Principles of general anaesthesia Flashcards

1
Q

What is important to remember about general anaesthetics

A

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

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2
Q
  1. What are the five clinically desirable effects of general anaesthetics? State which two effects are caused by ALL general anaesthetics.
A

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

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3
Q

At what concentrations of local anaesthetics do you get:

a) loss of consciousness
b) Suppression of reflex responses

A

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.

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4
Q

Summarise the history of general anaesthesia

A

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)

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5
Q

What are the two broad types of general anaesthetics

A

Gaseous/Inhalational

Intravenous

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6
Q

Describe the structural relationship between the different anaesthetic agents

A

They are all dissimilar!

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

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7
Q

List the inhalational general anaesthetics

A

Nitrous Oxide

Diethyl Ether

Halothane

Enflurane

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8
Q

List the intravenous general anaesthetics

A

Propofol

Etomidate

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9
Q

How can we define what is meant by general anaesthesia

A

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’

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10
Q

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

A

o IV generally contain rings.

o Inhalational GAs generally have halogens.

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11
Q

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

A

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.

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12
Q

Describe the problems that arised regarding the Meyer/Overton correlation

A
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.
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13
Q

Describe the two real mechanisms for how general anaesthetics work

A

Reduced neuronal excitability or

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

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14
Q

What are GABAa receptors

A

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.

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15
Q

What do intravenous general anaesthetics target

A

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

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16
Q

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

A

B3- suppression of spinal responses

A5- amnesia.

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17
Q

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

A

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.

18
Q

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

A

Like I.V- potentiate the transmission at these receptors

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

19
Q

What are glycine receptors

A

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

20
Q

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

A

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

21
Q

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

A

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.

22
Q

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

A

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.

23
Q

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

A

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

24
Q

Summarise the normal sleep-wake cycle

A

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.

25
Q

Where do general anaesthetics that cause a loss of consciousness act

A

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.

26
Q

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

A

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.

27
Q

Describe how general anaesthetics can suppress spinal reflex responses

A

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.

28
Q

Describe how general anaesthetics can cause amnesia

A

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.

29
Q

Compare the properties of brain, blood and inhales air

A
Brain (=lipid)- bi-directional communication with blood (=water)
Inhaled air (=gas) - bi-directional communication with blood.
30
Q

What is meant by the blood:gas coefficient

A

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.

31
Q

Explain the importance of blood:gas coefficient for general anaesthesia

A

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).

32
Q

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

A

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.

33
Q

Describe what happens to the gas in the alveoli

A

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.

34
Q

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

A

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.

35
Q

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

A

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.

36
Q

Summarise the pharmacokinetic properties of inhalational anaesthetics

A

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.

37
Q

Summarise the pharmacokinetic properties of intravenous anaesthetics

A

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.

38
Q

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

A

 Loss of consciousness. Induction – Propofol (IV).

 Suppression of reflex responses. Maintenance – Enflurane (inhalational). - because you get more control.

39
Q

How are the other desirable effects of general anaesthesia targeted

A

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.

40
Q

Describe the oil:gas partition coefficient

A

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.