General Anaesthetics – Medicinal Chemistry

General Anaesthetics

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1 General Anaesthetics


At the end of this
lecture, the student will be able to:

• Definition of anaesthesia

• Chart the history of general anaesthesia

• Enlist the ideal characteristics of general anaesthesia

• Describe the mode of action of general anaesthesia

• Categorize the stages of general anaesthesia

• Classify the GA according to their chemical structure

• Define the general anaesthisa

• Outline the scheme of synthesis of some GAs

• Recognize the specific uses of the various GAs


• General Anaesthesia

• History of general anaesthesia

• The ideal characteristics of general anaesthesia

• The mode of action of general anaesthesia

• The stages of general anaesthesia

• Classify the GA according to their chemical structure

• The scheme of synthesis of some GAs

• The specific uses of the various GAs

What is

• The absolute loss of sensation is termed as anaesthesia

• It is derived from a Greek word meaning insensitivity or
lack of feeling

• It is a reversible condition of comfort and a state of
quietness for a patient within the physiological limit before, during and after
performance of a procedure


• For surgical procedure to render the patient unaware/unresponsive
to the painful stimuli.

• – Drugs producing General Anaesthesia – are called General


• Reversible inhibition of impulse generation and
propagation in nerves.

• In sensory nerves, such an effect is desired when painful
procedures must be performed, e.g., surgical or dental operations

• – Drugs producing Local Anaesthesia – are called Local
Anaesthetics e.g. Procaine,

History of

• Pre-1846 – the foundations of anaesthesia

• 1846 – 1900 – establishment of anaesthesia

• 20th Century – consolidation and growth

• 21st Century – the future

Drug methods

• Alcohol

• Opium (poppy)

• Hyoscine (Mandrake)

• Cannabis (Hemp)

• Cocaine (New World)

Non-drug methods

• Cold

• Concussion

• Carotid compression

• Nerve compression

• Hypnosis

• Blood letting

• Middle ages the anesthetic effects of cold water and ice
were recognized.

• In 17th century, Marco Aurelio Severino described the
technique of “refrigeration anesthesia” in which snow was placed in parallel
lines across the incisional plane such that the surgical site became insensate
within minutes.

• The technique never became widely used, likely because of
the challenge of maintaining stores of snow year-round.

• Manipulation of the psyche to relieve surgical pain was
undertaken by French physicians Charles Dupotet and Jules Cloquet in the late
1820s with hypnosis, then called mesmerism.

• Greek physician from the first century AD, commented on
the analgesia of mandragora, a drug prepared from the bark and leaves of the
mandrake plant.

• He observed that the plant substance could be boiled in
wine, strained, and used “in the case of persons … about to be cut or
cauterized when they wish to produce anesthesia.

•”Mandragora was still being used to benefit patients as
late as the 17th century

• Alcohol was another element of the pre-ether armamentarium
because it was thought to induce stupor and blunt the impact of pain

• Laudanum was an alcohol-based solution of opium first
compounded by Paracelsus in the 16th century

• It was wildly popular in the Victorian and Romantic
periods, and prescribed for a wide variety of ailments from the common cold to
tuberculosis. it was frequently misused and abused

• Laudanum was given by nursemaids to quiet wailing infants
and abused by many upper-class women, poets, and artists who fell victim to its
addictive potential

• In 1773 Nitrous oxide was first prepared by Joseph

• In 1799 Davy commented that nitrous oxide transiently
relieved a severe headache, obliterated a minor headache, and briefly quenched
an aggravating toothache. Quoted; “As nitrous oxide in its extensive operation
appears capable of destroying physical pain, it may probably be used with
advantage during surgical operations in which no great effusion of blood takes

• Davy’s lasting nitrous oxide legacy was coining the phrase
“laughing gas” to describe its unique property

• 1818: Michael Faraday (1791-1867) described “narcotic
effects” of ether 1821:

• Benjamin Brodie (1783-1862) demonstrated to Royal College
of Surgeons that ether inhalation could induce insensibility in a guinea pig –
“….ether acted like a narcotic poison……”

• In 1831 David Waldie suggested chloroform, which had first
been prepared

• Horace Wells, a dentist, was the first person who
discovered the usage of nitrous oxide as an effective surgical anaesthetic in

• 1846, William Morton, a dentist, demonstrated the
anaesthetic action of diethyl ether which is not commonly used now a days due
to its adverse properties

• Pierre Cyprien Ore: introduced chloral hydrate in 1872

• Barbiturates were synthesised in 1603 for induction of

• Oct 16 1846 Gilbert Abbott underwent surgical excision of
a neck tumor at the Massachusetts General Hospital in the operating room now
known as “the ether dome.” The era of modern anesthesia and a
revolution in the medical care of the surgical patient had begun                                                                          

Chlorofom Popularised by James.Y.Simpson & practiced by
John Snow

John Snow used chlorofom to deliver the last two children of
Queen Victoria

• In 1934 the anesthetic properties of cyclopropane were
discovered accidentally by Ralph Waters’s chemists analyzing impurities in

• In 1956 came the introduction of halothane by Charles Suckling,
a nonflammable volatile halogenated alkane that quickly became the dominant

• The first intravenous anaesthetic, thiopentone, was
introduced in 1935


The Cardinal Features
of General Anaesthetics

• Loss of all sensation, especially pain

• Sleep (unconsciousness) and amnesia

• Abolition of somatic and autonomic reflexes

• Immobility and muscle relaxation

• General anaesthetics bring about descending depression of
the central nervous system; starting with the cerebral cortex, the basal
ganglia, the cerebellum and finally the spinal cord

• 1st – Cerebral cortex

• 2nd – Basal ganglia

• 3rd – cerebellum

• 4th – spinal cord

Stage I: Stage of
Analgesia or cortical stage

• Mild depression of higher cortical centers occurs

• Starts from beginning of anaesthetic inhalation and lasts
upto the loss of consciousness

• Pain is progressively abolished during this stage

• Patient remains conscious, can hear and see, and feels a
dream like state

• Reflexes and respiration remain normal

• It is difficult to maintain -use is limited to short
procedures only

Stage II: Stage of
Delirium and Excitement

• From loss of consciousness to beginning of automatic
breathing or entry into surgical anesthesia stage

• This is accompanied by excitement, delirium, uncoordinated
muscular movement and breath holding

• Like: Eyelash reflex disappear

• Excitement -patient may shout, struggle and hold his

• Muscle tone increases, jaws are tightly closed

• Breathing is jerky; vomiting, involuntary micturitionor

Stage III: Stage of
Surgical anaesthesia

• Extends from onset of spontaneous respiration to
respiratory paralysis, that movement ceases

• This has been divided into 4 planes:

– Plane 1: Roving eye balls. This plane ends when eyes
become fixed

– Plane 2: Loss of corneal and laryngeal reflexes

– Plane 3: Pupil starts dilating and light reflex is
lost.  This was the desired phase of
surgery when muscle relaxant were not used

– Plane 4: Intercostalparalysis, shallow abdominal
respiration, dilated pupil

The four planes described in other words

Plane-1) spinal reflexes are lost

Plane-2) muscle reflexes are lost

Plane-3) paralysis of intercostal muscles occur

Plane-4) muscle tone disappears

Stage IV: Medullary/
respiratory paralysis

• Cessation of breathing -failure of circulation -death

• Pupils: widely dilated

• Muscles are totally flabby

• Pulse is imperceptible

• BP is very low

• This stage is the toxic or overdose stage- Death occurs

• No stimulus or operative procedure carried out during this

• Potentially dangerous responses can occur during this
stage including vomiting, laryngospasm and uncontrolled movement.

• This stage is not found with modern anaesthesia– preanaesthetic
medication, rapid induction etc

characteristics of General Anaesthetics:

• Rapid and pleasant induction and withdrawal of surgical

• Adequate relaxation of skeletal muscle

• Safe, non-toxic, free from adverse effects

• Should me noninflammable, non-explosive

• Compatible with anesthetic devices – Inert

• Inexpensive

• Non-irritating to mucous membrane

• Should not produce hypotension, nausea and vomiting

• Compatible with adjuvant drugs used in anesthesia

of General Anaesthetics:

Classification of General Anaesthetics


• They could be either volatile liquids or gases and they
are administered through inhalation process

• They may be halogenated, non-halogenated compounds or
gaseous in nature

• Halogenated: I.
Hydrocarbons e.g. : Halothane, Chloroform

II. Ethers: e.g.: Methoxy flurane, Enflurane, Isoflurane

• Non halogenated:
I. Hydrocarbon e.g.: Cyclopropane

                                    II. Ethers e.g.:
Diethyl ether, vinyl ether

• Gaseous e.g.:
Nitrous oxide

Anaesthetics or nonvolatile anaesthetics:
Which are administered in the
form of injection through intravenous route

• Ultra short acting barbiturates:
e.g.: Methohexital sodium, Thiopental sodium

• Dissociative
e.g.: Ketamine hydrochloride


• Chemical name: 2bromo-2chloro-1,1,1trifluoroethane;  Ethane, 2 bromo2-chloro-1,1,1-trifluoro:

• Official In: BP,
U.S.P, Eur.P

• Marketed as Fluothane (Ayerst) and Halothane (May and

• It is the only inhalational anesthetic containing bromine

Chemical Structure of 

Chemical Structure of Halothane


• It is a clear, colourless, heavy, non-flammable liquid,
slightly soluble in water, miscible with ethanol, and with trichloroethylene

Medicinal Uses

• It is a relatively safe potent volatile anaesthetic
administered by inhalation

• It is twice as potent as chloroform and 4 times that of

• It may produce any depth of anaesthesia without causing

• It reduces the blood pressure and frequently decreases the
pulse rate and depresses respiration.

• It induces muscle relaxation and reduces pains sensitivity
by altering tissue excitability

Mechanism of action of Halothane:

• Halothane causes general anaethesia due to its actions on
multiple ion channels, which ultimately   depresses nerve conduction, breathing, cardiac contractility

• Its immobilizing effects have been attributed to its
binding to potassium channels in cholinergic neurons

• Halothane’s effect are also likely due to binding to NMDA
and calcium channels, causing hyperpolarization

Halothane synthesis

   Route 1

Halothane synthesis

   Route 2

Halothane synthesis

Particular aspects of
the use of Halothane:

• Moderate muscular relaxation is produced, but is rarely sufficient
for major abdominal surgery

• It potentiates the action of neuromuscular blockers

• Heat loss is accelerated

• It is useful in bronchitic and asthmatic patients.

• It is a potent, relatively safe general inhalation
anaesthetic used in conjunction with N2O

• For skeletal muscle relaxation, it is used with succinyl
choline or tubocurarine

Advantages of

• It is a volatile liquid halogenated hydrocarbon

• It is rapidly acceptable drug because of its
non-inflammable nature

• It has high potency and relatively lower blood/gas
partition coefficient

Disadvantages of

• It has narrow margin of safety

• It has high incidence of hepatic necrosis hence reduced in
its use

Storage: It
should be stored in well-closed airtight containers, protected from light, at a
temperature not exceeding 25°C in a nonreactive metal container


• Chemical Formula:

• Chemical Name:
2, 2-Dichloro-1, 1-difluoroethyl methyl ether; Ethane, 2, 2-dichloro-1, 1,

• Official In:
B.P., B.P.C., U.S.P., N.F.

Chemical Structure of Methoxyflurane

Chemical Structure of Methoxyflurane


• It is a clear, colourless liquid, noninflammable and
nonexplosive in air or oxygen in anaesthetic concentrations.

Medicinal Uses

• It is one of the most potent anaesthetic agents frequently
used in practice today

• In fact, it is employed to cause comparatively light
anaesthesia with deep analgesic and muscle relaxation, features which make it
convenient for short surgical operations, e.g., obstetrics

Mechanism of action of Methoxyflurane:

• Methoxyflurane induces a reduction in junctional
conductance by decreasing gap junction channel opening times and increasing gap
junction channel closing times

• Methoxyflurane also activates calcium dependent ATPase in
the sarcoplasmic reticulum by increasing the fluidity of the lipid membrane

• It also appears to bind the D subunit of ATP synthase and
NADH dehydogenase

• Methoxyflurane also binds to the GABA receptor, the large
conductance Ca2+ activated potassium channel, the glutamate receptor and the
glycine receptor


• Chemical Formula:

• Chemical Name:
2-chloro-1,1,2,-trifluoroethyl-difluoromethyl ether

• Official: USP

• Developed by Ross Terrell in 1963, It was first used
clinically in 1966.

• It was increasingly used for inhalational anesthesia
during the 1970s and 1980s but is no longer in common use due to less potency

Chemical Structure of Enflurane 

Chemical Structure of Enflurane


• Enflurane is a structural isomer of isoflurane

• It is a clear, colourless, volatile liquid with pleasant hydrocarbon-like

• Soluble in water, miscible with organic solvents,
chemically it is extremely stable.

• The induction of an emergence from anaesthesia and
adjustment of anaesthetic depth during maintenance is smooth    and moderately rapid.

• It is a noninflammable halogenated ether anaesthetic and
provides rapid induction with no excitement


Chemical Formula:

Chemical Name:

Official: USP

Chemical Structure of Isoflurane 

Chemical Structure of Isoflurane


• It is available as clear, colourless liquid at room
temperature, with sweet taste

• It is miscible with organic liquids including fats and
oils. Isoflurane is non-flammable and nonexplosive

Medicinal Uses

• General inhalation anesthetic drug


• Chemical Name:
1,2,2,2-tetrafluoroethyl difluoromethyl ether

• Chemical Formula:

Chemical Structure of Desflurane 

Chemical Structure of Desflurane

• It is a highly fluorinated methyl ethyl ether used for
maintenance of general anesthesia. Like halothane, enflurane, and isoflurane,
it is a racemic mixture of (R) and (S) optical isomers (enantiomers).


• Desflurane is a colorless, volatile liquid below 22.8°C

• It has a lower solubility in rubber and plastic than
halothane, isoflurane, or sevoflurane

• Desflurane is quite irritating to the airway and therefore
it is not suitable for an inhalation induction.


Chemical Name: 1,
1,1,3,3,3,hexafluro-2- fluro methoxy propane

Chemical Formula:

Chemical Structure of Sevoflurane 

Chemical Structure of Sevoflurane


• Low boiling liquid with a slight odour; miscible with most
organic solvents including fats or oils; practically insoluble in water. It is
a non-flammable, nonirritating agent

Medicinal Uses:

Sevoflurane is a non-explosive inhalation anesthetic used in
the induction and maintenance of general anesthesia

Nonvolatile or intravenous anaesthetics

• Intravenous anaesthetics usually cause unconsciousness
when administered parenterally.

• However, the duration of action can be safely monitored depending
on the amount of drug administered.

• Produced rapid onset of action within seconds and the
duration of action is for 30 sec.

• The rapid onset of action is attributed due to rapid
partition from blood across blood brain barrier to CNS

Ultra short
acting barbitutrates:

Sodium USAN, Methohexitone Sodium BAN,

• Chemical Name: Sodium
5 allyl-1-methyl-5-(1-methyl-2-pentynyl) barbiturate; 2, 4, 6 (1H, 3H, 5H) –
Pyrimidinetrione, 1-methyl-5-(1- methyl-2-pentynyl)-5-(2-propenyl)-, Sodium
salt, USP

• It has extensive hydrophobic character and lipid/water
partition coefficient so compound penetrates into CNS in few second after IV
injection and redistributed to other body site

• It undergoes rapid metabolic inactivation.

– Racemic mixture is used.

Chemical structure of
methohexital sodium

Chemical structure of methohexital sodium


• For intravenous and rectal route 10mg/ml is used.

• For continuous intravenous administration 2mg/ml is used.

• For intramuscular 50mg/ml is used.

Properties: White
to off-white hygroscopic powder, essentially odourless, and the solution is
alkaline to litmus, soluble in water.

• Methohexital produces more rapid recovery from
unconsciousness than thiopental.

Uses: It is more
potent and has shorter duration of action.

• It is used for the induction of anaesthesia through the
intravenous administration.

Advantages: It
has two advantages over thiopental sodium.

• First, being it has less affinity towards fatty tissues
and second, it has a greater potency.

Synthesis of
Methohexital sodium:

• Grignardization of 1-butynyl magnesium bromide with
acetaldehyde and subsequent treatment of the resulting alcohol with PCl5 yields
2-chloro-3-pentyne. Now, ethyl (1-methyl-2- pentynyl) – cyanoacetate is

• Therefrom by its condensation with ethyl cyanoacetate in
the presence of sodium ethylate.

• Further condensation of the resulting product with allyl
bromide gives rise to ethyl-(1-methyl- 2-pentynyl) allylcyanoacetate.

• Condensation with N-methyl urea and subsequent
neutralization with NaOH produces methohexital sodium.

Synthesis of Methohexital sodium

Medicinal uses

• Its onset of action is quite speedy comparable to
thiopental sodium while its recovery is more rapid.

• For these reasons, this intravenous anaesthetic is
specifically useful for short surgical operations, such as oral surgery,
gynaecological investigation, genitourinary procedures, and electroconvulsive


Thiopental sodium belonging to the class of
ultrashort-acting barbiturates (e.g., thiopental)

• are mostly employed IV to cause a rapid onset of
unconsciousness for both surgical and basal anaesthesia

• Importantly, it may be used first and foremost to cause
anaesthesia, which subsequently should be adequately sustained as well as
maintained in the course of a surgical operative procedure with the aid of a
general anaesthetic

It has high lipid water partition coefficient which forms
the base for the rapid partitioning.

• It can also be used in the combination with other
anaesthetic agent such as nitrous oxide.

Thiopental sodium

Sodium USAN, Sodium Thiamylal BAN:

• Chemical Name:
Sodium 5-allyl-5-(1-methylbutyl)-2-thiobarbiturate; 4, 6-(1H, 5H)-Pyrimidine-dione,
dihydro- 5-(1-methylbutyl)-5-(2-propenyl)-2-thioxo-, monosodium salt; U.S.P.,

• It is an ultra-short acting barbiturate mainly used for
intravenous anaesthesia in conditions of comparatively short-duration.

• It is also effective for the termination of convulsions of
unknown origin

Chemical structure of 

Thiamylal Sodium

Chemical structure of Thiamylal Sodium

• Thiomylal is a highly hydrophobic thiobarbiturate having
its structural featuresvery much related to thiopental.

• Its biological activities are almost identical to

• Used as intravenous anaesthetic

Dissociative anaesthesia

• A form of general anesthesia, but not necessarily complete
unconsciousness, characterized by catalepsy, catatonia, and amnesia

– Especially produced by phenylcyclohexylamine compounds, including

• A unique anesthesia characterized by analgesia and amnesia
with minimal effect on respiratory function.

• The patient does not appear to be anesthetized and can
swallow and open eyes but does not process information.

• This form of anesthesia may be used to provide analgesia
during brief, superficial operative procedures or diagnostic processes.

• It produces sense of dissociation from events being
experienced – i.e.produces feelings of detachment from the environment and

• It also reduces pain and overall feeling.

• Followed by anaesthesia, analgesia and sometimes amnesia.

• Anaesthesia produced is called as cataleptic anaesthesia-

– a condition of diminished responsiveness usually
characterized by a trancelike state and constantly maintained immobility

• It can used as a sole agent for surgical procedure in

Hydrochloride INN, BAN, USAN

• Chemical Name: 2-(o-Chlorophenyl)-2-(methylamino)
cyclohexanone hydrochloride; Cyclohexanone, 2-(2- chlorophenyl)-2- (methylamino)-,
hydrochloride; U.S.P., N.F

Chemical structure of 


Chemical structure of Ketamine

• Properties and uses:
It is a white or almost white crystalline powder, freely soluble in water,
methanol, and ethanol.

• Its another name is ‘dissociative anaesthetic’ because it
produces unpleasant hallucinations and strong feelings of dissociation from the
environment. It is a rapidly acting nonbarbiturate general anaesthetic that
produces anaesthesia   and is
characterized by profound analgesia

Synthesis of Ketamine

• It is prepared first by the interaction of
o-chlorobenzonitrile and bromo-cyclopentane 
in the presence  of  strong alkali to yield an epoxy compound.

• Secondly, the resulting epoxy compound on treatment with
methylamine forms an imine

• Which undergoes molecular rearrangement upon heating in
the presence of hydrochloric acid to yield ketamine hydrochloride.

Synthesis of Ketamine hydrochloride

• Ketalar:
Phencyclidine derivative

• It is a tasteless, odorless drug that can be a powder or
liquid. Racemic mixture is used

• Used for trauma patients with very unstable, low blood
pressure or for elderly patients, or children.

– Emergence may be accompanied by delirium, exciteme
disorientation, and confusion.

– Effect lasts for 30-60 minutes


• Agents which produce insensibility by successive or
progressive depression of central nervous system

• All GAs act on the mid-brain reticular activating system
and cerebral cortex to produce complete but reversible loss of consciousness

• They should be nontoxic, inert and should induce
anaesthesia smoothly

• The 4 stages of anaesthesia are

– Analgesia stage

– Delirium stage

– Surgical anesthesia

– Medullary depression

• General anaesthetics are broadly classified as inhalation and
IV anaesthetics

• Most of the GA also produce adequate skeletal muscle

• Dissociative anaesthetics cause dissociation from the suroundings-
cataleptic anaesthesia

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