Anesthetics, General 1

Anesthetics, General
→ Local Anesthetics is a separate keyword.

Hartmund Wollweber, Bayer AG, Wuppertal, Federal Republic of Germany

1. Introduction . . . . . . . . . . . . . . . . . 1 3.2. Thiobarbituric Acids . . . . . . . . . . . 7

2. Inhalation Anesthetics . . . . . . . . . . 3 3.3. Miscellaneous Compounds . . . . . . . 8
2.1. Nitrous Oxide . . . . . . . . . . . . . . . . 3 4. Combination Anesthetics . . . . . . . . 9
2.2. Hydrocarbons . . . . . . . . . . . . . . . . 3 4.1. Sleep-Inducing Anesthetics . . . . . . . 9
2.3. Halogenated Hydrocarbons . . . . . . . 3
4.2. Benzodiazepines . . . . . . . . . . . . . . 10
2.4. Ethers . . . . . . . . . . . . . . . . . . . . . 4
2.5. Halogenated Ethers . . . . . . . . . . . . 5 4.3. Steroid Derivatives . . . . . . . . . . . . 11
3. Intravenous Anesthetics . . . . . . . . . 6 4.4. Neuroleptanalgesics . . . . . . . . . . . . 12
3.1. Barbituric Acids . . . . . . . . . . . . . . 6 5. References . . . . . . . . . . . . . . . . . . 13

1. Introduction 1) The analgesic stage, permitting slightly

General anesthetics are agents that temporarily
produce a stupor- or sleeplike condition dur-
ing which “painless” operation is possible. In
this condition of general anesthesia (narcosis),
consciousness, pain sensitivity, defense reflexes,
and muscular reflexes are depressed to a large
extent, whereas the vital centers of the medulla
oblongata, particularly those controlling respi-
ration and circulation, are relatively unaffected.
In practice, the conditions depend entirely on the
dosage of the anesthetic. Agents with too narrow
a therapeutic range, i.e., too narrow a margin of
safety between anesthetic dose and lethal dose,
may not be employed.
The numerous theories regarding anesthesia
either deal with the effectiveness or distribution
of anesthetics within the body or speculate on
their modes of action. Because inert gases, even
the noble gases, are also effective anesthetics, the
mode of action is believed to be a purely physi-
cal, reversible effect on the lipid-containing cel-
lular membrane of the neurons. In principle, this
affects all body cells. Only the higher sensitivity
of the cells of the central nervous system (CNS)
makes the desired gradual anesthetization possi-
ble with an appropriate dosage of the anesthetic
agent.
Four different stages of anesthesia are distin-
guished:
painful procedures, such as changing dress-
ings.
2) The excitation stage, which must be over-
come quickly by premedication or additional
anesthetic.
3) The tolerance stage, in which the centers of
the cerebrum and spinal cord are inhibited,
allowing surgical operations to be carried
out.
4) The asphyxia stage, characterized by inhibi-
tion of the autonomic centers and the medulla
oblongata (the vasomotor and respiratory
centers), extreme muscle relaxation, and ces-
sation of thoracic respiration. In practice, this
stage must be counteracted immediately by
appropriate measures, such as artificial res-
piration and/or infusion therapy; indeed, this
stage should never be reached during anes-
thesia.
The tolerance stage can be subdivided into
a) Paralysis of the spinal cord and mesen-
cephalon, slight relaxation of the muscles
b) Drop in blood pressure and body tempera-
ture, relaxation of the skeletal musculature
c) Relaxation of the abdominal musculature,
onset of respiratory depression
d) Relaxation of the nonstriated musculature,
lack of reflexes, difficult and deep breath-
ing, abdominal breathing only, further drop

c 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

10.1002/14356007.a02 289
2 Anesthetics, General
in blood pressure and body temperature, on-
set of hypoxemia, cyanosis
During emergence from the tolerance stage,
the patient passes back through the excitation
and analgesia stages.
Effective anesthesia is required to bring
about
1) Unconsciousness
2) Complete analgesia and absence of pain re-
flexes
3) Relaxation of the muscles
The patient must receive sufficient anesthetic
to fulfill the third requirement; in practice, this
usually means overdosage regarding the first two
requirements. Consequently, a combined tech-
nique is currently in use: other pharmaceutical
agents, generally sedatives, neuroleptics, anal-
gesics, and muscle relaxants, are used to support
the anesthesia, particularly in the initial phase.
Depending on the duration of their action,
anesthetic agents are termed long acting, short
acting, or very short acting. Depending on how
they are administered, they also can be divided
into inhalation, intravenous, and combination
anesthetics.
Inhalation (Pulmonary) Anesthetics. A
large number of gases or vapors that are in-
haled in a mixture with air or oxygen produce
unconsciousness and analgesia. For practical
purposes, however, only a few have proved effi-
cacious.
Inhalation anesthetics are characterized by
great stability. They are taken up quickly in the
lungs and to a large extent are eliminated rapidly
and mostly unchanged through the lungs (only
minimally in the urine). They can be withdrawn
immediately should an untoward incident occur;
i.e., they can be controlled. Their main disad-
vantages are that they often cause a pronounced
excitation stage and that many patients expe-
rience discomfort (postnarcotic nausea, vomit-
ing). With inflammable gases the danger of ex-
plosion is always present.
Gas and vapor anesthetics exhibit different
distributions between the lipophilic and hy-
drophilic phases and so have different solubil-
ities in blood and different affinities to the lipid-
rich nervous tissue of the CNS. The gases are
less soluble in blood and require a higher par-
tial pressure to maintain the tolerance stage. The
steep concentration gradient makes it possible
to induce and withdraw anesthesia quickly, thus
providing better control of the narcosis.
The “minimum alveolar concentration”
(MAC), a concept introduced in 1965, is a mea-
sure of the potency of inhalation anesthetics. It
is expressed as the concentration in the alveo-
lar air that prevents 50 % of patients from re-
sponding to pain stimuli. The MAC levels are
changed by premedication agents or adjuncts,
and anesthetic dosage always must be adjusted
accordingly. However, the concentration of an
anesthetic agent cannot be increased arbitrarily
because of the narrow therapeutic range, which
for most agents is ≈ 1.5.
Intravenous (Parapulmonary) Anesthet-
ics. Metabolization and distribution gradually
render intravenous agents ineffective; i.e., they
are subject to processes over which the anesthe-
siologist has no influence. Further, these agents
cannot be controlled once they have been ad-
ministered. However, they are psychologically
well tolerated by patients, and they are quite use-
ful for brief narcosis and as induction agents
for inhalation anesthesia, providing the basic
anesthesia. Only intravenous anesthetics can be
used when the airways must be maintained com-
pletely patent.
Combination Anesthesia. Inhalation or in-
travenous anesthetics, used singly, depend on
dosage to achieve the conditions necessary for
surgery: autonomic depression, sleep, analge-
sia, and muscle relaxation. Nowadays, prefer-
ence is given to combinations of medications,
which broaden the therapeutic range. Moreover,
with several substances administered at minimal
dosages the particular goals of anesthesia can be
achieved.
Sleep-inducing anesthetics. To induce nar-
cosis and regulate sleep, the short-acting barbitu-
rates (the induction agents) – etomidate, steroid
anesthetics, and some benzodiazepine deriva-
tives – are used.
Neuroleptanalgesics. A stage that approxi-
mates that reached during the first stage of anes-
thesia can be attained by simultaneous admin-
istration of a potent analgesic and a neurolep-
tic agent. In this state of so-called neurolep-

tanalgesia, there are complete analgesia, psychic
and motoric depression, and amnesia. The auto-
nomic nervous system is depressed, whereas all
important reflexes are retained. In general, the
patient remains conscious, making this type of
narcosis particularly suitable for operations in
which active participation on the part of the pa-
tient is necessary, for example, brain, ear, and
laryngeal operations. If higher doses of anal-
gesics are given, artificial respiration is nec-
essary. Commonly, the patient is premedicated
with muscle relaxants, such as succinylcholine,
with atropine, and even with anesthetics, such as
propanidid or N2 O–O2 .
Neuroleptanalgesia is used for gentle narco-
sis, for lengthy operations, or for patients at risk
in senium or with cardiovascular diseases.
Relaxants. Muscular relaxation is necessary
for anesthesia and the operation. Some anesthet-
ics produce muscle relaxation by affecting the
central regulation of the tonus. However, periph-
eral muscle relaxation is achieved only by in-
hibiting the neurotransmitter acetylcholine with
depolarizing substances or substances that block
the acetylcholine receptor in the motor end plate.
Such relaxants ( → Skeletal Muscle Relaxants)
include tubocurarine, alcuronium, gallamine,
pancuronium, decamethonium or suxametho-
nium, neostigmine, and pyridostigmine. Pre-
medication with the anticholinergics atropine
and scopolamine is common practice. Adminis-
tered intramuscularly, these agents inhibit sali-
vary and gastric secretions (prophylaxis against
aspiration), prevent bradycardia, and provide
protection against acute vagal reflexes.
2. Inhalation Anesthetics
2.1. Nitrous Oxide
Nitrous oxide [10024-97-2], nitrogen monoxide
or laughing gas, N2 O, M r 44.02, is a colorless
gas with a slightly sweet odor and taste, mp –
90.81 ◦ C, bp −88.46 ◦ C. At a pressure of 1 bar
(100 kPa) one volume of water dissolves one vol-
ume of N2 O at 5 ◦ C and 0.596 volumes at 25 ◦ C.
Nitrous oxide also is soluble in alcohol and ether.
For manufacture → Nitric Acid, Nitrous Acid,
and Nitrogen Oxides.
Nitrous oxide exerts a shallow anesthetic ef-
fect, MAC > 80. Although deep anesthesia can-
Anesthetics, General 3
not be achieved with it alone, it is used mixed
with oxygen and ether or halothane as a basic
anesthetic for all types of surgery because of its
minimal toxicity. Further, N2 O does not irritate
the airways. Nitrous oxide is always mixed with
oxygen (20 %, in dentistry 20 – 50 %) to avoid
anoxia. The use of nitrous oxide considerably
reduces the requirements for other anesthetics
and analgesics.
Trade Names. Stickoxydul (Hoechst) and oth-
ers.
2.2. Hydrocarbons
Hydrocarbons have an anesthetic effect. How-
ever, despite their good anesthetic qualities and
low toxicities, they are now rarely used because
of the high risk of explosion. After serious explo-
sions during anesthesia, ethylene and acetylene
are no longer employed in Germany.
Cyclopropane [75-19-4], trimethylene,
USP XIX, C3 H6 , M r 42.08, is a colorless, odor-
less, inflammable gas, mp -127 ◦ C, bp −33 ◦ C.
At room temperature it liquefies at 4 – 6 bar
(400 – 600 kPa). The explosive range is between
2.4 and 10.3 vol % in air and between 12.5 and
60.0 vol % in oxygen. The blood – gas partition
coefficient at 37 ◦ C is 0.46. Cyclopropane is
mixed with oxygen (15 – 30 % cyclopropane)
for medical purposes. In contrast to nitrous
oxide, cyclopropane (MAC 9.2) at concentra-
tions of 20 % can produce anesthesia. It can be
controlled readily and has a broad therapeutic
range. Cyclopropane increases the sensitivity of
the heart to catecholamines.
Cyclopropane is manufactured commercially
from 1,3-dichloropropane with zinc in the pres-
ence of sodium iodide.
Trade Names. Cyclopropane (ICI; Mallinck-
rodt; Squibb). Cyclopropane USP is available
in sealed orange metal cylinders or in chrome-
plated cylinders with orange labels.
2.3. Halogenated Hydrocarbons
Low-boiling halogenated hydrocarbons exhibit
anesthetic activity. Compared to hydrocarbons,
they are more potent but also more toxic. Anes-
thetics previously in common use – chloroform,
4 Anesthetics, General
carbon tetrachloride, and ethyl chloride – are
now never or hardly ever employed because of
their hepatotoxic and carcinogenic side effects.
In addition, tribromoethyl alcohol is no longer
employed in the major industrial nations. The
chlorinated hydrocarbons increase the sensitiv-
ity of the heart to catecholamines.
Trichloroethylene [79-01-6], CCl2 =CHCl,
M r 131.4, is a colorless, noninflammable liquid
with a characteristic chloroform-like odor, bp
87.2 ◦ C. (For further information → Chlorinated
Hydrocarbons.) Trichloroethylene is highly hep-
atotoxic and nephrotoxic and causes hepatocel-
lular carcinomas in mice. In the presence of
alkali, trichloroethylene decomposes to highly
toxic dichloroacetylene and HCl. For anesthetic
purposes, the substance is stabilized with thymol
and mixed with a blue coloring agent.
Indication. For inhalation analgesia in ob-
stetrics and for minor surgical procedures, but
only with a special inhaler. Trichloroethylene
(MAC 0.17) should not be used in a closed-
circuit apparatus. Trichloroethylene is better tol-
erated than chloroform.
Trade Names. Anamenth (Brunnengräber)
contains menthol as a stabilizer; Chlorylen
(Schering); Ecrylène (Robert & Carrière, Paris);
Narkosid (Heyl); Trethylene (Davies-Rose-
Hoyt); Trichloran (Merck); Trilene (ICI; Ay-
erst).
Halothane [151-67-7], 2-bromo-2-
chloro1,1,1-trifluoroethane, CF3 CHBrCl, M r
197.39, is a colorless, noninflammable liquid
with a characteristic sweet odor, bp 50.2 ◦ C.
Halothane is soluble in water to the extent of
0.345 wt %, miscible with ether, and sensitive
to light. Anesthetic halothane contains 0.01 %
thymol as a stabilizer.
Halothane is manufactured by chlorination of
CF3 CH2 Br or bromination of CF3 CH2 Cl in the
gas phase at 250 – 475 ◦ C [2] or by the rearrange-
ment [3]
Indication. Because of its potent and rapid
effect, halothane (MAC 0.77) is used in spe-
cial vaporizers mixed with oxygen and water.
The high lipid – blood partition coefficient leads
to considerable accumulation in tissue and fat.
Halothane reduces the peripheral vascular re-
sistance, increases the possibility of arrythmias,
and has a negative effect on liver function. On
repeated use it is hepatotoxic.
Trade Names. Fluothane (ICI Pharma);
Halothan “Hoechst” (Hoechst); Halan
(Arzneimittelwerk Dresden); Halovis (Vister,
Italy); Narcotan (Spofa, Prague); Rhodialothan
(Rhodia Pharma).
Teflurane [124-72-1], 2-bromo-1,1,1,2-
tetrafluoroethane, CF3 CHFBr, M r 180.95, a
nonexplosive, noninflammable gas, bp 8 ◦ C.
Its anesthetic qualities are similar to those of
halothane [4]. Teflurane is prepared by bromina-
tion of 1,1,1,2-tetrafluoroethane at temperatures
above 400 ◦ C [5].
Trade Name. Teflurane (Dow; Abbott)
2.4. Ethers
The ethers have a broad anesthetic range; i.e., the
difference between the dose needed to produce
the tolerance stage and the lethal dose is large.
They have enjoyed a certain popularity as inhala-
tion anesthetics. The best known, diethyl ether,
usually is combined with other agents. There is
always the danger of explosion in mixtures with
oxygen or air. The solubility of ether in blood
and tissue results in a 15-min induction period,
which is accompanied by irritation of the mu-
cous membranes and airways and by salivation.
The recovery phase is long, and ether is no longer
in routine use by anesthesiologists, despite its fa-
vorable effects on the bronchial musculature and
cardiocirculatory system and its relatively good
relaxant effect on the muscles.
Diethyl ether [60-29-7], H5 C2 -O-C2 H5 ,
M r 74.12, is a mobile, colorless, inflammable
liquid with characteristic odor, bp 34.6 ◦ C. Mix-
tures of diethyl ether and air are explosive. Di-
ethyl ether is miscible with short-chain alcohols,
chloroform, and petroleum ether. An aqueous
solution saturated with ether contains 8.43 wt %
ether at 15 ◦ C and 6.05 wt % at 25 ◦ C. Ether
saturated with water contains 1.2 wt % water at
20 ◦ C (MAC 1.9). For details on preparation and
purification → Ethers, Aliphatic.

Trade Names. Aether puriss, pro narcosi
“Hoechst” (Hoechst); Aether puriss, pro narcosi
“Bonz” (Bonz).
Divinyl ether [109-93-3], vinyl ether,
CH2 =CH-O-CH=CH2 , M r 70.09, is a mobile,
colorless, inflammable liquid with a characteris-
tic sweet odor, bp 28.4 ◦ C. Approximately 4 %
ethanol is added as a stabilizer. Divinyl ether
may contain 0.0077 % of a stabilizer, phenyl-α-
naphthylamine, that produces a slightly reddish
fluorescence.
Divinyl ether is prepared by the reaction of
liquefied alkali hydroxide or sodium alkoxide
on β,β  -dihalodiethyl ether [6] or by pyrolysis
of α,α -dichlorodiethyl ether in the gas phase at
600 – 800 ◦ C in the presence of barium chloride
catalyst [7].
Indication. Divinyl ether is used for minor
surgery, obstetrics, dentistry, and inducing anes-
thesia. A certain degree of hepatotoxicity rules
out long-term use. Hypersecretion has also been
observed. Divinyl ether increases and decreases
in tissue levels faster than diethyl ether.
Trade Names. Vinydan (Lundbeck) contains N-
phenylnaphthylamine as a stabilizer and abso-
lute alcohol; Venesthene (May & Baker; Merck
Sharp & Dohme); Vinether (Robert & Carrière,
Paris); Ethydan (Lundbeck) is a 1 : 3 mixture
of divinyl ether and diethyl ether.
2.5. Halogenated Ethers
The polyfluorinated ethers have analgesic and
muscle-relaxing properties but are more dif-
ficult to control. In addition, some are read-
ily inflammable. They fall between the ethers
and the halogenated hydrocarbons in their ef-
fect on the heart. The importance of the flu-
orinated ethers varies from country to coun-
try. In 1985, enflurane was the most important.
Some fluorinated ethers – such as sevoflurane,
1,1,1,3,3,3-hexafluoro-2-(fluoromethoxy)-pro-
pane [8] (Baxter); aliflurane, 2-chloro-1-
methoxy-1,2,3,3-tetrafluorocyclopropane [9]
(W. R. Grace); dioxychlorane, 4,5-dichloro-
2,2-difluoro-1,3-dioxolane [10] (Ayerst); and
thiomethoxyflurane, 2,2-dichloro-1,1-difluoro-
1-methylmercaptoethane [11] (Ohio Medical
Products) – are still being tested clinically.
Anesthetics, General 5
Enflurane [13838-16-9], 2-chloro-1-
(difluoromethoxy)-1,1,2-trifluoroethane,
CHClFCF2 -O-CHF2 , M r 184.5, bp 56.5 ◦ C, is a
colorless, noninflammable liquid with a pleasant
odor. Enflurane (MAC 1.68) is used in special
vaporizers and, depending on the stage of anes-
thesia, is mixed with various amounts of oxygen
and nitrous oxide. Its advantage over halothane
is the more rapid induction and withdrawal. Ar-
rythmias are observed less frequently, which
makes the combination with catecholamines
less a problem.
Enflurane is prepared by dichlorination of
the methyl group of 1-chloro-1,2,2-trifluoro-2-
methoxyethane and replacement of these two
chlorine atoms by fluorine [12], [13]:
Trade Names. Ethrane (Deutsche Abbott);
Ethrane (Ohio Medical Products).
Methoxyflurane [76-38-0], 2,2-dichloro-
1,1- difluoro-1-methoxyethane, CHCl2 CF2 -O-
CH3 , M r 164.98, bp 104.65 ◦ C, is a colorless
liquid with a fruity odor. It is produced industri-
ally by the addition of methanol to 1,1-dichloro-
2,2-difluoroethylene in the presence of sodium
methoxide [14].
Methoxyflurane is used with special vaporiz-
ers and, depending on the depth of anesthesia de-
sired, is mixed with various amounts of oxygen
and nitrous oxide. Its high lipid solubility gives
it the lowest MAC, 0.2, found among inhalation
anesthetics in use. It does not sensitize the heart
to catecholamines; otherwise, the majority of its
side effects are those of halothane (see page 4).
Oxalate deposits and nephrotoxic fluoride con-
centrations are undesirable metabolic products
of methoxyflurane.
Methoxyflurane may not be administered to
patients with severe liver damage or renal insuf-
ficiency or those concomitantly receiving ami-
noglycoside antibiotics and tetracyclines.
Trade Names. Penthrane (Abbott) contains
0.01 % butylated hydroxytoluene as an antox-
idant; Analgizer (Abbott); Methofane (Pitman-
Moore).
6 Anesthetics, General
Isoflurane [26675-46-7], 1-chloro-1-
(difluoro- methoxy)−2,2,2-trifluoroethane,
CF3 CHCl-O-CHF2 , M r 184.5, is a colorless,
noninflammable liquid with a faint odor, bp
48.5 ◦ C. Isoflurane is prepared by chlorination
of 2,2,2-trifluoroethoxydifluoromethane, itself
obtained by alkylation of trifluoroethanol with
difluorochloromethane [12], [15]:
Isoflurane (MAC 1.3) has a low blood – gas
distribution coefficient, which leads to rapid re-
covery from the anesthesia. Myocardial func-
tions remain intact, and as the depth of anesthe-
sia increases, vasodilation progressively devel-
ops [16].
Trade Name. Forane (Ohio Medical Products).
Fluroxene [406-90-6], 2,2,2-trifluoro-1-
vinyloxyethane, CF3 CH2 -O-CH=CH2 , M r
126.8, bp 42.5 ◦ C, is a colorless liquid with a
pungent odor. It is inflammable and, at concen-
trations above 4 %, explosive in air. Fluroxene
(MAC 3.4) generally is used in a mixture with
oxygen and nitrous oxide. Several cases of liver
damage have been observed.
The compound is prepared by catalytic viny-
lation of 2,2,2-trifluoroethanol in the presence
of alkali-metal trifluoroethoxide [17]:
CF3 CH2 OH + CH≡CH −→ CF3 CH2 -O-CH=CH2
Another synthesis is based on acetalde-
hyde-bis(trifluoroethylacetal), from which tri-
fluoroethanol is split off in the presence of mont- pharmacokinetic properties that make them suit-
morillonite catalysts [18]:
(CF3 CH2 O)2 CHCH3 −→ CF3 CH2 -O-CH=CH2 + CF3 CH2 OH
Trade Name. Fluoromar (Ohio Medical Prod-
ucts).
3. Intravenous Anesthetics
Intravenous anesthetics, like inhalation anes-
thetics, can be used alone. Most have side ef-
fects. The majority cause respiratory depression.
Administration of oxygen is recommended, par-
ticularly with barbiturates and thiobarbiturates.
Intraarterial injection must be avoided because
of the danger of tissue necrosis.
3.1. Barbituric Acids
The 5,5-disubstituted barbiturates have at-
tained an extremely broad range of use as
anesthetics and also are employed in other
therapeutic areas (→ Hypnotics,→ Sedatives,
and→ Antiepileptics).
The effective anesthetics are methylated at po-
sition 1, and usually one of the substituents at
position 5 is unsaturated. The barbiturates are
so-called haloencephalic anesthetics; i.e., the
reversible inhibition of activity of all excitable
tissue is particularly marked in the central ner-
vous system. The redistribution of the lipophilic
barbiturates from the well-perfused cerebral tis-
sue into the peripheral storage depots of muscle
and fatty tissue is more important for the cessa-
tion of anesthesia than is metabolism. Balanced
distribution between plasma and fatty tissue
is attained only after a relatively long period,
e.g., for the thiobarbiturates, only after 1.5 – 2 h.
Repeated administration of barbiturates carries
with it the risk of accumulation.
Only a few of the many barbiturates have
able for use. The barbiturates are poor analgesics
and muscle relaxants. The tolerance stage of
anesthesia is reached quickly and can be main-
tained with an inhalation anesthetic. The barbi-
turates are employed generally for minor surgery
and as induction agents for anesthesia. Pheno-
barbital is used only for premedication.
The following classification is based on a
British evaluation of barbiturate and thiobarbitu-
rate anesthetics [19]; in other countries, assess-
ment is not necessarily identical:
Good, equally effective: thiopental, thiamy-
lal, thiobutabarbital, thialbarbital

Insufficient, frequent side effects: hexobar-
bital, methitural, buthalital
Some advantages, some side effects: metho-
hexital, narcobarbital
Methohexital sodium [309-36-4], sodium
5-allyl-1-methyl-5-(1-methyl-2-pentynyl)-
barbiturate, M r 284.30. The free acid
[18652-93-2] forms colorless crystals, mp
60 – 64 ◦ C. It is prepared by condensing di-
ethyl allyl(1-methyl-2-pentynyl)malonate with
N-methylurea [20].
Methohexital sodium is a short-acting anes-
thetic administered intravenously. It is very po-
tent and has the shortest duration of action
among the barbiturates used. A disturbing factor
is that rather frequently it causes hiccups directly
after injection. Patients are reported to recover
rapidly from anesthesia. Abuse can lead to ad-
diction.
Trade Names. Brevane (Elanco, USA); Brevital
Sodium (Eli Lilly).
Hexobarbital [56-29-1], 5-(cyclohexen-1-
yl)-1,5-dimethylbarbituric acid, M r 236.26. The
acid forms colorless crystals that turn pink on ex-
posure to light, mp 146 ◦ C. A 10 % aqueous so-
lution of the sodium salt [50-09-9], M r 258.25,
has a pH of 11.5.
Hexobarbital sodium is prepared by conden-
sation of methyl(cyclohexen-1-yl)cyanoacetic
ester with dicyanodiamide to 5-(cyclohexen-
1-yl)-5-methyl-2,6-diimino-3-cyanobarbituric
acid, followed by methylation with dimethyl
sulfate and hydrolysis with 25 % sulfuric acid
[21].
Hexobarbital sodium is an intravenous anes-
thetic for short procedures and combination
anesthesia. Hexobarbital is tolerated by tissue
much better than thiopental and has proved effi-
Anesthetics, General 7
cacious for almost 50 years, at least for induction
of anesthesia. Abuse can lead to addiction.
Trade Names (ampule with dry sub-
stance): Evipan-Natrium (Bayer); Evipal
Sodium (Winthrop-Stearns); Cyclonal Sodium
(May & Baker); Dorico Solubile (Winthrop);
Hexanastab (Boots); Toleran inj. (Kwizda).
3.2. Thiobarbituric Acids
The anesthetic effect of the thiobarbituric acids
differs from that of the barbiturates in that they
produce a somewhat longer period of sleep after
withdrawal of medication. Emergence is calmer
and quicker. The duration of anesthesia can be
lengthened considerably in patients having only
limited fat deposits outside of the central ner-
vous system (i.e., asthenic persons) or having fat
deposits saturated by several injections of thio-
barbiturates. The thiobarbiturates depress respi-
ration more than the barbiturates and are less
well tolerated by the veins.
The thiobarbituric acids are more acidic than
the barbituric acids. They dissolve in aqueous al-
kali, but the heterocyclic ring opens after a time.
They are prepared by condensation of substi-
tuted malonic esters, malononitrile, malononi-
trile esters, or malonamide esters with thioureas
or N-alkylthioureas, whereby the imino deriva-
tives initially produced are hydrolyzed to thio-
barbituric acids [22].
Thiopental sodium [71-73-8], the sodium
salt of 5-ethyl-5-(1-methylbutyl)thiobarbituric
acid [76-75-5], M r 264.35, a yellowish-white,
crystalline, slightly bitter powder, is very sol-
uble in water and soluble in alcohol. The com-
pound is hygroscopic and has a weak unpleasant
odor. The free acid forms colorless crystals, mp
158 – 159 ◦ C. A 10 % solution of the sodium salt
has a pH of 10.6.
It is prepared by condensation of thiourea with
a disubstituted malonic ester [23].
Thiopental sodium is a short-acting intra-
venous anesthetic used for brief surgical proce-
dures and induction of anesthesia. It is a potent,
8 Anesthetics, General
rapidly effective hypnotic. Sleep ensues within
30 – 60 s. A disadvantage is the lengthy hang-
over. In the United States and Great Britain it is
the most widely used injection anesthetic. Abuse
can lead to addiction.
Thiopental sodium is used in a mixture with
approximately 6 % sodium carbonate.
Trade Names. Farmotal (Farmitalia); Hypnos-
tan (Leiras, Turku); Intraval (May & Baker);
Leopental (Leo); Nesdomal (Specia); Pen-
tothal (Abbott); Pentothal-Natrium (Deutsche
Abbott); Thio-Barbityral (Amino, Neuenhof,
Switzerland); Thionembutal (Abbott); Thiobar-
bital (Miro, Palma de Mallorca); Thiopental
“Lentia” (Hormonchemie, Munich); Trapanal
(Promonta; Byk Gulden).
Thiobutabarbital sodium [947-08-0],
the sodium salt of 5-sec-butyl-5-ethyl-
thiobarbituric acid, M r 241.32, is a yellowish-
white amorphous powder soluble in water and
alcohol. The colorless crystals of the free acid
[2095-57-0] melt at 163 – 165 ◦ C. Thiobutabar-
bital is prepared from thiourea and a malonic
ester [24].
It is a short-acting intravenous anesthetic. It is
the least potent of the thiobarbiturates and there-
fore causes the least number of complications
during anesthesia. The compound is available
as 5 % and 10 % solutions.
Trade Names. Inaktin (Byk Gulden); Narkoth-
ion (Sanabo); Brevinarcon (Arzneimittelwerk
Dresden).
Thiamylal [77-27-0], 5-allyl-5-(1-
methylbutyl)-2-thiobarbituric acid, M r 254.36,
mp 132 – 133 ◦ C. The sodium salt [337-47-3],
M r 276.36, is an amorphous powder soluble in
water. It is prepared by condensation of thiourea
with a malonic ester [25], [26].
The properties of this rapidly effective anes-
thetic are similar to those of thiopental.
Trade Names. Surital (Parke-Davis); Thiosec-
onal (Eli Lilly); Bio-Tal (Philips Roxane, vet-
erinary anesthetic).
Buthalital sodium [510-90-7], the sodium
salt of 5-allyl-5-isobutyl-2-thiobarbituric acid,
M r 262.31, is a water-soluble amorphous pow-
der. The free acid [468-65-5], M r 240.33, melts
at 147 ◦ C. Buthalital sodium is prepared by con-
densation of thiourea with a malonic ester [27],
[28].
Buthalital sodium is eliminated so rapidly that
slow injection does not produce anesthesia [29].
For pharmacological properties, see [30].
Trade Names. Baytinal (Bayer); Transithal
(May & Baker); Ulbreval (Wyeth).
Thialbarbital [467-36-7], 5-allyl-5-(cy-
clohexen-2-yl)-2-thiobarbituric acid, Mr
264.36, mp 79 – 81 ◦ C. The sodium salt
[3546-29-0], M r 286.34, is a pale yellowish,
water-soluble, amorphous powder.
Thialbarbital is prepared from thiourea and a
malonic ester [31].
Trade Name. Kemithal (ICI; Avlon).
3.3. Miscellaneous Compounds
A miscellaneous group mainly includes com-
pounds that are readily soluble in lipids and
that must be brought into aqueous solution with
solubilizers. They are generally short- and very
short-acting anesthetics used for surgical inter-
vention and induction of inhalation anesthesia.
Propanidid [1421-14-3], propyl 3-
methoxy-4-(N,N-diethylcarbamoylmethoxy)-
phenylacetate, M r 337.42, is a colorless to pale
yellowish water-insoluble oil. It is prepared
from the propyl ester of sodium homovanillic
acid and N,N-diethylchloroacetamide [32].

Propanidid is used as a very short- to short-
acting intravenous anesthetic for minor surgery
and gynecology. It is characterized by rapid
onset of and quick recovery from anesthesia,
producing surgical anesthesia for 3 – 4 min. Re-
peated injections can be used to prolong the
anesthesia. Postanesthetic sleep does not occur
because the propyl ester is hydrolyzed rapidly
in the patient to form inactive 3-methoxy-4-
(N,N-diethylcarbamoylmethoxy)phenylacetic
acid. After 20 – 30 min the patients generally
are completely responsive [33].
The commercial 5 % aqueous solution con-
tains 20 % of the solubilizer Cremophor EL
(polyethoxylated castor oil) [34]. Histamine re-
lease is sometimes observed, in part because of
the Cremophor EL.
Trade Names. Epontol (Bayer; Theraplix);
Propanidid (Riker); Fabontal (Bayer); Propan-
tan (Leiras, Turku); Sombevrin (Gedeon
Richter).
Ketamine [6740-88-1], 2-(o-chloro-
phenyl)-2-methylaminocyclohexan-1-one, M r
237.74. The hydrochloride [1867-66-9] forms
colorless crystals, mp 262 – 263 ◦ C. Its solubil-
ity in water at 20 ◦ C is 20 g per 100 mL.
It is prepared by bromination of o-chloro-
phenyl cyclopentyl ketone, which is then reacted
with methylamine to give the methylimino al-
cohol. Thermolysis of the imino hydrochloride
yields ketamine by ring expansion [35]:
Anesthetics, General 9
Ketamine is a short-acting anesthetic effective
for 5 – 30 min, depending on the amount in-
jected. It is suitable for diagnostic purposes and
for surgical procedures that do not require mus-
cle relaxation. The occasional hallucinations
that occur during anesthesia suggest a chemical
relationship to phencyclidine, which was used
as a short-acting anesthetic until identified as a
dangerous drug of abuse.
The mode of action of ketamine differs from
that of the barbiturates. It suppresses the activi-
ties of the cerebral cortex (consciousness) and
the thalamic pain pathways (analgesia). Parts
of the upper brainstem and the limbic system
are not affected (so-called dissociative analge-
sia). The patient exhibits a characteristic super-
ficial sleep with complete elimination of pain.
Because of the psychomotor side effects, com-
bination with neuroleptics and tranquilizers is
necessary. Ketamine is used especially in pe-
diatrics. The usual preparations are 0.1 % and
0.5 % solutions.
Trade Names. Ketanest (Parke-Davis); Ketaject
(Bristol); Ketalar (Parke-Davis; Sankyo); Ke-
taset (Bristol); Vetalar (Parke-Davis, veterinary
anesthetic).
4. Combination Anesthetics
Combination anesthetics are used only in combi-
nations to produce balanced anesthesia (see page
2). Chemically and pharmacologically they be-
long to many different groups.
4.1. Sleep-Inducing Anesthetics
Etomidate [33125-97-2], ethyl (R)-(+)-1(α-
methylbenzyl)-imidazole-5-carboxylate, Mr
224.28, is a white to yellowish crystalline or
amorphous powder, mp ca. 65 – 70 ◦ C. It is in-
soluble in water at pH 7, but soluble in acidic
aqueous solutions at pH < 3. Etomidate is sol-
uble in propylene glycol and readily soluble in
alcohol.
The preparation of etomidate involves
a modification of Jones’ synthesis: α-
phenylethylamine is alkylated with ethyl chloro-
acetate to the N-(α-phenylethyl)-glycine ester,
whose NH group is formylated. This product
is condensed with methyl formate and cyclized
10 Anesthetics, General
with HCl-KSCN to yield ethyl 2-mercapto-1-(α-
methylbenzyl)-5-imidazolecarboxylate, which
is then oxidatively desulfurized [36]. The (R)
isomer is obtained by separating the racemic
acid with (R)-(+)-1-phenylethylamine.
Etomidate is administered intravenously as
a short-acting anesthetic for the induction of
lengthy anesthesia, especially for the induction
of neuroleptanalgesia (Section 4.4) and inhala-
tion anesthesia [37], [38]. Etomidate produces
3 – 5 min of sleep.
Trade Names. Hypnomidate (Janssen; John-
son & Johnson; Sanwakagaku Kankyusho; Ab-
bott) as a 0.2 % solution; Radenarcon
(Arzneimittelwerk Dresden).
Sodium oxybate [502-85-2], sodium γ-
hydroxybutyrate, HOCH2 CH2 CH2 COONa, M r
126.09, is recrystallized from alcohol and is sol-
uble in water. It is prepared by saponification of
γ-butyrolactone [39].
The substance is related to γ-aminobutyric
acid, a cerebral metabolite that is supposed to
be sleep inducing. When given i.p., it produces
a shallow anesthesia (tolerance stage a: paraly-
sis of the spinal cord and mesencephalon, slight
relaxation of the muscles, see Chap. 1) that
resembles natural sleep as seen via the elec-
troencephalograph. It is employed as an anes-
thetic during labor and in combination anesthe-
sia with nitrous oxide, barbiturates, or neurolep-
tanalgesics.
The sodium salt is available as a 24 % aque-
ous solution.
Trade Names. Somsanit (Kühler Chemie);
Gamma-OH (Ebifarm); Anetamin (Sankyo);
Gioron (Kaken-Ono, Japan).
Disoprofol [2078-54-8], 2,6-diisopro-
pylphenol, bp 136 ◦ C at 40 mbar, mp 19 ◦ C,
belongs to a new group of anesthetics. Its ef-
fects are similar to those of Althesin (see page
11) and thiopental (see page 7). However, it
is more effective and may be given repeatedly
without lengthening the reapplication interval.
It has been in phase II of clinical trials since
1982 [40].
4.2. Benzodiazepines
Among the benzodiazepines, diazepam and flu-
nitrazepam were used because of their sedative,
anxiolytic, muscle relaxant, and anesthetic po-
tentiating effects; initially, they were adminis-
tered perorally but later also by injection. The
frequency of pain at the injection site and of
postoperative phlebothromboses led to the de-
velopment of the water-soluble midazolam.
Midazolam maleate [59467-70-8], 8-
chloro-6-(2-fluorophenyl)−1-methyl-4H-
imidazo[1,5-a]-[1,4]benzodiazepine maleate
[59467-94-6], M r 441.59, mp 148 – 151 ◦ C, is a
stable, water-soluble powder. The solubility in
water depends on pH: ≈ 85 mg/mL at pH 2.7 and
0.3 mg/mL at pH 7.6. The free base, M r 325.78,
melts at 152 – 154 ◦ C. The maleate is subject to
reversible ring opening. Below pH 4 the ring is
open; above pH 4 the cyclic form is present. The
anesthetic formulation is a buffered aqueous
solution containing 2.5 mg/mL at pH 3.5.

The preparation starts with 7-chloro-
5-(2-fluorophenyl)−1,3-dihydro-2H-1,4-
benzodiaze-pinone [41]. For the literature, also
see [42].
Midazolam is approximately twice as active
as diazepam, causes less pain at the injection
site, and has a shorter half-life than diazepam.
Side effects: dose-dependent cerebral depres-
sion with tranquilization, sedation, and dryness.
Reduction in blood pressure, respiratory depres-
sion, and cardiovascular effects were slight.
Trade Names. Dormicum (Hoffmann-La
Roche, Switzerland); Hypnovel (Hoffmann-La
Roche, United Kingdom).
4.3. Steroid Derivatives
A number of pregnane derivatives with oxy-
gen substituents on C-3, C-20, and C-21 ex-
hibit anesthetic properties without hormonal ac-
tivity [43]. The preparations are used for brief
Anesthetics, General 11
narcosis and for induction of lengthy anesthe-
sia. The first commercially available as an anes-
thetic was 21-hydroxypregnane-3,20-dione, as
the water-soluble sodium hemisuccinate, un-
der the generic name hydroxidione and by the
trade names Presuren (Schering) and Viadril
(Boehringer Mannheim; Pfizer).
The compound has been withdrawn in Great
Britain and other countries, for, even when
strongly diluted, it irritates the venous wall, in-
creasing the risk of thrombosis, and elicits a
long recovery phase. It is characterized by a
late onset of the anesthesia after a relatively
long, excitation-free induction period of 5 min.
The induction period depends on the hydrolysis
of the hemisuccinate ester to the active steroid
alcohol. Viadril G, in which the hemisuccinate
is combined with glycine, is supposed to be
better tolerated. Most of the disadvantages can
be avoided by dissolving the active pregnane
derivative in Cremophor EL (BASF) [45].
A marked oversensitivity of patients to Al-
thesin [45] led to the development of the
water-soluble steroid minaxolone [44] (Glaxo-
Allenbury), which is still being tested clinically.
Alphaxalone [23930-19-0], 3α-hydroxy-
5αpregnane-11,20-dione, M r 332.49, forms col-
orless prisms, mp 172 – 174 ◦ C, [α]26
D + 113.4
(c = 1.2 mg/mL in CHCl3 ). It is prepared by
reduction of 3,11,20-trioxo-5-α-pregnane with
trimethyl phosphite in the presence of an irid-
ium catalyst. Only this reducing agent forms the
axial alcohol (3α) [46], [47].
12 Anesthetics, General
Alphaxalone is the more potent component
of Althesin. Addition of alphadolone increases
the total amount of active steroidal anesthetic in
the Cremophor solution.
Alphadolone [14107-37-0], 3α,21-
dihydroxy-5α-pregnane-11,20-dione-21-
acetate, M r 390.52, forms colorless crystals,
mp 175 – 177 ◦ C, [α]26
D + 97 (c = 1.02 mg/mL in
CHCl3 ). To prepare alphadolone, alphaxalone
is reacted with lead tetraacetate in the presence
of a Lewis acid, such as BF3 etherate [47].
Althesin is an effective intravenous anes-
thetic for short surgical procedures or for in-
duction of lengthy anesthesia [45]. Doses of
0.050 – 0.075 mL per kg of body weight produce
anesthesia in adults for 5 – 20 min and analgesia
to surgical stimuli for 2 – 5 min. Althesin causes
cardiodepressive side effects. Although it is used
in countries in which French pharmaceuticals
dominate, it is hardly used in Germany.
Trade Names. Althesin and Saffan (Glaxo); Au-
rantex (Glaxo, Bad Oldestoe).
4.4. Neuroleptanalgesics
Even with adequate somnolence and analgesia,
surgical stress factors can be suppressed only
if the activity of the deeper cerebral regions is
subdued also. This is accomplished with small
doses of neuroleptics ( → Neuropharmacology)
to induce the so-called neuroleptanalgesia (see
page 2). A potent analgesic is used in conjunc-
tion with a neuroleptic, the dosage usually ad-
justed for each individual. The first neurolep-
tanalgesic was the “coctail lytique” of Laborit
and Huguenard, a mixture of pethidine as the
analgesic, chlorpromazine as the neuroleptic,
and promethazine as an antihistamine with pro-
nounced sedative effect. In the course of further
development, two combinations of neuroleptic
and very potent analgesic emerged:
1) Haloperidol and phenoperidine (≈ 70 times
more active than pethidine)
2) Droperidol and fentanyl ( ≈ 100 times more
active than morphine)
Only the second is still important. A
newer development is alfentanyl, N-[1-
[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-
yl)-ethyl]-4-(methoxymethyl)-4-piperidinyl]-
N-phenylpropanamide hydrochloride (John-
son & Johnson), which was developed from fen-
tanyl and is an effective anesthetic analgesic in
phase III of clinical trials [48].
Droperidol [548-73-2], 1-[3-(4-fluorobenzoyl)-
propyl]-4-(2-oxo-1-benzimidazolinyl)-1,2,3,6-
tetrahydropyridine, M r 379.44. The monohy-
drate melts at 145 – 146.5 ◦ C. It is prepared
by alkylating (2-oxo-1-benzimidazolinyl)-
1,2,3,6-tetrahydropyridine with 4-fluoro-γ-
chlorobutyrophenone [49].
Droperidol is a very potent neuroleptic from
the phenylbutyrophenone group. It is never
used in outpatient practice. To induce narcosis,
15 – 25 mg is injected, followed by further doses
as needed. Narcosis begins rapidly, and the du-
ration of action is short. Extrapyramidal symp-
toms are absent to a large extent. For anesthesia,
the analgesic fentanyl is administered simulta-
neously.
Trade Names. Dehydrobenzperidol (Janssen,
Düsseldorf); Thalamonal, Innovar in the USA,
(Janssen) is a combination of droperidol with
fentanyl. (One milliliter contains 0.05 mg of fen-
tanyl base and 2.5 mg dehydrobenzperidol.)
Fentanyl [437-38-7], N-phenyl-N-[1-(2-
phenylethyl)-4-piperidinyl]-propanamide, M r
336.46, forms colorless crystals, mp 83 – 84 ◦ C.
The bitter-tasting dihydrogen citrate [990-73-8],

mp149 – 151 ◦ C, is soluble in water (1 g per
40 mL at 20 ◦ C) and methanol. For prepara-
tion → Analgesics and Antipyretics.
Fentanyl belongs to the group of base-
substituted propionanilide analgesics [50] and
is a typical morphine agonist. Because of the
danger of addiction, the short-acting fentanyl
is used exclusively for anesthesia. A dose of
just 0.2 – 0.3 mg produces complete short-term
analgesia in adults. Because it depresses respi-
ration, it is necessary to control breathing dur-
ing neuroleptanalgesia. Afterward, respiratory
depression can be alleviated by a morphine an-
tagonist such as 1-N-allyl-3-hydroxymorphinan
(Lorfan).
Trade Names. Fentanyl (Janssen, Düsseldorf),
Sublimaze (Janssen); Thalamonal, see trade
names for Droperidol.
5. References
General References
1. M. E. Greig in V. E. Grill (ed.): Theories of
Anaesthesia in Pharmacology and Medicine,
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Weese: Die Narkose, Thieme Verlag, Stuttgart
1954. M. B. Chenoweth (ed.): “Modern
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28th ed., The Pharmaceutical Press, London
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