General Anesthetics
General anesthetics are agents that cause loss of sensation, loss of
consciousness and impair of motor function.
History
1. Physically: by ice, tourniquets making ischemia or blow to the head.
2. Chemically: by ethanol or opium, nitrous oxide (laughing gas), diethyl
ether (not used) due to its toxicity and (inflammable and explosive).
3. Now, ethers or halogenated hydrocarbons are used.
General anesthesia employs multiple regimens to augment its action as
barbiturates, benzodiazepines, skeletal muscle relaxants and also narcotic
analgesics.
Stages of Anesthesia:
Stage I: Cortical stage or stage of analgesia and sleep (for surgeries which do not
require skeletal muscle relaxation, e.g. tonsils removal).
Stage II: Delirium stage (between unconsciousness and surgical anesthesia).
Stage III: Surgical anesthesia; it is characterized by loss of excitement, muscle
relaxation, unconsciousness, decreasing eye movement and regular respiration.
Stage IV:
Respiratory paralysis or medullary depression; characterized by
depression of vital centres of the medulla and brain stem ⇒ respiratory and
cardiac failure. This stage represents an overdose or toxic level that should be
avoided (normally this stage should not be reached).
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 An ideal general anesthetic agent must produce loss of all sensation, analgesia
and muscle relaxation.
According to the route of administration, general anesthetics are
classified into:
1. Inhalation Anesthetics.
2. Intravenous or Parentral Anesthetics.
3. Rectal (Basal) Anesthetics.
1.
Inhalation Anesthetics:
 They are administered through the respiratory tract.
 They are either gases as N2O nitrous oxide gas, cyclopropane, ethyl
chloride, or volatile liquids (more potent than gases), e.g. chloroform,
ethers and other halogenated hydrocarbons.
Cyclopropane
CH2
H2C
CH2
It is the most potent gaseous anesthetic agent (not currently used)
characterized by rapid onset of action and fast recovery(highly inflammable).
Synthesis:
CH2 Br
H2C
CH2 Br
CH2
Zn

2
H2C
CH2
Ethyl Chloride
CH3CH2
Cl
Chloroethane
Ethyl chloride is mainly used as local anesthetic by spraying to the skin
and it also exerts general anesthetic properties when inhaled but its adverse side
effects suppresses its use as general anesthetic (liver damage and cardiac
arrhythmias).
Synthesis:
CH3CH2OH
HCl
ZnCl2
CH3CH2
Cl
+
H2O
Nitrous Oxide
N2O
Nitrous oxide was used in the past for rapid induction of anesthesia in
minor operations. It is prepared by heating ammonium nitrate.
NH4NO3
Heat
N2O
Diethyl Ether
CH3CH2
O
CH2CH3
Diethyl oxide
3
+
2 H2O
 It is the most widely used general anesthetic. It is prepared by careful
dehydration of ethanol with sulphuric acid at 135-140°C, or via Williamson
reaction using ethyl bromide and sodium ethoxide.
2 CH3CH2OH
H2SO4
CH3CH2
O
CH2CH3
135-140C
CH3CH2Br
+
CH3CH2ONa
CH3CH2
O
CH2CH3
 Diethyl ether prepared by the first-method is usually accompanied by several
by-products as ethylene and acetaldehyde. It is easily oxidized when exposed
to air forming the highly explosive diethyl peroxide.
 It has prolonged induction time of anesthesia.
Divinyl Ether
CH2
CH O
CH
CH2
Divinyl oxide
It has the advantage of rapid induction time (few seconds) compared to
diethyl ether.
Chloroform
CHCl3
Trichloromethane
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Chloroform was introduced as general anesthetic in 1847, its toxic effects
on the liver and heart suppressed its medicinal use.
Chloroform could be
prepared as follows:
1.
Controlled Chlorination of Methane
CH4
2.
+ 3 Cl2
+
3 HCl
Alkaline Hydrolysis of Chloral Hydrate
Cl3CH(OH)2
3.
CHCl3
NaOH
CHCl3
+
HCOONa
+
H2O
Haloform Reaction using ethanol or acetone by the action of bleaching
powder.
CH3CH2OH
+
2 CH3CHO +
2 CCl3CHO
+
CaOCl2
60C
CH3CHO +
Oxidation
6 CaOCl2
2 CCl3CHO +
Ca(OH)2
2 CHCl3
+
CaCl2
+
H2O
3 Ca(OH)3 + 3 CaCl2
(HCOO)2Ca
Anesthetic chloroform must be phosgene-free, which may be formed via
photo-oxidation of chloroform. To avoid the formation of toxic phosgene, it must
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be kept away from direct sunlight and 0.5% ethanol must be added to convert
phosgene (if formed) to the non-toxic diethyl carbonate.
2 CHCl3 +
Cl
h
O2
+
2O
2 HCl
Cl
OC2H5
COCl2
+
2 C2H5OH
+
O
2 HCl
OC2H5
Halothane (Fluothane)
F
F
Cl
C
CH
F
Br
1,1,1-Trifluoro-2-chloro-2-bromoethane.
Halothane is four times as potent as diethyl ether, it is prepared from
trichloroethylene as follows:
Cl
Cl
C
CH Cl
HCl
Cl
Cl
C
CH2Cl
Cl
3 HF
F
F
Cl
C
CH
F
Br
F
Br2
F
C
F
6
CH2Cl
In general, the rate of anesthesia induction (onset of action) depends on:
a) Rate of respiration of the patient.
b) Rate of delivery of the drug to the site of action (brain) which depend
on the physicochemical properties of the drug (solubility in lipids and
water).
c) So if the drug  water soluble ⇒ slow onset and long duration (long
recovery period).
d) If the drug is  lipid soluble ⇒ rapid onset and short duration.
SAR:
1.  Number of carbons ⇒  lipid solubility.
2.  Number of halogens ⇒  lipid solubility and  H2O solubility (lipid
> H2O).
3.  Number of ethers ⇒ H2O solubility and  lipid solubility (H2O >
lipid).
2-
Intravenous Anesthetics:
The sodium salts of ultrashort acting barbiturates are the major members
of this group, they may be administered intravenously in aqueous solutions for
the induction of anesthesia. Respiratory depression is the main disadvantage of
barbiturates; consequently, these agents are not used to maintain surgical
anesthesia. Unconsciousness is produced within few seconds of intravenous
injection, and the duration of action is about 30 minutes. In addition to the
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ultrashort acting barbiturates, some miscellaneous compounds like Propfol and
Ketamine hydrochloride are used for intravenous anesthesia.
Thiopental Sodium (Pentothal Sodium)
O
N
H3C
S-Na+
H3C
NH
H3C O
Sodium 5-ethyl-5-(1-methylbutyl)-2-thiobarbiturate

It has ↑ lipid solubility due to branching and the presence of thio (S) group.

It is the prototype of ultrashort-acting barbiturates.

It has very short duration of action.
Methohexital Sodium (Brevital Sodium)
H3C
O
N
O-Na+
N
O
CH3
Sodium 1-methyl-5-allyl-5-(1-methyl-2-pentynyl)barbiturate

It has ↑ lipid solubility due to branching and the presence of CH3 groups.

It has short duration of action.

It is more potent than thiopental.
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Ketamine Hydrochloride (Ketalar)
O
CH3
NH.HCl
Cl
2-(o-Chlorophenyl)-2-methylaminocyclohexan hydrochloride

It is the most widely used general anesthetic.

It is very potent, rapid onset (rapid acting).

Recovery is accompanied by “emergence delirium,” characterized by visual,
auditory and confusional hallucinations, nightmares and dissociation from
reality.

Termination of action of ketamine occurs by its distribution from the brain
into other tissues.
Propofol
CH3
OH
H3C
CH3
CH3
2,6-Diisopropylphenol
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3-
Rectal (Basal) Anesthetics:
Tribromoethanol (Avertin)
Br
Br
C
CH2OH
Br

It is an example of this group.

It is administered rectally as a solution in amylene hydrate.

It is prepared by the reduction of bromal (tribromoacetaldehyde) with
aluminium isopropoxide.
Br
Br
Br
C
CHO + Al(OCH(CH3)2)3
H2O
Br
Br
Br
C
CH2OH +
Br
O
+ Al(OH)3
Br
Tribromoethanol
Adjuvants to General Anesthesia:
1- Narcotic analgesic as morphine.
2- Sedatives as benzodiazepines e.g. midazolam (sleep-inducing).
3- Anticholinergic agents e.g. atropine.
4- Skeletal muscle relaxants, such as, succinyl choline.
An ideal general anesthetic must have these previous four properties.
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