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Signs and Stages of Anesthesia (Somewhat related to the response from Diethyl Ether):
1.
2.
3.
4.
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.
Aveoli
Aveoli
Blood
Blood
Tissues,including
Tissues,including
Brain
Brain
Properties
Lipid vs Protein
Br
Cl
H
F
Cl
Enflurane
Isoflurane
Halothane
Cl
NitrousOxide
F
Desflurane
Sevoflurane
CH
CH
3
CHCl
O
2
CH
CH
2
Chloroform
DiethylEther
CH
CH
2
Fentanyl
N
(5080xMorphine)
N
CH
CH
2
Sufentanil
(10xFentanyl)
S
OCH
3
CH
CH
2
CH
CH
2
Alfentanil
(25xMorphine)
N
N
N
O
OCH
3
Fentanyls
O
O
N
O
N
N
N
N N
O
N
O
Remifentanil
Alfentanil
Fentanyl
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. Didnt turn out so well. 42 terrorists and 130 hostages died. Works well on bears.
Davis MDCH 5210 - General Anesthetics 2006
OH
O
CH
CH
3
OOC
2
NH
H
C
3
Cl
Propofol
Ketamine
Etimodate
10
11
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 GABA A (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.
12
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 didnt 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.
13
14
Wallner, M. et al. (2003) Proc. Natl. Acad. Sci. USA 100, 15218-15223
16
Another View
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