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Diethyl ether first used by William T.G. Morton in the USA
Chloroform was the next agent to receive attention, by James
Simpson in 1847 it was discontinued due to:-
a. severe cardiovascular depression (sudden death ? VF)
b. 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 inflammable agent.
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- (1981), Desflurane-1996
a variety of other agents were investigated but
discarded for various reasons
A.Explosive mixtures with oxygen –
- ethyl chloride
- divinyl ether
b. postoperative liver necrosis / sudden death -
c. postoperative renal failure - methoxyflurane
Minimal alveolar concentration (MAC):
Is defined as the conc. At 1 atmosphere of
anesthetic in the alveoli that is required to
produce immobility in 50% of adults patient
subjected to a surgical incision
MAC is important to compare the potencies
of various inhalational anesthetic agents
1.2 -1.3 MAC prevent movement in 95% of
N2O = 105%
Halothane = 0.75%
Isoflurane = 1.16%
Euflurane = 1.68%
Sevoflurane = 2%
Deslurane = 6%
N2O alone is unable to produce adequate
anesthesia ( require high conc. )
No Effect on MAC
Duration of anesthesia
Carbon dioxide tension (21-95 mmHg)
Metabolic Acid base status
Pressure exerted by the molecules of the vapor phase at
equilibrium of molecules moving in and out of liquid phase
Vapor Pressure dependent on temperature and physical
characteristics of liquid, independent of atmospheric
↑ Temperature→↑ Vapor Pressure
Vapor pressure is a measure of the agent’s ability to
evaporate (volatility) .The greater is the vapor pressure,
the greater the concentration of inhalant deliverable to
the patient (and environment).
Boiling Point: Temperature at which vapor pressure
equals atmospheric pressure
Vapour Pressure & BP
Vapour Pressure & BP
Agent BP (0
C) VP (20 0
Halothane 50 243
Enflurane 56 175
Isoflurane 48 238
Sevoflurane 58 160
Desflurane 23 664
Nitrous Oxide -89
1. Transfer from Inspired Air to Alveoli
i. the inspired gas concentration FI
ii. alveolar ventilation VA
iii. characteristics of the anaesthetic circuit
2. Transfer from Alveoli to Arterial Blood
i. blood:gas partition coefficient τB:G
ii. cardiac output CO
iii. alveoli to venous pressure difference dPA-vGas
3. Transfer from Arterial Blood to Tissues
i. tissue:blood partition coefficient τT:B
ii. tissue blood flow
iii. arterial to tissue pressure difference dPa-tGas
A)Inspired Gas Concentration FI:-
according to Dalton's law of partial pressures, the
tension of an individual gas in inspired air is equal to,
PIgas = FIgas x Atm
the greater the inspired pressure the greater the
approach of FA to FI = the concentration effect
this is only significant where FI is very high, as is
the case for N2O (or cyclopropane)
when another gas is used in the presence of such an
agent, there is increased uptake of the second gas, the
Second gas effect
each inspiration delivers some anaesthetic to the
lung and, if unopposed by uptake into the blood,
normal ventilation would increase FA/FI to 95-98%
in 2 minutes
this rate of rise is dependent upon minute
ventilation and FRC
the greater the FRC, the slower the rise in FA
hyperventilation will decrease CBF, and this tends
to offset the increased rise of FA/FI
A) Blood:Gas Partition Coefficient
the solubility of a gas in liquid is given by its
Ostwald solubility coefficient, τ
this represents the ratio of the concentration in blood
to the concentration in the gas phase
lower B:G coefficients are seen with,
haemodilution ,obesity , hypoalbuminaemia and
higher coefficients are seen in, adults versus
children, hypothermia & postprandially
Solubility of Inhaled Drugs
solubility (partition) coefficient - the extent to
which a gas will dissolve in a given solvent
Predicts the speed of induction, recovery, and change in
anesthetic depth for an inhalant.
Ideal inhaled anesthetics should have low blood/gas and
low tissue/blood solubility and low solubility in plastic
Low solubility means rapid induction and emergence and
more precise control
Effective pulmonary blood flow determines the
rate at which agents pass from gas to blood
an increase in flow will slow the initial portion of
the arterial tension/time curve by delaying the
approach of FA to FI
a low CO state, conversely, will speed the rise of
these effects are greater for highly soluble
this represents tissue uptake of the inhaled
blood cannot approach equilibrium with alveolar air
until the distribution of anaesthetic from the blood
to the tissues is nearly complete
with equilibration, the alveolar/mixed venous
tension difference progressively falls as tissue
since diffusion is directly proportional to the tension
difference, the rate of diffusion into the blood
A) Tissue:Blood Partition Coefficient:-
the rate of rise of tension in these regions is
proportional to the arterial-tissue tension difference
conversely, their solubility in lipid tissues is far
greater than that for blood
at equilibrium the concentration in lipid tissues will be
far greater than that in blood
the tissue concentration will rise above that of blood
well before pressure equilibrium, even though the
tissue tension is lower
the higher the blood flow to a region, the faster the
delivery of anaesthetic and the more rapid will be
the body tissues have been divided into groups
according to their level of perfusion and tissue
a. vessel rich group VRG - brain, heart,
kidney & liver
b. the muscle group MG - muscle & skin
c. the fat group FG - large capacity/minimal
d. vessel poor group VPG - bone, cartilage,
with equilibration tissue tension rises and the rate
of diffusion slows, as does uptake in the lung
the rate is determined by the tissue time constant,
which in turn depends upon both the tissue
capacity (τT:B) and the tissue blood flow
TC(τ)= Tissue Capacity / 100g
Blood Flow/ 100g
Concentration and Second Gas Effects
- increasing the inspired concentration not only
increases the alveolar conc but also increases the
rate of rise of volatile anaesthetic agents in the
eg., during the inhalation of 75% N2O/O2, initially
as much as 1 l/min may diffuse into the
bloodstream across the lungs ,this effectively draws
more gas into the lungs from the anaesthetic circuit,
thereby increasing the effective minute
this effect is also important where there is a
second gas, such as 1% halothane, in the
the removal of a large volume of N2O from the
alveolar air increases the delivery of the second
gas, effectively increasing its delivery to the alveoli
and increasing its diffusion into arterial blood K/A
Second Gas Effect
1. Rapid and pleasant induction
2. Rapid changes in the depth of anesthesia
3. Adequate muscle relaxation
4. Wide margin of safety
5. Absence of toxic/adverse effects
CHARACTERISTICS OF AN
No single agent yet identified is an ideal anesthetic
- Good Analgesic
- Weak anesthetic
- Excreted via lungs
- MAC = 105%
- Lower water solubility
- Not Metabolized in the body
- Diffusion Hypoxia.
- Effects on closed gas spaces.(nitrous oxide can
diffuse 20 times faster into closed spaces than it can be
removed, resulting in expansion of pneumothorax, bowel
gas, or air embolism or in an increase in pressure within
noncompliant cavities such as the cranium or middle ear.
- CVS depression
What is diffusion hypoxia?
Diffusion hypoxia is a decrease in PO2 usually
observed as the patient is emerging from an
inhalational anesthetic where nitrous oxide (N2O)
was a component. The rapid outpouring of
insoluble N2O can displace alveolar oxygen,
resulting in hypoxia. All patients should receive
supplemental O2 at the end of an anesthetic and
during the immediate recovery period.
Second gas effect: The ability of the large
volume uptake of one gas (first gas) to
accelerate the rate of rise of the alveolar
partial pressure of a concurrently
administered companion gas (second
gas) is known as the second gas effect.
•Colorless, highly volatile, pungent odor,
flammable, explosive, stored in cool area.
Lungs: Stimulates resp, increases secretion, not
good in respiratory diseases
Kidney: decreases urine output
Liver: Minimum effect, decreases liver glycogen
Heart: Initially increases cardiac output, then
decreases card. output, suppresses
Ether as an anesthetic
•Advantage: CNS depression, excellent muscle
relaxant, causes surgical anesthesia
•Disadvantage: Flammable, irritates mucus
membrane, breath holding, induces nausea &
•Contraindications: Resp., kidney and liver
•Better agents are available now, so not used now.
Synthesized in 1951.
* Most potent inhalational anesthetic
•MAC of 0.75%
It has low blood/gas solubility coeffient of 2.5 and
thus induction of anasthesia is relatively rapid.
Chemical and Physical Properties
Halogenated compound chemically:
Volatile, so kept in sealed bottles
Colorless, Pleasant odor, Non-irritant
Corrosive, Interaction – rubber and plastic tubing
quantitatively as the minimum
alveolar concentration (MAC),
Numerically, MAC is small for
potent anesthetics such as
Halothane and large for less
potent agents such as nitrous
Halothane is a potent anesthetic but a relatively
weak analgesic. Thus, it is usually coadministered
with nitrous oxide, opioids, or local anesthetics.
It is a potent bronchodilator.
Halothane relaxes both skeletal and uterine muscles
and can be used in obstetrics when uterine relaxation
Halothane is not hepatotoxic in children (unlike its
potential effect on adults).
Combined with its pleasant odor, it is suitable in
pediatrics for inhalation induction, although
sevoflurane is now the agent of choice.
No specific receptor has been identified as the locus of
general anesthetic action –generally-.
It appears that a variety of molecular mechanisms may
contribute to the activity of general anesthetics.
Halothane activates GABAA , glycine receptors, 5-HT3and
twin-pore K+ channels
It antagonizes NMDA receptor.
It inhibits nACh(block excitatory postsynaptic currents of
nicotinic receptors) and voltage-gated sodium channels.
At clinically effective concentrations, general anesthetics
increase the sensitivity of the γ-aminobutyric acid (GABA-A)
receptors to the inhibitory neurotransmitter GABA. This
increases chloride ion influx and cause
Hyperpolarization Decrease Excitability CNS Depression
20% metabolized in liver by oxidative
Major metabolites : bromin, chlorine,
Trifloroacetic acid, Trifloroacetylethanl
The induction dose varies from patient to patient.
The maintenance dose varies from 0.5 to 1.5%.
Halothane may be administered with either
oxygen or a mixture of oxygen and nitrous oxide.
Halothane is indicated for the induction and
maintenance of general anesthesia.
Halothane is not recommended for obstetrical
anesthesia except when uterine relaxation is
Halothane anesthesia progressively depresses
Its cause inhibition of salivary & bronchial secretion.
Its may cause tachypnea & reduce in tidal volume and
alveolar ventilation .
Its cause decrease in mucocillary function which lead
to sputum retention.
It causes bronchodilation. Hypoxia, acidosis, or apnea
may develop during deep anesthesia.
Halothane anesthesia reduces the blood pressure, and cause
bradycardia.(atropin may reverse bradycardia.).
It cause myocardial relaxation & Hypotention.
Its also causes dilation of the vessels of the skin and skeletal
Halothane maybe advantages In pts with CAD , bcz of
decrease of oxygen demand.
Arrhythemias are very common .(especially with
◦ To minimize effects :
Avoid hypoxemia and hypercapnia
Avoid conc. Of adrenaline higher than 1 in 10000
Gastro intestinal tract:
Inhibition of gastrointestinal motility.
Cause sever post. Operative nausea & vomiting
Halothane relaxes uterine muscle, may cause postpartum
Concentration of less than 0.5 % associated with increase
blood loss during therapeutic abortion.
Its cause skeletal muscle relaxation .
Postoperatively , shivering is common , this increase oxygen
requirement>>> which cause hypoxemia
Two type of dysfunction:
1- Type I hepatotoxicity ,mild, associated with derangement
in liver function test , this result from metabolic of Halothane
in liver. results from reductive (anaerobic) biotransformation
of halothane rather than the normal oxidative pathway.
2- Type II hepatotoxicity: fulminate (uncommon); sever
jaundice ,fever,progressing to fulminating hepatic necrosis,
Its increased by repeated exposure of the drugs.
high mortality 30-70%
1- A careful anasthetic history .
2- repeated exposure of halothane within
3 months should be avoided.
3- History of unexplained jaundice or
pyrexia after previous exposure of
Post operatively shivering.
Possibility of liver toxicity.
•Potent cardiovascular depressant
Sweet and ethereal odor.
Generally do not sensitizes the heart to
Seizures occurs at deeper levels –
contraindicated in epileptics.
Caution in renal failure due to fluoride.
- Least soluble of the modern inhalational agent
equilibrate more rapidly
- Induction rapid theoretically (pungency??)
- pungency cough, breath holding.
effects on systems:-
dose dependent depression of vetilation.
- myocardial depressant (vitro Vs Clinical),
coronary vasodilatation (coronary steal
uterus: relaxation of uterine muscles (same).
effects on systems:-
low concentration Vs High concentration.
Low : no change on the flow.
High : increase blood flow by
vasodilatation of the cerebral arteries.
-Muscles: relaxation (dose-dependent).
Advantages and Disadvantages
-Rapid induction and recovery.
-Little risk of hepatic or renal toxicity.
-Low blood/gas partition coefficient faster
- non irritant so the fastest for induction.
effects on systems
-CVS: same as isoflurane (slightly lower
-CNS: same as halothane and isoflurane.
-Muscle relaxation: same as isoflurane.
Advantages and Disadvantages
1.Well tolerated (non-irritant, sweet odor), even at high
concentrations, making this the agent of choice for
2.Rapid induction and recovery (low blood:gas coefficient)
3.Does not sensitize the myocardium to catecholamines as
much as halothane.
4.Does not result in carbon monoxide production with dry
1.Less potent than similar halogenated agents.
2.Interacts with CO2
absorbers. In the presence of soda lime
(and more with barium lime) compound A (a vinyl ether) is
produced which is toxic to the brain, liver, and kidneys.
3.About 5% is metabolized and elevation of serum fluoride
levels has led to concerns about the risk of renal toxicity.
4.Postoperative agitation may be more common in children
then seen with halothane.
MAC =6 %
It is delivered through special vaporizer.
It is a popular anesthetic for day care surgery.
Induction and recovery is fast, cognitive and
motor impairment are short lived
It irritates the air passages producing cough and
Anesthetic Blood: Gas
Halothane 2.3 220 PLEASANT Arrhythmia
Enflurane 1.9 98 PUNGENT Seizures
Isoflurane 1.4 91 PUNGENT Widely used
Sevoflurane 0.62 53 PLEASANT Ideal
Desflurane 0.42 23 IRRITANT Cough
Nitrous oxide 0.47 1.4 PLEASANT Anemia