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Print version ISSN 0034-7094
Rev. Bras. Anestesiol. vol.52 no.1 Campinas Jan./Feb. 2002
Action mechanism of inhalational anesthetics *
Mecanismo de acción de los anestésicos inhalatorios
Renato Ângelo Saraiva, TSA
Coordenador de Anestesiologia da Rede Sarah de Hospitais do Aparelho Locomotor; Professor Titular do Centro de Ensino e Formação da Associação das Pioneiras Sociais (Universidade Sarah); Professor Titular da Universidade de Brasília
BACKGROUND AND OBJECTIVES: Clinical
and experimental studies have been developed to identify inhalational anesthetics
action sites to determine clinically observed functional changes produced on
central nervous system structures responsible for the anesthetic status. This
study aimed at reviewing results obtained by several authors in recent clinical
and experimental studies in an attempt to explain action mechanisms of inhalational
anesthetics on the central nervous system.
CONTENTS: To help understanding the complex action mechanisms of inhalational anesthetics on the central nervous system, these were divided in three levels: macroscopic, microscopic, and molecular. A group of authors have recently divided those action mechanisms in: organic, cellular, and entropy inhibitors. These mechanisms would try to explain the anesthetic status able to provide patients with two major reactions: 1) immobility in response to noxious stimuli and 2) amnesia. Other desirable effects, such as analgesia and hypnosis are also obtained by inhalational anesthesia, however such effects per se or in combination, do not define the anesthetic status. Based on those concepts, this group classifies inhalational anesthetics as: 1) complete anesthetics, or providing immobility and amnesia; and 2) incomplete anesthetics, or not providing immobility, but providing amnesia.
CONCLUSIONS: According to several recent studies, it is possible that amnesia and unconsciousness are a consequence of the anesthetic action predominantly on the brain, while immobility, that is, inhibition of motor response to noxious stimuli, would be a consequence of the preferential and initial anesthetic action on the spinal cord. These actions occur by energy transformation inhibition (entropy) generating action potentials in nervous cells (fibers), particularly the synapses.
Key Words: ANESTHETICS, Inhalational
JUSTIFICATIVA Y OBJETIVOS: Estudios
clínicos y experimentales han sido desarrollados para identificar los locales
donde los anestésicos (inhalatorios) actúan y para determinar cuales
las alteraciones funcionales que eses fármacos producen en las estructuras
del sistema nervioso central, determinantes del estado de anestesia que es observado
clínicamente. El objetivo de este trabajo es describir los resultados obtenidos
por varios autores en estudios clínicos y experimentales realizados recientemente
en la tentativa de esclarecer los mecanismos de acción de los anestésicos
inhalatorios en el sistema nervioso central.
CONTENIDO: Para facilitar la comprensión de los complejos mecanismos de acción de los anestésicos inhalatorios en el sistema nervioso central, ellos fueron divididos en tres niveles: el macroscópico, el microscópico y el molecular. Recientemente un grupo de autores describieron estos mecanismos de acción en: orgánicos, celulares, e inhibidores de la entropía. Estos mecanismos tentarían explicar el estado de anestesia que tendría como característica la capacidad de prevenir al paciente dos acciones principales: 1) inmovilidad, inhibición de la respuesta a estímulos nociceptivos; y 2) amnesia. Otros efectos (deseables) también son obtenidos por la administración de anestésicos: analgesia e hipnosis. Entretanto, tales efectos sea aisladamente o juntos, no definen el estado de anestesia. Teniendo como base estos conceptos, este grupo adopta y divulga la clasificación de los anestésicos en: 1) anestésicos completos, los que producen inmovilidad y amnesia; e 2) incompletos o no inmovilizantes, los que no producen inmovilidad más producen amnesia.
CONCLUSIONES: De acuerdo con los resultados de varios estudios realizados recientemente, probablemente la amnesia y la inconsciencia ocurren por la acción del anestésico predominantemente en el cerebro, en cuanto la inmovilidad, o sea, la inhibición de la respuesta al estímulo nociceptivo por movimiento, seria por la acción del anestésico preferencialmente e inicialmente en la médula espinal. Estas acciones ocurren por inhibición de la transformación de energía (entropía) que forma los potenciales de acción en las células (fibras) nerviosas, especialmente en las sinapsis.
Pharmacological anesthetic action is defined based on clinical effects. Its mechanism, however, is not easily understood because it has not yet been clearly and objectively explained. Clinical and experimental studies are recently being developed to identify anesthetic action sites and functional changes produced on central nervous system structures and which would determine clinically observed anesthetic status.
The inhalation of an anesthetic agent for some minutes and in a given concentration will clearly make the individual unconscious and with no reaction to painful stimuli. Searching in the literature to understand such drug action, we have found a wide variety of publications showing actions on the brain cortex explained by changes in EEG waveforms. Actions on the brain stem, from the ascending activator reticular system (AARS) to the hypothalamus, thalamus and spinal cord have also been described.
In the past there was a concept that low anesthetic concentrations would develop a state of unconsciousness or hypnosis which, when increased, would produce muscle relaxation and immobility. Currently it is known that several anesthetics may have different pharmacological actions in low concentrations, according to their characteristics. This has been recently shown both in clinically used anesthetics and in experimental agents.
Such actions are part of pharmacodynamics, that is, the explanation of a physiological change to obtain a certain clinical result by the drugs action on the CNS. Some experimental studies have tried to describe cellular and molecular mechanisms which could inhibit nervous impulse transmission and produce a state of anesthesia.
Since the analysis of such mechanisms is rather complex, they were divided in three levels: macroscopic, microscopic and molecular 1. Some authors have recently classified such action mechanisms in organic, cellular and entropy inhibitors 2-4 in an attempt to explain anesthetic status aiming at providing patients with two major reactions: 1) immobility, or response inhibition to noxious stimuli; and 2) amnesia. Other equally desirable effects, such as analgesia and hypnosis, are also obtained by anesthesia, however the latter, per se or in combination, does not define anesthetic status 5.
These concepts were the basis for the following classification: 1) complete anesthetics, inducing immobility and amnesia; and 2) incomplete anesthetics or not inducing immobility but inducing amnesia 3,6.
CNS is the primary action site for anesthetic agents. There are reports on their action on different CNS organic sectors. It has been difficult to specifically determine the site where nervous impulse conduction discontinuity starts to produce amnesia, unconsciousness and immobility; recent experimental studies, however, have shown evidences of such complex process.
Action on the Brain
In the past it was believed that general anesthetics would act only on the brain and that the state of anesthesia would be simply a consequence of such pharmacological action in a higher or lower intensity.
In fact, there are very feasible reasons to accept this concept. Brain stem and all attached organs making up the encephalon were considered as brain. Currently it is known that, although an arguable anesthetic action on the brain, being it the primary information integration site, it is possible that such drugs would act on its structures, especially the synapses, interfering in memory and alertness. However, there are no evidences of total cortical activity inhibition by anesthetic agents. On the other hand, it has been shown that some synapses may be inhibited and others excited by different anesthetics 7-9.
An experimental study with ewes 10 has shown that isoflurane alveolar concentration to inhibit motor response to painful stimuli is more than twice when the brain is preferentially anesthetized, as compared to anesthesia distributed throughout the body. In this experimental model using partial bypass with preferential circulation to the brain, 2.9% isoflurane alveolar concentration was needed to inhibit motor responses to painful stimuli, while with normal circulation, 1.3% was enough. The conclusion was that subcortical structures, including spinal cord, are very important for motor response to painful stimuli.
It has been shown in experimental rats that anesthetic inhibition of motor responses to noxious stimuli is independent of brain cortex structure 11. Rats were anesthetized with 1.3% isoflurane alveolar concentration and presented a satisfactory motor response to noxious stimuli. After brain cortex aspiration, motor response inhibition to noxious stimuli was obtained with virtually the same concentration (1.26%). Alveolar concentrations were established after incremental administrations and motor inhibition as response to noxious stimuli was investigated.
Non immobilizing or incomplete anesthetics have less pronounced and well selective action on CNS structures.
Complete or immobilizing anesthetics, such as isoflurane, are effective in inhibiting fear-conditioned learning and in depressing medium latency auditory evoked potential (MLAEP), while non-immobilizing agents, such as dichlorohexafluorcyclobutane, interfere in learning but do not change MLAEP. This was experimentally shown in rats 3. In a different study it has been observed that isoflurane changes thermoregulation in rats, while dichlorohexafluorcyclobutane does not 12.
It is known that the auditory evoked potential is transported by the brain stem via lemniscus and AARS. Thermoregulation is subcortically controlled, while learning depends on memory which is coordinated in the brain.
For what has been said, it is understandable that brain areas associated to memory and consciousness are more sensitive to inhalational anesthetics than subcortical areas associated to transmission and control of other functions, such as auditory afference, thermoregulation (brainstem) and stimulated movement (spinal cord).
As a consequence, it may be said that amnesia and unconsciousness are a result of the anesthetic action on the brain and that minimum alveolar concentration (MAC) needed to obtain them is approximately 25% to 40% the concentration needed to suppress motor response to painful stimuli on the brain 10.
There are evidences of anesthetic actions on the Ascending Activator Reticular System (AARS). Since this structure is very important during alertness, it is understandable that sleep and unconsciousness-inducing drugs may act on it. However, there are no experimental evidences that AARS is the single or even the major anesthetic action site.
Experimental studies have shown the importance of CA1 structure neurons of the hippocampus on anterograde memory and, as a consequence, on amnesia related to recent events, under the action of inhalational anesthetics 2,13,14. In addition, it must be reminded that the thalamus has been considered for a long time considered as part of the ascending ways (sensitivity), being admitted that pain perception center is part of its structure with connections to the brain cortex where painful sensitivity is perceived and classified. The analgesic action of general anesthetics is related to painful sensitivity inhibition in the thalamus.
There are also reports on anesthetics action on other encephalic structures. Experimental studies in rabbits have shown the inhibitory action of intravenous and inhalational anesthetics on the olfactory bulb evoked potential, with stimuli on the lateral olfactory tract 7,8.
Action on the Spinal Cord
Currently, there are several experimental studies showing evidences of the action of complete or immobilizing anesthetics on the spinal cord. It is even admitted that the immobilizing action of such agents is initially and especially processed in cordal structures 2. A study with ewes has reported that isoflurane acts on the spinal cord by hampering nervous impulse transmission to the thalamus and brain cortex and may contribute to final anesthesia states such as amnesia and unconsciousness 15. A different study in rats has concluded that somatic motor response and isoflurane sensitivity are unchanged after acute loss of cortical, subcortical and bulbar (medullar section in C7) controls. Such observation suggests that spinal cord may be the motor response inhibition site 16.
Since spinal cord is an organ receiving stimuli and sending response to most of the body, it is clear that it has specific and non-specific neurotransmitter receptors where nervous impulses inhibition is certainly processed.
Electroneouromonitoring of Anesthesia and Evidences of General Anesthetics Action Mechanisms
Anesthetics change the amplitude and latency of EEG waves, thus proving the action of such drugs on the brain cortex.
Bispectral EEG analysis is expressed by the bispectral index (BIS) which varies from 0 to 100, where 100 is the maximum alertness and 0 the maximum unconsciousness (hypnosis). During anesthesia, BIS is always below 50, in general approximately 40. At emergence it is close to 90 17.
Somatosensory evoked potential (SSEP) may be changed by anesthetics, especially inhalational anesthetics. So, it may be used to study the action of such agents on different central nervous system sites 18.
Clinical and experimental studies support the statement that: 1) complete anesthetics significantly decrease BIS and inhibit SSEP. These are agents with hypnotic amnesic and immobilizing action; 2) incomplete anesthetics have no pronounced action on SSEP, but significantly decrease BIS 17-19.
Studying anesthetics action on SSEP, it is seen that they act primarily on the brain (N19 and P22 waves) with a moderate action on the spinal cord (N13 wave). It is possible that the action starts on the spinal cord although the binding between agent and nervous fiber receptors is not so strong. Nevertheless it exists and is responsible for the immobilizing action while brain inhibition is related to hypnosis and amnesia (Figure 1, Figure 2A and Figure 2B).
Neurons have axons (long) and dendrites (short). They are connected to other fibers through the synapses, which may be monosynapses, when there is only one axon binding to another axon or to a dendrite; or polysynapses, when there are several axons of the same neuron binding to other axons or to several dendrites of the following neuron.
Pre-synaptic fibers contain neurotransmitters stored in synaptic vesicles and released by the ionic action of the electric current which propagates the nervous impulse. These neurotransmitters are sent to post-ganglionary fibers to interact with receptors and continue transmitting the impulse. Pharmacological actions of anesthetic agents on pre-synaptic fibers in general inhibit vesical neurotransmitters release, or even destroy its molecule.
In post-synaptic fibers where neurotransmitter receptors are located, the action of such drugs is especially by blocking receptor nervous stimuli transportation.
GABA (gamma aminobutyric acid) is the most important neurotransmitter inhibiting CNS in mammals. It is the target for a wide variety of pharmacological agents with CNS depressing action.
There are reports on the stimulating action of anesthetics on GABA, especially GABAA, which is related to ion chloride (IC) transportation. GABAA increases membrane patency for the entrance of chloride, thus helping neuronal hyperpolarization. GABAB is related to potassium ion (K+) which activates the 2nd messenger in nervous impulse transmission without relation with inhibitory actions 20,21.
Neurotransmitters movement toward complex receptors/channels is achieved on the synaptic cleft. The specific site might be close to the membrane side coated with protein and water (interface) 22,23 or a different adequate site of membranes protein structure.
CELL ENTROPY INHIBITION
Cell entropy and molecular mechanisms of nervous impulse generation and transportation.
Body fluid molecules and ions are in constant move. This movement generates heat and the faster the movement, the higher the temperature. Molecules and ions are spread through cell membranes 24.
Spread depends on molecular movement (energy), which depends on electrostatic and nuclear forces of the molecules in attraction or repulsion contact. So, molecules and ions move (jump) in several directions, billions of times per second (entropy).
Spread may be simple, by electric attraction or repulsion, or mediated by a carrier. In the latter case, the substance needs a specific carrying protein to facilitate the spread from one membrane side to the other. This is the case, for example, of specific receptors or certain transmitters and also of the insulin-mediated glucose cell entry process.
Active transportation occurs when there is no electrochemical gradient. ATP, through ATPase, forms ADP and energy (ionic) used to transport Na+ outside the cell and introduce K+ (countercurrent). It is the so-called ion pump the Na+ and K+ is the most studied pump. Currently, Ca++ and CI+ pumps are also being studied.
Membrane depolarization occurs when it becomes too patent to Na+ and the polarized status of -90mV is lost with membrane potential varying from +35 to +60mV. This is depolarization.
Repolarization occurs with the exit of Na+ and the entrance of K+ in the cell and the return to the negative charge of -90mV. These successive Membrane Potential variations form the Action Potential which transmits the nervous impulse.
Other ions participate on the action potential. The calcium pump (Ca++) directs the ion from inside to outside the cell. Ca++ channels are frequency electrodependent. Such channels are far slower than Na+ channels. Calcium channels are more frequent in smooth muscles, especially heart and vessels.
Chloride ions (CI+) leak through the resting membrane similarly to K+ and Na+. The pump of such ion seldom works and is more frequent in the nervous fiber. When the inside of the fiber is at -90mV, such frequency prevents the entrance of CI+. This ion is spread inside the fiber in small amounts. The movement of such ion successively changes membrane frequency during action potential. GABAA interferes with this movement.
Action potential and spread are achieved through Na+ ions entering the fiber. This process may be triggered by mechanical, electrical and chemical stimuli which may transform energy and mobilize ions. Na+ entrance in the cells undoes hyperpolarization (-90mV) which is followed by repolarization by K+, and more specifically CI+ entering the nervous fiber by GABAA interference. Such continuous electric changes generate the action potential.
Action potential generated in any membrane site excites regions adjacent to the excited site. There is ion movement (electrons) which is spread throughout the fiber (propagation).
Cell Entropy Inhibition by Anesthetic Agents
Mechanisms forming cell entropy which trigger action potentials and their respective propagation through the nervous fiber have already been described. Now it is time to describe possible ways through which anesthetics may inhibit cell entropy and the consequent interruption of nervous impulse transportation.
First it is necessary to understand the forces producing interactions between anesthetic molecules and the site of the nervous fiber molecule where it is fixed. Then, why such interactions change nervous fibers function in this site, resulting in anesthesia.
There are recent studies on anesthetics action site, especially complete anesthetics which are amnesic and immobilizing. These studies suggest a hypothesis different from Meyer Overtons theory, which is based on the anesthetic binding to the fatty membrane and on the anesthetic action directly on a specific protein membrane site, as well as on neurotransmitter receptors 25.
Meyer Overtons theory describes the anesthetic-lipidic membrane binding as a hydrophobic reaction (water release and isolation). Recent studies describe the anesthetic binding to the membrane protein, in its protein-water interface, inserted in the lipidic mass, thus having affinity with water. However, they also admit the possibility of anesthetic binding to membranes lipidic site in some action phase, according to physical-chemical properties of the agent 23,25,26.
These actions were observed in GABAA receptors and also in brain and spinal cord glutamate, respectively 26.
There is a hypothesis that polar bindings (electrovalency), chemically more stable, would take place on the interactions between complete anesthetics and receptors or specific sites of the protein membrane. On the other hand, non immobilizing anesthetics have non polar bindings (covalency), which are less stable 2.
The anesthetic presence in neurotransmitter receptors and in a supposed site considered important for its membrane fixation results in bipolar electron attraction and the consequent interruption of ionic (electric) activities, momentarily disorganizing cell entropy and decreasing local temperature.
This subject has been recently studied in an experimental trial that showed that energy interaction by bipolar function (anesthetic/receptor) decreases entropy and affects temperature which increases with binding and is afterwards decreased 4. In this same study, it was observed that noble gases such as Xenon, although not distributing electrons to interact with membrane receptors or specific sites to form a classic dipole, might form a temporary bipole through physical characteristics of gases atoms where repulsion forces overcome retraction forces. This way, one may conclude that such gases have a weak immobilizing power, proven by their high MAC (71%) which indicates low potency.
More recent studies have reported that amnesia and unconsciousness are a result of anesthetics action predominantly on the brain, while immobility, that is, the inhibition of motor response to noxious stimuli would result of the anesthetic preferential and initial action on the spinal cord.
These actions are a function of inhibition of energy transformation which creates nervous cell (fibers) action potentials, especially on the synapses, by interacting with neurotransmitters.
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Submitted for publication April 9, 2001 * Received from Hospital
Sarah Brasília, Brasilia, DF
Accepted for publication July 18, 2001
Submitted for publication April 9, 2001
* Received from Hospital Sarah Brasília, Brasilia, DF