[UMP021] Pharmacology Of General Anaesthesia

Question 1

How is general anaesthesia often defined?

Answer 1

As a drug-induced reversible loss of consciousness

How do you define consciousness? In some form or other a lack of responsiveness is often taken as the measure of anaesthesia
- eg “can u open ur eyes”, or lack of responsiveness to a painful stimulus

Question 2

What measure is the relative effectiveness of general anaesthetic often compared by?

Answer 2

ED₅₀

Question 3

What is ED₅₀

Answer 3

The dose (or concentrations) that is effective in 50% of the population being tested
= dose/ concentration which, on average, is effective in putting 50% of a population to sleep

Question 4

How is potency in the field of anaesthesia defined

Answer 4

Reciprocal of ED₅₀
Ie (1/ED₅₀)

When you need high concentration of drug, drug is not very potent

Question 5

General anaesthetic are usually split into two classes of agent. What are these classes?

Answer 5

Intravenous agents and inhalational agents

Question 6

Pros n cons of inhalational anaesthetic agents

Answer 6

Pros:
- possible to very precisely control concentration of anaesthetic the patient equilibrates with, by altering partial pressure of anaesthetic agent in ‘air’ —> makes anaesthesia relatively safe, despite narrow safety margin

Cons:
- for some inhalational agents, takes q awhile for individuals to reach unconsciousness (not v helpful esp if patients nervous)

Question 7

Pros n cons of intravenous anaesthetic agents

Answer 7

Pros:
- able to render patients unconscious quickly

Cons:
- often more difficult to control (so they have not, traditionally been sued to maintain anaesthesia)

Question 8

What are inhalational anaesthetic agents usually used for

Answer 8

Used to maintain anaesthesia during long operations

Question 9

Give examples of intravenous anaesthetic agents

Answer 9

• propofol
• etomidate
• Thiopentone

Question 10

What is the mechanism of action for intravenous agents propofol, etomidate and thiopentone

Answer 10

Enhancement of GABA_A

• enhance at relatively Low and hence clinically relevant concentrations
• ## etomidate enhancement of GABA_A is stereoselective ( + isomer more potent than -)

Question 11

Examples of inhalational anaesthetic agents

Answer 11

Desflurane, isoflurane, sevoflurane (they are often combined with nitrous oxide)

Older anaesthetics include Halothane, enflurane (these are less widely used)

Question 12

Mechanism of action for volatile agents halothane, enflurane and isoflurane

Answer 12

• able to enhance GABA_A receptor activity at clinically relevant concentrations like intravenous agents
  However this activation is less than that w intravenous, and their mechanism of action less certain
• most likely target more than one protein type
• all three of these agents also able to enhance activity of glycine receptors at clinically relevant conc

Question 13

Which anaesthetic gases activate the potassium channel TREK-1 at clinically relevant concentration

Answer 13

Nitrous oxide,
Cyclopropane
Xenon

Question 14

Mechanism of action of nitrous oxide, cyclopropane and xenon

Answer 14

These anaesthetic gases do not appear to activate GABA_A receptors

• all three do activate potassium channel TREK-1 at clinically relevant concentrations
• nitrous oxide and xenon also able to inhibit NMDA receptors at clinically relevant conc

Question 15

Benefits of xenon
And why is it not used more widely?

Answer 15

Benefits:
- Low blood solubility = anaesthesia can be induced rapidly
- lacks vasodilatation effects compared to other agents
- Low toxicity
- several studies have shown that it may protect neuronal cells against ischaemic injury

Limitations: cost and limited availability of this gas

Question 16

What does ‘dissociative anaesthesia’ mean?

Answer 16

Meaning that in addition to analgesia,
There’s
- marked sensory loss
- amnesia
- paralysis
BUT WITHOUT LOSS OF CONSCIOUSNESS

Question 17

Which drug produces profound analgesia, but ‘dissociative anaesthesia ‘

Answer 17

Ketamine

Question 18

Ketamine’s theorised mechanism of action target

Answer 18

May also target NMDA receptors and this may account for its neuroprotective effects

Question 19

Conventional stages of anaesthesia, which are somewhat arbitrary

Answer 19

Stage I: analgesia. Still conscious but becoming insensitive to pain (not all generate anaesthetic agents are good analgesics)

Stage II: excitement. Delirium and excitement. Respiration irregular

Stage III: surgical anaesthesia. Unconscious. Respiration and reflexes progressively depressed as anaesthesia deepens

Stage IV: medullary compression. No spontaneous respiration and depressed vasomotor centres. Coma and death follow in absence of artificial respiration and circulatory support

Question 20

How is the potency for inhalational anaesthetics commonly expresssed as

Answer 20

Minimum alveolar concentration (MAC)

• despite its name, it is an eD50 thiiugh expressed as conc in air, not blood

Question 21

Minimum alveolar concentration (MAC)
What is it

Answer 21

Alveolar concentration (% by volume) of inhalational anaesthetic which will, when equilibrium has been attained, prevent movement response to surgical incision in 50% of individuals

Question 22

What is the relationship between solubility of anaesthetic agents and rate at which anaesthetics are absorbed

Answer 22

Rate at which anaesthetic are absorbed is faster for less-soluble agents

Question 23

Why do less soluble anaesthetic agents get absorbed faster

Answer 23

Less-soluble agents like nitrous oxide have a larger MAC
Concentration in inspired air therefore much higher, so amount of anaesthetic required to produce effective blood concentrations can be delivered faster

With a soluble agent like halothane or methoxyflurane, MAC Low
So amount present in lungs Low, even if all were extracted into blood, would not be enough to raise blood concentration very much at each inspiration

Question 24

Solubility of inhalational anaesthetics and relationship with rate of elimination after stopping administration

Answer 24

Elimination after stopping administration is faster for anaesthetics with Low solubility eg nitrous oxide
(Slower for halothane or methoxyflurane)

Answer 25

Fat not well perfumed

Question 26

Factors influencing how quickly the inhaled anaesthetic gets to brain to produce unconsciousness

Answer 26

1. Concentration in inspired air
2. Rate and depth of breathing
3. Permeability of alveolar capillary membrane (high)
4. Blood flow through lungs (variable)
5. Solubility of drug in blood (= blood/ gas partition coefficient)
6. Blood flow to brain (high)
7. Partition coefficient between brain and blood of drug (high)

Question 27

Ideally, a general anaesthetic should have _____ MAC and _____(high/Low?) blood solubility?

Answer 27

Low MAC (high potency)
Low blood solubility (rapid onset and offset)

Question 28

Blood flow through fat is slow. What are the implications of this for anaesthetics

Answer 28

Equilibrium of fat very slow
Recovery slower in obese patients
Prolonged hangover effect

Question 29

Thiopentone (IV administered)
Thiopentone is often called “short-acting” although it is not really short acting at all; is metabolise daytime slowly in liver

So why is thiopentone called ‘short-acting’

Answer 29

The redistribution of thiopentone that reduces its once traction at active sites and leads to short-acting nature of this drug

Question 30

What intravenous anaesthetics are used for induction of anaesthesia

Answer 30

1. ‘Short- acting’ barbiturates eg thiopentone (not an analgesic, respiratory depression)
2. Propofol (has now largely replaced thiopentone. ADVANTAGES; rapid recovery, no hangover
3. Etomidate (similar uses to propofol)

Question 31

Use of intravenous anaesthetics for total intravenous anaesthesia

Answer 31

Propofol
- quite rapidly metabolised —> little accumulation

Disadvantages
- irritant at site of injection, hence development of fospropofol (a prodrug for propofol and less of an irritant