GENERAL ANAESTHETICS

GROUP ONE (1)

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GROUP MEMBERS
 DZIKUNU KINGSLEY ELORM SP/PHA/16/0012
 EUGENE RICHMAN OKO SP/PHA/16/0030
 BANAHENE YEBOAH SP/PHA/16/0018
 AYISHATU INUSAH ABUKARI SP/PHA/16/0009
 ABIATE RICHARD SP/PHA/16/0007

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OUTLINE
• At the end of this presentation, the student should be able to:
 Know general overview of general anesthesia
 Know the stages of anesthesia produced by general anesthetics
 Know the structure and synthesis of some of the general
anesthetics
 Know the key metabolites and pathways that enables
excretion.

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 INTRODUCTION
• General anaesthesia refers to the loss of sensation with loss of
consciousness.

• Anesthetics are depressant drugs that produce a partial or total

loss of the sensation.

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Stages of General Anesthesia
 Stage I (Stage of analgesia):
• beginning of anesthetic administration
• to the loss of consciousness
• progressive lose of pain.
 This stage is also called stage of analgesia.

 Stage II (Stage of delirium):

• from the loss of consciousness through a stage of irregular and
specific breathing.
• to the establishment of regular breathing.
• Respiration is normal and regular.
 The patient may laugh, vomit or struggle and for this reason it is
called the stage of excitement.
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Stages of General Anesthesia con’t
 Stage III (Stage of surgical anesthesia):
• Excitement lost
• Skeletal muscle relax
• Most types of surgeries are done in this stage.

 Stage IV (Stage of medullary depression):

• Overdose of the anesthetic may bring the patient to this stage.
• Respiratory and circulatory failure occur in this stage.

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INTRODUCTION CON’T
 General anesthesia involves administration of different drugs:
 Premedication

 Inducing agents

 Maintenance agents

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PREMEDICATION
• Prevention of bradycardia, bronchial secretion, muscle spasm
and some classes of drugs used are:
 Benzodiazepines (Diazepam)
 Narcotic analgesics
 Anticholinergic rugs (scopolamine)
 Skeletal muscle relaxants (CNS)

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INDUCING AGENTS
• Normally an intravenous anaesthetic such as:
 Barbituate (thiopentone, methohexitone)
 Non- barbiturate ( propofol, ketamine)

MAINTENANCE ANAESTHESIA
 Normally an inhaled gas such as
 Halogenated hydrocarbons and ethers
 Nitrous oxide

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MECHANISM OF ANAESTHESIA
 BLOCKING THE NMDA AND GLUTAMATE CONTROLED
CHANNELS.
• Glutamate or NMDA (N-METHYL-D-ASPARTATE) receptors in
the CNS are activated by the excitatory amino acid-neurotransmitter
glutamic acid.

 AGONISTS INTERCATION WITH THE ABOVE RECEPTORS:

• Leads to the activation opens the channel, allowing K+ to flow to the
extra cellular fluid and Na+ and Ca2+ to flow into the nerve cell. The
increased intracellular Ca2+ activates the liberation of the (NO),
which causes alertness (consciousness).

 KETAMINE ACTS AS ANTAGONISTS

• Ketamine blocks NMDA receptors, causes CNS depression
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(anaesthesia).
 MECHANISM OF ANAESTHESIA
 ACTIVATION OF THE INHIBITORY GABA
RECEPTOR CONTROLLED CHANNEL
• Binding of GABA (inhibitory transmitter) to their
receptors will open the Cl- channel, leading to influx of
Cl- and hyperpolarization of the neuron.

• Halothane and isoflurane inhibits the synaptic destruction

of GABA, thereby increasing the GABAergic
neurotransmission.
• Benzodiazepines and barbiturates enhances GABA
Opening of Cl- channels

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 CLASSIFICATION DUE TO ROUTE
OF ADMINISTRATION
 INHALATION (pulmonary) Anesthetics:- Gases or vapors
of volatile liquids that are inhaled in a mixture with air or O2.

 INTRAVENOUS ANESHTETICS: Agents are

psychologically well tolerated. They are quite useful as
induction agents for inhalation anesthesia.

 COMBINATION ANESTHESIA: Combinations of

medications is preferred to broaden the therapeutic range.
Moreover, minimal doses of several substances are
administered for particular goals of anesthesia.
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INHALED ANAESTHETICS
1. NITROUS OXIDE
• A colorless gas, exerts low anesthetic effect. It is mixed with
oxygen and ether or halothane, as deep anesthesia and cannot
be achieved with it alone.

• It has good analgesia and minimal toxicity, it has poor muscle

relaxant effect.

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INHALED ANAESTHETICS CONT’D
2. NON-HALOGENATED HYDROCARBONS
• They have the tendency to produce cardiovascular toxicity.
• The longer chain of hydrocarbon, the higher the potency.

 CYCLOPROPANE
• A major prototype of the non-halogenated hydrocarbon
anesthetic.
• Its colorless, explosive, inflammable and it’s the only
hydrocarbon still in use.

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 Structure Activity Relationship (SAR) of the
Inhaled General Anesthetics
• ALKANE OR CYCLOALKANE

 The potency of alkanes, cycloalkanes, and aromatic

hydrocarbons increases in direct proportion to the number of
carbon atoms in the structure up to a cutoff point.
• In the n-alkanes, the cutoff number is 10 while that of the
cycloalkanes is 8.

 The cycloalkanes are more potent anesthetics than the straight

chain analogue with the same number of carbons. 15
3. HALOGENATEDHYDROCARBONS
• Effect of halogenation/ether halogenation.
• Addition of a halogen reduce or eliminate flammability and
increases potency.
• Higher atomic mass halogens increases potency when
compared to lower atomic mass halogens.
• For the n-alkane series, fully saturating the alkane with
fluorine abolishes its activity except when n equals one.
• When n was 2-4 carbons, the highest potency was seen when
the terminal carbon contained one H as in (CHF2(CF2)nCHF2).
• When n was greater than 5 carbons the potency decreased in
this series.

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EXAMPLES OF INHALED
ANAESTHETICS

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 HALOTHANE (2-bromo-2-chloro-1,1,1-
trifluoroethane)
 Chemistry
• Chemically halothane is 2-bromo, 2-chloro, 1,1,1-trifluoroethane.
• It is prepared from trichloroethylene.

 Properties
• Halothane is a colorless, non-inflammable liquid having
chloroform like odor.
• It is non-irritant to the skin and mucous membrane. 18
 HALOTHANE (2-bromo-2-chloro-1,1,1-
trifluoroethane) CONT’D
 Uses
• Halothane is one of the most widely used potent anesthetic
agents (2-2.5%).
• It is usually administered through N2O-air mixture.
• It has more rapid induction and recovery compared to ether
(generally discouraged as an explosive hazard) and
Methoxyflurane.
• It is more potent than chloroform and ether.

 Some disadvantages of halothane are

• It reduces cardiac output.
• It causes peripheral vasodilation leading to hypotension or low
blood pressure.
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• It is a dose-dependent respiratory depressant.
HALOTHANE SYNTHESIS

HALOTHANE METABOLISM

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 ENFLURANE (2-chloro-1,1,2-trifluoroethyl
difluoromethyl ether)
• Non inflammable liquid, mixed with various amounts of O2 and
N2O.
• Its advantage over halothane is the more rapid induction and
recovery.
• Arrhythmias are observed less frequently.
• Its low frequency of nephrotoxicity is due to low Fluorine
released from metabolism.
• Only 2% is metabolized to fluoride ions and fluoromethoxy
difluoroacetic acid.
 Drug’s Toxicity is due to the ff. reasons:
• Increased doses produces convulsions, and its not used in
patients with epilepsy.
• Enflurane relaxes the uterus, and its not used as an anaesthetic 21
during labor.
 ISOFLURANE (1-chloro-2,2,2,-trifluoroethyl
difluoromethyl ether)
• Isoflurane is an isomer of enflurane. Chemically isoflurane is 2-
chloro-2-(trifluoromethoxy)-1,1,1-trifluoroethane.
• It is available as clear, colorless liquid at room temperature, with
sweet taste.
• It is miscible with organic liquids including fats and oils.
• Isoflurane is nonflammable and non-explosive.
• Isoflurane has a more rapid induction and emergence than
halothane.
• It has higher margin of safety than enflurane or halothane.
• Below is the structure of Isoflurane:

isoflurane
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ISOFLURANE (1-chloro-2,2,2,-trifluoroethyl
difluoromethyl ether)
• It has a low blood/gas distribution coefficient, which leads to
rapid recovery from the anesthesia.
• Only 0.2% of the drug is metabolized to Fluorine and
trifluoroacetic acid, therefore kidney, liver and myocardial
functions remain intact.
• It is the best General Anesthetic so far.
• Isoflurane is a structural isomer of Enflurane.
• Isoflurane reduces renal blood flow, glomerular filtration rate
and urinary flow.
• Isoflurane’s metabolism to organic and inorganic fluorides is
less than any other halogenated agent available.
• If a minimally metabolized anesthetic is needed, isoflurane is
the choice 23
 METABOLISM OF ISOFLURANE

• .

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 PHARMACOKINETICS OF
INHALATIONAL ANAESTHETICS
Uptake into the blood: Inhalational anesthetics are taken up
passively via diffusion, which depends on:
 Blood solubility of the anesthetics based on:
• Blood-gas partition coefficient: the ratio of anesthetic
concentrations in the blood and alveolar space when partial
pressures in the two compartments are equal.

• The higher the blood-gas partition coefficient of an

inhalational anesthetic, the higher the solubility of that
substance in the blood.

 Lung ventilation, volumes, and perfusion also moderately

affects blood solubility of the inhalational anesthetics. 25
 PHARMACOKINETICS OF
INHALATIONAL ANAESTHETICS CONT’D
 Distribution and uptake into the brain
• Transport to and uptake into the brain depend on cerebral
perfusion and the fat solubility of the inhalational anesthetic
and is based on Brain-Blood Partition Coefficient.
• Brain-blood partition coefficient: the ratio of anesthetic
concentrations between blood and brain tissue when partial
pressures are equal.
• The higher the brain-blood partition coefficient, the higher the
solubility of that substance in brain tissue.

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 PHARMACOKINETICS OF
INHALATIONAL ANAESTHETICS CONT’D
 Onset of effect: The lower the blood-gas partition coefficient
of an inhalational anesthetic, the faster the substance takes
effect (less induction time).

 Elimination: Inhalational anesthetics are eliminated by the

lungs but the lower the blood-gas partition coefficient of an
inhalational anesthetic, the faster the effect ceases (less
recovery time).

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 PHARMACODYNAMICS OF
INHALATIONAL ANAESTHETICS
• Measure of potency of inhalational anesthetics: minimal
alveolar concentration (MAC).

• MAC is the fraction of volume of the anesthetic present in the

inspired air that provides sufficient analgesia in 50% of
patients.

• MAC is, therefore, a measure of anesthetic potency and

represents the ED50 value.

• The lower the MAC value, the more fat soluble the
anesthetic.
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 Pharmacokinetics and pharmacodynamics of common inhalational anesthetics

Blood-gas partition Brain-blood partition Minimal alveolar

coefficient coefficient concentration (MAC)
Nitrous  0.47  1.1  > 104%
oxide
 0.42  1.3  6–7%
Desflurane
 0.69  1.7  2%
Sevoflurane
 1.40  2.6  1.4%
Isoflurane
 1.80  1.4  1.7%
Enflurane
 2.30  2.9  0.75%
Halothane

www.amboss.com/us/knowledge/inhalational_anesthetics(Accessed: 25/03/19, 20:00 GMT).

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Specific characteristics of common inhalational anesthetics
Specific characteristics
 Usually insufficient if used alone → often
combined with a more potent inhalational
Nitrous oxide anesthetic to achieve the “second gas effect”
 Rapid onset and recovery
 Very rapid onset and recovery
Desflurane  Pungent odor; irritates airways → not
suitable for induction of anesthesia
 Most commonly used inhalational anesthetic
 Rapid onset and recovery
Sevoflurane
 Non-pungent → suitable for induction of
anesthesia
 Most potent of the fluranes
 Relatively slow onset and recovery
Isoflurane
 Pungent odor → not suitable for induction of
anesthesia
Enflurane  Medium speed of onset and recovery
Halothane  Medium speed of onset and recovery
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 INTRAVENOUS ANESTHETIC
• Intravenous anesthetics are non explosive solids.

• They produce rapid loss of consciousness but

insufficient anesthesia so the’re seldom used alone.

• Administration of oxygen is recommended,

particularly with barbiturates and thiobarbiturates.

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 PROPOFOL (DEPRIVAN)
2,6-di-isopropylphenol

• Propofol is a short acting anesthetic that acts via enhancing

GABA-ergic neurotransmission in the CNS.
• It binds allosterically to the GABA receptor at the site different
from that of the benzodiazepines. It achieves hypnosis in ONE
minute and lasts for FIVE minutes.
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• Maintenance of anesthesia is achieved with inhalatonal
anesthetics or additional doses of it (Propofol).
• It is more effective than thiopental.
• Again, its rarely associated with vomiting.
• Also, metabolism proceeds rapidly via glucuronide and sulfate
conjugation in the liver.

PROPOFOL METABOLISM

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 PROPANIDID
• Propanidid is an ultra short-acting phenylacetate general
anesthetic.
 Chemistry: Propanidid is a non-barbiturate general anesthetic.
 Properties: Propanidid is available as a colourless or pale
greenish-yellow hygroscopic liquid and having a faint odor
• It is slightly soluble in water but miscible with alcohol,
chloroform and ether.
 Uses:
• Propanidid has been used as a short acting general anesthetic.
• It also possesses local anesthetic activity.
• Below is its structure:

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 CHLOROFORM
 Chemistry: Chloroform is an important halogenated hydrocarbon.
• It is prepared from bleaching powder and ethyl alcohol.

 Properties: Chloroform is a colorless, volatile liquid having

characteristic odour and burning taste
• It is non-inflammable and is freely miscible with ether and ethyl
alcohol.

• Chloroform must be protected from light and air, otherwise

poisonous phosgene is formed.

• Formation of phosgene (COCl2, its deposition in the lungs brings

about Noncardiogenic Pulmonary Edema causing asphyxia that
can lead to Respiratory Depression) is prevented by addition35
of 1-2% ethanol as a stabilizer.
 Uses:
• Chloroform is a widely used general anesthetic agent.
• Its also used as solvent for fats and oils
• Again, it’s also used as flavoring agent in some antacids’ and
pharmaceutical emulsions’ preparation.

• SYNTHESIS OF CHLOROFORM

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 TRICHLOROETHYLENE
 Chemistry
Trichloroethylene is a trichloro derivative of ethane.
It is prepared by the alkaline decomposition of tetrachloroethane.

 Properties and application

• Trichloroethylene is a clear colorless liquid, having chloroform like
odor and taste.
• It contains about 0.008% of thymol as preservative.
• It is insoluble in water but it is miscible with alcohol, chloroform
and ether.
• It is a weak volatile anesthetic.
• It possesses potent analgesic action.
• It is recommended for dental extractions, orthopedic manipulations
and short surgical procedures. 37
 METHOXYFLURANE
• Methoxyflurane is the most potent of all inhalation anesthetics.

 Chemistry
• Methoxyflurane is 2,2-dichloro-1,1-difluoro-1-methoxyethane.
• It is available as a colorless liquid with sweet odor.
• Methoxyflurane is nonflammable, non-explosive, and a potent analgesic.
• Low vapor pressure makes it the only agent suitable for the open drop
method.

 Disadvantages of Methoxyflurane
• Compared to other inhalents, is its relatively slow induction phase that
can result in a modest respiratory and cardiovascular depression.
• Metabolization leads to flouride ions release which is nephrotoxic.
• Below is its structure:

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 ENFLURANE
• Chemically: Enflurane is 2-chloro-1,1,2-
trifluoroethyldifluoromethylether.

• Properties: Enflurane is available as a clear, colourless non-

inflammable liquid with sweet odor.

• Uses: The induction and emergence from anesthesia of

enflurane is smooth and moderately rapid.

• It is used as an alternative to halothane.

• Compared to halothane, isoflurane causes: less depression of

cardiopulmonary function, less sensitization of the heart to
catecholamine (β-adrenoceptor agonist) release, less profound39
respiratory depressant effect.
 KETAMINE
 Ketamine is a cyclohexanone derivative.
 Chemistry
• ketamine is (+)-2 (o-chlorophenyl)-2- methylaminocyclohexanone.
• Ketamine is prepared by Grignard’s reaction of o-
chlorobenzonitrile with bromocyclopentane in presence of strong
alkali to form an expoxy compound, which converts to an imine by
the action of methylamine. The imine rearranges to ketamine on
heating with HCl.
• Ketamine is available as colorless crystalline compound having
characteristic odor. It melts at 258 ̊C.

 Uses :
• Ketamine is used as a general anesthetic.
• It has analgesic effect and also relaxes skeletal muscles.
STRUCTURE OF KETAMINE

SYNTHESIS OF KETAMINE

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 KETAMINE
 Mechanism of Action and its Adverse Reactions
• It produces anesthesia by blocking the NMDA controlled
channels.

• Unpleasant emergence reactions after administration are the

main factor limiting ketamine’s use. Such reactions may
include vivid colorful dreams, hallucinations, out-of-body
experiences, and increased and distorted visual, tactile, and
auditory sensitivity.

• However, the combination with a benzodiazepine may be

indicated to limit the unpleasant emergence reactions and also
increase amnesia.
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 KETAMINE
 Distribution & Metabolism
• The termination of action is due to redistribution from
the brain into the other tissues.
• In the liver, Ketamine is N-demethylated into
Norketamine (active metabolite), which accounts for
the longer effect of this anesthetic.
• Norketamine is further conjugated with glucuronic acid
into inactive metabolites that is renally excreted.

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METABOLISM OF KETAMINE

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ULTRASHORT-ACTING BARBITURATES
• It is used to produce rapid unconsciousness for surgical and
basal anesthesia ( induce anesthesia).

• The induction is very rapid. The long side chain substitution at

position-5 is an essential feature for increasing lipid solubility
and hence the rate of passing through the Blood Brain Barrier.

• There is an inverse correlation between the total number of

carbon atoms substituted on the 5th position and the duration
of action.
• General Barbiturates structure:

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 THIOPENTAL
 Chemistry
• Thiopentone is an intravenous anesthetic. It is a barbituric acid
derivative and is synthesized by condensing thiourea with
ethyl (ethyl-1-methyl butyl) malonate.

 Properties
• Thiopentone is available as thiopentone sodium
• It is a yellowish hygroscopic powder, having characteristic
odour and bitter taste.
 Uses
• Thiopentone sodium solutions (2.5%) are administered by
intravenous route to produce anesthesia. It has short duration
of actions .
• It is also used to control convulsions. 46
SYNTHESIS OF THIOPENTAL

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 METHOHEXITAL
 Chemistry
Methohexital is also a derivative of barbituric acid.

• It is prepared by condensation of ethylcyanoacetate with 2-chloro-

3-pentyne in
presence of sodium ethylate yielding ethyl-1-methyl-2-pentnyl
cyanoacetate which on further condensation with allylbromide yields
ethyl (1-methyl-2-pentynyl) allylcyanoacetate.

• Reaction with N-methyl urea yields the iminobarbituric acid

which on acid catalyzed hydrolysis forms methohexital.

• Below is its structure:

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 Properties
• Methohexital is available as methohexital sodium.
• It is a colorless or slightly yellowish crystalline powder.
• Methohexital sodium is freely soluble in water.
• It can rapidly penetrate the CNS after IV injection and the
redistribute rapidly to other body sites and undergo rapid
metabolic inactivation.
• It has an accessible site of metabolic inactivation, the CH2
alpha to the triple bond.

 Uses
• It is used as a general anesthetic and hypnotic. It is
administered either by intravenous route or intramuscular
route
• It is more potent than thiopentone sodium.
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 Pharmacokinetics
• It is N-methylated barbiturate that has pka of 8.4, versus 7.6
for the non-methylated compound.

• This pka value increases the concentration of the lipid soluble

free acid form at the physiological pH as we’ve learnt during
the Barbiturates’ lecture.

• N-methylation decreases duration of action.

• The compound also has extensive hydrophobic character

because of the long unsaturated side chain (9-Cs).

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 ADJUVANT TO
GENERALANESTHESIA
 NARCOTIC ANALGESICS: Such as morphine and
meperidine to reduce anxiety.

 SEDATIVES: Such as benzodiazepines, to produce sedation

and to reduce anxiety.

 ANTICHOLINERGICS: Such as Scopolamines, to inhibit

excessive respiratory secretions.

 SKELETAL MUSCLE RELAXANTS: Such as

succinylcholine and vencuronium (Neuromuscular Blocking
Agents) to relax the muscles for optimum surgical working
conditions. 51
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edition, Oxford, 2009.
2. Wilson and Gisvolds text book of organic medicinal and pharmaceutical
chemistry by John H. Black and John M. Beale, jr. 12th edition, Lippincott
Williams and Wilkings 2011.
3. Foyes principle of medicinal chemistry by David H. Williams, Thomas
L. Leuke, Williams O. Foye. Lippincott William and Wilkins. 7th edition,
2013.
4. Eger E. I. Characteristics of anesthetic agents used for induction and
maintenance of general anesthesia. Am J Health Syst Pharm. 2004:
61(20).
5. www.amboss.com/us/knowledge/inhalational_anesthetics (Accessed: 52
25/03/19, 20:00 GMT).