

EFFECT

 ANESTHETIC UPTAKE:
Three factors affect anesthetic uptake
1. Solubility of anesthetic in the blood. i.e., blood: gas
partition coefficient
2. alveolar blood flow i.e., Cardiac output
3. Partial pressure diff. between alveolar gas and venous blood
(PA-v ).

1). Effect of Solubility on uptake:

Solubility is defined in terms of the partition coefficient.

Blood : Gas partition coefficient [B/G = CB /CG ]
It is the ratio of the concentration of the anesthetic gas present in the
blood to the concentration present in gas phase at steady state(equal
partial pressure at two phases).

The higher the blood/gas coefficient, the greater the anesthetics

solubility and the greater its uptake by the pulmonary
circulation. As a consequence of this increased solubility,
alveolar partial pressure rises more slowly, and induction is

Comparative solubility's of inhaled anesthetics

Anesthetic agents

Blood:gas partition
coefficient

Methoxyflurane

12

Halothane

2.54

Enflurane

1.90

Isoflurane

1.46

Sevoflurane

0.69

Desflurane

0.42

Nitrous oxide

0.46

The more soluble an anesthetics in blood, the more of it which must be dissolved to raise partial pressure
(the more soluble , the slower the rate of PA & Pa increase relative to PI, and the slower the induction.)
The principal determinant of the approach of FA/FI

FA /FI ratio.

A common way to assess anesthetic uptake is to

follow the ratio of the alveolar anesthetic
concentration (FA) to the inspired anesthetic
concentration (FI) over time (FA/FI).
This determines how quickly alveolar
concentration(FA) reaches inspired
concentration FI.

FA /FI CURVE
0.47
0.65

This curve shows the effect of

solubility of anesthetic gas on
rate
of
rise
of
alveolar
concentration with respect to
inspired conc of anesthetic gas.
Less solubility - Rapid induction

1.4

The more soluble the anesthetic

The more drug will be taken up

by the blood

15
The slower the rise in alveolar
concentration
More solubility -Slow induction

2 . Effect of pulmonary flow or

cardiac output on uptake

Pulmonary blood flow = Cardiac

output (CO)
CO causes rapid uptake ;
rate of rise of FA/FI
CO

less uptake ; rate

of rise of FA/FI

Effects are greater for highly

soluble agents.

Thus, anesthetic - induced CVS

depression may cause a more rapid
rise in arterial tension.
Cardiac output is lowered
cerebral circulation
less
Induction
slower

maintained (shock)
Induction
rapid

3. Alveolar- to-venous partial pressure gradient:

Partial pressure in venous blood depends on tissue uptake of

anesthetic.
If tissue uptake is more than there is more partial pressure
gradient and more uptake of anesthetic by lungs .
At equilibrium, there is no tissue uptake, so there is no uptake of
anesthetic by lungs.
The venous partial pressure = arterial partial pressure = alveolar
partial pressure
PA P V = 0
The transfer from blood to tissue depends on three factors, that
are analogous to systemic uptake ( tissue solubility ,tissue blood
flow & partial pressure differences of arterial and tissue)

Distribution to tissues
To better understand inhaled anesthetic uptake and
distribution, tissues have been classified into four groups
based on their solubility and blood flow
Tissue Group
Characteristic
Vessel Rich

(brain, heart,
lungs,
kidney,
splanchnic
bed, glands)

Vessel Poor
Muscle
muscle+skin

Fat

(bones,
cartilage,
ligaments)

Percent Body
Mass

10

50

20

20

Percent Cardiac
Output

75

19

Distribution to tissues
Equilibration of the
VRG complete in 4 to 8
minutes

After 8 minutes, the

Muscle group (MG)
determines most of
uptake.

Once MG equilibration
is complete Fat group
(FG) determines the
uptake

This graph shows the uptakes of individual tissue groups with respect to time
The initial steep rate of uptake is due to unopposed filling of the alveoli by
ventilation. The rate of rise slows as the vessel-rich groupand eventually
the muscle groupapproach steady state levels of saturation.

 Ventilation (VA):
Increase in Minute
alveolar ventilation can
Increases FA/FI
The change is greatest
for more soluble
anesthetics
For insoluble agent , the
effect is minimal as
FA/FI is already high .
Halothane depress
Valveolar
and decreases the rate
of rise in alveolar
concentration and
create a negative
feedback loop

Factors That Increase or Decrease the Rate of Increase of

Alveolar Anesthetic Concentration (FA)/Inspired Anesthetic
Concentration (FI)

Other Factors Affecting Uptake & Distribution:

CONCENTRATION EFFECT :

Reflects the impact of FI on the rate of rise of the

FA

States that; the higher the inspired

concentrations FI, the more rapidly the FA
approaches the FI

Delivering a higher FI than the FA actually desired

for the patient is analogous to an intravenous
bolus and thus speeds the induction of
anesthesia.

Second gas effect:

Reflects ability of high volume uptake of one gas (1 st

gas ) to accelerate the rate of increase of FA of a
concurrently administered companion gas ( 2nd gas ).
A special case of the concentration effect is
administration of two gases simultaneously e.g.
nitrous oxide (as 1st gas ) and a potent volatile
anesthetic ( as 2nd gas ) in which the high volume
uptake of nitrous oxide increases the FA (concentrates)
of the volatile anesthetic.
this shows increase tracheal inflow of all inhaled
gases & concentration of 2nd gas in smaller lung
volume (concentrating effect ).

 The concentration
effect is demonstrated
in the top half of the
graph in which 70%
nitrous oxide produces
a more rapid increase
in the alveolar
anesthetic
concentration
(FA)/inspired anesthetic
concentration (FI) ratio
of nitrous oxide than
does administration of
10% nitrous oxide.
The second gas effect
is demonstrated in the
lower graphs in which
the FA/FI ratio for
halothane increases
more rapidly when

Diffusion Hypoxia

This is reverse of second gas effect

Occurs when inhalation of nitrous oxide is
discontinued abruptly at the end of a case.
The large outpouring of nitrous oxide from blood
to alveoli effectively dilutes alveolar air, and
decreases available oxygen, so that when room
air is inspired hypoxia may occur
This is usually only mild and rarely clinically
significant .
Managed with supplemental oxygen for a few
minutes following termination of the nitrous
oxide.

FACTORS AFFECTING
ARTERIAL CONCENTRATION(Fa):
Ventilation-perfusion mismatch :

Poorly soluble agents are more affected

Because hyperventilation to ventilated alveoli can only
minimally PA for less soluble agents , so induction will
be slower.
Thus, a bronchial intubation or a right-to left intra-cardiac
shunt will slow the rate of induction with nitrous oxide(less
soluble) more than with halothane(more soluble).

ELIMINATION of inhalational agents:

Recovery depends on lowering anesthetic conc. in
brain tissue

Elimination is via three routes :

1. Exhalation-most significant route of
elimination
2. Biotransformation-only significant for
soluble agents that are metabolized in body
significantly such a halothane.
3. Trans-cutaneous loss- insignificant route

Factors speeding recovery

Factor that speed recovery are identical to those

present during induction:By Increased ventilation
Elimination of rebreathing, and high fresh gas
flows,
Anaesthetic washout from the circuit volume,
Decreased solubility and uptake,
High cerebral blood flow,
Short duration of exposure

PHARMACODYNAMICS
(what the drug does to the body).
Mechanism of action
Minimum alveolar concentration
Saturated vapour pressure
Boiling point

Mechanism of action
General

anesthesia is an altered physiological state

characterized by reversible loss of consciousness,
analgesia, amnesia, and some degree of muscle relaxation.

The

exact mechanism of action of inhalational

anesthetics is unknown.

The

most common understanding is that there are multiple

sites of action, which may not be uniform for all inhalational
agents.

ANESTHETIC SITES OF ACTION:

There does not seem to be a single macroscopic site of

action that is shared by all inhalation agents.
Specific brain areas affected by various anesthetics include
the reticular activating system, the cerebral cortex, the
cuneate nucleus, the olfactory cortex, the hippocampus and
also spinal cord dorsal horn.

Possible mechanisms of
anesthesia

Opening of inhibitory ion channels (Cl- or

K+)

Closing of excitatory ion channels (Na+)

Hyperpolarization of nerve cell membrane

Diminished propensity to action potential

Multiple sites of action

Theories of Anesthetic Action: Meyer overton rule

The Meyer-Overton rule states that the potency of an anaesthetic is
proportional to its lipid solubility. This suggests a lipophilic site of
action.

Inhalational anesthetic agent act via the lipid rich cells of the
CNS thus anesthetic potency increase with lipid solubility.
There are some clear exceptions to this rule e.g enflurane and
isoflurane are isomers and have same lipid solubility but
isoflurane is more potent .
Critical volume hypothesis

Neuronal membrane contain a multitude of hydrophobic sites

in their phospholipids bilayer.
Anesthetic binding to this sites could expand the bilayer
beyond the critical amount (alter membrane function by
obstruction of ion channel/ alter electrical properties of
neuron)
Hydrophilic Site

Anesthetic agents form microcrystalline hydrate (cage like

water molecule) that can alter transmission of electrical

Membrane protiens as site of anaesthetic action

Inhlational agent may enhance GABA and glycine receptor
activity ( that are inhibitory neurotranmitters in CNS.) by
binding to channel protein and increase in chloride
conductance..
Modulation of ligand gated ion channel ( nAch receptors and
NMDA receptors.)

Interruption of neuronal transmission

This interruption may occur at axonal and/or synaptic
transmission.
Interruption in normal synaptic transmission can be
caused by interfering in release of neurotransmitter from
presynaptic to synaptic cleft, alteration in reuptake,
changing neurotransmitters binding sites and by
influencing ionic conductance)

Minimum alveolar concentration (MAC)

Alveolar concentration at 1 atm that prevents skeletal

muscle movement in response to painful stimulus
(e.g.surgical skin incision ) in 50% of patients.

This is most useful index of anesthetic potency

(FA reflects the partial pressure at site of anesthetic
action-brain and spinal cord) .
It is equivalent of a median effective dose(ED 50).
It provides uniformity in dosages
Establish relative amounts of inhaled anesthetics to
reach specific end-points (MAC awake , MACBAR )
MAC values are additive ;example : adding nitrous
oxide will decrease MAC of another volatile agent.

EXAMPLES OF MAC:
MAC awake:
Allows a voluntary response to commands in 50%
of patients, this is used to imply the amnesic dose
of the agent.
= 0.3-0.4 x MAC
MAC 95:
Prevents 95% of patients from responding = 1.3 x
MAC
MAC BAR:
Blocks Adrenergic Response in 50% of patients =
1.5 x MAC.
MAC intubation:
=2 x MAC

Factors affecting MAC :

Increases

MAC:

Hyperthermia
Young
Hypernatremia
Drug-induced increase in
CNS catecholamine levels
Chronic alcohol abuse

No changes in MAC:
Duration of anesthesia
Gender
Weight
Hypo/Hyperkalemia
Thyroid gland dysfunction

Decreases

MAC:

Hypothermia & Hyperthermia (if

>42 C)
Preoperative medication
Acute alcohol abuse
Pregnancy
Increasing age
(6% decrease/decade)
Hypoxaemia (PaO2< 40 mmHg)
Hypotension(<40 mm Hg- MAP)
Anaemia (Haematocrit<10%)
Hypercarbia PaCO2 > 95mmHg
Hyponatremia
Drugs
lithium,lidocaine,opioids,-2
agonist,barbiturates,BDZ

MAC of inhaled anesthetics

in 100% oxygen:
AGENT

MAC(%)

Methoxyflurane

0.16
(Most Potent)

Chloroform

0.5

Halothane

0.75

Isoflurane

1.17

Enflurane

1.63

Sevoflurane

1.8

Ehyl Ether

3.2

Desflurane

6.6

Xenon

72

Nitrous oxide

104
(Least potent)

SATURATED VAPOUR PRESSURE:

Pressure exerted by molecules escaping from
surface of a liquid to enter gaseous phase at
equilibrium.
When equilibrium is reached (at any
temperature), no of leaving liquid phase equals
no entering it ( equals to SVP)
Indicates the degree of volatility

SVP increases with temperature, therefore SVPs

of volatile agents are quoted at standard
temperature
at 20C
PHYSIOCHEMICAL PROPERTIES OF VOLATILE ANESTHETICS
Vapor pressure at 20C (mm
Hg)

Sevo

Des

Iso

Enf

Halo

N2O

157

669

238

172

243

38,770

BOILING POINT:

Temperature of a substance at which its SVP

equals external atmospheric pressure.
Additional heat does not raise the
temperature further but provides the latent
heat of vaporization necessary for the liquid
to evaporate.

PHYSIOCHEMICAL PROPERTIES OF VOLATILE ANESTHETICS

Boiling point (C)

Sevo

Des

Iso

Enf

Halo

N2O

59

24

49

57

50

88

Individual inhalational
agents

Halotha
ne::

Halothane:

Physiochemical properties:
Halogenated alkane
Colourless liquid with pleasant smell
Stored in amber- coloured bottle with thymol
( prevent oxidative decomposition )
Non-irritant , pleasant to breath
Low B:G coefficient rapid induction &
recovery
Rapid loss of laryngeal & pharyngeal reflex
Least expensive.

Halothane:

EFFECTS ON ORGAN SYSTEM

CARDIOVASCULAR:
Dose dependent reduction of arterial blood pressure
by
1. direct myocardial depression (CO by 20-50%)
2. obtund baroreceptors response (no reflex
tachycardia)
.Causes Bradycardia due to :
1. cardiac sympathetic activity with vagal
dominance
2. Direct slowing of SA node
.Causes Tachyarrthymia (re-enterant type) due to
1. Slowing of conduction velocity (AV node & Purkinje
fibres )
2. refractory period in conducting tissue

Halothane:

Respiratory :
tracheobronchial secretion & mucociliary flow.
Causes rapid ,shallow breathing.
Decrease in alveolar ventilation and Paco2
elevated.
Potent bronchodilator.
Inhibit hypoxic pulmonary vasoconstriction
( thus effective increase in physiological shunt &
dead space )
CNS :
Cerebral vasodilatation (CBF, ICP loss of
autoregulation)
metabolic rate of O2
Post-op shivering( heat loss/ill-defined neuro

Halothane:

Neuromuscular:
Relaxation ;rarely ,malignant
hyperthermia

Renal :
1MAC reduced RBF & GFR up to 4050%

GIT :
Reduces salivation , gastric motility
and splanchnic BF

Liver :
Metabolism : upto 20 % by
cytochrome p450 to producr
trifluroacetic acid Br and Cl ;
1.5% halothane reduces BF by
25-30%
reduce hepatocellular function ,
drug clearance

Halothane:

Hepatotoxicity:
Halothane causes hepatic damage which may take
one of two forms
Type I : A reversible form that is often subclinical and
associated with a rise in hepatic transaminases. this is
probably due to hepatic hypoxia.
Type II : Fulminant hepatic necrosis (halothane
hepatitis).
Trifluoroacetyl chloride (an oxidative metabolite of
halothane) may behave as a hapten, binding covalently
with hepatic proteins, inducing antibody formation. Which
causes hepatic damage.

The diagnosis of halothane hepatitis is based on the

exclusion of all other forms of liver damage.

S/S:
D2-D5 post-anaesthesia-fever, nausea, rash, eosinophilic

Halothane:
CONTRAINDICATIONS:

Unexplained liver dysfunction.

Intra-cranial mass lesions.
Hypovolemic patient with severe
cardiac diseases

ADVANTAGES

Moderately high
potency
Moderate low B:G
coefficient -induction
and recovery not
prolonged
Non irritant and
bronchodilatory
laryngospasm and
bronchospasm
uncommon

DISADVANTAGES

Only sleep is
completely obtainedrequire analgesia &
muscle relaxant
Hypotension
Transient arrythmias
esp. with Adrenaline
Post op Hepatitis

Enfluran
e:

Enflurane

Physiochemical properties:
Clear , colorless agent with ethereal smell
Non-flammable ,stable
Rapid induction & recovery
High potency can be used alone or with opioids.

EFFECTS ON ORGAN SYSTEM

CNS :

Cerebral vasodilatation ( CBF if arterial BP is

maintained)
May produce abnormal EEG/seizure activity
/epileptogenic (accentuated by hypocapnia)
Effects on ICP ~variable

Cvs:

Dose-dependent cardiovascular depression ~ causes

dec myocardial contractility, and CO.

Enflurane

Respiratory

Dose-dependent
depression of alveolar
ventilation ~ VT ,RR
not changed
No increase in secretion
Bronchodilatation

Renal

RBF, GFR
Produce inorganic
fluoride ~ no toxicity

Enflurane

ADVANTAGES
Moderately high
potency
Rapid induction and
recovery
Non irritant and
bronchodilator
Muscle relaxation
often adequate for
surgery
Arrhythmias is less
than halothane
Little
biotransformation ~
low risk of hepatic
dysfunction

DISADVANTAGES
Deep anaesthesia
with enflurane
resp. And circ.
Depression
(hypoxia,hypercapnia
& hypotension)
Seizure activity may
occur with high
concentration or
hypocarbia
Uterine relaxation- C.I
at parturition

Isoflurane:

Isoflurane
:

Physiochemical properties:

It is a Colourless volatile liquid with pungent smell

(unpleasant to child)

Stable ( no preservative require), non flammable

Rapid induction & recovery

High incidence of coughing & breath holding

Metabolism:
Only 0.2% is metabolized and none of the products has been
linked to toxicity.

Toxicity

Owing to the presence of a CHF2 group in its structure

it may react with dry soda lime (or baralyme), producing
carbon monoxide.

Isoflurane
:

EFFECT ON ORGAN
SYSTEMS:

CNS :
Limited changes in CBF within 1MAC
If con> 1 MAC causes increase in CBF and Intracranial
pressure.
Oxygen consumption decreased
Auto-regulation- somewhat preserved

CVS:
A myocardial depressant (less than Halothane/ Enflurane)
Cause systemic hypotension by decreasing SVR.
Also causes coronary vasodilatation
Possibility of coronary steal syndrome in CAD pt.
maldistribution of blood from ischaemic to non ischaemic area
( risk is less compared with other potent vasodilators)

Isoflurane
:
Respiratory :
Cuases respiratory depression .
Acts as a good bronchodilator.
Neuromuscular :
Dose-depedent. muscle
relaxation
Relaxes uterine muscles

INDICATED- For Cardiac and NeuroSurgery

CONTRAINDICATIONS:

No such contraindication.
Patient with severe
hypovolemia may not tolorate
its vasodilating effects.

Isoflurane
:
Advantages:
Moderately high potency
Low blood/gas part.
Coeff.
Enhanced muscle
relaxation
Less incidence of
arrythmia than
halothane
Maintain CO,
Less myocardial
depression
Minimal
biotransformation
ICP controllable via
paco2

Disadvantages:
Deep anaesthesia
~may cause resp &
circulatory depression
More pungent odour
(initial resp. Irritation)
Possible
subendocardial steal
syndrome, with low
BP in IHD pts
Uterine relaxation (CI
at parturition)
More expensive

Sevofluran
e:

Sevoflurane:

Physiochemical properties:
It is a fluorinated methyl isopropyl ether
Non flammable ; pleasant to smell (enables
rapid induction & emergence.)
Highly suitable for paediatric pts
Low blood/ gas solubility (coef. 0.6 )
Stable and stored in amber -colored bottle (nonstable in soda lime, but metabolites are non
toxic)
Non-irritant to UR tract
Rate of recovery is slower

Sevoflurane:

Biotransformation :

3% metabolized by deflourination in liver by cytochrome

P450 (isoform 2E1. to produce hexafluoroisopropanol and
inorganic F (known to cause renal toxicity).

Effects On Organ Systems:

Respiratory :
Least effect on ventilation
It reverses broncho-spasm
Potentiates non-depolarising muscle relaxant
CVS :
Less CVS depression than Halothane, less coronary
vasodilatation
Does not sensitize myocardium to catecholamines
May prolong QT interval, but of no clinical significance.
CNS:
Increases CBF and intra-cranial pressure.
No signs of increased CNS activity have yet been found

Sevoflurane:

RENAL :
Slightly decreases renal
blood flow. Higher Conc
Causes Nephro-toxicity
HEPATIC:
Decreases portal vein blood
flow but increases hepatic
artery blood flow thus
maintaining total hepatic
blood flow.
NEUROMUSCULAR:
Adequate muscle relaxation

Sevoflurane:

Toxicity:
Sevoflurane does not decompose to carbon monoxide when
use in presence of carbon dioxide absorbents but rather is
degraded to a vinyl halide (compound A), which is a dosedependent nephro toxin in rats.
Renal injury has not been shown to occur in patients, even
when fresh gas flows are 1 L/min or less.

Contraindications
It is relatively contraindicated in severe hypovolemia,
susceptibility to malignant hyperthermia and intracranial
hypertension.

Sevoflurane:

Advantages:
Advantages:
Smooth, fast
Smooth, fast
induction
induction
Rapid recovery
Rapid recovery
Ease of use,
Ease of use,
requiring
requiring
conventional
conventional
vaporizers
vaporizers
(particularly when
(particularly when
compared with
compared with
desflurane).
desflurane).

Disadvantages:
Disadvantages:
Production of
Production
of
potentially toxic
potentially toxic
metabolites in the
metabolites in the
body (more a
body (more a
theoretical problem)
theoretical problem)
Instability with
Instability with
carbon dioxide
carbon dioxide
absorbers
absorbers
Relatively expensive.
Relatively
expensive.

Desfluran
e:

Desflurane:

Physiochemical properties:

A fluorinated methyl ethyl ether

Structure much similar to that of isoflurane.
Recovery time is approximately 50 % less than those
of Isoflurane.
A colorless agent, in amber-coloured bottle ,no
preservatives
Non flammable, not broken down by soda lime, light
or metals
Need a special vaporizer to use ( the TEC 6)
Ethereal pungent odour .
Irritant to resp. tract
Low blood/ gas solubility (coef. 0.42)
Induction is rapid, but limited by pungency.
Rapid emergence, highly suitable for Paeds

Desflurane:

Metabolism
Very little metabolism in plasma (by
deflourination), so causes less flourine
production than Isoflurane

Effects on organ systems:

Resp :
Causes decrease in tidal volume and increase in
resp rate.
Pungency and airway irritation so causes
coughing and sometime bronchospasm. (not
recommended for induction)

CVS :
CVS depression similar to Isoflurane

CNS:
CNS system are similar to Isoflurane.

Indicated in Hepatic and Renal Surgery

Contraindicated in Severe hypovolemia,

malignant hyperthermia and Intracranial hpt.

Desflurane:

Advantages:
It has a low blood
solubility; therefore it
offers more precise
control of maintenance
of anaesthesia and
rapid recovery.
It is minimally
biodegradable and
therefore nontoxic to
the liver and kidney.
It does not cause
convulsive activity on
EEG.

Disadvantages:
It cannot be used for
inhalational induction
because of its irritant
effects on the airway.
It causes tachycardia at
higher concentrations.
It requires a special
vaporizer. Although the
TEC-6 vaporizer is
reasonably easy to use, it
is more complex than the
more conventional
vaporizers. And the
potential for failure may

Nitrous Oxide N2O:

O

N N=

N2O:

Physiochemical properties:
It is a laughing gas.
It is only inorganic anesthetic gas in clinical use.
A sweet smelling, non irritant colorless gas.
Not flammable but supports combustion of fuels in
absence of O2
A good analgesic, but weak anaesthetic.
N2O alone is insufficient to produce an adequate depth
of anaesthesia.
Has lowest blood/ gas solubility ( coef.0.47),
so induction is very fast.
Prepared commercially by heating ammonium nitrate
to 245-270 C, then stored in cylinders in compressed
form as a liquid
N2O cylinders should be kept vertical
It is excreted unchanged ( no metabolism in the body )

N2O:

EFFECTS ON ORGAN SYSTEMS:

CVS:

Directly depresses myocardial contractility.

But Stimulate sympathetic nervous system.

so Arterial blood pressure ,heart rate and cardiac output are slightly
increased.
RESPIRATORY:

Increases respiratory rate with decreases tidal volume.

Minimal change in minute ventilation.

CNS:
Increases CBF thus increasing intracranial pressure.
RENAL:
It decreases renal blood flow thus leads to drop in glomerular filtration
rate and urinary output.
HEPATIC :
Decreases the Hepatic blood flow but to a lesser extent than other
inhalation agents.
GASTROINTESTINAL:
It causes post operative Nausea and Vomiting.

Effect of N2O on closed space:

As N2O is 34 times more soluble than N2 gas , it
diffuses into air filled cavities leading to volume and
pressure of the cavities.
Toxicity :
N2O Interference with DNA synthesis by decreasing
the activity of methionine synthetase- a vitamin B12dependent enzyme. Which can cause
Megaloblastic anemia if exposure is > 6hrs, bone
marrow suppression ,agranulocytosis , BM aplasia.
Teratogenic changes :
Observed in pregnant rats but no evidence in human
So nitrous should be avoided in early pregnancy.

N2O:
ADVANTAGES

Non flammable, non explosive

Non irritant
Potent analgesic
Very rapid onset, recovery and
changes in anaes. depth
Little or no toxicity during
normal applications

CONRAINDICATIONS:
Air embolism
Pneumothorax
Acute Intestinal Obstruction
Tension Pneumocephalus
Tympanic membrane
grafting

DISADVANTAGES

Weak anaesthetic agent

No augmentation of muscle
relaxation
Diffusion hypoxia on recovery
Expansion of closed internal air
spaces

Depress methionine synthase

activity

Megaloblastic marrow changesDemylenation of the cord in long

term abusers

Xenon:

This inert gas has many characteristics of

an ideal inhaled anesthetic such as

Blood gas partition coefficient of 0.14,

Provides some analgesia,
Non pungent,
Does not produce myocardial depression

The principal disadvantages of xenon are

its expense (difficult to obtain) and

high minimum alveolar concentration (MAC)
(71%).

Entonox:
Entonox is a 50:50 mixture of N2O and
O2.
The two gases effectively dissolve into
each other and do not behave in a
way that would be predicted from
their individual properties. ( Poynting

effect.)

Entonox is widely used for analgesia

during labour and during dental
procedures.

COMPARATIVE PHARMACOLOGY

CVS effect:

All inhalational agents adversely affect the cardiovascular

system to some extent . Several mechanisms are involved:
1. Direct depression of the vasomotor centre
2. Depression of baroreceptor reflexes
3. Depression of cardiac contractility
4. Dilatation of peripheral vessels causing a fall in systemic
vascular resistance
5. Sensitization of the myocardium to catecholamines .

Sevoflurane has the best cardiovascular profile and

halothane the worst.
Desflurane is associated with a sympathetically mediated
sinus tachycardia when the concentration is increased rapidly
above 1 MAC.( attenuated by the addition of nitrous oxide.)

Halothane causes dose-related bradycardia, slowing of AV nodal

conduction and ventricular arrhythmias.

Halothane and enflurane decrease calcium ion release from the

sarcoplasmic reticulum and marked hypotension may occur in
patients taking calcium antagonists.

Halothane has the greatest catecholamine-sensitizing effect and

enflurane the least.

Isoflurane has been linked to cause Coronary artery steal

syndrome ( in which epicardial resistance vessels are dilated), but
there is no evidence of an increase in perioperative cardiac events
in clinical studies.

Sevoflurane - preserve the balance of epicardial to endocardial BF,

and cuases less reduction in MAP

The order of potency for direct myocardial depression, in

decreasing order is:
Enflurane > Halothane > Methoxyflurane > Isoflurane /
Desflurane > Sevoflurane

The effect of increasing MAC on mean arterial pressure (MAP)

All volatile
anesthetics causes
similar dosedependent decrease
in MAP
Halothane cause this
by decreas in
myocardial
contractility & CO
Isoflurane ,
desflurane &
sevoflurane by
decreased systemic
vascular resistance

Effect Of Increasing MAC

On CO

CO decreases in dose dependent way by

halothane, enflurane, and sevoflurane
But is well preserved with isoflurane & desflurane

Respiratory effects :

All of the volatile agents depress the ventilatory

response to hypercarbia and, to a greater extent,
to hypoxia ( dose-related )

Enflurane has the greatest respiratory depressant

effect and halothane the least.

Isoflurane at 1 MAC depresses the ventilatory

response to hypercarbia by 50% and the response
to hypoxia is abolished.

Airways irritation - most marked with desflurane

and least with sevoflurane

Central Nervous System:

All the volatile agents impair the normal

autoregulation of cerebral blood flow

CBF increased four-fold by 1.6 MAC of halothane

and doubled by 1.6 MAC of enflurane.

The effect of isoflurane, sevoflurane and desflurane

is less.

The increase in cerebral blood flow can be

attenuated by deliberate prior hyperventilation.

All the agents, except halothane, cause a doserelated reduction in cerebral oxygen consumption.
EEG activity is reduced in a dose-related fashion.

Enflurane produces characteristic excitatory spikes at

concentrations above 1.5 MAC, particularly in
association with hypocapnia
So it should be avoided in epileptic patients.

Sevoflurane is associated with persistent EEG activity

at 1014 Hz at deeper planes of anaesthesia than the
other agents, but is not epileptogenic.

Renal effects
All agents causes dose dependent, reversible
reductions of,
Glomerular filtration rate
Renal blood flow, and
Urine production
Doses of more than 2 MAC often have plasma
concentrations above the renal threshold for toxicity
(40-50 mol/l)
Which will result in direct distal tubular damage ,
polyuria, dehydration, hypernatraemia,.

Liver:
All agents causes hepatic blood flow in a dose
dependent fashion which may interfere with hepatic
drug clearance ( apart from inhibition of drug
metabolising enzyme)
Halothane has a potential to cause severe
hepatotoxicity.
Other agents cause mild , self limiting post op hepatic
dysfunction ( due to altered hepatic O2 delivery )
Skeletal muscle :
Dose-dependent enhancement effect on NMJ by ether
derivative fluorinated volatile agents (sevoflurane >
desflurane - isoflurane - enflurane >halothane )
N2O > 1MAC (hyperbaric chamber ) muscle rigidity
Malignant hyperthermia
All can trigger (halothane > potent)

OBSTETRIC EFFECT :
Dose dependent relaxation of uterine smooth
muscle
May need in removal of retained placenta.
May contribute to blood loss due to uterine atony.
N2O provide analgesia during vaginal delivery
only
Total body O2 requirement :
Reduce, so protect tissue from ischemia .
Reflect metabolic depression & functional needs

Halothane

Cardiovasc

Enflurane

Isoflurane

Desflurane

Sevoflurane

Nitrous

Xenon

Dosedependantdepression

Inotropy

Noeffect

--

---

Noeffect

Chronotropy

-(SAnode)

++

++++

++

Noeffect

Dromtropy

-(AVnode)

Noeffect

Lusitropy

Noeffect

+++

SVR

---

----

---

--

Noeffect

MAP

--

---

--

--

Noeffect

Coronary

Dilatation

Noeffect

Arrhythmia

Cerebral

Anaesthesiaandanalgesia,decreasingmetabolicrateandoxygenrequirements

Bloodflow

++++

+++

++

++

++

Nil

Pressure

++++

+++

++

++

++

Nil

CBF/ICP

+++

++

Nil

Seizures

Bursts-EEG

FlatEEG

DosedependantdepressionXe>E>I>S>D>H>N2O

Respiration
Rate

Dec

TidalVolume

--

--

---

--

--

Inc

Bronchi

Dosedependantdilatation,abolishhypoxicpulmonaryvasoconstriction

GUT

UterineRelaxation

Hepaticbufferlost

Musclerelaxation,potentiationofmusclerelaxation.

No
boweldistension

Boweldistension