General anaesthetics

General anaesthetics (GAs) are drugs which produce reversible loss of all sensation and consciousness. The cardinal features of general anaesthesia are: Loss of all sensation, especially pain, Sleep (unconsciousness) and amnesia Immobility and muscle relaxation and Abolition of somatic and autonomic reflexes.
In the modern practice of balanced anaesthesia, these modalities are achieved by using combination of inhaled and intravenous drugs, each drug for a specific purpose. 
Anaesthesia has developed as a highly specialized science in itself. The aim of general anesthesia for surgical operations is to eliminate consciousness and pain and to prevent motor (muscle tension, defense movements), autonomic, and cardiovascular reflex responses (rise in blood pressure and heart rate).
Anaesthesia is a relatively new field in modern medicine. Prior to its development, most surgical procedures were either minor or emergency operations. It is clear that modern surgery and the considerable benefits it brings would be impossible without the significant academic, pharmacological, and practical advances in anaesthesia during the 19th and 20th centuries. First and foremost among these is the development of safe and effective general anaesthesia.
Carbon dioxide was first explored as an anaesthetic in the 1820s by the English physician Henry H. Hickman. By inducing partial asphyxiation, Hickman demonstrated that animals could be rendered unconscious for a prolonged period, enabling surgical procedures to be performed. This was a major breakthrough, however the risks associated with hypoxic anaesthesia were too great to see the widespread adoption of carbon dioxide as an anaesthetic.
The mechanism of action of general anesthesia is not precisely known. A wide variety of chemical agents produce general anaesthesia. Therefore, general anesthesia action had been related to some common physicochemical property of the drugs. Mayer and Overton (1901) pointed out a direct parallelism between lipid/water partition coefficient of the general anesthesia and their anaesthetic potency.
Minimal alveolar concentration (MAC) It is the lowest concentration of the anaesthetic in the pulmonary alveoli needed to produce immobility in response to a painful stimulus (surgical incision) in 50% individuals. It is accepted as a valid measure of potency of inhalational general anesthesias, because it remains fairly constant for most young adults. The minimal alveolar concentration of all inhalational anaesthetics declines progressively as age advances beyond 50 years.
The minimal alveolar concentration of a number of general anesthesia shows excellent correlation with their oil/gas partition coefficient. However, this only reflects capacity of the anaesthetic to enter into CNS and attain sufficient concentration in the neuronal membrane, but not the mechanism by which anaesthesia is produced. The unitary hypothesis that some single common molecular mechanism (like membrane expansion or membrane perturbation or membrane fluidization) is responsible for the action of all inhalational anaesthetics has now been replaced by the agent specific theory according to which different general anesthesias produce anaesthesia by different mechanisms.
Recent evidence favours a direct interaction of the general anesthesia molecules with the hydrophobic domains of membrane proteins or the lipid protein interface.
Not only different anaesthetics appear to act by different molecular mechanisms, they also may exhibit stereospecific effects, and that various components of the anaesthetic state may involve action at discrete loci in the cerebrospinal axis. The principal locus of causation of unconsciousness appears to be in the thalamus or reticular activating system, amnesia may result from action in cerebral cortex and hippocampus, while spinal cord is the likely seat of immobility on surgical stimulation.
Recent findings show that ligand gated ion channels (but not voltage sensitive ion channels) are the major targets of anaesthetic action. The GABA receptor gated CI channel is the most important of these. Many inhalational anaesthetics, barbiturates, benzodiazepines and propofol potentiate the action of inhibitory transmitter GABA to open Cl channels. Each of the above anaesthetics appears to interact with its own specific binding site on the GABA, receptor-Cl channel complex, but none binds to the GABA binding site as such; though some inhaled anaesthetics and barbiturates (but not benzodiazepines) can directly activate CI channels. Action of glycine (another inhibitory transmitter which also activates Cl channels) in the spinal cord and medulla is augmented by barbiturates, propofol and many inhalational anaesthetics. This action may block responsiveness to painful stimuli resulting in immobility of the anaesthetic state. Certain fluorinated anaesthetics and barbiturates, in addition, inhibit the neuronal cation channel gated by nicotinic cholinergic receptor which may mediate analgesia and amnesia.
On the other hand, NO and ketamine do not affect GABA or glycine gated CI channels. Rather they selectively inhibit the excitatory NMDA type of glutamate receptor. This receptor gates mainly Ca selective cation channels in the neurones, inhibition of which appears to be the primary mechanism of anaesthetic action of ketamine as well as N,O. The volatile anaesthetics have little action on this receptor.
Neuronal hyperpolarization caused by general anesthesias has been ascribed to activation of a specific type of potassium (k) channels called 'two-pore domain' channels. This may cause inhibition of presynaptic trans- mitter release as well as postsynaptic activation. Inhibition of transmitter release from presynaptic neurones has also been related to interaction with certain critical synaptic proteins. Thus, different facets of anaesthetic action may have distinct neuronal basis, as opposed to the earlier belief of a global neuronal depression. Unlike local anaesthetics which act primarily by blocking axonal conduction, the general anesthesias appear to act by depressing synaptic transmission.

For ideal anaesthetic for the patient It should be pleasant, non irritating, should not cause nausea or vomiting. Induction and recovery should be fast with no after effects. For the surgeon It should provide adequate analgesia, immobility and muscle relaxation. It should be noninflammable and nonexplosive so that cautery may be used. For the anaesthetist Its administration should be easy, controllable and versatile.
Margin of safety should be wide-no fall in blood pressure, Heart, liver and other organs should not be affected. It should be potent so that low concentrations are needed and oxygenation of the patient does not suffer. Rapid adjustments in depth of anaesthesia should be possible. It should be cheap, stable and easily stored. It should not react with rubber tubing or soda lime.

Published : Oct 20 2023