Transcript Historical information

General principles of
anesthesia
 Historical information
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People always wanted to overcome the
sufferings caused by pain. The history of civilization left
numerous documented evidences of permanent search
for ways and methods of anaesthesia. The first written
mention of the pain relieving medicines was found in
Egypt (described in Ebers papyrus 4 - 5 thousand
years ago). Much attention was paid to this problem by
the doctors of ancient Greece and Rome. They used
wine, mandrake root, opium, Indian hemp, henbane
and thorn-apple. In the East, in the mountains of Tibet,
acupuncture and massage were widely used with
anaesthetic aim.
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However, until the eighteenth century there was no radical ways of pain
relieving. At this time, because of the fundamental discoveries in natural
sciences the preconditions of new medical possibilities appeared. In 1776
chemist Priestley synthesized nitrous oxide - an anaesthetic, which is still
widely used in anaesthesiology. Another chemist, Davy, on April 9, 1779
for the first time tested the effect of nitrous oxide on himself. Later he
wrote: “Nitrous oxide, along with other properties, has the ability to relieve
pain and thus can be successfully used in surgical operations”. And only
25 years later, an English surgeon Hickman began to use the "laughing
gas" in medical practice. However, this method of anaesthesia had not
received adequate acceptance in Europe. At the same time in America
dentist Wells began to apply nitrous oxide anaesthesia. In April 1842 his
compatriot surgeon Long first used ether anaesthesia in practice. (It
should be noted, that diethyl ether was synthesized by well-known
chemist Paracelsus a few centuries before). With ether anaesthesia Long
performed eight operations, and his observations were never published.
 However, priority in the use of ether narcosis belongs
to another American researcher - Morton. On October
16, 1846 at Boston University clinic he successfully
administered ether narcosis during surgical removing
of hemangioma in public. The operation was performed
by surgeon Warren. A special Morton’s contribution
was a preliminary study of ether narcosis effect on
animals, which was the beginning of the experimental
study of general anaesthesia techniques.
 Therefore, the 16th of October, 1846 is considered to
be the birthday of anaesthesiology.
 In few months enthusiastic followers of ether narcosis appeared in
all civilized countries. At the beginning of February 1847 this type
of narcosis was performed by professor F.I. Inozemtsev in
Moscow clinic, two weeks later it was performed in St. Petersburg
by our compatriot, surgeon Mykola Ivanovych Pirogov. This
outstanding surgeon and the first anaesthesiologist played
prominent role in the history of ether narcosis. He was the first to
argument theoretical basis for the action mechanism of ether on
the central nervous system; he proposed alternative ways of
administration of ether (into the trachea, in the blood, into the
gastrointestinal tract). Invaluable experience of ether narcosis M. I.
Pirogov described in his monograph “On the application of
sulphuric ether vapours in operational medicine” published in
1847.
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In the Crimean-Turkish war (1853 – 1856) our compatriot performed
hundreds of successful ether anaesthesias during surgeries on gunshot
injuries.
In 1937 Guedel determined the clinical stages of ether narcosis, which
are still considered to be classic.
In 1847 a prominent scientist Simpson introduced into clinical practice
another preparation for narcosis - chloroform.
Since that time anaesthesiology has begun its scientific development.
For 150 years of anaesthesiology history scientists proposed and
implemented in clinical practice dozens of anaesthetic preparations, both
inhalation and non-inhalation, as long as various types and methods of
pain relief. This stimulated development of operative surgery and allowed
various range of surgical interventions in all organs and systems of the
body.
 Anaesthesiology is a science that studies
how to protect the organism from
operating injuries. It improves the wellknown and develops new methods of
preparing patients for surgeries,
providing anaesthesia, controlling the
body functions during the operation and
in postoperative period.
Ether
Single agents like ether produce the 4 distinct stages. The volatile anesthetics may
produce a similar response. Non-anesthetic agents may be used to individually
produce analgesia, muscle relaxation, amnesia, and loss of consciousness.
Is ether the perfect anesthetic?
The depth of anesthesia that can be achieved is dependent on the potency relative
to the amount that can be vaporized. That is the MAC % relative to the maximum
vapor concentration. The common inhalation anesthetics have a much greater
potential vapor concentration than is required for effect anesthesia. Therefore
they are all sufficiently potent.
The issue of flammability has been addressed with the halocarbon agents, and most
of these also cause little airway irritation which can be another concern.
Induction and Recovery
Induction rate and recovery are important considerations. The more lipophilic
compounds (higher blood:gas ratio) have slower induction and recovery, distribution
into fat can also slow recovery. N2O is not lipophilic, has low solubility, and therefore
has fast induction and recovery. The low solubility of N2O means that the equilibration
with blood from gas is quite rapid.
Solubility in blood is somewhat counterintuitive! More lipophilic (greater oil:gas
ratio) compounds also have a greater blood:gas ratios. The more lipophilic compounds
are more potent as indicated by the lower MAC% values.
Induction of anesthesia involves a series of equilibration events. The anesthetic first
equilibrates with the aveoli and may be slow, equilibration into the blood is rapid. The
blood must become saturated for transfer to the tissues to occur, this can be slow.
Inhaled and
exhaled gases
Aveoli
Blood
Tissues, including
Brain
Properties
Lipid vs Protein
Inhalation Anesthetic
Structures
F
F
Br
C
C H
F
Cl
H
F
F
F
C
C O
C H
Cl F
F
F
Enflurane
Halothane
F
H
F
C
C O
C H
F
F
F
Isoflurane
F
F
F
H
F
F
C
C
C O
C H
H
C O
C H
F
Cl
F
F
C
F
F
F
H
O
Nitrous Oxide
F
Desflurane
N N
Sevoflurane
CHCl3
Chloroform
CH3 CH 2 O CH2 CH3
Diethyl Ether
Analgesic Anesthetics Fentanyls
O
CH 2 CH 3
Fentanyl
(50-80 x Morphine)
N
N
O
CH 2 CH 3
N
Sufentanil
(10 x Fentanyl)
S
N
OCH 3
O
CH 2 CH 3
N
N
OCH 3
N
N
N
N
O
CH 2 CH 3
Alfentanil
(25 x Morphine)
Fentanyls
O
O
O
N
O
O
O
N
N
N
O
N
N
N
N
N N
O
O
O
O
Remifentanil
Alfentanil
Fentanyl
O
O
N
O
N
N
N
S
Sufentanil
Carfentanil
Fentanyl - Actiq (fentanyl on a stick), Duragesic transdermal patches (12, 25, 50, 100 g/h) Therapeutic
index=400, morphine = 70
Alfentanil - Ultra-short acting, 5-10 minutes analgesic duration
Remifentanil - Shortest acting opioid - 1/2 time is 4-6 minutes. Used in MAC anesthesia. TI=30,000
Sufentanil - 5-10x Fentanyl, used for heart surgery.
Carfentanil - (100x Fentanyl) Thought that it was used in the 2002 Moscow theater crisis to subdue
Chechen hostage takers. Didn’t turn out so well. 42 terrorists and 130 hostages died. Works well on bears.
Other Important anesthetic and pre-anesthetic
compounds.
Barbiturates (thiopental, methohexital),
benzodiazepines (diazepam, lorazepam, midazolam);
Etimodate;
neuroleptic butyrophenones (droperidol);
muscle relaxers” – neuromuscular blocking agents, i.e. nicotinic antagonists could be either
depolarizing or non-depolarizing (succinylcholine or tubocurarine);
ketamine, propofol.
How do analgesics potentiate anesthetic action?
I.e. lower the MAC value of volatile anesthetics.
Injectable anesthetics - Mechanisms
Ketamine (Ketalar) – Causes dissociative anesthesia. Patients feel dissociated from the
environment. Similar to neuroleptic anesthesia, but caused by a single agent. Phencyclidine
(PCP) has similar effects. Ketamine is injectable.
Mechanism – Blocks NMDA glutamate receptors
Etimodate (Amidate) – is a ultrashort acting hypnotic without analgesic properties. Used only
for induction because of the very short, 5 minute, duration.
Mechanism – GABA receptor. Similar to barbiturates
Propofol (Diprivan) – Another IV anesthetic. Similar to thiopental in anesthetic effects and
application, but has little renal or hepatic interaction and/or toxicity. Low incidence of side
effects, little post-operative confusion.
Mechanism – Probably similar to the volatile anesthetics and ethanol. GABA, nACh
N
O
H3 C NH
Cl
Ketamine
CH3CH2 OOC
OH
N
H3C C H
Propofol
Etimodate
How Do General Anesthetics Work
What is the Evidence that They Work This Way?
Molecular and Neuronal Substrates for General Anesthetics
Nature Reviews Neuroscience (2004) 5, 709-720. Rudolph, U. and Antkowiak, B.
Anesthetics and Ion Channels: Molecular Models and Sites of Action. Annu. Rev.
Pharmacol. Toxicol. (2001) 41, 23-51. Yamakura, T., Bertaccini, E., Trudell, J.R., Harris,
R.A.
Ethanol enhances 43 and 63 gamma-aminobutyric acid type A receptors at low
concentrations known to affect humans. Proc. Natl. Acad. Sci. (2003) 100, 15218-15223.
Wallner M, Hanchar HJ, Olsen RW.
Comment by Franks and Lieb on
Mihic et al. (1997) Nature, 385389 (1997)
Figure 1 Mihic et al.5 have found that single amino-acid substitutions at two positions
remove the potentiating effects of volatile anaesthetics and ethanol on GABAA (aminobutyric acid) and glycine receptors. a, GABAA and glycine receptors bind the
neurotransmitters that are released at inhibitory chemical synapses, and open to allow
chloride ions to diffuse across the postsynaptic membrane. b, The main effect of volatile
anaesthetics is to prolong channel opening and, hence, to increase postsynaptic inhibition.
c, The receptor channels consist of pentamers of closely related subunits, and the
structure of a single subunit is shown in d. The authors suggest that the two critical
amino acids may form a binding site for general anesthetics and ethanol.
Summary of 1997 Nature Article
on Anesthetics.
The GABAA Cl- channel is structurally related to Na+, 5HT and nACh
channels
Anesthetics inhibit nACh, but potentiate the others.
A specific anesthetic binding site was mapped using mutational genetics.
Mutational experiments didn’t necessarily prove that these were the
binding sites, one would need to do pharmacological experiments for that.
Ion channel mutations in vivo would prove that these were the channels
involved in anesthesia. An experiment similar to the  opioid receptor
that we learned about. Could also be good for looking at anticonvulsants.
Ethanol Binding ot GABA-A
Receptors
Ethanol enhances 43 and 63 gamma-aminobutyric acid type A receptors at low
concentrations known to affect humans. Proc. Natl. Acad. Sci. (2003) 100, 1521815223. Wallner M, Hanchar HJ, Olsen RW.
gamma-Aminobutyric acid type A receptors (GABARs) have long been implicated in
mediating ethanol (EtOH) actions, but so far most of the reported recombinant
GABAR combinations have shown EtOH responses only at fairly high concentrations
(> or = 60 mM).
We show that GABARs containing the delta-subunit, which are highly sensitive to
gamma-aminobutyric acid, slowly inactivating, and thought to be located outside of
synapses, are enhanced by EtOH at concentrations that are reached with moderate,
social EtOH consumption.
Synaptic versus extrasynaptic receptors
Wallner, M. et al. (2003) Proc. Natl. Acad. Sci. USA 100, 15218-15223
Copyright ©2003 by the National Academy of Sciences
Summary of Anesthetic
mechanisms.
•Membrane fluidity seems to be unsupported except in non-physiological model systems.
•Temperature dependence: Increasing temperature decreases anesthetic potency, but
increases fluidity.
•Age correlations of anesthetic potency are the reverse of fluidity.
•Differential sensitivity of different types of neurons argues against a generic fluid model.
You would think the membranes would be similar.
•Mutational experiments show specific amino acids are involved in the receptors.
•Many general anesthetics have a stereochemical preference, even though physical
properties are the same.
•Some lipid soluble, halogenated compounds do not have anesthetic activity.
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