General Anesthetics

General Anesthesia

“Global but reversible depression of CNS function resulting in the loss of response to and perception of all external stimuli”

Drugs which produce reversible loss of response and perception to external stimuli are called general anesthetics.

Characteristics of General Anesthesia

1. Analgesia

These drugs have pain relieving property. Different anesthetic agents have different levels of analgesia.

2. Amnesia

Loss of memory of events takes place while patient is under the effect of these drugs.

3. Attenuation of sensory / autonomic responses

Both are suppressed or inhibited.

4. Muscle relaxation / Immobility

Ultimately, immobility results in these patients’.

5. Unconsciousness

Patient does not respond to external stimuli.

General Anesthesia	Sleep (Hypnosis)
Patient cannot be aroused by external stimuli	Patient can be aroused by external stimuli
Painful stimuli on muscles do not make the person conscious.

History

1^st anesthetic discovered during the 19^th century was ether, which was used by dentists. Later, chloroform was in use for some time, but was more hepatotoxic and affected CNS.

Both are not used anymore but are still in use for the animals.

During 20^th century, nitrous oxide, cyclopropane and halothane were used as anesthetics.

Halothane/Nitrous oxide are still in use and are cheap. But more effective analgesics are available, which are in use.

Classification of General Anesthetics

Inhalational Anesthetics

a. Volatile Liquids

b. Gases

Nitrous Oxide

Cyclopropane

Intravenous Anesthetics

a. Ultra Short Acting Barbiturates

Thiopentone Sodium
Methohexital

b. Phencyclidine Derivatives

Ketamine

c. Steroids

Althesin

d. Eugenol Derivatives

Propanidid

e. Alkyl Phenols

Propofol

Etomidate

Neuroleptanaesthesia

Droperidol + Fentanyl + Nitrous oxide

Combination of these three drugs is used especially in psychopharmacology and psychiatry. By this combination, patient is made somewhat drowsy, decreasing the level of consciousness for different psychiatric conditions.

When only Droperidol and Fentanyl combination is used, it is known as Neuroleptanalgesia.

Stages of General Anesthesia

Guedel’s Signs – Ether

When anesthesia is administered, patient progressively loses consciousness and passes through different stages. These stages are more prominent with local anesthetics like Ether. They were first noticed by Guedel, so called Guedel’s sign.

Newer drugs act rapidly, thus these stages cannot be recognized nowadays.

Stage-I Stage Of Analgesia

Patient no more feels pain.
He is drowsy
Although all reflexes are intact, there is no amnesia
Not much change in heart rate, blood pressure or size of pupil occurs.

Stage-II Stage of Excitement

This is the stage anesthetic wants to pass immediately, as is the most dangerous stage. During this:

Patient is excited
Delirious
Respiration becomes irregular, rate increases
Blood pressure is variable
Jerky movements of different body parts. Due to these jerky movements, patient may injure himself
Eye movements are rapid
There are chances of vagal stimulation leading to cardiac arrest or cardiac arrhythmias due to excess of catecholamines or inhibition of inhibitory centers.

Stage-III Stage of Surgical Anesthesia

There are four planes:

– Plane-I

Pupils are slightly constricted
Respiration becomes regular but rate is still increased
Muscle tone starts decreasing, making the patients muscles relax
Corneal and conjunctival reflexes are lost

– Plane-II

Pupils start dilating
Respiration rate is decreased, while respiration is regular
Eye balls become fixed
Muscle tone is further decreased
Respiration is abdominothoracic
Light reflex is lost

– Plane-III

Thoracic respiration ceases and becomes mainly abdominal
Pupils are fully dilated
Muscles completely relax
Laryngeal and pharyngeal reflexes are suppressed

This is the phase where surgery is usually performed. The surgeon wants to keep the patient in this stage of anesthesia.

– Plane-IV

Abdominal respiration also seizes.
All reflexes are lost

Patient is avoided to go into this stage. This is a warning sin for anesthetics.

Stage-IV Stage of Medullary Paralysis

During this stage of medullary paralysis, cardiovascular and respiratory centers in medulla are so much suppressed by anesthetics that it could lead to cardiovascular collapse or respiratory failure.

Patient should not go into this stage.

Phases of Anesthesia

– Induction – I/V

Time from the onset of administration of anesthesia till the surgical anesthesia is attained. Usually I/V anesthetic agents are used for induction.

– Maintenance – Inhalational

Provision of sustained surgical anesthesia, maintained for period of surgery. Most of the time done by inhalational method.

– Recovery – reverse of induction

Time from discontinuation of anesthetic administration till the patient attains consciousness and protective physiological reflexes. Although I/V used for induction and inhalational for maintenance still vice versa may be used.

Ideal Anesthetic

The criterion for an ideal anesthetic is different for the patient, surgeon and the anesthetic.

– For patient

Should not be causing nausea, vomiting
There should be smooth induction and recovery
Without any long term side effects

– For surgeon

One which provides complete muscle relaxation and immobility
Complete loss of sensations and analgesia to perform easily
Non inflammable agent, non-explosive

– For anesthetist

Cheap, easily available
Easy to administer, monitor
Does not interfere with oxygenation
With less side effects

Balanced anesthesia

Balanced anesthesia is attained by combination of I/V and inhalational routes, provided differently to different patients, according to conditions and time period of operation.

Mechanism of Action of General Anesthetics

Old Theories

– Unitary Theory

Unitary theory is commonly considered as the mechanism of action. According to this

“All anesthetics act on same site and have same mechanism of action”

– Meyer-Overton Theory

This theory tells more about the potency than the mechanism of action. According to this

“Lipid solubility of anesthetic agent is directly proportional to the potency of that agent”.

Greater the lipid solubility, more enters the lipid bilayer, so that small concentration of highly lipid soluble agent produces anesthesia. Less the solubility, more dose is required.

– Pauling’s Theory

When drug molecules enter lipid bilayer of cell membrane of neurons, they cause fluid like state called fluidization, due to which disorientation produced in membrane leads to anesthesia.

– Ferguson’s Theory

This disorientation causes change/disruption in ion channels in membrane, e.g. closing Na+ channels. This leads to inhibition of action potential and excitation of neuron.

– Mullin’s Theory

When we increase atmospheric pressure by giving oxygen from outside, this disruption in membrane can be reversed back, which is responsible for recovery form anesthesia

Newer Concepts

– Specific Targets

All anesthetic agents act at specific targets (negating unitary theory). Although these mechanisms may be overlapping for different groups, each group has special proteins the body.

– Differential Sensitivity of Neurons- Stages

Differential sensitivity of neurons is responsible for the stages to different concentration of anesthesia. E.g. during 1^st stage, neurons in substantia gelatinosa (responsible for pain perception) are first inhibited by low concentration of anesthesia, given during 1^st stage of anesthesia.

As concentration and depth of anesthesia is increased, inhibitory pathways are suppressed, because of which inhibition of inhibitory neurons (called disinhibition) leads to a stage of excitement. Ascending pathways in reticular system and spinal cord are inhibited which leads to stage of surgical anesthesia.

Stage of medullary paralysis occurs when depth of anesthesia is further increased, due to suppression of cardiovascular center and respiratory center in medulla.

Newer Mechanisms

Different neurons act at different sites in CNS are responsible for different characteristics seen, like

– Site of Action

Unconsciousness, because anesthetic action in thalamus and reticular activating system.
Amnesia is because of action on hypothalamus.
Spinal cord is responsible for immobility

– Cellular Mechanisms

Inhibition of synaptic transmission. Activation of inhibitory pathways and excitatory pathways.

– Molecular Actions

Channels & Receptors

Act on different channels and ligand gated receptors to produce anesthetic effect.

* Different binding sites

They bind different sites on receptors. Each agent binds specific binding sites on receptors or channels.

a. GABA_A receptor-chloride channels

Most commonly ligands gated receptors are GABA A receptor-chloride channels.

Calcium channels are coupled with GABA A receptor when inhibitory neurotransmitter GABA binds. Chloride channels open, leading to hyperpolarization and inhibitory action potential.

Drugs acting are

Inhalational agents, barbiturates, propofol, etomidate

b. Glycine receptor-chloride channels

Glycin is the neurotransmitter which leads to change in permeability to chloride channels, leading to hyperpolarization and inhibition of neuron present in spinal cord.

Drugs acting are

Inhalational agents, barbiturates, propofol

c. Glutamate receptor-NMDA channels

Glutamate acts on excitatory channels and produce excitation.

Drugs acting inhibit these channels, and include

Ketamine, nitrous oxide, cyclopropane

d. K⁺ channels (TREK) – Hyperpolarization

These are the two pore domain potassium channels. They are a special type. Different agents bind these channels leading to increased potassium efflux, resulting in hyperpolarization, which has inhibitory action.

Drugs acting are

Inhalational agents, nitrous oxide, cyclopropane

e. Nicotinic receptor-activated cation channels

These are activated by acetyl choline and are inhibited by inhalational agents.