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

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. Blunting of 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:
Causes muscle relaxation and
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

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/epileptogenic
(accentuated by hypocapnia)
Effects on ICP ~variable

CVS:

Dose-dependent cardiovascular depression ~ by 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
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 pts. which is
maldistribution of blood from ischaemic to non ischaemic
area due to coronary vasodilation ( 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 contraindications as such.
Patient with severe
hypovolemia may not tolerate
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