Principles of general anaesthesia

Question 1

What is important to remember about general anaesthetics

Answer 1

Although they are very useful drugs. they are also very dangerous and you have to be very skilled to use them

Question 2

1. What are the five clinically desirable effects of general anaesthetics? State which two effects are caused by ALL general anaesthetics.

Answer 2

Loss of consciousness (ALL)

Suppression of reflex responses (ALL)

Relief of pain (important- don’t necessarily have pain relief if you are unconscious or immobile)

Muscle relaxation (important for surgery- to get through muscle mass).

Amnesia

Question 3

At what concentrations of local anaesthetics do you get:

a) loss of consciousness
b) Suppression of reflex responses

Answer 3

Loss of consciousness at low concn
Suppression of reflex responses at high concn

So you get loss of consciousness first.
NB G.A.s vary greatly in their ability to induce analgesia, muscle relaxation and amnesia.

Question 4

Summarise the history of general anaesthesia

Answer 4

Crawford Long (1842) —- CH3-CH2-O-CH2-CH3 (ether)

Horace Wells (20th Jan, 1845) — N N O (nitrous oxide)

William Morton & Charles Jackson —- CH3-CH2-O-CH2-CH3 (ether)
(16th Oct, 1846)

Question 5

What are the two broad types of general anaesthetics

Answer 5

Gaseous/Inhalational

Intravenous

Question 6

Describe the structural relationship between the different anaesthetic agents

Answer 6

They are all dissimilar!

Extraordinary chemical diversity ranging from simple chemically inert gases to complex barbiturates

Question 7

List the inhalational general anaesthetics

Answer 7

Nitrous Oxide

Diethyl Ether

Halothane

Enflurane

Question 8

List the intravenous general anaesthetics

Answer 8

Propofol

Etomidate

Question 9

How can we define what is meant by general anaesthesia

Answer 9

Only one defining feature for all general anaesthetics;

‘Induce a loss of consciousness at low concentrations’

Additionally;
‘Induce an increasing lack of responsiveness at higher concentrations’

Question 10

Describe the general structural differentiation between I.V and general anaesthetics

Answer 10

o IV generally contain rings.

o Inhalational GAs generally have halogens.

Question 11

What was an early theory for the mechanism of action of general anaesthetics

Answer 11

Meyer/Overton
Correlation

Anaesthetic potency increases
in direct proportion with oil/water
partition coefficient
That is the more lipid soluble the drug- the more potent it was. Therefore, the site of action for general anaesthetics must have been in disrupting lipid bilayers.

Question 12

Describe the problems that arised regarding the Meyer/Overton correlation

Answer 12

Problems:
At relevant anaesthetic concns,
change in bilayer was minute
2. How would this change impact 
membrane proteins?- which are involved in transmitting action potentials.

Question 13

Describe the two real mechanisms for how general anaesthetics work

Answer 13

Reduced neuronal excitability or

Altered synaptic function (i.e effect on neurotransmitter release).

Question 14

What are GABAa receptors

Answer 14

Most abundant, fast inhibitory, ligand-gated ion channels in the CNS
Different GABA channels are composed of different subunits- binding of different general anesthetics to different subunits effects the pharmacodynamics of the drug.

Question 15

What do intravenous general anaesthetics target

Answer 15

GABAA
receptors
Bind to and potentiate their action to enhance GABA transmission.

Question 16

Describe the subunits of the GABAa receptor that etomidate targets and the different effects produced

Answer 16

B3- suppression of spinal responses

A5- amnesia.

Question 17

What is important to remember about the targets of inhalational drugs and intravenous drugs

Answer 17

Inhalational drugs- not as selective for the GABAa receptors as the intravenous drugs- but they can target more sites- but their potency at the GABAa receptor is 50% of that of intravenous drugs.

Question 18

Describe the effects of inhalational agents on GABAa/glycine receptors (particualry the halogenated ones)

Answer 18

Like I.V- potentiate the transmission at these receptors

alpja 1 subunit of glycine receptors- leads to suppression of spinal responses

Question 19

What are glycine receptors

Answer 19

Glycine receptors, which are homologous to, and often colocalized with, GABAA receptors, are a potential anaesthetic target. Glycine receptors have an inhibitory role, particularly in the lower brainstem and spinal cord, where they might mediate the action of volatile anaesthetics

Question 20

Describe how inhalational agents (particuarly nitrous oxide) can block NMDA-type glutamate receptors

Answer 20

Nitrous oxide competes for the glycine-binding site on NMDA receptors (glutamate receptors)
Glycine is an important coagonist of NMDA receptors – it allows the full receptor response to be transduced

Question 21

Describe the effects of inhalational agents (particuarly the halogenated ones) on neuronal nAChR

Answer 21

Volatile anaesthetic inhibit neuronal nicotinic Ach receptors and this contributes to the analgesic effects of these anaesthetics. Intravenous drugs can act on these targets but only at concentrations above that required for anaesthesia. Ach receptors do not seem to contribute to the hypnotic effects.

Question 22

Describe the effects of the inhalational agents (particuarly the halogenated ones) on TREK (background leak) K+ channels

Answer 22

This is the only target that reduced neuronal excitability- the others alter synaptic function
a. Enhance background leak of K-channels to cause hyperpolarisation of cells.
i. TREK (background leak) of K+-channels.
This reduces the excitability of neurones
These channels May be involved in the normal sleep wake cycle and thus these drugs may have an effect on consciousness.

Question 23

Describe a general difference between inhalational GAs and I.V GAs in terms of their molecular targets and potencies.

Answer 23

Generally, IV GAs are much more selective and the inhaled GAs are much more non-selective but equally as potent.

Question 24

Summarise the normal sleep-wake cycle

Answer 24

Variety of different sensory inputs into the cortex- these are relayed through the thalamus to the reticular activating system in the brainstem.
The reticular activating system (RAS) emanates from the brainstem and projects upward to the cerebral cortex via the thalamus.All the cortical varieties of consciousness depend upon the integrity of these subcortical structures. Acetylcholine is released from cholinergic nerve terminals projecting from RAS to the thalamus and cortex in highest concentrations in association with cortical activation that occurs naturally during wakefulness.

If you were to decrease these sensory stimuli (i.e sitting in a dark room)- you would reduce input to and hence the activity of RAS.

Question 25

Where do general anaesthetics that cause a loss of consciousness act

Answer 25

Depress excitability of thalamocortical neurons - these are GABAa rich Influences reticular activating neurons -GABAa and TREK channels The GAs will disrupt the communication between the RAF, cortex and thalamus.

Question 26

What does normal consciousness depend on and how do general anaesthetics effect this

Answer 26

Consciousness depends on feedback loops between cortex, thalamus and reticular activating system. Sensory information received by the cortex is the primary starting point for consciousness. Anaesthetics can directly hyperpolarize thalamocortical neurons by activating TREK channels and/or by potentiating GABAAreceptors - information transfer through the thalamus is disrupted. Although the thalamus might control the state of consciousness, processing in the cortex is responsible for the detailed content of consciousness, and during anaesthetic-induced LOC the cortex is profoundly deactivated.

Question 27

Describe how general anaesthetics can suppress spinal reflex responses

Answer 27

Depression of reflex pathways in the dorsal horn of the spinal cord This is done by anaesthetics that enhance GABA-A and glycine function Essentially, this prevents the transmission of painful stimuli from the spinal cord to the brain.

Question 28

Describe how general anaesthetics can cause amnesia

Answer 28

The impairment of memory is one of the most potent effects of many general anesthetics. Memory is particularly sensitive to general anesthetics because amnesia occurs at concentrations well below those that cause sedation and analgesia. Although the ratio of the GABAA receptor subunits that have α5 is low, they are distributed at the extrasynapse of the hippocampus in a relatively high ratio. Therefore, it can be assumed that general anesthetics potentiate the tonic currents acting on the α5GABAA receptor in the hippocampus, which can be considered as one of the amnesia mechanisms that occur during anesthesia. Essentially, they reduce synaptic transmission in the hippocampus and amygdala.

Question 29

Compare the properties of brain, blood and inhales air

Answer 29

``` Brain (=lipid)- bi-directional communication with blood (=water) Inhaled air (=gas) - bi-directional communication with blood. ```

Question 30

What is meant by the blood:gas coefficient

Answer 30

The blood/gas partition coefficient describes how the gas will partition itself between the two phases after equilibrium has been reached. Isoflurane for example has a blood/gas partition coefficient of 1.36. Thus if the gas is in equilibrium the concentration in blood will be 1.36 times higher than the concentration in the alveoli. A higher blood gas partition coefficient means a higher uptake of the gas into the blood and therefore a slower induction time. It takes longer until the equilibrium with the brain partial pressure of the gas is reached.

Question 31

Explain the importance of blood:gas coefficient for general anaesthesia

Answer 31

The blood:gas partition coefficient is the main factor that determines the rate of induction and recovery of an inhalation anaesthetic, and the lower the blood:gas partition coefficient, the faster is induction and recovery (Table 42.2). This is because it is the partial pressure of the gas in the alveolar space that governs the concentration in the blood. The lower the blood:gas partition coefficient, the more rapidly the partial pressure of the gas in the alveolar space will equal that being administered in the inspired air (see later).

Question 32

Describe how the blood:gas coefficient concept works in general anaesthesia practically

Answer 32

When a volatile anaesthetic is first administered, the initial breaths are diluted into the residual gas volume in the lungs resulting in a reduction in the alveolar partial pressure of the anaesthetic as compared with the inspired gas mixture. With subsequent breaths, the alveolar partial pressure rises towards equilibrium. For an anaesthetic with a low blood:gas partition coefficient, the absorption into the blood will be slower, so with repeated breaths the partial pressure in the alveolar space will rise faster than with an agent of high blood:gas partition coefficient. Thus a smaller number of breaths (i.e. a shorter time) will be needed to reach equilibrium. Therefore, contrary to what one might intuitively suppose, the lower the solubility in blood, the faster is the process of equilibration.

Question 33

Describe what happens to the gas in the alveoli

Answer 33

Diffuses across the alveoli (remember that the alveoli is basically permeable to everything!). It will travel in the blood in its gaseous form (if it has a low blood:gas partition coefficient) and will then cross the BBB to exert its effects.

Question 34

Describe the onset of action for an anaesthetic with a high blood:gas partition coefficient

Answer 34

Often causes confusion – A highly soluble agent will dissolve in the blood very effectively. However, this means that the gas component (partial pressure) will be lower and it is this that determines the speed of brain penetration (not the total amount in the blood). Thus a poorly soluble agent will have a very rapid onset of action. Less will reach the brain.

Question 35

Why is the bi-directional relationship between the transfer of anaesthetic between different tissues important

Answer 35

It means that once you stop inhaling the anaesthetic, the concentration gradients (pressure gradients) reverse- and so the anaesthetic will move form the brain to be excreted via the lungs This process is rapid if the blood:gas partition coefficient is low.

Question 36

Summarise the pharmacokinetic properties of inhalational anaesthetics

Answer 36

Rapidly eliminated Good control of the depth of anaesthesia (due to quick removal and onset) o Inhaled agents pass from the air to the blood and to the brain so have an extra membrane to diffuse through.

Question 37

Summarise the pharmacokinetic properties of intravenous anaesthetics

Answer 37

Fast induction Less coughing/excitatory phenomena o The time the IV agent is active is dependent on the liver metabolism. o The IV agents are injected directly into the blood where they pass to the brain.

Question 38

Describe how we take advantage of the differing pharmacokinetic properties of IV. and inhalational anaesthetics in a clinical setting.

Answer 38

 Loss of consciousness. Induction – Propofol (IV). |  Suppression of reflex responses. Maintenance – Enflurane (inhalational). - because you get more control.

Question 39

How are the other desirable effects of general anaesthesia targeted

Answer 39

Relief of pain (analgesia)–Opioid (e.g. i.v. fentanyl) Muscle relaxation – Neuromuscular blocking drugs (e.g. suxamethonium Amnesia – Benzodiazepines (e.g. i.v. midazolam) This is why an anaesthetist must be very skilled- need to control a lot of different drugs.

Question 40

Describe the oil:gas partition coefficient

Answer 40

The oil:gas partition coefficient, a measure of fat solubility, determines the potency of an anaesthetic (as already discussed) and also influences the kinetics of its distribution in the body, the main effect being that high lipid solubility, by causing accumulation in body fat, delays recovery from anaesthesia Fat recieves a low cardiac output- so it will take a while for the GA to leave and enter the fat.