CPTP 3.23 Neuropharmacology 8 General anaesthetics Flashcards
Do local anaesthetics have a hydrophobic or a hydrophilic group?
Both. They are amphiphilic
One drug has a pKa of 7.9. Another has a pKa of 8.9. Which has more of its neutral form?
The drug with a pKa of 7.9 (which happens to be lidocaine)
pKa is dissociation constant, so higher number means more ionised form
How are general anaesthetics administered?
Systemically via:
• Inhalation (volatile anaesthetics)
• Injections (liquid anaesthetics)
What is the triad of anaesthesia?
The three things that is required of a general anaesthetic:
• Unconsciousness
• Analgesia
• Muscle relaxation
How is the triad of anaesthesia usually achieved?
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)
What are the three kinds of adjunct medications in surgery?
Premedication
• Medication given before surgery
Peri-operative
• Medication given during surgery
Post-operative
• Medication given after surgery
What are benzodiazepines used for in surgery?
- Presurgery anxiolysis for extremely stressed patients
* Presurgery amnesia to make them not remember ‘going under’
What are H2 blockers used for in surgery?
Give an example drug
To prevent gastric acid secretion in high-risk GORD (or pregnant) patients and prevent them breathing in gastric acid
Ranitidine
What are antimuscarinic drugs used for in surgery?
Give an example drug
Decrease salivary secretions and bradycardia during surgery
Atropine
Name the formulary neuromuscular blocking drugs and what they are used for
Suxamethonium and Atracurium
• Intubation
• Suppress muscle tone for fine surgery
What is the mechanism of action of suxamethonium?
Depolarising neuromuscular blocking drug
• Activates the acetylcholine receptor so much that it enters a state whereby it can no longer generate an EPSP
Describe the solubility of general anaesthetics
Lipid soluble
In general, how do general anaesthetics work?
Reducing neuronal activity in the CNS by decreasing excitatory activity and increasing inhibitory activity (in particular the reticular activating system)
What adverse effects can result from general anaesthetics?
There is a very fine line of a therapeutic window between sedation and:
• Cardiovascular depression
• Respiratory depression
What are the theories of the mechanisms of action of general anaesthetics?
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
Describe the lipid solubility theory of general anaesthetic mechanism of action
What observation supports this?
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
What evidence overturns the lipid solubility theory of general anaesthetics?
- 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
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?
Inhibited:
• NMDA
• 5-HT3
• Nicotinic
Potentiated:
• GABA-A
• Glycine
GABA-A is the most important receptor
How do general anaesthetics work on GABA-A receptors?
When anaesthetic is present, GABA is enhanced, and stays on the receptor for longer, thus allowing in more Cl- and hyper-polarising the cell
Which formulary general anaesthetics are inhaled?
- Nitrous Oxide
* Isoflurane
What causes loss of consciousness when inhaling nitrous oxide recreationally?
Oxygen starvation
What is nitrous oxide used for (with reference to the triad of anaesthesia)?
Good at pain relief
Poor at unconsciousness
Poor at neuromuscular suppression
Which formulary general anaesthetics are intravenously administered?
- Propofol
* Thiopental sodium
What are the stages of anaesthesia, as it anaesthesia is deepened?
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
How is stage 2 moved through as quickly as possible?
Induction of anaesthesia is done with an intravenous anaesthesia
How is anaesthesia administered during surgery? Explain why it is administered in this way.
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
What is level of anaesthesia correlated with when using inhaled anaesthetics?
The partial pressure of the volatile anaesthetic in brain tissue
What is the movement of an inhalation agent driven by?
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
What is a partition coefficient
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
What do partition coefficients affect?
- How rapidly the drug is absorbed
- Onset time
- Offset time
- Potency
What are the two main partition coefficients which are important?
blood/gas partition coefficient
• How soluble the substance is in blood
oil/gas partition coefficient
• How soluble the substance is in fats
What are the effects on pharmacodynamics if there is a higher solubility in blood (high blood/gas partition coefficient)?
Explain this effect
- 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
What are the effects on pharmacodynamics if there is a higher solubility in fats (high oil/gas partition coefficient)?
Explain this effect
• More potent general anaesthetic
This is because the general anaesthetic is held at the site of action in the lipid membrane (and its proteins)
What is the ‘potency’ of a general anaesthetic?
What is it measured in?
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.)
How can MAC values be used to increase potency while minimising side effects?
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
One anaesthetic has an oil:gas of 91, another has one of 53. What can we deduce?
The former has a higher potency.
One anaesthetic has a blood:gas of 1.4, another has one of 0.6. What can we deduce?
The former has a longer onset and offset.
Halothane has an oil:gas ratio of a very high 220. Why is it no longer used?
High oil:gas ratios will cause the drug to accumulate and sequester in lipid-bilayers, giving a very long GA hangover
How long do intravenous GAs last? Why?
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
How are GAs removed from the body?
Inhaled GAs are exhaled
Injected GAs are metabolised or excreted in urine
Which anaesthetic is a ‘total intravenous anaesthesia’? What does this mean?
Propofol
can be used alone for induction and maintenance of anaesthesia
Which anaesthetic used today gives a profound hangover? Why does it do this?
Thiopental sodium
It has a high oil:gas partition coefficient (is very lipophilic)
