Transcript General Anesthetics - University of Utah

General Anesthetics
Signs and Stages of Anesthesia (Somewhat related to the response from Diethyl Ether):
1.
Analgesia. Mild CNS depression. Suitable for surgical procedures not
requiring muscle relaxation. All anesthetics do not produce analgesia.
2.
Delirium: An excited state resulting from cortical motor depression. This
can be avoided with rapidly acting, potent anesthetics. This stage extends
from the lack of consciousness in stage 1 to surgical anesthesia in stage 3.
3.
Surgical Anesthesia: Further subdivided into stages representative of
increasing muscle relaxation, the final stage is disappearance of muscle
tone.
4.
Respiratory paralysis: Generally not desirable.
References: G&G Ch. 13-14, Foye (5th Ed.) Ch. 14.
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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.
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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
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Properties
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Lipid vs Protein
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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
CHCl 3
Chloroform
CH 3 CH 2 O CH 2 CH 3
Diethyl Ether
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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
N
N
N
N
CH 2 CH 3
Alfentanil
(25 x Morphine)
O
OCH 3
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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.
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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.
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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
OH
O
H3 C NH
Cl
CH3CH2 OOC
N
H3C C H
Propofol
Ketamine
Etimodate
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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.
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Comment by Franks and Lieb on Mihic et al. (1997) Nature, 385-389 (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.
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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.
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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.
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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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Another View
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