General anaesthetic

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General anaesthetics (or anesthetics) are often defined as compounds that induce a loss of consciousness in humans or loss of righting 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 as analgesics and should also not be confused with sedatives. 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]

Contents

General anesthetics elicit a state of general 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]

Mode of administration

General anaesthetics can be administered either as gases or vapours (inhalational anaesthetics), or as injections (intravenous or even intramuscular). All of these agents share the property of being quite hydrophobic (i.e., as liquids, they are not freely miscible—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]

Inhalation

General anesthetics are frequently administered as volatile liquids or gases. US Navy 030513-N-1577S-001 Lt. Cmdr. Joe Casey, Ship's Anesthetist, trains on anesthetic procedures with Hospital Corpsman 3rd Class Eric Wichman aboard USS Nimitz (CVN 68).jpg
General anesthetics are frequently administered as volatile liquids or gases.

Inhalational anaesthetic substances are either volatile liquids or gases, and are usually delivered using an anaesthesia 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 and sevoflurane are the most widely used volatile anaesthetics today. They are often combined with nitrous oxide. Older, less popular volatile anaesthetics include halothane, enflurane, and methoxyflurane. Researchers are also actively exploring the use of xenon as an anaesthetic. [5]

Injection

Injectable anaesthetics are used for the induction and maintenance of a state of unconsciousness. Anaesthetists prefer to use intravenous injections, as they are faster, generally less painful and more reliable than intramuscular or subcutaneous injections. Among the most widely used drugs are:

Benzodiazepines are sedatives and are used in combinations with other general anaesthetics. [2] [5]

Mechanism of action

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 inhibitory central nervous system (CNS) receptors, and the inactivation of CNS excitatory 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:

GABAA receptor agonists

NMDA receptor antagonists

Two-pore potassium channels (K2Ps) activation

Others

Stages of anesthesia

During administration of an anesthetic, the receiver goes through different stages of behavior ultimately leading to unconsciousness. 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]

Stage I: Analgesia

The receiver of the anesthesia primarily feels analgesia followed by amnesia and a sense of confusion moving into the next stage. [4]

Stage II: Excitement

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]

Stage III: Surgical Anesthesia

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]

Stage IV: Medullary Depression

No respiration occurs in stage IV. This is shortly followed by circulatory failure and depression of the vasomotor centers. Death is common at this stage of anesthesia if no breathing and circulatory support is available. [4]

Physiological side effects

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 increase in heart rate, due to a baroreceptor-mediated feedback mechanism. Some anesthetics, however, disrupt this reflex. [3] [4]

Patients under general anesthesia are at greater risk of developing hypothermia, as the aforementioned vasodilation increases the heat lost via peripheral blood flow. By and large, these drugs reduce the internal body temperature threshold at which autonomic thermoregulatory 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 elicit bronchodilation, an increase in respiratory rate, and reduced tidal 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 in lower esophageal sphincter tone, which increases the frequency of regurgitation, patients are especially prone to asphyxiation while under general anesthesia. Healthcare providers closely monitor individuals under general anesthesia and utilize a number of devices, such as an endotracheal tube, to ensure patient safety. [3]

General anesthetics also affect the chemoreceptor trigger zone and brainstem vomiting center, eliciting nausea and vomiting following treatment. [3]

Pharmacokinetics

Intravenous general anesthetics

Induction

Intravenously delivered general anesthetics are typically small and highly lipophilic 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]

Elimination

Following distribution into the central nervous system (CNS), the anesthetic drug then diffuses out of the CNS into the muscles and viscera, followed by adipose tissues. In patients given a single injection of drug, this redistribution results in termination of general anesthesia. Therefore, following administration of a single anesthetic bolus, duration of drug effect is dependent solely upon the redistribution kinetics. [3]

The half-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 be context-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]

Inhalational general anesthetics

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 the potencies of various inhalational general anesthetics and impacts the partial-pressure of the drug utilized by healthcare providers during general anesthesia induction and/or maintenance. [3] [4]

Induction

General Anesthesia WIKI - Figure.tif

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's partial 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]

The partition 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]

Elimination

Inhaled anesthetics are eliminated via expiration, following diffusion into the lungs. This process is dependent largely upon the anesthetic blood: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 generally context-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]

History

Ethanol

While most research focuses on the intoxicating effects of ethanol, it can also produce a general anesthesia. [10] Since antiquity, prior to the development of modern agents, alcohol was used as a general anaesthetic. [11]

See also

Related Research Articles

<span class="mw-page-title-main">Sodium thiopental</span> Barbiturate general anesthetic

Sodium thiopental, also known as Sodium Pentothal, thiopental, thiopentone, or Trapanal, is a rapid-onset short-acting barbiturate general anesthetic. It is the thiobarbiturate analog of pentobarbital, and an analog of thiobarbital. Sodium thiopental was a core medicine in the World Health Organization's List of Essential Medicines, but was supplanted by propofol. Despite this, thiopental is listed as an acceptable alternative to propofol, depending on local availability and cost of these agents. It was the first of three drugs administered during most lethal injections in the United States until the US division of Hospira objected and stopped manufacturing the drug in 2011, and the European Union banned the export of the drug for this purpose. Although thiopental abuse carries a dependency risk, its recreational use is rare.

<span class="mw-page-title-main">Anesthesia</span> State of medically-controlled temporary loss of sensation or awareness

Anesthesia or anaesthesia is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia, paralysis, amnesia, and unconsciousness. An individual under the effects of anesthetic drugs is referred to as being anesthetized.

<span class="mw-page-title-main">Halothane</span> General anaesthetic

Halothane, sold under the brand name Fluothane among others, is a general anaesthetic. It can be used to induce or maintain anaesthesia. One of its benefits is that it does not increase the production of saliva, which can be particularly useful in those who are difficult to intubate. It is given by inhalation.

<span class="mw-page-title-main">Local anesthetic</span> Medications to reversibly block pain

A local anesthetic (LA) is a medication that causes absence of all sensation in a specific body part without loss of consciousness, providing local anesthesia, as opposed to a general anesthetic, which eliminates all sensation in the entire body and causes unconsciousness. Local anesthetics are most commonly used to eliminate pain during or after surgery. When it is used on specific nerve pathways, paralysis also can be induced.

<span class="mw-page-title-main">Isoflurane</span> General anaesthetic given via inhalation

Isoflurane, sold under the brand name Forane among others, is a general anesthetic. It can be used to start or maintain anesthesia; however, other medications are often used to start anesthesia, due to airway irritation with isoflurane. Isoflurane is given via inhalation.

<span class="mw-page-title-main">Sevoflurane</span> Inhalational anaesthetic

Sevoflurane, sold under the brand name Sevorane, among others, is a sweet-smelling, nonflammable, highly fluorinated methyl isopropyl ether used as an inhalational anaesthetic for induction and maintenance of general anesthesia. After desflurane, it is the volatile anesthetic with the fastest onset. While its offset may be faster than agents other than desflurane in a few circumstances, its offset is more often similar to that of the much older agent isoflurane. While sevoflurane is only half as soluble as isoflurane in blood, the tissue blood partition coefficients of isoflurane and sevoflurane are quite similar. For example, in the muscle group: isoflurane 2.62 vs. sevoflurane 2.57. In the fat group: isoflurane 52 vs. sevoflurane 50. As a result, the longer the case, the more similar will be the emergence times for sevoflurane and isoflurane.

<span class="mw-page-title-main">General anaesthesia</span> Medically induced loss of consciousness

General anaesthesia (UK) or general anesthesia (US) is a method of medically inducing loss of consciousness that renders a patient unarousable even with painful stimuli. This effect is achieved by administering either intravenous or inhalational general anaesthetic medications, which often act in combination with an analgesic and neuromuscular blocking agent. Spontaneous ventilation is often inadequate during the procedure and intervention is often necessary to protect the airway. General anaesthesia is generally performed in an operating theater to allow surgical procedures that would otherwise be intolerably painful for a patient, or in an intensive care unit or emergency department to facilitate endotracheal intubation and mechanical ventilation in critically ill patients. Depending on the procedure, general anaesthesia may be optional or required. Regardless of whether a patient may prefer to be unconscious or not, certain pain stimuli could result in involuntary responses from the patient that may make an operation extremely difficult. Thus, for many procedures, general anaesthesia is required from a practical perspective.

<span class="mw-page-title-main">Propofol</span> Intravenous medication used in anesthesia

Propofol is the active component of an intravenous anesthetic formulation used for induction and maintenance of general anesthesia. It is chemically termed 2,6-diisopropylphenol. The formulation was approved under the brand name Diprivan. Numerous generic versions have since been released. Intravenous administration is used to induce unconsciousness after which anesthesia may be maintained using a combination of medications. It is manufactured as part of a sterile injectable emulsion formulation using soybean oil and lecithin, giving it a white milky coloration.

<span class="mw-page-title-main">Theories of general anaesthetic action</span> How drugs induce reversible suppression of consciousness

A general anaesthetic is a drug that brings about a reversible loss of consciousness. These drugs are generally administered by an anaesthetist/anesthesiologist to induce or maintain general anaesthesia to facilitate surgery.

<span class="mw-page-title-main">Anesthetic</span> Drug that causes anesthesia

An anesthetic or anaesthetic is a drug used to induce anesthesia ⁠— ⁠in other words, to result in a temporary loss of sensation or awareness. They may be divided into two broad classes: general anesthetics, which result in a reversible loss of consciousness, and local anesthetics, which cause a reversible loss of sensation for a limited region of the body without necessarily affecting consciousness.

<span class="mw-page-title-main">Desflurane</span> Chemical compound

Desflurane (1,2,2,2-tetrafluoroethyl difluoromethyl ether) is a highly fluorinated methyl ethyl ether used for maintenance of general anesthesia. Like halothane, enflurane, and isoflurane, it is a racemic mixture of (R) and (S) optical isomers (enantiomers). Together with sevoflurane, it is gradually replacing isoflurane for human use, except in economically undeveloped areas, where its high cost precludes its use. It has the most rapid onset and offset of the volatile anesthetic drugs used for general anesthesia due to its low solubility in blood.

<span class="mw-page-title-main">Inhalational anesthetic</span> Volatile or gaseous anesthetic compound delivered by inhalation

An inhalational anesthetic is a chemical compound possessing general anesthetic properties that is delivered via inhalation. They are administered through a face mask, laryngeal mask airway or tracheal tube connected to an anesthetic vaporiser and an anesthetic delivery system. Agents of significant contemporary clinical interest include volatile anesthetic agents such as isoflurane, sevoflurane and desflurane, as well as certain anesthetic gases such as nitrous oxide and xenon.

Alfaxolone/alfadolone is a short acting intravenous anesthetic agent. It was withdrawn from the market due to severe drug reactions. It is composed of a 3:1 mixture of alfaxalone and alfadolone, two neurosteroids.

<span class="mw-page-title-main">Methoxyflurane</span> Chemical compound

Methoxyflurane, sold under the brand name Penthrox among others, is an inhaled medication primarily used to reduce pain following trauma. It may also be used for short episodes of pain as a result of medical procedures. Onset of pain relief is rapid and of a short duration. Use is only recommended with direct medical supervision.

Dental anesthesia is the application of anesthesia to dentistry. It includes local anesthetics, sedation, and general anesthesia.

Guedel's classification is a means of assessing the depth of general anesthesia introduced by Arthur Ernest Guedel (1883–1956) in 1920.

<span class="mw-page-title-main">Flurothyl</span> Chemical compound

Flurothyl (Indoklon) is a volatile liquid drug from the halogenated ether family, related to inhaled anaesthetic agents such as diethyl ether, but having the opposite effects, acting as a stimulant and convulsant. A clear and stable liquid, it has a mild ethereal odor whose vapors are non-flammable. It is excreted from the body by the lungs in an unchanged state.

Blood–gas partition coefficient, also known as Ostwald coefficient for blood–gas, is a term used in pharmacology to describe the solubility of inhaled general anesthetics in blood. According to Henry's law, the ratio of the concentration in blood to the concentration in gas that is in contact with that blood, when the partial pressure in both compartments is equal, is nearly constant at sufficiently low concentrations. The partition coefficient is defined as this ratio and, therefore, has no units. The concentration of the anesthetic in blood includes the portion that is undissolved in plasma and the portion that is dissolved. The more soluble the inhaled anesthetic is in blood compared to in air, the more it binds to plasma proteins in the blood and the higher the blood–gas partition coefficient.

The following outline is provided as an overview of and topical guide to anesthesia:

Nicholas Peter Franks FRS FRSB has been Professor of Biophysics and Anaesthetics at Imperial College London since 1993. His research focuses on how general anaesthetics act at the cell and molecular levels as well as with neuronal networks. Franks holds patents on use of xenon gas as a neuroprotectant and has published research on the use of the anesthetic properties of xenon.

References

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