General anaesthetics (oranesthetics) are often defined as compounds that induce a loss of consciousness in humans or loss ofrighting reflex in animals. Clinical definitions are also extended to include an induced coma that causes lack of awareness to painful stimuli, sufficient to facilitate surgical applications in clinical and veterinary practice. General anaesthetics do not act asanalgesics and should also not be confused withsedatives. General anaesthetics are a structurally diverse group of compounds whose mechanisms encompass multiple biological targets involved in the control of neuronal pathways. The precise workings are the subject of some debate and ongoing research.[1]
General anesthetics elicit a state ofgeneral anesthesia. It remains somewhat controversial regarding how this state should be defined.[2] General anesthetics, however, typically elicit several key reversible effects: immobility, analgesia,amnesia, unconsciousness, and reduced autonomic responsiveness to noxious stimuli.[2][3][4]
General anaesthetics can be administered either as gases or vapours (inhalational anaesthetics), or as injections (intravenous or evenintramuscular). All of these agents share the property of being quite hydrophobic (i.e., as liquids, they are not freelymiscible—or mixable—in water, and as gases they dissolve in oils better than in water).[3][5] It is possible to deliver anaesthesia solely by inhalation or injection, but most commonly the two forms are combined, with an injection given to induce anaesthesia and a gas used to maintain it.[5]
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Inhalational anaesthetic substances are eithervolatileliquids orgases, and are usually delivered using ananaesthesia machine. An anaesthesia machine allows composing a mixture of oxygen, anaesthetics and ambient air, delivering it to the patient and monitoring patient and machine parameters. Liquid anaesthetics are vapourised in the machine.[5]
Many compounds have been used for inhalation anaesthesia, but only a few are still in widespread use.Desflurane,isoflurane andsevoflurane are the most widely usedvolatile anaesthetics today. They are often combined withnitrous oxide. Older, less popular volatile anaesthetics includehalothane,enflurane, andmethoxyflurane. Researchers are also actively exploring the use ofxenon as an anaesthetic.[5]
Injectable anaesthetics are used for the induction and maintenance of a state of unconsciousness. Anaesthetists prefer to useintravenous injections, as they are faster, generally less painful and more reliable thanintramuscular orsubcutaneous injections. Among the most widely used drugs are:
Benzodiazepines are sedatives and are used in combinations with other general anaesthetics.[2][5]
Induction and maintenance of general anesthesia, and the control of the various physiological side effects is typically achieved through a combinatorial drug approach. Individual general anesthetics vary with respect to their specific physiological and cognitive effects. While general anesthesia induction may be facilitated by one general anesthetic, others may be used in parallel or subsequently to achieve and maintain the desired anesthetic state. The drug approach utilized is dependent upon the procedure and the needs of the healthcare providers.[2]
It is postulated that general anaesthetics exert their action by the activation of inhibitorycentral nervous system (CNS) receptors, and the inactivation of CNSexcitatory receptors. The relative roles of different receptors is still under debate, but evidence exists for particular targets being involved with certain anaesthetics and drug effects.[2][6][7]
Below are several key targets of general anesthetics that likely mediate their effects:
During administration of an anesthetic, the receiver goes through different stages of behavior ultimately leading tounconsciousness. This process is accelerated with intravenous anesthetics, so much so that it is negligible to consider during their use. The four stages of anesthesia are described using Guedel's signs, signifying the depth of anesthesia. These stages describe effects of anesthesia mainly on cognition, muscular activity, and respiration.[4]
The receiver of the anesthesia primarily feelsanalgesia followed by amnesia and a sense of confusion moving into the next stage.[4]
Stage II is often characterized by the receiver being delirious and confused, with severe amnesia. Irregularities in the patterns of respiration are common at this stage of anesthesia. Nausea and vomiting are also indicators of Stage II anesthesia. Struggling and panic can sometimes occur as a result of delirium.[4]
Normal breathing resumes at the beginnings of Stage III. Nearing the end of the stage, breathing ceases completely. Indicators for stage III anesthesia include loss of the eyelash reflex as well as regular breathing. Depth of stage III anesthesia can often be gauged by eye movement and pupil size.[4]
No respiration occurs in stage IV. This is shortly followed by circulatory failure and depression of thevasomotor centers. Death is common at this stage of anesthesia if no breathing and circulatory support is available.[4]
Aside from the clinically advantageous effects of general anesthetics, there are a number of other physiological consequences mediated by this class of drug. Notably, a reduction in blood pressure can be facilitated by a variety of mechanisms, including reduced cardiac contractility and dilation of the vasculature. This drop in blood pressure may activate a reflexive increases in heart rate, due to abaroreceptor-mediated feedback mechanism. Some anesthetics, however, disrupt this reflex.[3][4]
Patients under general anesthesia are at greater risk of developinghypothermia, as the aforementionedvasodilation increases the heat lost via peripheral blood flow. By and large, these drugs reduce the internal body temperature threshold at which autonomicthermoregulatory mechanisms are triggered in response to cold. (On the other hand, the threshold at which thermoregulatory mechanisms are triggered in response to heat is typically increased.)[9]
Anesthetics typically affect respiration. Inhalational anesthetics elicitbronchodilation, an increase in respiratory rate, and reducedtidal volume. The net effect is decreased respiration, which must be managed by healthcare providers, while the patient is under general anesthesia.[4] The reflexes that function to alleviate airway obstructions are also dampened (e.g. gag and cough). Compounded with a reduction inlower esophageal sphincter tone, which increases the frequency of regurgitation, patients are especially prone toasphyxiation while under general anesthesia. Healthcare providers closely monitor individuals under general anesthesia and utilize a number of devices, such as anendotracheal tube, to ensure patient safety.[3]
General anesthetics also affect thechemoreceptor trigger zone andbrainstem vomiting center, eliciting nausea and vomiting following treatment.[3]
Intravenously delivered general anesthetics are typically small and highlylipophilic molecules. These characteristics facilitate their rapid preferential distribution into the brain and spinal cord, which are both highly vascularized and lipophilic. It is here where the actions of these drugs lead to general anesthesia induction.[3]
Following distribution into thecentral nervous system (CNS), the anesthetic drug then diffuses out of the CNS into the muscles and viscera, followed byadipose tissues. In patients given a single injection of drug, this redistribution results in termination of general anesthesia. Therefore, following administration of a single anestheticbolus, duration of drug effect is dependent solely upon the redistribution kinetics.[3]
Thehalf-life of an anesthetic drug following a prolonged infusion, however, depends upon both drug redistribution kinetics,drug metabolism in the liver, and existing drug concentration in fat. When large quantities of an anesthetic drug have already been dissolved in the body's fat stores, this can slow its redistribution out of the brain and spinal cord, prolonging its CNS effects. For this reason, the half-lives of these infused drugs are said to becontext-dependent. Generally, prolonged anesthetic drug infusions result in longer drug half-lives, slowed elimination from the brain and spinal cord, and delayed termination of general anesthesia.[3]
Minimal alveolar concentration (MAC) is the concentration of an inhalational anesthetic in the lungs that prevents 50% of patients from responding to surgical incision. This value is used to compare thepotencies of various inhalational general anesthetics and impacts thepartial-pressure of the drug utilized by healthcare providers during general anesthesia induction and/or maintenance.[3][4]
Induction of anesthesia is facilitated by diffusion of an inhaled anesthetic drug into the brain and spinal cord. Diffusion throughout the body proceeds until the drug'spartial pressure within the various tissues is equivalent to the partial pressure of the drug within the lungs.[3] Healthcare providers can control the rate of anesthesia induction and final tissue concentrations of the anesthetic by varying the partial pressure of the inspired anesthetic. A higher drug partial pressure in the lungs will drive diffusion more rapidly throughout the body and yield a higher maximum tissue concentration. Respiratory rate and inspiratory volume will also affect the promptness of anesthesia onset, as will the extent of pulmonary blood flow.[4]
Thepartition coefficient of a gaseous drug is indicative of its relative solubility in various tissues. This metric is the relative drug concentration between two tissues, when their partial pressures are equal (gas:blood, fat:blood, etc.). Inhalational anesthetics vary widely with respect to their tissue solubilities and partition coefficients.[3] Anesthetics that are highly soluble require many molecules of drug to raise the partial pressure within a given tissue, as opposed to minimally soluble anesthetics which require relatively few.[4] Generally, inhalational anesthetics that are minimally soluble reach equilibrium more quickly. Inhalational anesthetics that have a high fat:blood partition coefficient, however, reach equilibrium more slowly, due to the minimal vascularization of fat tissue, which serves as a large, slowly-filling reservoir for the drug.[3]
Inhaled anesthetics are eliminated via expiration, following diffusion into the lungs. This process is dependent largely upon the anestheticblood:gas partition coefficient, tissue solubility, blood flow to the lungs, and patient respiratory rate and inspiratory volume.[4] For gases that have minimal tissue solubility, termination of anesthesia generally occurs as rapidly as the onset of anesthesia. For gases that have high tissue solubility, however, termination of anesthesia is generallycontext-dependent. As with intravenous anesthetic infusions, prolonged delivery of highly soluble anesthetic gases generally results in longer drug half-lives, slowed elimination from the brain and spinal cord, and delayed termination of anesthesia.[3]
Metabolism of inhaled anesthetics is generally not a major route of drug elimination.[4]
While most research focuses on the intoxicating effects of ethanol, it can also produce a general anesthesia.[10] Sinceantiquity, prior to the development of modern agents,alcohol was used as a general anaesthetic.[11]
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