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General Anaesthetics 55
3.6 STAGES OF ANAESTHESIA
Stage-I (Analgesia): Features are loss of consciousness, pain is progressively abolished, patient
remains conscious, i.e., he can hear, see and feel, skeletal muscles relaxed and respiration normal.
Stage-II (Delirium): Stage of delirium are, loss of consciousness, apparent excitement, patient may
shout, struggle and hold his breath, muscle tone increases, jaws are tightly closed, breathing jerky,
vomiting and involuntary micturition.
Stage-III (Surgical Anaesthesia): In this stage the following planes show the activities:
Plane-I – Roving eyeballs
Plane-II – Loss of corneal and laryngeal reflexes
Plane-III – Pupils start dilation.
Plane-IV – Intercostal paralysis, shallow, abdominal respiration, pupils dilated, muscles tone
decreases, B.P. decreases and decrease in respiration.
Stage-IV (Medullary Paralysis): This stage consists of cessation of breathing to failure of circulation
and further pupil widely dilated, muscles are totally flabby, pulse thready and ultimately death.
3.7 CLASSIFICATION OF GENERAL ANAESTHESIA
I. Inhalation Anaesthetics
A. Liquid Anaesthetics
(i) Enflurane: 2-chloro-1, 1, 2-trifluoroethyldifluoro-methyl ether
CHClF — CF
2
— OCHF
2
Fig. 3.1
(ii) Isoflurane: 1-chloro-2, 2, 2-trifluoroethyl-di-fluoromethyl ether.
CF
3
CHCl — O — CHF
2
Fig. 3.2
(iii) Methoxyflurane: 2, 2-dichloro-1, 1-difluoroethyl-methylether
CHCl
2
— CF
2
— OCH
3
Fig. 3.3
(iv) Halothane: 2-bromo-2-chloro-1,1,1-trifluoroethane
CF
3
CHCl Br
Fig. 3.4
(v) Ether: Diethyl ether
C
2
H
5
—O—C
2
H
5
Fig. 3.5
56 A Textbook of Medicinal Chemistry
B. Gaseous Anaesthetics
(i) Cyclopropane:
C
CH
2
HC
2
H
2
Fig. 3.6
(ii) Nitrous oxide
N
2
O
Fig. 3.7
II. Intravenous Anaesthetics
A. Ultra Short Acting Barbiturates
(i) Thiopental sodium: 5-Ethyl-5-(1-methyl butyl)-2-thiobarbiturate
H
N
N
H
CH
25
O
NaS
O
CH — CH — CH — CH
223
CH
3
Fig. 3.8
(ii) Methohexital Sodium: 5-allyl-1-methyl-5-(1-methyl-2-pentynyl) barbiturate
N
N
CH —CH=CH
22
O
NaO
O
CH — CH — CH — CH
223
CH
3
CH
3
Fig. 3.9
(iii) Thiamylal Sodium: 5-allyl-5-(1-methyl butyl)-2-thiobarbiturate
H
N
N
CH —CH=CH
22
O
NaS
O
CH — CH — CH — CH
223
CH
3
Fig. 3.10
General Anaesthetics 57
B. Arylcyclo Hexylamine Derivatives
(i) Ketamine: 2-(2’-chlorophenyl)-2-(methylamino)-cyclohexanone
CH
NH
3
O
Cl
Fig. 3.11
C. Benzodiazepine
(i) Midazolam: 8-chloro-6-(2’-fluorophenyl)-2-methyl-imidazo benzodiazepine.
N
N
H
F
N
CH
3
Cl
Fig. 3.12
D. Narcotic Analgesics
(i) Fentanyl Citrate: N-(1-phenylethyl-4-piperidinyl)-Propionalide citrate
HC —C—N
52
N — CH — CH
22
HO — C — COOH
CH COOH
2
CH COOH
2
O
Fig. 3.13
(ii) Alfentanil: N-[1-[2-(4-ethyl-4, 5-dihydro-5-oxo-lH-Tetrazol-1-yl)ethyl]-4-(methoxymethyl)-4-
piperidinyl]-N-phenyl propionamide
N N—CH —CH —N
22
N
N
O
HC
52
N
|
COC H
25
CH OCH
23
Fig. 3.14
58 A Textbook of Medicinal Chemistry
E. Miscellaneous Drugs
(i) Propofol: 2,6-disopropyl Phenol
CH
3
CH
3
OH
CH
3
HC
3
Fig. 3.15
3.8 RECEPTORS INVOLVED IN THE MECHANISM
1. NMDA (N-methyl-D-asparate) Receptors
These receptors are activated by excitation of amino acid neurotransmission and glutamate to increase
the conductance of sodium ions resulting in convulsant action. Ketamine hydrochloride exhibits
antagonist action on this receptor site and shows anticonvulsants, sedative and anaesthetic properties.
2. G-Protein Coupled Receptors
G-protein coupled receptors acted via K
+
conductance to maintain polarized state of neurons and to
assist in repolarization of neurons followed by stimulation-induced depolarization.
3. GABA (γ-amino butyric Acid) Receptors
It is initiated by chloride ion channel and normally mediated, inhibitory response to central nervous
system. Some agents like halothan, isoflurane and other general anaesthetics are capable of increasing
GABA-ergic inhibitory neurotransmission.
3.9 STEREOCHEMISTRY OF VOLATILE ANAESTHETICS
Volatile anaesthetics consist of asymmetrical carbon atom in their structure, for examples, isoflurane,
desflurane, enflurane and halothane and thus can exist in their both (+) or (–) enantiomers. Anaesthetic
properties and MAC value also depend on the specific enantiomer of anaesthetic for illustration (+)
if isoflurane enantiomer is 50% more potent than (–) enantiomer.
3.10 TOXICITY OF FLUORINATED GENERAL ANAESTHETICS
(i) Hepatotoxicity
(ii) Malignant hyperthermia
(iii) Nephrotoxicity
(iv) Low level chronic exposure
General Anaesthetics 59
3.11 GENERAL ANAESTHETICS AGENTS
1. Fluorinated Hydrocarbons
During anaesthesia formation of toxic degradants is a major concern with used carbon dioxide
absorbants. This reaction converts to secondary chemical structure from primary structure. For
example, Halothane converts into -2-bromo-2-chloro-1, 1-difluoroethylene and sevoflurane converts
into 2-(fluoromethoxy)-1, 1, 3, 3, 3-pentafluoro-1-propene. Fluorinated hydrocarbon anaesthetics
are potent anaesthetics because of the presence of fluorine and halogen atoms in the structures
which makes the compound more potent and non-inflammable as well as intermediate blood solubility.
It has been observed that during short-term infrequent administration shows nephrotoxicity,
hepatotoxicity by halothane and methoxy flurane.
Synthesis:
Enflurance (Ethrane)
®
CHClF — — OCH CHClF — CF — OCHCl
23 2 2
CF
Cl
2
hv
SbF
3
(Antimony
fluoride)
CHClF — CF — OCHF
22
Enflurane
2-Chloro - 1, 1, 2-Trifluoro
ethyl-methyl ether
Fig. 3.16
Isoflurane (Forane)
®
CF CH OH CF CH OCH F CH — O — CHC
32 32 3
Cl
32 2
(CH ) SO
32
DMS
HF/SbCl
5
C CHCl — O — CHF
32
F
Isoflurane
Cl
2
hv
Trifluoroethanol
(Methylation)
Fig. 3.17
Methoxyflurane: (Penthrane)
®
CCl CHF
32
KOH
CC
Cl
F
Cl
F
CH OH
3
KOH
CHCl CF — CH
22 3
O
1, 1-Difluro-2, 2, 2-trichloroethane
Methoxyflurane
Fig. 3.18
2. Ultrashort Acting Barbiturates
(i) Thiopental Sodium (Pentothal)
®
: Thiopental sodium is clinically used intravenously. It produces
rapid unconsciousness for surgical and basal anaesthesia within 30–40 seconds. These agents
are used initially to induce anaesthesia. Unwanted reactions like respiratory depression,
myocardial depression, cardiac arythmia have been seen during anaesthesia.
60 A Textbook of Medicinal Chemistry
Fig. 3.20
Synthesis:
H
N
N
CH
25
O
NaS
O
CH — CH — CH — CH
223
CH
3
C
H
COOC H
25
H
52
C
HC
2
COOC H
25
COOC H
25
COOC H
25
CH Br
25
C H ONa
25
C
H C(CH ) HC
322
COOC H
25
HC
52
COOC H
25
CH
3
CS
HN
2
NH
2
(Thiourea)
H C(CH ) — CH — Br
C H ONa
322
25
CH
3
Fig. 3.19
3. Arylcyclo Hexylamine Agents
(i) Ketamine: Hydrochloride (Ketalar)
®
: Ketamine is available in injactable form. Ketamine is
meant for rapid acting anaesthetic agent. Its duration of anaestheic property is very short
about (10–25 minutes). The clinical anaesthetic state induced by ketamine is known as
dissociative anaesthesia. Unwanted side effects of ketamine include elevated blood pressure
and pulse rate.
Synthesis:
Thiopental sodium
Diethylmalonate
C
N
+
Cl
C
NMgBr
Cl
3-chlorobenzonitril
Cyclopentyl
magnesium
bromide
C
NH
Cl
C
O
Cl
HO
+
3
(Hydrolysis)
(Imine)
HO
+
3
(Hydrolysis)
Br
2
C
O
Cl
Br
C
NCH
3
Cl
OH
CH NH
32
NaOH
D
HCl
1, 2, shift
Cl
O
NH
|
CH
3
Ketamine
MgBr
General Anaesthetics 61
4. Narcotic Anaesthesia
(i) Propofol (Diprivin)
®
: Propofol is the most common parenteral anaesthetic used in the United
States. It is supposed that propofol acts via enhancing Gabargic neurotransmissions within
the central nervous system. It is a poor water soluble agent thus it is formulated as 1 to 2%
emulsion with soyabean oil, egg lecithin and glycerol. Propofol is used as an induction agent
and for short anaesthtic procedure.
Synthesis:
OH
OH
ClCH(CH )
32
AlCl
3
CH
3
CH
3
CH
3
CH
3
Alkylation
Propofol
Fig. 3.21
3.12 NEWER AGENTS
(i) Desflurane: 2-(difluoromethoxy)-1, 1, 1, 2-tetrafluoroethane.
Disflurane contains a number of fluorine atoms, used for maintenance of general anaesthesia with
sevoflurance. It has rapid onset of action and low solubility in blood.
F
O
F
F
FC
3
Fig. 3.22
(ii) Sevoflurane: 2, 2, 2-Trifluoro-1-[trifluoromethyl] ethyl fluoromethyl ether.
Sevoflurane also contains a number of fluorine atoms in its structure. It possesses sweet smelling,
non-inflammable properties. It is used for induction and maintenance of general anaesthesia in
surgical operation.
CF
3
O
F
FC
3
Fig. 3.23
(iii) Minaxolone: 1-(11-dimethylamino)-2-ethoxy-hexadecahydro-3-hydroxy-10, 13-dimethyl-1H-
cyclopenta[a]phenenthrene-17-yl)ethane
O
HO
HC
3
HC—N
3
CH
3
CH
3
C
O
Fig. 3.24
62 A Textbook of Medicinal Chemistry
Minaxolene is new water soluble steroidal anaesthetic. It is a safe and effective intravenous
anaesthetic agent.
EXERCISE
1. Write a note on intravenous anaesthetic and ultra short acting barbiturates.
2. Write in detail on different stages of anaesthesia.
3. Write the synthesis of
(a) Ketamine
(b) Thiopental sodium.
4. Classify general anaesthesia with examples.
5. Write a note on narcotic anaesthetic agents.
4
Local Anaesthetics
4.1 INTRODUCTION
The term anaesthesia is loss of sensation with or without loss of conscioussness. Local anaesthetics
are those chemical agents which are applied topically or administered parenterally to a localized area
and produce a state of local anaesthesia by reversible blocking the nerve potential that transmits the
feeling of pain.
Local anaesthetics are used for soreness, itching, insect bites, wounds, cut, rashes, allergic
condition and fungal infection and in minor surgical operation. Method of administration of local
anesthetics is governed by the following properties like toxicity, stability, duration of action, water
solubility, membrane permeability and point of application. On the other hand, local anaesthetics
mode of action depends on their lipid solubility, PKa, vasodilation and protein binding characteristics.
The drug exerts a systemic effect due to transport into blood from the site of administration. This
effect depends on its concentration in the blood. Number of unwanted side effects may occur like
sedation, restlessness, nausia and anxiety. Sometimes convulsions, respiratory and cardial depressions
may occur due to high toxicity.
4.2 METHODS OF ADMINISTRATION
Table 4.1: Method of administration of local anaesthetics
S. No. Types Site of action Drugs used (conc.)
1. Topical anaesthesia Mucous membrane of nose, Phenlephrine (0.005%)
throat, tracheobronchial, Lignocaine (2-10%)
oesophagus, urinary tract Cocaine (1–4%)
Tetracaine (2%)
2. Infiltration anaesthesia Directly injected into tissue Epinephrine (5 µg/ml)
(skin, intra-abdominal organs) Lignocaine (0.5–1.0%)
Procaine (0.5–1.0%)
Bupivacaine (0.125–0.25%)
64 A Textbook of Medicinal Chemistry
3. Nerve block anaesthesia Peripheral nerves Lignocaine (1–1.5%)
Mepivacaine (1–2%
4. Field block anaesthesia Subcutaneous area Lignocaine (0.5–1.0%)
Procaine (0.5–1.0%)
5. Intravenous anaesthesia Nerve trunks ending of forearms, Lignocaine (0.5%)
hand Procaine (0.5%)
6. Spinal anaesthesia Cerebrospinal fluid in lumber space Lignocaine (1–1.5%)
Tetracaine
Bupivacaine
7. Epidural anaesthesia Epidural space Bupivacaine (0.5–0.75%)
Lignocaine (2%)
Chloroprocaine (2–3%)
4.3 CLASSIFICATION OF LOCAL ANAESTHETICS
I. Ester Linkage Derivatives
1. Benzoic Acid Derivatives: Basic structure
R
1
O
C—O—R
2
Substitution by
small groups
(favoured)
Substitution by
large groups
(favoured)
Fig. 4.1
Derivatives R
1
R
2
(i) Cocaine H
N—CH
3
COOCH
3
(ii) Isobucaine H
CH
3
H
N
CH
3
CH
3
CH
3
(iii) Hexylcaine H
NH
CH
3
(iv) Meprylacaine H
CH
3
H
N
CH
3
CH
3
(v ) Piperocaine H
—HC—CH —CH —N
222