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3. general anaesthetics
1. General Anaesthetics
General anaesthetics is class of CNS depressants drugs which
produce partial or total loss of the sense of pain with a controlled and
reversible depression of the functional activity of CNS.
In order to perform more complicated surgical operations, the
surgeon needs time and needs a patient whose muscles are
relaxed. General anaesthetics serve both these objectives.
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2. Characteristics of General Anaesthetics:
•The agents in this class possess wide structural variations and hence
strict structure-activity relationship cannot be framed out.
•These agents are non specific in action that is they do not interact
with specific receptor. Hence they are thought to be simple general
cellular poison.
•They are used at high concentrations and have access to all areas of
the body.
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3. Overton-Meyer Hypothesis of Anaesthetic
Activity:
Anaesthesia refers to the complete lack of somatic sensation. Overtone attempted
to explain drug induced anaesthesia. Overton and H. H. Meyer stated that:
•All neutral lipid soluble substances have depressant properties on neurons.
•This activity is more pronounced in lipid rich cells’
•The effect increases with increasing partition coefficient, regardless of the
structure of the substance.
Although the absolute drug concentration necessary to achieve anaesthesia varies
greatly. The drug concentration in the lipid phase that is in the cell membrane is
about 20-50 mm for all anaesthetic agents.
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4. In 1954, Mullins, in a modification to the Overton Meyer hypothesis, proposed
that besides the membrane concentration of the anaesthetic, its volume, is
important. This reasoning implies that the anaesthtic expands the cell membrane,
and that anaesthesia occurs when critical expansion value is reached at about 0.3-
0.5 % of the original volumes. The surface area of the membrane will also expand
by several percentage points.
In general lipophilic and unionized molecules pass most readily into the central
nervous system.
In case of general anaesthetic agents, as the concentration is increased,
penetration into the CNS increases, resulting into increased depth of
anaesthesia. For convenience, Guedel divided anaesthesia into four separate
stages in 1937:
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5. Stage I Analgesia: Consciousness is maintained, analgesia is produced. Since
higher cortical centers are depressed, this stage is also called as cortical stage.
Stage II Delirium or stage of excitement: Consciousness is lost. It is characterized
by excitement and the patient may shout and struggle violently. He may salivate,
vomit or develop cough.
The first two stages are combinely called as induction period.
Stage III Surgical Anaesthesia: Skeletal muscles are relaxed and hence most of the
operative procedures are performed at this stage. It is further subdivided into four
planes representing progressive increase in the depth of anaesthesia and decreased
respiration.
Stage IV Respiratory Paralysis or Medullary Paralysis: This is toxic or overdose
stage in which there is respiratory and cardiovascular collapse and the tissues
rapidly becomes anoxic.
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6. Preanaesthetic Medication:
•Generally hypnotic is given on the night before to assure good night
sleep.
•One or two hours before surgery. Atropine is usually administered to
prevent excess secretion of saliva or mucus which might impede the
work of anaesthetist.
•Morphine or Pethidine is also given to minimize the fear and
apprehension.
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8. •Hydrocarbons:
In homologous series of alkanes, alkenes and alkynes, the anaesthetic activity is
directly proportional to the chain length. But since the toxicity also increases
simultaneously, only ethylene and Cyclopropane remain the anaesthtic agents of
clinical value.
•Cyclopropane:
H2
C
H2C CH2
It is dense, colorless gas with sweetish odor and taste. 15-20% V/V Cyclopropane
mixed with 80-85% V/V oxygen is sufficient to achieve the stage of surgical
anaesthesia. It is having the following advantages:
•High potency and wide margin of safety.
•Non irritant and pleasant to use.
•Since catecholamine releases is greater with Cyclopropane, blood pressure is
maintained during anaesthesia.4/11/2020 8
9. •Ethylene:
H2C CH2
It has no particular advantage over the other anaesthetic agents which
are currently in use. On the other hand, its lack of potency and its
highly inflammable and explosive properties, preclude its use in recent
clinical practices.
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10. •Halogenated Hydrocarbons:
The replacement of hydrogen of low molecular weight ethers and
hydrocarbons by halogen results in an increase in its anaesthetics
potency with the proportional decreases in its flammability.
CCl4
CHCl3
CH2Cl2
CH3Cl
AnaestheticPotency
Flammability
But this halogen substitution is also accompanied by increase in
toxicity which has limited their use in anesthetics.
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11. •Among the halogens, some of the chlorinated analogues are used
clinically to some extent. E.g. Chloroform, ethyl chloride and
trichloroethylene.
CHCl3
Chloroform Ehtyl Chloride
CH3CH2Cl C
Cl
Cl CHCl
Trichloroethylene
•Bromination of hydrocarbons is also tried but none of the
compounds is found clinically applicable.
•Additional qualifications like decreased toxicity, decreased
flammability, decreased boiling point with an increase in the
anaesthetic potency are associated with the fluorinated hydrocarbons
and ethers e. g. Halothane, Fluroxene, Methoxyflurane, Enflurane,
Isoflurane and Sevoflurane.
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12. Halothane
F3C CHBrCl F3C CH2 O CH CH2
Fluroxene
CH3O C CHCl2
F
F
Methoxyflurane
CHF2OCF2CHFCl
Enflurane
CHF2OCHClCF3
Isoflurane
FCH2OCH(CF3)2
Sevoflurane
Halothane, a volatile and non-inflammable liquid, is one of the most
commonly employed anaesthetic agents (2-2.5%). Since it is light
sensitive, it is stored in brown bottles and stabilized by 0.01% thymol.
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13. •Ethers:
In this series, an increase in the chain length results in an increased
anaesthetic activity with the simultaneous increase in toxicity. Hence
only diethyl ether and divinyl ether are found to be clinical
importance.
CH3 CH2 O CH2 CH3
Diethylether
CH2 CH O CH CH2
Divinylether
•Diethyl ether:
•Ether takes comparatively more time to saturate the alveoli (slowly saturating
agent) and here induction period is long. But since the blood gas partition
coefficient is high, the perfusion of anaesthetic from alveoli to blood and from
blood to fatty and muscle tissue is rapid. This safety factor contributed towards
ether popularity.
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14. •Ethers vapors form an explosive mixture with air or oxygen.
•Ether undergoes oxidation rapidly on exposure to air, light or moisture to form
peroxide and acetaldehyde which can be inhibited by copper.
•Premedication with atropine is essential since irritation by ether vapors can causes
excessive bronchial secretion.
•Cardiac stimulation is observed when ether is used as an anaesthetic since ether
causes release of catecholamine into circulation.
•Ether is usually administered in nitrous oxide-oxygen-carbon dioxide mixture.
Generally high concentration of ether (11-15%) is required for induction but once
attained can be maintained with much lower concentration of ether.
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15. •Divinyl ether:
It resembles with diethyl ether in its odor, properties and its action. It
is more unstable than diethyl ether and hence stored in amber glass
bottles. The inflammability and high volatility makes vinyl ether
unfit for the use in hot climates. Since induction with vinyl ether is
very fast, it should only be used for operations of short duration,
which otherwise may cause irreversible liver damage. Hence vinyl
ether is clearly of very limited utility.
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16. •Alcohols:
From long time alcohols are known for their utility to depress certain
higher centers of the central nervous system. The depressant activity is
retained only upto 8 carbon atoms. None of the alcohol is used for
maintainance of anaesthesia but some halogenated alcohols e. g.
tribromo ethanol and trichloro ethanol are potent hypnotic and are
capable for producing basal anaesthesia.
Cl3C CH2OH
Trichloroethanol
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17. •Ultrashort acting Barbiturates:
For rapid induction of anaesthesia, the sodium salt of ultra short acting barbiturates
is usually administered intravenously. The advantages associated with these agents
are:
•Smooth induction
•Fair muscle relaxation
•Non explosive nature
•Short and uncomplicated recovery
The potent respiratory depression is the risk generally associated with their use
and hence they are used to produce rapid and pleasant anaesthesia, which is then
maintained with the volatile anaesthetics. Their high lipid solubility and rapid
destruction of these drugs by liver, contribute to their short duration of action.
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19. •Miscellaneous agents:
•Ketamine hydrochloride:
Generally used as an induction anaesthetic prior to use of other anaesthetic due to
its rapid onset and short duration of action on parentral administration and may be
of value in short surgical procedure which do not require skeletal muscle
relaxation.
The side effects include an increase in blood pressure, delirium, hallucination .
Cl
NHCH3.HCl
O
Ketamine hydrochloride
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20. b) Nitrous oxide (laughing gas):
Nitrous oxide was introduced in 1844. Nitrous oxide is non-flammable, non-
irritating and powerful analgesic with least potent anaesthetic properties. If used
alone, concentration of 80-85% of nitrous oxide is required to produce surgical
anaesthesia, which is associated with the risk of hypoxia and hence it is currently
used as adjunct to ether or halothane in most of the procedures. But since it is good
analgesic in sub therapeutic concentration (20-30%), it is used for minor dental
operations, painful procedures e. g. dressing of burns etc.
It is one of the safest anaesthetic agents. It does not exert any toxic effect on liver,
kidney, the gastrointestinal tract and CNS, it is rapidly excreted in unchanged form,
mainly through lungs.
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21. •Propanidid:
It is eugenol derivative which is principle constituent of oil of cloves. It is an oily
liquid having anaesthetic action of very short duration when given intravenously.
Unlike other anaesthetics it has stimulant action on respiration while depressant
action on myocardium, resulting into hypotension. The nausea and vomiting is more
frequent with propanidid than any other IV anaesthetics.
Propanidid is attacked at its ester linkage by the serum cholinesterase in plasma and
liver. The resulting acid further undergoes metabolism with the loss of diethyl amino
group.
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22. Mechanism of action:
Due to wide structural variation general anaesthetics are thought to be of non-
specific in their action that is they do not act on specific receptor sites. The most
recent theories include the lipid solubility hypothesis proposed by Overton and
Meyer, which correlates the potency of the anaesthetics agents with its lipid
solubility. The hydrocarbon core of the lipid bilayer region of nerve membrane
accommodates the anaesthetics molecules which expand the membrane by fluidizing
or disordering the phospholipids bilayer and thus inhibits the essential
conformational changes of membrane protein involved in the ionic conductance. The
membrane protein itself may also be the site of action. These proteins comprise the
apolar amino acid residues embedded in the lipid bilayer of the nerve membrane.
The anaesthetic agents modify the properties of the lipid bilayer in which these
proteins function and thus inactivate these proteins which are essential for
functioning of CNS.
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23. Metabolism of volatile anaesthetics:
A small amount of anaesthetics undergoes the metabolism.
•Hydrocarbons are mainly converted to alcohols, aldehydes and acids
CF3CHClBr CF3CH2OH + CF3CHO + Cl-
+ Br-
Halothane
CF3COOH + Cl-
+ Br-
•Halogenated hydrocarbons undergo de halogenations by microsomal enzymes.
•Ether metabolism occurs in two phases, in the first phase, ether is converted to an
alcohol and aldehydes which are further metabolized to carbon dioxide in the second
phase.
CH3 CH2 O CH2 CH3
Diethylether
CH3CH2OH + CH3CHO
Ethanol Acetaldehyde
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24. Classification:
Besides on chemical basis, general anaesthetics may also be classified on the basis of
their physical state like.
•Volatile anaesthetics: e. g. Ether, chloroform, trichloroethylene, halothane,
Fluroxene, Methoxyflurane, vinyl ether and ethyl chloride
•Gaseous anaesthetics: e. g. Nitrous oxide and Cyclopropane
•Non volatile anaesthetics: e. g. Ultra short acting barbiturates, ketamine and
propanidid.
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