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DRUGS ACTING ON CENTRAL NERVOUS SYSTEM | General Anaesthetics

General anaesthetics (GAs) are drugs which produce a 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
• Abolition of somatic and autonomic reflexes.

In the modern practice of balanced anaesthesia, these modalities are achieved by using a combination of inhaled and I .v. drugs, each drug for a specific purpose. Anaesthesia has developed as a highly specialized science in itself. History Before the middle of the 19th century a number of agents like alcohol, opium, cannabis, or even concussion and asphyxia were used to obtund surgical pain, but operations were horrible ordeals. Horace Wells, a dentist, picked up the idea of using nitrous oxide (N2O) from a demonstration of laughing gas in 1844. However, he often failed to relieve dental pain completely and the use of N2O had to wait till other advances were made. Morton, a dentist and medical student at Boston, after experimenting on animals, gave a demonstration of ether anaesthesia in 1846, and it soon became very popular. Chloroform was used by Simpson in Britain for obstetrical purpose in 1847 and despite its toxic potential, it became a very popular surgical anaesthetic.

Cyclopropane was introduced in 1929, but the new generation of anaesthetics was heralded by halothane in 1956. The first I .v. anaesthetic thiopentone was introduced in 1935.

MECHANISM OF GENERAL OF ANAESTHESIA

The mechanism of action of GAs is not precisely known. A wide variety of chemical agents produce general anaesthesia. Therefore, GA action had been related to some common physicochemical property of the drugs. Mayer and Overton (1901) pointed out the direct parallelism between lipid/water partition coefficient of the GAs and
their anaesthetic potency. Minimal alveolar concentration (MAC) is the lowest concentration of the anaesthetic in
pulmonary alveoli needed to produce immobility in response to a painful stimulus (a surgical incision) in 50% of individuals. It is accepted as a valid measure of the potency of inhalational GAs because it remains fairly constant for most young adults. The MAC of all inhalational anaesthetics declines progressively as age advances beyond 50 years.

The MAC of a number of GAs shows excellent correlation with their oil/gas partition coefficient. However, this only reflects the 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/perturbation/
fluidization) is responsible for the action of all inhalational anaesthetics has now been replaced by the ‘agent-specific theory’ according to which different GAs produce anaesthesia by different
mechanisms.

Recent evidence favours a direct interaction of the GA molecules with hydrophobic domains
of membrane proteins or the lipid-protein interface. Not only different anaesthetics appear to act
by different molecular mechanisms, but 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 the action in cerebral cortex and hippocampus, while the 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 GABAA receptor gated Cl¯ 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 GABAA 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 Cl¯ channels.

The 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 the immobility of the anaesthetic state. Certain fluorinated anaesthetics and barbiturates, in addition, inhibit the neuronal cation channel gated by nicotinic cholinergic
a receptor which may mediate analgesia and amnesia. On the other hand, N2O and ketamine do not
affect GABA or glycine gated Cl¯ channels. Rather they selectively inhibit the excitatory NMDA type of glutamate receptor. This receptor gates mainly Ca2+ selective cation channels in the neurones, inhibition of which appears to be the primary mechanism of anaesthetic action of ketamine as well as N2O. The volatile anaesthetics have little action on this receptor.

Neuronal hyperpolarization caused by GAs has been ascribed to activation of a specific type
of K+ channels called ‘two-pore domain’ channels. This may cause inhibition of presynaptic transmitter 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 a 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 GAs appear to act by depressing synaptic transmission.

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