General anesthesia is a reversible state of central nervous system (CNS) depression, resulting in loss of response and perception of external stimuli. They depress the central nervous system and normal homeostatic reflexes to a sufficient degree to permit the performance of surgery and other noxious or unpleasant procedures.  

For patient General anesthesia should be:

•  Pleasant
•  Non irritating
•  No nausea and vomiting
•  Quick induction and recovery 

For surgeon General anesthesia should be:

•  It should provide adequate analgesia, immobility, muscle relaxation
•  Non inflammable and non explosive
•  Blood gas solubility ratio in range of 0.3-2 

For anesthetist General anesthesia should be:

•  Easy and controlled administration  
•  Stable and easily stored
•  Potent
•  No major organ affected 

Mechanism of Action 

• The molecular and cellular mechanisms by which general anesthetics produce their effects have remained one of the great mysteries of pharmacology. 
•  For most of the 20th century, it was theorized that all anesthetics act by a common mechanism (the unitary theory of anesthesia).  
• The leading unitary theory was that anesthesia is produced by perturbation of the physical properties of cell membranes.  

• This thinking was based largely on the observation that the anesthetic potency of a gas correlated with its solubility in olive oil. 
•  This correlation, referred to as the Meyer-Overton rule, was interpreted as implicating the lipid bilayer as the likely target of anesthetic action. 

Cellular Mechanisms of Anesthesia 

• First, the inhalational anesthetics can hyperpolarize neurons.  
•  It also may be important in synaptic communication, since reduced excitability in a postsynaptic neuron may diminish the likelihood that an action potential will be initiated in response to neurotransmitter release. Different anesthetic agents produce specific components of anesthesia by actions at different molecular targets. Given these insights, the unitary theory of anesthesia has been largely discarded.  

• Second, at anesthetizing concentrations, both inhalational and intravenous anesthetics have substantial effects on synaptic transmission and much smaller effects on action-potential generation or propagation. 
• The inhalational anesthetics inhibit excitatory synapses and enhance inhibitory synapses in various preparations.  
• Inhalational anesthetics also can act postsynaptically, altering the response to released neurotransmitter.  
• These actions are thought to be due to specific interactions of anesthetic agents with neurotransmitter receptors. 
• IV anesthetics: Their predominant actions are at the synapse, where they have profound and relatively specific effects on the postsynaptic response to released neurotransmitter. 

•  Most of the intravenous agents act predominantly by enhancing inhibitory neurotransmission, whereas ketamine predominantly inhibits excitatory neurotransmission at glutamatergic synapses. 

Molecular Actions of General Anesthetics 

• A variety of ligand-gated ion channels, receptors and signal transduction proteins are modulated by general anesthetics.  
• Of these, the strongest evidence for a direct effect of anesthetics exists for the GABAA and NMDA receptors and the two-pore K+ channels. 
• Chloride channels gated by the inhibitory GABAA receptors are sensitive to clinical concentrations of a wide variety of anesthetics, including the halogenated inhalational agents and many intravenous agents (propofol, barbiturates, etomidate, and neurosteroids). 
• At clinical concentrations, general anesthetics increase the sensitivity of the GABAA receptor to GABA, thus enhancing inhibitory neurotransmission and depressing nervous system activity. 
• Glycine receptors may play a role in mediating inhibition by anesthetics. 
• Glycine-gated chloride channels (glycine receptors):  play an important role in inhibitory neurotransmission in the spinal cord and brainstem. 
• Propofol, neurosteroids, and barbiturates also potentiate glycine-activated currents, whereas etomidate and ketamine do not.
• Ketamine, nitrous oxide, cyclopropane, and xenon : inhibit a different type of ligand-gated ion channel, the N-methyl-D-aspartate (NMDA) receptor. 
• Halogenated inhalational anesthetics activate some members of a class of K+ channels known as two-pore domain channels. 

 Article by Dr. Siri P. B.