INHALATION ANAESTHETIC
AGENTS
PROF ATIM.I. ESHIET
Introduction
An inhalational anaesthetic agent is introduced into the body
through the upper airway. Usually administered for the
maintenance of general anaesthesia and may be used for
induction particularly in paediatric and
debilitated adult patients.
Pharmacokinetics of inhaled anaesthetic agent describes;
-Uptake from alveolar to the systemic circulation
- Distribution and elimination by the lungs or
metabolism by the liver.
Introduction
The goal of pharmacokinetics
- To obtain an optimal brain partial
pressure of the inhalational anaesthetic
agent.
The alveolar partial pressure(PA) of the
inhaled anaesthetic agent is a reflection
of the brain partial pressure(Pbr). PA is
an index of the depth of anaesthesia
DEFINITION
Inhalational anaesthetic agents are
gases and volatile liquids possessing
anaesthetic
properties.
History Of Inhalational
Anaesthetic
Agents
Nitrous Oxide was introduced by
Humphrey Davy in 1799
Nitrous oxide was formerly used as
anaesthetic 1844 by Horace Wells
and Colton
Ether- first public demonstration by
William T. G. Morton on the 16th of
October,1846 in Boston, USA
Chloroform was introduced by Simpson
in 1847.
First death from chloroform was in 1848
when a 16 year old girl, Hannah Greener
died from chloroform anaesthesia
administered for the excision of an
ingrowing toe nail.
Other inhalational agents synthesized
for clinical use:
- Ethyl chloride
- Methoxyflurane
- Trichloroethylene
- Halothane
- Enflurane
- Isoflurane
- Sevoflurane
- Desflurane
CLASSIFICATION:
Inhalational anaesthetic agents are
either gas or volatile liquid.
Gas – Nitrous oxide
Volatile Liquid
Ether e.g. Di-ethyl ether
Halogenated Hydrocarbon e.g. Halothane
Halogenated ether e.g. Enflurane,
Isoflurane, Sevoflurane, Desflurane
IDEAL INHALATIONAL
ANAESTHETIC AGENT
The search for an ideal inhalational anaesthetic led
to the development of series of agents. Initially,
ether (Di-ethyl ether), nitrous oxide and chloroform.
Thereafter, Cyclopropane, Halothane,
Methoxyflurane, Trichloroethylene, Enflurane and
Isoflurane were developed and approved for use in
humans.
Recently, newer agents such as Sevoflurane and
Desflurane have been introduced.
Di-ethyl ether, cyclopropane,trichloroethylene and
chloroform have been withdrawn because of
flammability and systemic toxicity.
PROPERTIES OF AN IDEAL
INHALATIONAL ANAESTHETIC
AGENT
Pleasant odour: This is to encourage breathing
and to avoid breath holding/coughing during
induction.
Cardiovascular System stability
Respiratory System stability and also
bronchodilatation.
No Biotransformation
Not inflammable in air, oxygen nor nitrous
oxide
Not decomposed by heat
High saturated vapour pressure to allow easy
vaporization (but not so high to boil at room
temperature).
Provide muscle relaxation
Devoid of systemic toxicity or
undesirable side effect.
No sensitization of the heart to
exogenous catecholamine
No interaction with other drugs.
Low solubility in blood to allow rapid
induction and recovery.
Should be compatible with soda lime.
Should be cheap to manufacture.
STAGES OF ANAESTHESIA
The stages of anaesthesia is the process
from the commencement of induction to
the stage of surgical anaesthesia (stage 3) and
beyond.
Anaesthesia becomes unsafe beyond stage 3 plane 1.
Stage 4 is a stage of anaesthetic overdose.
John Snow described five stages of narcosis
in 1847. Arthur Ernest Guedel, in 1937
described the classical stages of
Anaesthesia in unpremedicated patients breathing
di-ethyl ether in air.
Stage 1- Stage of analgesia. From commencement
of induction to loss of eye
lash reflex and unconsciousness.
Stage 2- Stage of excitement
Irregular breathing, struggling and
dilated pupils. Vomiting, coughing and
laryngospasm may occur.
Onset of automatic breathing and loss of
eye lid reflex ends this stage.
Stage 3-Stage of Surgical Anaesthesia. It is from
the onset of regular breathing to onset of
diaphragmatic paralysis.
Stage 3 into four planes.
Plane 1 -eye ball is central
-loss of conjunctival reflex
-depressed swallowing and vomiting
reflexes
- lacrimation is increased
Plane 2 – onset of intercostal muscle
paralysis
- regular and deep breathing
- loss of corneal reflex
- dilatation of the pupils
- increased lacrimation
Plane 3 –completion of intercostal
paralysis
- shallow breathing
- depressed laryngeal reflex
-depressed lacrimation
Plane 4-complete diaphragmatic
paralysis
- carinal depression
Stage 4 –Stage of Overdose
-Apnoea
-Dilated pupils
-Death
With modern agents and techniques , these
stages occur too rapidly to be distinguished
easily. CAUTION should be the watch word!
MINIMUM ALVEOLAR CONCENTRATION
(MAC)
This term is used to express the dose of an
inhalational anaesthetic agent.
MAC is the minimum alveolar concentration
at one atmosphere in which 50% of patients
do not react in response to a standard
surgical stimulus. MAC measures the potency
of an inhalational agent. The lower the MAC
value, the more potent the inhalational
anaesthetic agent.
Uptake, Distribution And
Elimination of Inhalational
Anaesthetic Agent
The factors that affect uptake,
distribution and elimination are
divided into two phases.
Pulmonary phase
Circulatory phase
Pulmonary Phase
Inspired Concentration
Alveolar ventilation
Blood - Gas Solubility Coefficient
Pulmonary Blood Flow
Second Gas Effect
Breathing Circuit
CIRCULATORY PHASE
Cardiac Output (CO):
Increase CO leads to increase uptake from the
blood and slow induction of anaesthesia.
Cerebral Blood Flow (CBF):
Increase CBF leads to rapid induction of
anaesthesia.
Ventilation – Perfusion (V/Q) Abnormalities:
V/Q abnormalities (e.g. shunt) leads to alveolar –
arterial difference. In this situation, induction will
be slow with agents with low solubility e.g. N2O
than halothane
TISSUE TRANSFER
This is determined by three factors similar to systemic
uptake:
Tissue Solubility – increase solubility in blood – slow
induction
Tissue blood flow – increase blood flow – increase uptake
Partial pressure difference between arterial blood and
the tissue.
The tissues are into four groups:
Vessel rich group e.g. heart, brain, kidneys
Muscle rich group
Fat group
Vessel poor group e.g. bone, cartilage, teeth and hair.
Uptake is more in tissue which are highly perfused.
Elimination of Inhalational
Anaesthetic Agent
Recovery from anaesthesia is determined by the
decreasing concentration in the brain.
Elimination of inhalational anaesthetic agent from the body
is by exhalation, biotransformation and transcutaneous
route.
Recovery from anaesthesia is determined by the
decreasing concentration in the brain.
Discontinuation of inhalational anaesthetic agent
decreases tissue and alveolar partial pressure. The first
compartment from which the agent is cleared is VRG.
Elimination is slow in the fat group.
BIOTRANSFORMATION: Contributes minimally
to awakening. Biotransformation has impact on a
soluble agents which undergoes extensive
metabolism. Hepatotoxicity may be due to the
extensive biotransformation.
TRANSCUTANEOUS ROUTE: The amount
eliminated by transcutaneous route is minimal
Inhalational Anaesthetic
Agent
Partition Coefficient
-Blood- Gas Partition Coefficient describes
the distribution of an anaesthetic agent
between blood and gas at the same partial
pressure.
A high blood-gas coefficient correlates with
High solubility of the agent in blood and
thus slowing the rate of induction
Inhalational Anaesthetic
Agent
NITROUS OXIDE
-Manufactured by heating ammonium
nitrate at 240oC and removing
impurities
such as higher oxide of nitrogen
ammonia and nitric acid by passing the
gas through scrubbers.
Water vapour is also removed.
PROPERTIES OF NITROUS OXIDE
Colourless
Denser than air
Boiling point, - 88’C
Partition coefficient
blood/gas 0.47
oil gas 1.4
MAC = 105%
Non-flammable but supports combustion
Stored in a blue cylinder at a pressure 54 bar at room
temperature.
Ice flakes forms on the cylinder when in use because of latent
heat of vaporization available
In a 50:50 mixture of N2O and O2 = Entonox.
It is not a trigger for malignant hyperthermia
OTHER SYSTEMS:
Liver and renal functions are not affected
Uterine muscle tone is also not affected
Interacts with methionine synthase and as such
prolonged use may cause bone marrow depression,
megaloblastic anaemia and peripheral neuropathy.
Expands air-filled cavities because it diffuses from
blood into cavities faster than nitrogen can diffuse
out.
Expands pneumothorax and air embolism.
Implicated as being a teratogenic agent.
It increases skeletal muscle tone
Inhalational Anaesthetic
Agent
Volatile Anaesthetic Agents
These are potent evaporative liquid employed in
vapour form as inhalational anaesthetic.
Halothane
it is a halogenated alkane hydrocarbon {2-bromo
-2-chloro-1,1,1-trifluroethane}
Physical properties
Colourless liquid
Pleasant odour which encourages breathing
Halogenated to prevent explosion and fire.
Non-flammable
Compatible with soda lime
Compatible with diathermy
Saturated vapour pressure {mmHg} 243
Blood gas-solubility coefficient 2.4
Oil-gas solubility coefficient - 225
Boiling point – 50oc
MAC – 0.75
Effect on the systems
CNS
Dilates cerebral blood vessels
resulting in a decrease in cerebral
vascular resistance with consequent
increase in intra-cranial pressure. Not
desirable in patients with intra-
cranial tumour. Causes a dose-
dependent decrease in cerebral
metabolism.
CVS
Causes the following
1. Peripheral vasodilatation
2. Direct myocardial depression
3. Sympathetic ganglion depression. The resultant
effect is hypotension
- Sensitizes the heart to exogenous catecholamines
with a consequent dysrrhythmia.
- Causes bradycardia by reducing the rate of
conduction at the sino–atrial node.
RS
Non irritant
produces a dose dependent
respiratory depression.
Produces bronchodilatation which is
desirable in the asthmatic patient.
Hepatic system
Halothane reduces hepatic blood
flow.
Impairs the metabolism and
clearance of fentanyl and phenytoin.
May cause hepatic artery spasm
Halothane induced hepatitis may
develop
Renal system
Halothane reduces renal blood flow following
hypotension and decreased cardiac output.
Uterus
Halothane relaxes the uterine smooth muscle in
clinical dose. It is therefore not desirable in
obstetric anaesthesia because of the risk of post
partum haemorrhage
Neuromuscular system.
Cause skeletal muscle relaxation
Does not depress skeletal muscle twitch
in response to electrical stimulation of
motor nerves.
Potentiates the effect of non-
depolarization neuromuscular blocking
drugs
A trigger agent for malignant
hyperthermia.
Enflurane
It is a halogenated ether- {2-chloro-1,1,2-
trifluroethyl difluoro-methyl ether.}
PHYSICAL PROPERTIES:
Colourless Liquid
Mild, sweet ethereal odour
Not flammable
Compatible with diathermy
Saturated vapour pressure = 175mm hg
Blood – gas solubility =1.8
Minimum Alveolar concentration =1.68
Boiling Point =57 0C
EFFECT ON THE SYSTEMS
CNS
It increases CBF
Increase the secretion of CSF while restricting its outflow
Epileptiform changes may be observed on EEG.
Frank tonic-clonic seizures may occur. ( this is exacerbated by
hypocarpnia)
Decreases cerebral metabolism.
CVS
Dose-dependent myocardial depression (less than halothane) and
vasodilatation.
Cardiac output, arterial blood pressure and myocardial oxygen
consumption are reduced with Enflurane.
Enflurane may sensitize the heart to exogenous catecholamine at
doses of epinephrine greater than 4.5ug/kg
RS
Causes a dose dependent respiratory
depression
It reduces tidal volume
Increases ventilatory rate (in
unpremedicated patient)
Causes an increase in arterial CO2
concentration.
RENAL SYSTEM
Renal functions are depressed:
Renal blood flow
Glomerular filtration rate
Urinary output
UTERUS
No adverse effect when used in a range of 0.5 –
0.8%
NEUROMUSCULAR SYSTEM
It relaxes skeletal muscles. It also potentiates the
effect of non-depolarizing neuromuscular blocking
drugs.
DRUG INTERACTION
Isoniazid induces Enflurane
defluorination.
METABOLISM
2.5% of the absorbed Enflurane is
metabolized mainly to fluoride. Serum
fluoride ion concentration is higher in
the obese patients after Enflurane
anaesthesia.
ISOFLURANE
It is a halogenated ether (1-chloro-2,2,2
trifluroethyl difluoromethyl ether)
It is a chemical isomer of Enflurane but has
different physio-chemical properties.
It is Colourless
It has a pungent ethereal odour
Saturated vapour pressure =239
Blood – gas solubility coefficient =1.4
MAC (%) =1.15
Boiling point (oC) =48
EFFECT ON THE SYSTEMS
CNS
It increases CBF
It increases ICP
It reduces the CMRO2
It causes EEG suppression
CVS
Myocardial depression is minimal
Rise in heart rate (due to partial preservation of the baroreceptor
reflexes.
Causes mild B-adrenergic stimulation (results in skeletal muscle blood
flow, reduction in vascular resistance and a decrease in arterial blood
pressure)
Isoflurane is not desirable in the severely hypotensive patients
It dilates the coronary arteries (not proven)
Mild sensitization of the heart to exogenous catecholamine.
RS
Causes respiratory system depression
(to a lesser extent than Enflurane but
greater than Halothane) in a dose-
dependent manner. There is a
decrease in tidal volume but an
increase in ventilatory rate.
It is a good bronchodilator but it may
cause airway irritation.
HEPATIC SYSTEM
It reduces hepatic blood flow
Oxygen supply to the liver is maintained better
than during halothane anaesthesia
RENAL SYSTEM
Isoflurane decreases renal blood flow, glomerular
filtration and urinary output.
NEUROMUSCULAR SYSTEM
Muscle relaxation is achieved at relatively light
plane of anaesthesia.
The muscle relaxation effect is potentiated by
neuromuscular blocking drugs.
BIOTRANSFORMATION
Undergoes minimal biotransformation. The
major end product is trifluoroacetic acid.
Elevated level of plasma fluoride has not
been observed with Isoflurane.
CONTRAINDICATION
Ischaemic heart disease due to the
theoretical coronary steal syndrome
Severe hypovolaemia.
SEVOFLURANE
It is a halogenated ether (1,1,1,3,3,3
hexa-flouroisopropyl fluoromethyl ether)
It is Colourless
It has a pleasant odour
Boiling point =580C
Saturated vapour pressure
=160mmHg
Blood-gas partition coefficient =0.69
Oil-gas partition coefficient =53
MAC (varies according to age!
* 3.3% in neonates
* 2.5% in children and young adult
* 1.4% in patients 80 years and above.
It is non-flammable
It is non-corrosive
React with soda lime to form compounds A, B, C,
D.
Compound A (Pentaflouroisopropenyl
flouromethyl ether) has been proven to be toxic
in rats.
SYSTEMIC EFFECTS
CNS
Has poor analgesic property
Has minimal effect on ICP in normal patients
Preserve cerebral autoregulation in patients
with cerebrovascular disease
Reduces CMRO2
Decreases intraocular pressure.
CVS
Causes mild myocardial depression
Causes vasodilatation and hypotension
but less than that of Isoflurane
Causes mild tachycardia
Arrhythmias are rare
Sensitizes the heart slightly to the effect
of exogenous catecholamine.
RS
Has pleasant odour but irritates the airway
minimally
Depresses respiratory system (decrease in
tidal volume and respiratory rate)
Causes bronchodilatation; desirable in the
asthmatic patients.
RENAL SYSTEM
Renal blood flow is persevered.
UTERUS
Causes a dose-dependent uterine relaxation.
HEPATIC SYSTEM
Hepatic blood flow is presevered.
GIT
Sevoflurane causes post-operative nausea and vomiting (PONV) in
25% of patients.
NEUROMUSCULAR SYSTEM
Causes skeletal muscle relaxation
Its effect is potentiated by non-depolarizing neuromuscular
blocking drugs.
May precipitate malignant hyperthermia.
BIOTRANSFORMATION
Undergoes less than 5% biotransformation in the
liver to hexafluoroisopropanol and inorganic
fluoride.
The rest is excreted unchanged.
DRUG INTERACTION
Isoniazid and alcohol increase the metabolism of
Sevoflurane.
DESFLURANE
It is a halogenated ether (1-fluoro-2,2,2-tri-
fluoromethyl ether)..
Its structure differs from that of Isoflurane in the
substitution of fluorine for chloride
PHYSICAL PROPERTIES
It is a Colourless liquid
It has a slight pungent odour
Boiling point =23oC
Saturated vapour pressure =673mmHg
Blood-gas solubility coefficient
=0.42
Oil-gas solubility coefficient =19
MAC is 7.2 – 10.7% in children and 5-7% in adults
Interacts with dry soda lime to produce carbon
monoxide.
SYSTEM EFFECTS
CNS
No analgesic property
Increases CBF and ICP
No effect on EEG (beneficial in cerebral ischaemia)
Induction is rapid, but maybe limited by the pungent odour
Recovery is also rapid.
CVS
Causes vasodilatation with consequent hypotension. But in the
absence of premedication, may cause tachycardia and
hypertension because of sympathetic stimulation when high
concentration is introduced rapidly.
Myocardial ischaemia may occur
Arrhythmia is rare with Desflurane although there is slight
myocardial sensitization to exogenous catecholamine.
RS
Pungent odour.
Causes airway irritation
Not desirable for induction of anaesthesia
because of coughing, laryngospasm and
apnoea.
Depresses respiratory centre resulting in
decreased tidal volume and increased
respiratory rate.
NEUROMUSCULAR SYSTEM
Potentiates the effect of non-
depolarizing muscle relaxant.
Effect on the uterine muscle-causes
dose dependent uterine relaxation.
May precipitate malignant
hyperthemia.
