General Anaesthetics Drugs Mechanism of Action | Stages of General Anaesthesia
General-Anaesthesia

General Anaesthetics Drugs Mechanism of Action | Stages of General Anaesthesia

General Anaesthetics

General anaesthetics are drugs which easily 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 reflexes.

In the latest practice of balanced anaesthesia, these modalities are achieved by using combinations of drugs, each drug for a specific purpose, anaesthesia has developed as a highly specialized science in itself.




History of General anaesthetics

Earlier than 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 General Anaesthetics in 1844 However, he often failed to relieve dental pain completely and the use of N2O had to wait till another advance were made. Morton, a great 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 Action of General Anaesthesia

    The mechanism of action of GENERAL ANAESTHEICS is not precisely known. A very wide variety of chemical agents produce general anaesthesia. Therefore, GENERAL ANAESTHETIC action had been related to some common physicochemical property of the drugs. Mayer and Overton (1901) pointed out direct parallelism between lipid/water partition coefficient of the General Anaesthetics and their anaesthetic potency.

Minimal Alveolar Concentration (MAC) is the least concentration of the anaesthetic in pulmonary alveoli needed to produce immobility in response to a painful stimulus in 50% of individuals. It is accepted only as a valid measure of the potency of inhalational General Anaesthetics because it remains fairly constant for a given species even under varying conditions.

The Minimal Alveolar Concentration (MAC)  of a number of General Anaesthetics shows excellent correlation with their oil / General Anaesthetics partition coefficient. However, this only tells 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.

It has been proposed that the anaesthetic by dissolving in the membrane lipids increases the degree of disorder in their structure favouring a gel-liquid transition (fluidization) which secondarily affects the state of membrane-bound functional proteins or expands the membrane disproportionately (about 10 times molecular volume) closing the ion channels. However, recent evidence favours a direct interaction of the GA molecules with hydrophobic domains of membrane proteins or the lipid-protein interface.

It has now been realised that different anaesthetics may be acting through different molecular mechanisms and various components of the anaesthetic state involve action at discrete loci in the cerebrospinal axis. The principal causing of unconsciousness appears to be in the thalamus or reticular activating system, amnesia may result from the action in the hippocampus, while the spinal cord is the likely seat of immobility on surgical stimulation.




Recent findings that ligand-gated ion channels (but not voltage-sensitive ion channels) are the major targets of anaesthetic action. The GABAA (Gamma-Amino Butyric Acid) receptor gated Clchannel is the most important of these. Many inhalational anaesthetics, barbiturates, benzodiazepines and propofol potentiate the action of inhibitory transmitter GABA to open Clchannels. Each of the above anaesthetics appears to interact with its own specific binding site on the GABAA receptor- Clchannel complex, but none binds to the GABA binding site as such. The action of glycine (another inhibitory transmitter which also activates Clchannels) 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 anaesthetics and barbiturates, in addition, inhibit neuronal cation channel gated by the nicotinic cholinergic receptor.

On the other hand, N2O and ketamine do not affect GABA or glycine gated Clchannels. Rather they selectively inhibit the excitatory NMDA type of glutamate receptor. This receptor gates mainly Ca2+ selective cation channels in the neurones and their inhibition appears to be the primary mechanism of anaesthetic action of ketamine as well as N2O. The volatile anaesthetics have little action on the receptor.

Neuronal hyperpolarization caused by general anaesthetics has been ascribed to activation of a specific type of K+ channels, while inhibition of transmitter release from presynaptic neurones has 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 General Anaesthetics appears to act by depressing synaptic transmission.




Stages of General Anaesthesia

General Anaesthetics causes an irregularly descending depression of CNS, i.e., the higher functions are lost first and progressively lower areas of the brain are involved, but in the spinal cord lower segments are affected somewhat earlier than the higher segments. The vital centres located in the medulla are paralysed the last as the depth of anaesthesia increases. Guedel (1920) described four stages with ether anaesthesia, dividing the III stage into 4 planes. These clear-cut stages are not seen nowadays with the use of faster-acting General Anaesthetics, premedication and employment of many drugs together. The precise sequences of events differ somewhat with anaesthetics other than ether. However, ether continues to be widely used in India and the description of these stages still serves to define the effects of light and deep anaesthesia.

1. Stage of Analgesia: Starts from beginning of anaesthetic inhalation and lasts up to the loss of consciousness. Pain is progressively abolished during this stage. The patient remains conscious, can hear and see, and feels a dream-like state. Reflexes and respiration remain normal. Though some minor and even major operations can be carried out during this stage, it is rather difficult to maintain-use is limited to short procedures.

2. Stage of Delirium: From the loss of consciousness to the beginning of regular respiration. Apparent excitement is seen-patient may shout, struggle and hold his breath; muscle tone increases, jaws are tightly closed, breathing is jerky; vomiting, involuntary micturition or defecation may occur. Heart rate and BP may rise and pupils dilate due to sympathetic stimulation. No stimulus should be applied or operative procedure carried out during this stage. This stage can be cut-short by rapid induction and appropriate premedication. It is inconspicuous in modern anaesthesia.

3.Surgical Anaesthesia: Extends from onset of regular respiration to cessation of spontaneous breathing. This has been divided into 4 planes which may be distinguished as:

Plane 1- Roving eyeballs. This plane ends when eyes become fixed.

Plane 2- Loss of corneal and laryngeal reflexes.

Plane 3- Pupil starts dilating and light reflex is lost.

Plane 4- Intercostal paralysis, shallow abdominal respiration, dilated pupil.

As anaesthesia passes to deeper planes, progressively-muscle tone decreases, BP falls, HR increases with weak pulse, respiration decreases in-depth and later in frequency also-thoracic lagging behind abdominal.

4.Medullary Paralysis: -Cessation of breathing to failure of circulation and death. A pupil is widely dilated, muscles are totally flabby, a pulse is thready or imperceptible and BP is very low. Many of the above indices have been robbed by the use of atropine (pupillary, heart rate), morphine (respiration, pupillary), muscle relaxants (muscle tone, respiration, eye movements, reflexes) etc. and the modern anaesthetic has to depend on several other observations-

  • If eyelash reflex is present and the patient is making swallowing movements-Stage II has not been reached.
  • Incision of the skin causes a reflex increase in respiration, BPraise or other effects; insertion of the endotracheal tube is resisted and induces coughing, vomiting, laryngospasm; tears appear in the eye; passive inflation of lungs is resisted-anaesthesia is light.
  • Fall in BP, cardiac and respiratory depression are signs of deep anaesthesia.

In the present day practice, anaesthesia is generally kept light; adequate analgesia, amnesia and muscle relaxation are produced by the use of intravenous drugs. Concentrations of inhalational anaesthetics exceeding 1.2 MAC are rarely used.




Pharmacokinetics Of Inhalational Anaesthetics

Inhalational anaesthetics are gases or vapours that diffuse rapidly across pulmonary alveoli and tissue barriers. The depth of anaesthesia depends on the potency of the agent (MAC is an index of potency) and its partial pressure (PP) in the brain, while induction and recovery depend on the rate of change of PP in the brain. Transfer of the anaesthetic between lung and brain depends on a series of tension gradients which may be summarised as-

Alveoli <==> Blood <==> Brain

Factors affecting the PP of anaesthetic attained in the brain are-

1. PP of anaesthetic in the inspired gas: This is proportional to its concentration in the inspired gas mixture. higher the inspired tension more anaesthetic will be transferred to the blood. Thus, induction can be hastened by administering the GA at high concentration in the beginning. However, irritancy of the agent can limit the concentration which can be used.

2. Pulmonary ventilation: It governs the delivery of the GA to the alveoli. Hyperventilation will bring in more anaesthetic per minute and respiratory depression will have the opposite effect. Influence of minute volume on the rate of induction is greatest in the case of agents which have high blood solubility because their PP in blood takes a long time to approach the PP in alveoli. However, it does not affect the terminal depth of anaesthesia attained with any concentration of a GA.

3. Alveolar exchange: The GAs diffuse freely across alveoli, but if alveolar ventilation and perfusion are mismatched (as occurs in emphysema and other lung diseases) the attainment of equilibrium between alveoli and blood is delayed: well-perfused alveoli may not be well ventilated-blood draining these alveoli carries less anaesthetic and dilutes the blood coming from well-ventilated alveoli. Induction and recovery both are delayed.

4. Solubility of anaesthetic in blood: This is the most important property determining induction and recovery. A large amount of an anaesthetic that is highly soluble in the blood (ether) must dissolve before its PP is raised. The rise, as well as fall of PP in blood and consequently induction as well as recovery, are slow. Drugs with low blood solubility, e.g. N2O, sevoflurane, desflurane induce quickly.

Blood: gas partition coefficient (λ) given by the ratio of the concentration of the anaesthetic in the blood to that in the gas phase at equilibrium is the index of solubility of the GA in blood.

5. Solubility of anaesthetic in tissue: Relative solubility of anaesthetic in blood and tissue determines its concentration in tissues at equilibrium. Most of GAs are equally soluble in lean tissues as in blood but more soluble in fatty tissue. Anaesthetics with higher lipid solubility (halothane) continue to enter adipose tissue for hours and also leave it slowly. The concentration of these agents is much higher in white matter than in grey matter.

6. Cerebral blood flow: Brain is a highly perfused organ; as such GAs are quickly delivered to it. This can be hastened by CO2 inhalation which causes cerebral vasodilatation-induction and recovery are accelerated. Carbon dioxide stimulates respiration and this also speeds up the transport.

  • Elimination: When anaesthetic administration is discounted, gradients are reversed and the channel of absorption (pulmonary epithelium) becomes the channel of elimination. Same factors which govern induction also govern recovery. Anaesthetics, in general, persist for long periods in adipose tissue because of their high lipid solubility and low blood flow through fatty tissues. Muscles occupy an intermediate position between the brain and adipose tissue. Most GAs are eliminated unchanged. Metabolism is significant only for halothane which is about 20% metabolized in the liver. Others are practically not metabolized.
  • Second gas effect and diffuse hypoxia: In the initial part of induction, diffusion gradient from alveoli to blood is a high and larger quantity of anaesthetic is entering the blood. If the inhaled concentration of anaesthetic is high, substantial loss of alveolar gas volume will occur and the gas mixture will be sucked in, independent of ventilatory exchange-gas flow will be higher than tidal volume. This is significant only with N2O since it is given at 70-80% concentration; though it has low solubility in blood, about 1 litre/min of N2O enters the blood in the first few minutes-gas flow is 1 litre/min higher than minute volume. If another potent anaesthetic, e.g. halothane (1-2%) is being given at the same time, it also will be delivered to blood at a rate 1 litre/min higher than minute volume and induction will be a faster-second gas effect.

To reverse occurs when N2O is discounted after prolonged anaesthesia-N2O having low blood solubility rapidly diffuses into alveoli and dilutes the alveolar air-PP of oxygen in alveoli is reduced. The resulting hypoxia, called diffusion hypoxia, is not of much consequence if the cardiopulmonary reserve is normal, but maybe dangerous if it is low. It can be prevented by continuing 100% O2 inhalation for a few minutes after discontinuing N2O, instead of straight away switching over to air. Diffusion hypoxia is not significant with other anaesthetics because they are administered at low concentrations (0.2-4%) and cannot dilute alveolar air by more than 1-2%.




Techniques of Inhalation of Anaesthetics

Different techniques are used according to the facility available, the agent used, condition to the patient, type and duration of the operation.

  1. Open drop method: Liquid anaesthetic is poured over a mask with gauze and its vapour is inhaled with air. A lot of anaesthetic vapour escapes in the surroundings and the concentration of anaesthetic breathed by the patient cannot be determined. It is wasteful-can be used only for cheap anaesthetic. Some rebreathing does occur in this method. However, it is simple and requires no special apparatus. Ether is the only agent used by this method, specially in children.
  2. Through anaesthetic machines: Use is made of gas cylinders, specialized graduated vaporisers, flow maters, unidirectional valves, corrugated rubber tubing and reservoir bag.

The gases are delivered to the patient through a tightly fitting face mask or endotracheal tube. Administration of the anaesthetic can be more precisely controlled and in many situations its concentration determined. Respiration can be controlled and assisted by the anaesthetist.

  • Open system: The exhaled gases are allowed to escape through a value and fresh anaesthetic mixture is drawn in each time. No rebreathing is allowed-flow rates are high-more drug is consumed. However, inhaled O2 and anaesthetic concentration can be accurately measured.
  • Closed system: The patient rebreaths the exhaled gas mixture after it has circulated through soda lime which absorbs CO2. Only as much O2 and anaesthetic as having been taken up by the patient are added to the circuit. The flow rates are low; specially useful for expensive and explosive agents (little anaesthetic escapes in the surrounding air) e.g. halothane, enflurane, isoflurane. However, the determination of inhaled anaesthetic concentration is difficult. It should not be used for trichloroethylene which forms a toxic compound with soda lime.
  • Semiclosed system: Partial rebreathing is allowed through a partially closed valve. Conditions are intermediate with moderate flow rates.




Properties of an 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. The margin of safety should be wide-no fall in BP. 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 the depth of anaesthesia should be possible. It should be cheap, stable and easily stored. It should not react with rubber tubing or soda lime.

Most inhalational anaesthetics have a steep concentration-response curve: increasing the concentration only by 1/3 over MAC makes almost all individuals immobile ( at MAC only 50% are immobilized), and 2-4 MAC is often lethal.

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