CPTP 3.23 Neuropharmacology 8 General anaesthetics

Question 1

Do local anaesthetics have a hydrophobic or a hydrophilic group?

Answer 1

Both. They are amphiphilic

Question 2

One drug has a pKa of 7.9. Another has a pKa of 8.9. Which has more of its neutral form?

Answer 2

The drug with a pKa of 7.9 (which happens to be lidocaine)

pKa is dissociation constant, so higher number means more ionised form

Question 3

How are general anaesthetics administered?

Answer 3

Systemically via:
• Inhalation (volatile anaesthetics)
• Injections (liquid anaesthetics)

Question 4

What is the triad of anaesthesia?

Answer 4

The three things that is required of a general anaesthetic:
• Unconsciousness
• Analgesia
• Muscle relaxation

Question 5

How is the triad of anaesthesia usually achieved?

Answer 5

No agent provides all three so is achieved by using combinations of drugs and adjunct medicines. Depends on the surgery needed (i.e. intubation needs lots of relaxation)

Question 6

What are the three kinds of adjunct medications in surgery?

Answer 6

Premedication
• Medication given before surgery

Peri-operative
• Medication given during surgery

Post-operative
• Medication given after surgery

Question 7

What are benzodiazepines used for in surgery?

Answer 7

• Presurgery anxiolysis for extremely stressed patients

* Presurgery amnesia to make them not remember ‘going under’

Question 8

What are H2 blockers used for in surgery?

Give an example drug

Answer 8

To prevent gastric acid secretion in high-risk GORD (or pregnant) patients and prevent them breathing in gastric acid

Ranitidine

Question 9

What are antimuscarinic drugs used for in surgery?

Give an example drug

Answer 9

Decrease salivary secretions and bradycardia during surgery

Atropine

Question 10

Name the formulary neuromuscular blocking drugs and what they are used for

Answer 10

Suxamethonium and Atracurium
• Intubation
• Suppress muscle tone for fine surgery

Question 11

What is the mechanism of action of suxamethonium?

Answer 11

Depolarising neuromuscular blocking drug

• Activates the acetylcholine receptor so much that it enters a state whereby it can no longer generate an EPSP

Question 12

Describe the solubility of general anaesthetics

Answer 12

Lipid soluble

Question 13

In general, how do general anaesthetics work?

Answer 13

Reducing neuronal activity in the CNS by decreasing excitatory activity and increasing inhibitory activity (in particular the reticular activating system)

Question 14

What adverse effects can result from general anaesthetics?

Answer 14

There is a very fine line of a therapeutic window between sedation and:
• Cardiovascular depression
• Respiratory depression

Question 15

What are the theories of the mechanisms of action of general anaesthetics?

Answer 15

Physicochemical theory
• Lipid solubility theory - anaesthetic effect is exerter through some perturbation of the lipid bilayer

Structural theory
• Anaesthetic effect is exerted through interactions with proteins

Question 16

Describe the lipid solubility theory of general anaesthetic mechanism of action

What observation supports this?

Answer 16

Anaesthesia results when a sufficient amount of anaesthetic dissolves in the lipid bilayer to perturb the physical properties of that layer, altering the excitability of proteins within it.

The Meyer-Overton Rule:
• General anaesthetics which are more soluble in lipids are more potent

Question 17

What evidence overturns the lipid solubility theory of general anaesthetics?

Answer 17

• Not all small lipid-soluble molecules are general anaesthetics
  
  • Not all general anaesthetics are small lipid-soluble molecules
  • Stereoisomers of existing anaesthetics do not work as general anaesthetics

Question 18

Which proteins are interacted with in the structural theory of general anaesthetics?

Which of these is the ‘most important’ protein, which all anaesthetics are thought to work on?

Answer 18

Inhibited:
• NMDA
• 5-HT3
• Nicotinic

Potentiated:
• GABA-A
• Glycine

GABA-A is the most important receptor

Question 19

How do general anaesthetics work on GABA-A receptors?

Answer 19

When anaesthetic is present, GABA is enhanced, and stays on the receptor for longer, thus allowing in more Cl- and hyper-polarising the cell

Question 20

Which formulary general anaesthetics are inhaled?

Answer 20

• Nitrous Oxide

* Isoflurane

Question 21

What causes loss of consciousness when inhaling nitrous oxide recreationally?

Answer 21

Oxygen starvation

Question 22

What is nitrous oxide used for (with reference to the triad of anaesthesia)?

Answer 22

Good at pain relief

Poor at unconsciousness

Poor at neuromuscular suppression

Question 23

Which formulary general anaesthetics are intravenously administered?

Answer 23

• Propofol

* Thiopental sodium

Question 24

What are the stages of anaesthesia, as it anaesthesia is deepened?

Answer 24

Stage 1: Analgesia
  •  Amnesia
  •  Analgesia
  •  Euphoria
Stage 2: Excitement
  •  Excitement
  •  Delirium
  •  Combative
Stage 3: Surgical anaesthesia 
  •  Unconsciousness
  •  Regular respiration
Stage 4: Medullary depression (side effects)
  •  Too far
  •  Respiratory arrest
  •  Cardiac arrest
  •  No eye movement

Question 25

How is stage 2 moved through as quickly as possible?

Answer 25

Induction of anaesthesia is done with an intravenous anaesthesia

Question 26

How is anaesthesia administered during surgery? Explain why it is administered in this way.

Answer 26

At the start of surgery: intravenous
• Ensures stages I and II are passed as quickly as possible

During surgery: inhalation
• Maintains the patient steadily in stage III
• This is achieved through a self-regulating negative feedback, whereby too much anaesthesia will depress breathing, reducing the anaesthetic administered

Question 27

What is level of anaesthesia correlated with when using inhaled anaesthetics?

Answer 27

The partial pressure of the volatile anaesthetic in brain tissue

Question 28

What is the movement of an inhalation agent driven by?

Answer 28

The partial pressure gradients:
• The pressure generated by a compartment is affected by the partition coefficient of the volatile anaesthetic in blood and body tissue

Question 29

What is a partition coefficient

Answer 29

A coefficient that represents the solubility of volatiles in different media, and thus the AMOUNT of anaesthetic in each compartment in equilibrium (the only thing that is evened out is the pressure)

e.g. the blood/gas coefficient is the ratio of the amount of anaesthetic dissolved in blood to the amount of the same volume of gas in contact with that blood
• ‘2’ would imply twice the anaesthetic dissolved in blood compared to the amount in alveoli

Question 30

What do partition coefficients affect?

Answer 30

• How rapidly the drug is absorbed
  
  • Onset time
  • Offset time
  • Potency

Question 31

What are the two main partition coefficients which are important?

Answer 31

blood/gas partition coefficient
• How soluble the substance is in blood

oil/gas partition coefficient
• How soluble the substance is in fats

Question 32

What are the effects on pharmacodynamics if there is a higher solubility in blood (high blood/gas partition coefficient)?

Explain this effect

Answer 32

• Slow induction
  
  • Slow recovery
  • Slow adjustment of depth of anaesthesia

This is because the blood acts as a reservoir for the drug and so doesn’t enter the brain until saturation is reached

Question 33

What are the effects on pharmacodynamics if there is a higher solubility in fats (high oil/gas partition coefficient)?

Explain this effect

Answer 33

• More potent general anaesthetic

This is because the general anaesthetic is held at the site of action in the lipid membrane (and its proteins)

Question 34

What is the ‘potency’ of a general anaesthetic?

What is it measured in?

Answer 34

The percentage of anaesthetic in lungs that abolishes a movement response in 50% of patients to a surgical incision (kind of like EC50 but for gaseous anaesthetics)

MAC - Median alveolar concentration (sometimes incorrectly called minimum alveolar conc.)

Question 35

How can MAC values be used to increase potency while minimising side effects?

Answer 35

MAC values are additive, and so anaesthetics can be used together at lower concentrations to have a higher aggregate concentration but themselves having low concentrations with no individual toxicity

Question 36

One anaesthetic has an oil:gas of 91, another has one of 53. What can we deduce?

Answer 36

The former has a higher potency.

Question 37

One anaesthetic has a blood:gas of 1.4, another has one of 0.6. What can we deduce?

Answer 37

The former has a longer onset and offset.

Question 38

Halothane has an oil:gas ratio of a very high 220. Why is it no longer used?

Answer 38

High oil:gas ratios will cause the drug to accumulate and sequester in lipid-bilayers, giving a very long GA hangover

Question 39

How long do intravenous GAs last? Why?

Answer 39

No longer than 15mins (which is why they are used for putting people under then inhaled GAs take over)

Due to ‘REDISTRIBUTION’:
• Intravenous GA reaches the highly-perfused tissues first (i.e. the brain)
• It then redistributes to other tissues in the order of highly to lowly perfused tissues (i.e. muscle, until eventually adipose)
• These tissues take up drug from where the drug already is (brain and blood) slowly

IMG 23

Question 40

How are GAs removed from the body?

Answer 40

Inhaled GAs are exhaled

Injected GAs are metabolised or excreted in urine

Question 41

Which anaesthetic is a ‘total intravenous anaesthesia’? What does this mean?

Answer 41

Propofol

can be used alone for induction and maintenance of anaesthesia

Question 42

Which anaesthetic used today gives a profound hangover? Why does it do this?

Answer 42

Thiopental sodium

It has a high oil:gas partition coefficient (is very lipophilic)