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tance of physical interactions that lead to perturbation Also, anesthetics enhance other processes known to
of membrane macromolecules. For example, exposure of inhibit neuronal function, such as the glycine recep-
membranes to clinically relevant concentrations of anes- tor gated chloride channel. A smaller number of anes-
thetics causes membranes to expand beyond a critical thetics, including ketamine, N2O, and xenon, produce
volume (critical volume hypothesis) associated with nor- neuronal inhibition by antagonizing excitatory neu-
mal cellular function. Additionally, membrane structure ronal transmission mediated via the N-methyl-D-aspar-
becomes disorganized, so that the insertion of anesthetic tic acid (NMDA) receptor. In addition, some inhala-
molecules into the lipid membrane causes an increase in tional drugs activate K channels and so contribute to
the mobility of the fatty acid chains in the phospholipid hyperpolarization and reduced neuronal excitability;
bilayer (membrane fluidization theory) or prevent the they also inhibit the function of the protein complex in-
interconversion of membrane lipids from a gel to a liq- volved in neurotransmitter release.
uid form, a process that is assumed necessary for normal Clearly much must be explained of the complex
neuronal function (lateral phase separation hypothesis). changes in the CNS that eventually produce uncon-
sciousness. Although physical interactions of anesthet-
ics with hydrophobic membrane components may lead
Anesthesia from Selective Interactions
to conformational changes that alter neuronal function,
of Anesthetics with Cellular Components
specific interactions at critical receptors and ion chan-
While current observations do not rule out that anes- nels are also likely to contribute to anesthesia. Thus,
thetics may require a hydrophobic environment near structurally and pharmacologically diverse anesthetic
the site of their action, they do suggest that various drugs produce unconsciousness through qualitatively
agents may also have distinct interactions with tissues. different mechanisms and through actions occurring at
For example, enantiomers of newer agents have selec- anatomically distinct sites in the nervous system.
100
carbon tetrafluoride
10 sulfur hexafluoride
nitrous oxide
1
xenon
fluroxene
0.1
cyclopropane
ether
halothane
0.01
chloroform
methoxyflurane
0.001
0.0001
0.01 0.1 1 10 100 1000 10000
Oil/gas Partition Coefficient
FI GURE 25. 6
A comparison of the minimum alveolar concentration (MAC) with the oil gas partition coefficient
of several inhalational anesthetic agents.
MAC (atmospheres)
25 General Anesthesia: Intravenous and Inhalational Agents 307
GABA site Barbiturate site Benzodiazepine site
e.g. bicuculline e.g. thiopental e.g. midazolam
Cl
Steroid site
Convulsant site
Membrane
inhalation and
e.g. picrotoxin
steroid anesthetics
FI GURE 25. 7
The GABAA-receptor chloride ionophore sites of drug action.
Study Questi ons
1. A patient whose anesthesia is being managed only reduced blood flow is compromised when hemor-
with isoflurane (Forane) delivered at an inspired rhagic shock occurs.
concentration near the MAC occasionally moves (C) The diffusion of lipid-soluble drugs through
and exhibits facial grimacing, apparently in re- the blood-brain barrier is enhanced.
sponse to surgical manipulation of the bowel. These (D) Tissues with a characteristically high blood
responses are flow per unit mass receive less blood and less anes-
(A) Natural consequences of physical manipula- thetic when blood volume is low.
tions that induce noxious sensory input to the CNS (E) Anesthetics bind more readily to tissue recep-
(B) An indication that neuromuscular blocking tors when hypotension and poor oxygenation occur.
agents should be administered without delay 3. With which hypothetical anesthetic would you ex-
(C) Not likely to be blocked by coadministering an pect anesthetic partial pressure to be achieved rela-
analgesic drug such as morphine tively quickly?
(D) Signs suggesting that the patient should be (A) An agent that is highly soluble in blood and
given twice the MAC of isoflurane other body tissues
(E) Not avoidable because the bowel is unusually (B) An agent with a low MAC (in range less than [ Pobierz całość w formacie PDF ]