General anaestetics
© Oldřich Farsa 2018
Functions of general anaesthesia
●neither terapeutic nor diagnostic
●make surgical and other painful procedures easier
Demands on effects of general anaesthetics
1. Analgesia (pain relief)
2. Amnesia
3. Lost of conciousness
4. Decrease of movability of skeletal musculature
5. Atenuation of autonomic responses
6. Reversibility of effect
●all anaesthetics do not reach all demands
Classification of general anesthetics according to the route of
administration
1. Inhaltion – gases, volatile liquids
●effect is less dependent on a particular stucture more on lipophilicity
2. Intravenous
●more specific - receptor mechanisms of action
Sites of action
CNS: Brain cortex, reticular system, thalamus, spinal cord
Effect
Anaesthetics block nervous impulses transfer
●decrease of activity of excitably acting synapses
●increase of activity of inhibitory synapses
●
synaptic channels for Ca2+
and Clligand-activated
ones = Cl-
channels
activated by GABA or glycine are influenced by anaesthetics (propofol,
barbiturates, benzodiazepins, inhalation ansestetics)
●increase of quiescent steady state membrane potential – hyperpolarization
●attenuation of neurons forming impulses – not elucidated – ventilation and heart
frequence also influenced by anaesthetics
Lipide theory
●anaesthetic is dissolved in a lipide membrane and causes some
changes of physical properties of the membrane
●based on the Meyer-Overton rule
●higher lipids solubility expressed as Poil/air
implies higher anaesthetic potency i.e.
lower minimal alveolar concentration
●valid for inhalation anaesthetics only
Protein theory
●interaction of anaesthetic with a hydrophobic part of an integral
transmembane protein
Mixed effect on the protein-lipide interface
Mechanisms of action of general anaesthetics
Dependence of effect of inhalation anaesthetic on Poil/air
GABAA
receptor
GABAA
receptor and its role in general anaesthesia
GABAA
receptor = ligand controled chloride channel
●opening of the channel causes cell hyperpolarization
and thus its insensitiveness to impulses
●agonists: GABA, barbiturates, benzodiazepins, steroids
(have identified binding sites)
NMDA (N-methyl-D-aspartate) receptor
●a subtype of glutamate receptor
●anaesthetics are its antagonists
activation  cell depolarization by entrance of Ca2+
and Na+
●takes part in effects of N2
O, Xe a ketamine
Inhalation general anesthetics
1. Gases
Nitrous oxide N2
O
„laughing gas“, „Lachgas“
●used since 19th
century (dentist Wells 1845)
●patient reaction badly predictable
●contemporarirly sometimes in obstetrics – rather analgesia with conciousness retention
O
-
N
+
N
Xenon Xe
●inert gas
●name from Greek „xenos“ - stranger
●invented by Sir W. Ramsay and M.W. Travers 1898
●modern and secure inhalation anaesthetic
Preparation: heating of ammonium nitrate to 180 – 250°C:
NH4
NO3
 N2
O + H2
O
Inhalation general anaesthetics
2. Volatile liquids
2.1 Ethers
Diethylether, aether, „aether sulphuricus“
CH3 O CH3
CH3
OH
H2SO4
CH3 O CH3 OH2
2 +
Preparation
●
known since 10th
-11th
century: Abu al-Khasim al-Zahravi Ibn Zuhr, an Arab alchemist
●as an anaesthetic used since 1846 (William Morton; the first patient Gilbert Abbott)
●well controlled introduction of a patient into anaesthesia: all phases clearly expressed
●disadvantages: highly inflammable, mixture of vapours with air highly explosive
●
forming of explosive peroxides  stabilization needed (Cu sealing of bottles, phenidone)
●Ether anaestheticus, Ether solvens PhEur, Aether pro narcosi PhBs IV
N
NH
O
1-phenylpyrazolidin-3-one
phenidone
●antioxidant stabilizing agent added into diethylether
according to some pharmacopoeias
Ether anaesthesia in U.S. army at the end of 19th
century
Halogenated ethers
●non-toxic, non-inflammable
F
O
F
F
F F
Cl
enfluran isofluran
*
*
F
F
O
Cl
F
F
F
Isofluranum PhEur
Halogenated ethers
F
O
F
F F
F
F
*
desfluran
O F
F
F
F
F F
F
sevofluran
Desfluranum PhEur
2.2 Halogenated alkans
Br
Cl
F
F
F
*
halothan
Cl
Cl Cl
H
chloroform
trichloromethane
Halothanum PhEur
b. p. 49 - 51°C
Cl
Cl
Cl
H
SbCl3/HF
F
F
F Cl
H
Br2
F
F
F Cl
Br
Synthesis of halothan
●at first Simpson 1847
●strongly hepatotoxic, suspect
cancerogene, not used as
anaesthetic now (decomposition to
COCl2
)
3. Intravenous general anaesthetics
Barbiturates and thiobarbiturates
N
N
H
O
O
X
R
1
R
2
R
3
N
H
N
H
O
O
S
CH3
CH3
CH3
N
N
H
O
O
O
CH3
CH3
R1
=R2
=R3
=H; X=O barbituric acid
R1
, R2
= alkyl, aryl, R3
= H or alkyl; X=O barbiturates
R1
, R2
= alkyl, aryl, R3
= H or alkyl; X=S thiobarbiturates
thiopental
N
N
H
O
O
O
CH3
CH3
CH3
CH2
hexobarbital methohexital
●
one- or dibasic acids (lactame/lactime-tautomerism  N- or O-/S-acids  used as water
soluble Na+
salts
Intravenous general anaesthetics
Cl
ONH
CH3
N
N
O
CH3
O
CH3
(S)-(+)-ketamine (R)-(+)-etomidate
●neuroleptic and strongly pain relieving
effects
●short surgical procedures
●stunning (narcotization) projectiles for
catching wild animals
Narkamon Spofa ® 1%
●ultrashortly acting narcotic
●used as hydrochlorides
Intravenous general anaesthetics
OH
CH3
CH3
CH3
CH3
propofol
7
8
N
6 N
5
4
1
N
2
3
CH3
Cl
F
midazolam
●derivative of 4H-imidazo[1,5-a][1,4]benzodiazepine
●for both onset and keeping of anaesthesia
●combined with ketamine
●hydrochloride
Dormicum® inj. sol.
●
poor solubility in water  use in
emulsions
●very fast onset of action and very
fast awakeing after finishing of
infusion also (in several minutes)
●anticonvulsive and antiemetic effects
Diprivan