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General anaesthetics
Anton Kohút
General anaesthetics (GA)
GA is a state of drug-induced loss of
consciousnes whereby surgical
procedure can be caried out painlessly
General anaesthetics
History of general anaesthesia

Hwa Tuo in the second
century performed operations
under general anaesthesia
with "foamy narcotic powder"
(110 - 208)

William Morton on September
30, 1846, etherized Boston
merchant Eben Frost before
extracting his ulcerous tooth
(1819 - 1868)
Robert C. Hinckley’s painting “First Operation Under Ether”(1883)
Drugs given to induce or maintain general
anaesthesia are either given as:
 Gases or vapours (inhalational anaestheticsvolatile liquids or gases and are usually
delivered using an anaesthesia machine.

Injections
Most commonly these two forms are
combined, with an injection given to induce
anaesthesia and a gas used to maintain it,
Groups of GA
I. Inhalation GA

Halothane

Nitrouse oxide

Enflurane

Isoflurane

Desflurane
most commonly these two forms
are combined, with
an injection given to induce
anaesthesia &
a gas used to maintain it
II. Intravenous GA

Thiopental

Etomidate

Ketamine

Propofol
III. Neurolept-analgesia
Droperidol + Fentanyl
Inhalation anaesthetics
GENERAL ANAESTHESIA

a state of total unconsciousness resulting from general anaesthetic
drugs

stages of anaesthesia:
stage 1 - "induction" - the period between the initial administration of
the induction medications & loss of consciousness
stage 2 - "excitement stage" - the period following loss of
consciousness & marked by excited & delirious activity
stage 3 - “surgical anaesthesia” - during this stage, the skeletal
muscles relax & the patient's breathing becomes regular - surgery can
begin
stage 4 - "overdose" - too much medication has been given & the
patient has severe brain stem or medullary depression - cessation of
respiration & potential cardiovascular collapse - lethal without
cardiovascular & respiratory support
Characteristics of inhalation GA
1. are nonspecific, they do not act by interacting
with specific one receptor (there are not specific
antagonists)
2. effects: hypnosis, analgesia sceletal muscle
relaxation, reduction of certain autonomic reflexes
(there are among GA quantitative defferences).
3. elimination is mainly by pulmonary rout (do not
depends on the hepatic metabolism or renal
excretion).
4. At supra-anaesthetics doses all GA can cause the
death by the loss of cardiovascular function
and respiratory paralyses.
Mechanism of action of GA
Lipid -volume expansion theory

Anaesthetics disolves
in the phospholipids
bilayer of neuronal
mambrane, causing
membrane expand,
this impedes opening
of ion channels
necessary for
generation and
propagation of action
potential
Mechanism of action
Lipid theory
GA exert their action by acting on the
plasma membrane. The potency of the
drug has a direct, positive correlation
with the lipid solubility of the blood.
- increased fluidity of the membrane.
Extent and rate of GA




To achieve their effects, must pass from the
alveolar air into the blood and hence into the
CNS. Extent and rate depend upon:
concentration (or partial pressure),
solubility - GA with low solubility produce
rapid induction and recovery –nitrous oxide
and vice versa –halothane),
pulmonary physiology (ventilation, blood
flow).
agents with smaller λ(blood/gas) such as nitrous oxide,
the alveolar partial pressure approaches the inspired
partial pressure quickly,







Figure 15-4. Distribution of cardiac output and volume capacity for
general anesthetics among the major tissue compartments. The
tissues of the body can be divided into four groups based on their level of
perfusion and their capacity to take up anesthetic.
These include the Vessel-Rich Group (VRG),
Muscle Group (MG),
Fat Group (FG), and
Vessel-Poor Group (VPG).
(The contribution of the VPG is generally ignored in most pharmacokinetic
models of anesthesia.) The VRG, which contains the internal organs including
the brain, constitutes a small percentage of the total body weight (9%), has
the lowest capacity for anesthetic, and receives most of the cardiac output
(75%). The high perfusion and low capacity allow PVRG to equilibrate rapidly
with Part. Also, the VRG makes the largest contribution to the mixed venous
return partial pressure PMVR, which is equal to (0.75 PVRG + 0.18 PMG +
0.055 PFG + 0.015 PVPG).
Stages of general anaesthesia
Stage 1: analgesia - is partial until stage 2
Consciousnes and sense of touch are retained and sense of
hearing is increased.
Stage 2: delirium. Uncounsciuos - but automatic movements
may occur. Laryngospasm may develop. Suden death,
probably due to vagal inhibition of the heart or to sensitisation
of the heart to adrenaline by the anaesthetic agent.
Stage 3: surgical anaesthesia. This is divided into four
planes. Depth is determined by changes in respiration, pupils,
spontaneous eyeball position, reflexes and muscle tone.
Stage 4: medullary paralysis.
Halothane
1.
2.
3.
4.
5.
6.
drugs now in common use, and it is the standard
to which others are compared
has weak analgesic action
respiratory depresant – assistant ventilation
bronchial dilatation – suitable for asthmatic
patients
relaxant effect on the uterus – limited using for
obstetric purposes
hepatotoxic effect of metabolites
Halothane – cont.
Heart and Circulation




A dose-dependent reduction of arterial blood
pressure.
The myocardium is depressed directly and cardiac
output is decreased. (cardiac output is reduced by
20% to 50%) - vagal predominance).
Increases sensitization of myocard to
catecholamines
May increase the automaticity of the myocardium
Nitrous oxide





strong analgesic – weak anaesthetic
it does not produce surgical anaesthesia – is not
used on its own anaesthesia
is used other with anaesthetics (halothane,
enflurane)
nitrous oxide/oxygen mixture 50:50 – rapid
analgesia – obstetric analgesia
generally is non-toxic


Isoflurane and enflurane are somewhat less
potent than halothane (they have a smaller
λ(oil/gas)), but they equilibrate faster because
they have a smaller λ(blood/gas). Enflurane is
metabolically defluorinated to a greater extent
than isoflurane, and may thus have a greater risk
of causing renal toxicity. It also induces seizurelike activity in the EEG of some patients.
Isoflurane is probably the most widely used
general anesthetic today.
Desflurane and sevoflurane are newer anesthetics
that, by design, have low λ(blood/gas); times of
equilibration between their alveolar and inspired
partial pressures are nearly as short as that of
nitrous oxide. Furthermore, they are much more
potent than nitrous oxide because their oil/gas
partition coefficients are higher.
Adverse effects of inhalation GA
(rare, unpredictable)
Idiosyncratic reactions to the volatile agents:
 malignant hyperpyrexia (triggered most often by
halothane with suxamethonium)
 halothane hepatitis (direct toxicity from the products
of reductive metabolism or immunologically mediated
haptens formed by liver proteins & the products of
oxidative metabolism)
 prolonged nitrous oxide (N2O) exposure can cause:
bone marrow depression
life-threatening pressure effects by expansion of air-filled spaces
within the body
Intravenous anaesthetics

Anesthetics potentiate the action of endogenous
agonists at inhibitory receptors, such as GABAA and
glycine receptors, anesthetics both decrease the
EC50 of GABA (i.e., GABA becomes more potent)


Inhibit the action of endogenous agonists at
excitatory receptors, such as nicotinic acetylcholine,
5-HT3, and NMDA glutamate receptors. and
increase the maximum response At excitatory
receptors, anesthetics decrease the maximum
response while leaving the EC50 unchanged; these
are the pharmacologic hallmarks of
noncompetitive inhibition.
II. Intravenous GA

Thiopental

Etomidate

Ketamine

Propofol

Thiopental /Thiamylat/
 III. Neurolept-analgesia

Droperidol + Fentanyl
Intravenous anaesthetics
1. most of them have documented effect on
membrane receptor
thiopental (barbiturate)- GABA
ketamin – NMDA receptor
2. are often used for rapid induction of
anaesthesia – then combination with
inhalation agent
3. advantages – rapid onset, controled dosage
ease administration
Effects of GA on ligandgated ion channels
dark green = potentiation; dark pink = inhibition; light green = little
potentiation; light pink = little inhibition; empty = no effect
Thiopental





most widely used ultra short-acting –onset less than
1 min.
no analgesic action
cardiac depression – decrease of cardiac output, no
change in peripheral resistance
depresses respiratory center, induction often
accompanied with coughing or laryngospazm
decreases cerebral blood flow and oxygen
consumption in the brain



Propofol is an important intravenous anesthetic
prepared in an intralipid formulation. This agent
produces anesthesia at a rate similar to the
ultrashort-acting barbiturates.
Etomidate is an imidazole that is used for
induction of anesthesia because its kinetics are
similar to those of propofol. This agent causes
minimal cardiopulmonary depression, perhaps
because of its unique lack of effect on the
sympathetic nervous system.
ketamine produces dissociative anesthesia, in
which the patient seems to be awake but is actually
in an analgesic and amnesic state. Ketamine has
the unusual property that it increases cardiac
output by increasing sympathetic outflow; for this
reason, it is occasionally useful in emergency
trauma situations. However, it can also produce
unpleasant hallucinations. This agent is rarely used
today.
Adverse effects of injection GA
(rare, unpredictable)
Idiosyncratic reactions to the i.v. agents:
• anaphylactoid reactions (rare)
• triggering of acute porphyria - thiopenthal
• etomidate is immunologically 'clean', but it
inhibits cortisol synthesis
Preanesthetic medication
Before surgery. Aims are to provide:
1. Anxiolysis and amnesia
Benzodiazepines – temazepam, diazepam, midazolam.
2. Analgesia – morphine, fentanyl,
3. Anticholinegic drugs. To prevent gastric and
bronchial secretion and vomiting (H2 blockers
(ranitidine, cimetidine, atropine, scopolamine,
chlorpromazine).
4. Muscle relaxation
Medication during and after surgery
During surgery
a. Induction – thiopentone,
etomidate or propofol,
b. Maintanance
usually with nitrous oxide
and oxygen + vollatile
agent (halotane or
isoflurane) i.v.
less often with nitrous oxide
and oxygen + analgesic
(fentanyl, morphine,
pethidine) + competitive
neuromuscular blocking
agent if muscular
relaxation is needed (for
abdominal surgery),
After surgery
a. Relief of pain (morphine
and its derivates are
commonly used and other
analgesics NSAIDs).
b. Postoperative vomiting –
antiemetics
(metoclopramide,
ondansetron,
prochlorperazine).