Anaesthesia

Question 1

Outline the first anaesthetics used.

Answer 1

1540- ether
1776- nitrous oxide discovered by Priestley
1831- chloroform discovered
The discovery of anaesthetics paved the way for the advanced surgeries that are able to take place today.

Question 2

Describe how local and general anaesthetics differ.

Answer 2

Local anaesthetics can be given topically or administered directly and produce an anaesthetic effect by blocking nerve conductance which prevents the transmission of pain from a localised area.
General anaesthetics act on the brain to produce the loss of sensation. They affect synaptic transmission and neuronal excitability. They are made of small, lipid soluble molecules which are able to cross the BBB.

Question 3

Describe the route that anaesthetics take once entered the brain.

Answer 3

They travel from the spinal cord to the reticular system to the midbrain, hippocampus, thalamus and then finally to the cortex.

Question 4

What is reticular formation?

Answer 4

Runs through the central core of the brainstem with connections throughout cerebral hemispheres. It is made up of ascending and descending fibers. It plays a big role in filtering incoming stimuli to discriminate irrelevant background stimuli. The Reticular Activating System (RAS) is made up of the reticular formation and its widespread connections. It maintains consciousness and alertness and functions during sleep and arousal from sleep.

Question 5

What is the reticular activating system?

Answer 5

The Reticular Activating System (RAS) is made up of the reticular formation and its widespread connections which extend upwards into the nonspecific
nuclei of the thalamic sensory relay and
connects to hypothalamus, cerebellum
through to the cerebral cortex.

Question 6

What is the main function of the reticular activating system?

Answer 6

It maintains consciousness and alertness and functions during sleep and arousal from sleep. Therefore by inhibiting this pathway as general anaesthetics do, they reduce the level of consciousness and provides analgesia.

Question 7

What is amnesia and why does it occur with the administration of anaesthetic?

Answer 7

Amnesia means memory loss and it occurs with the administration of analgesia as a result of hippocampal inhibition.

Question 8

Do anaesthetics target one particular part of the brain?

Answer 8

No it is not one particular site in the brain which is affected by anaesthetic. Instead it is the progression loss of nerve conductance from the reticular formation projecting to the thalamic sensory relay, to the hippocampus, midbrain and cerebral cortex.

Question 9

What functions are affected by anaesthesia?

Answer 9

Motor control
Reflex activity
Respiration
Autonomic regulation

Question 10

How do different stages of anaesthesia occur?

Answer 10

Different stages of anaesthesia occur as because the concentration of anesthesia increase this increases the extent of neuronal depression resulting in inhibition of different functions.

Question 11

Describe what effects are seen in Stage I anaesthesia.

Answer 11

Analgesia
This is due to mild depression of the cortical hormones. This can be used for some minor surgeries.

Question 11

Describe what effects are seen in Stage II anaesthesia.

Answer 11

Delirium
Depression of inhibitory neurons in the CNS progresses especially within the reticular formation. There is excitation of cortical motor neurons which results in involuntary movements - there is an increase in muscle tone.

Question 12

Describe what effects are seen in Stage III anaesthesia.

Answer 12

Surgical anaesthesia
This is divided into four planes with:
Gradual loss of thoracic respiration
Loss of muscle tone
Loss of laryngeal and pharyngeal reflexes
Eye movements

Question 13

What occurs in Stage IV anaesthesia?

Answer 13

Death
This is due to overdose of the anaesthesia causing respiratory and circulatory paralysis.
With no cardiac output this causes death

Question 14

Recap by outlining the main effects of general anaesthesia.

Answer 14

Loss of memory
Loss of motor reflexes
Loss of response to painful stimuli
Changes in CV and respiratory physiology

Question 15

What is the concentration range of loss of conscious with general anaesthetics?

Answer 15

0.2 of a log unit
This is a remarkable difference from agonist/antagonist activity at normal receptors

Question 16

How are general anaesthetics administered at induction and at maintenance?

Answer 16

At induction by intravenous administration
At maintenance by inhalation administration

Question 17

Give some examples of anaesthetics administered at induction.

Answer 17

Ketamine
Thiopental (older drug, less commonly used)
Propofol
Etomidate

Question 18

Give some examples of anaesthetics administered at maintenance.

Answer 18

Halothane
Nitrous oxide
Isoflurane
Sevoflurane
Desflurane

Question 19

What are the ideal properties of a general anaesthetic?

Answer 19

Should be readily controllable to ensure the induction and recovery is rapid, so they can be put under and brought out very quickly by adjusting the levels.

Question 20

How quickly do anaesthetics induce consciousness?

Answer 20

Within seconds of reaching the brain

Question 21

Using the example of Thiopental, describe the redistribution of general anaesthetics across the different compartments of the body.

Answer 21

Different components include:
Blood, in which the general anaesthetic is administered directly into
Brain, heart, viscera, lungs which together compose of 2/3 of the cardiac output
Muscle and skin, composing of 1/3 of cardiac output
Fat which forms 2% of the cardiac output

Upon administering the anaesthetic the blood concentration quickly depletes and within 0.5-1 minute the concentration is highest within the brain/viscera as they have the highest cardiac output with blood distribution occurring within seconds. At the same time a much lower concentrations is found within the muscle and skin and none at all within the fat. Gradually there is redistribution at a time period of about an hour after administration, concentration within lean muscles peaks at a much higher concentration, amount within brain/viscera has gradually reduced to a much lower level, whilst concentration within fat stores are increasing. At a terminal time period the concentration of anaesthetic within fat stores are the highest with a lower concentration within lean muscles and none within the brain/viscera.

Question 22

Why does a hangover period occur with Thiopental?

Answer 22

Due to awaiting deposition into the fat stores before elimination can occur this is known as a ‘hangover period’.

Question 23

Aside from the hangover period what is the other disadvantage with use of Thiopental?

Answer 23

Thiopental has saturation kinetics meaning that large and repeated doses of the drug accumulate causing a plateau concentration as metabolism is saturated.

Question 24

What are the advantages of using Propofol?

Answer 24

Although sadly responsible for causing Michael Jackson’s death in 2009, Propofol displays a lot of advantageous properties in comparison to Thiopental for use as a general anaesthetic for induction.
It has a rapid onset but also rapid redistribution and therefore the ‘hangover’ period seen with Thiopental is not experienced with this drug especially as it also has a rapid metabolism so doesn’t have the same cumulative effect.
Displays first order kinetics so is a linear process with the rate of elimination proportional to the concentration of drug.
Can be used for day case surgery.

Question 25

In which way does Ketamine work in comparison to Thiopental and Propofol?

Answer 25

Increases heart rate and blood pressure but has no effect on respiration

Question 26

What are some of the advantages of using Ketamine?

Answer 26

Can be used in third world countries where surgery needs to be performed, as it is administered IM.
It is a powerful analgesic

Question 27

What are the disadvantages of using Ketamine?

Answer 27

1-2 minutes of onset rather than seconds
Has side effects including increasing the intracranial pressure, hallucinations and delirium

Question 28

Why are maintenance anaesthetics administered through inhalation?

Answer 28

Maintenance of anaesthetics are given through inhalation as through their pharmacokinetics they fulfil the criteria of:
Being readily controllable so induction and recovery are controllable.

Question 29

Describe the equilibration events that are required in order for inhaled anaesthetics to exert an effect.

Answer 29

Through inhalation there is deposition of anaesthetics within the alveoli. This is the first equilibration from the alveoli which is highly vascularised into the bloodstream. Small and lipophilic molecules are readily able to cross the alveoli into the bloodstream.
Ideally this partitioning should occur rapidly in order to maintain concentration of anaesthetic within the arterial bloodstream which then mirrors the concentration within the brain. Therefore the kinetics within the bloodstream determine the pharmacological effect. The arterial blood must become saturated before the slow equilibration of anaesthesia can occur into tissues.

Question 30

Explain how low soluble drugs have a faster rate of reaching equilibrium.

Answer 30

With increasing breaths with low soluble anaesthetics, there is an increase in drug accumulation within the alveoli due to the poor absorption into the bloodstream.
With drugs that are highly soluble there is a lack of accumulation within the alveoli. With each breath a greater proportion of the drug is absorbed into the bloodstream. This means it takes longer for the drug to accumulate within the alveoli to a point of reaching equilibrium as a low partial pressure remains.

Question 31

Which induction anaesthetics have poor solubility?

Answer 31

Nitrous oxide

Question 32

Which induction anaesthetics have a high solubility?

Answer 32

Halothane
Ether

Question 33

What is the blood:gas co-efficient?

Answer 33

Essential the principal that has just been described is an important determinant of the speed of anesthetic induction and recovery. It describes the partition of an agent between a gaseous phase, such as alveolar air, and the blood. The greater the blood:gas partition coefficient, the greater the solubility in blood and therefore it takes longer for equilibrium to be reached, whereas drugs that have a low blood gas co-efficient they have a lower solubility in the blood and equilibrium can be reached much quicker.

Question 34

What is the blood:gas co-efficient of the maintenance anaesthetics?

Answer 34

Nitrous oxide 0.5
Halothane 2.4
Ether 12
Methoxyflurane 13

Question 35

What is the oil:gas co-efficient?

Answer 35

This time it describes the partition of an agent in fat compared to air which is determined by the lipid solubility of the anaesthetic agent. The oil:gas partition coefficient has been correlated to anesthetic potency – the higher the coefficient, the more potent the agent.

Question 36

What are some of the factors that affect the rate of equilibration of anaesthetic?

Answer 36

Ventilation rate affects the concentration of anaesthetic
The rate of perfusion - for examples within lean tissue there is a fast rate of perfusion whereas in fat where is a much more slower rate of diffusion.
In lean tissue there is a small partition co-efficient whereas this is large in fat.
This ultimately means rapid equilibration occurs within the lean tissue whereas in fat this is much slower - any drastic changes in arterial blood concentration of anaesthetic has very limited effects on the concentration within the fat.

Question 37

What is the oil: gas co-efficient for Nitrous oxide, Halothane and ether, what affect does this has on the recovery period?

Answer 37

Nitrous oxide 1.4, Blood gas is 0.5 - fast
Halothane 220, Blood gas is 2.4 - medium
Ether 65, Blood gas is 12 - slow

Question 38

How does the weight of the patient influence the choice of the anaesthetic used?

Answer 38

In a patient with a higher proportion of body fat, there will be greater distribution into the fat and the slower the recovery. Particularly within a very long surgery this will result in a very long hangover period.

Question 39

What is balanced anaesthesia?

Answer 39

Describes the array of drugs used during surgery:
* Sedative premedication e.g. benzodiazepine
* Intravenous anaesthetic for rapid induction e.g. propofol
* Inhalation anaesthetics e.g. nitrous oxide and isoflurane
* Muscarinic antagonist to reduce bronchial and salivary secretions e.g.
atropine
* Analgesia for pain relief at the end of surgery e.g. morphine

Question 40

What are the physiological factors which determine the induction
and recovery of inhalation anaesthesia?

Answer 40

1. Alveolar ventilation rate: the greater the minute volume i.e. the amount of air that the patient breaths in 1 minute (tidal volume x respiratory rate) the faster the equilibration
2. Cardiac output: reduction of alveolar perfusion reduces alveolar absorption of the anaesthetic so speeds up induction. However this has to balanced with the reduced cerebral blood flow and delivery of the drug to the brain.

Question 41

What is the minimal alveolar concentration?

Answer 41

Minimal alveolar concentration (MAC) required to abolish the response to surgical incision in 50% of subjects. The partial pressure in the alveoli is equal to that within the brain; the concentration within the brain most closely mimics the concentration at the site responsible for the anaesthetic action - therefore the MAC is often used as a measure of the potency of anaesthetic agents.

Question 42

What did Overton and Meyer find?

Answer 42

Overton and Meyer 1937 showed a correlation between MAC and the lipid solubility of the drug i.e. the oil : gas coefficient - can be plotted on a graph positive correlation between oil:gas co-efficient and MAC.

Question 43

Which targets could be responsible for anaesthesia?

Answer 43

1. GABAA receptors: increase activity
2. Glutamate receptors: decrease in activity e.g. ketamine blocks NDMA receptors
3. Voltage-gated sodium, potassium and calcium channels

Question 44

Where do anaesthetics bind in GABA?

Answer 44

GABAA receptors which are formed of 5 different subunits bind to hydrophobic pockets within the receptors

Question 45

How did scientists try and go about trying to work out the anaesthetic binding sites within GABAA receptors?

Answer 45

Essentially mutated specific regions of the transmembrane domains and then measured the percentage potentiation of anaesthetics in the presence and absence of these mutations.
Examples included:
Serine 270 - affected Isoflurane responses
B3N265 - affected Propofol response

Question 46

Which anaesthetics work at the Glutamate receptor?

Answer 46

Nitrous oxide
Xenon
Isoflurane

Question 47

Mutations where in the glutamate receptor altered the response to anaesthetics?

Answer 47

Mutation in membrane domain 3 and 4 specifically NR1 F639 reduce alcohol-induced inhibition of these
receptors i.e. xenon and isoflurane.

Nitrous oxide blocks the channel pore; ketamine is a selective antagonist (Potentially noncompetitive and possibly allosteric mechanism of action)

Question 48

What are two pore domain channels responsible for?

Answer 48

Two pore domain K channels: from a family of ‘background K+ channels which
modulate neuronal excitability - act to regulate membrane potential (leak channels)

Question 49

Which subunits do two pore domain channels consist of?

Answer 49

Consist of TREK1, TREK2, TASK1, TASK3 or TRESK subunits

Question 50

What was the effect of TASK3 M159 mutation?

Answer 50

Reduction in the response to halothane - this is where it reacts.

Question 51

Where are nicotinic receptors found?

Answer 51

At the neuromuscular junction, at the somatic efferent nervous system with alpha motor neurons releasing acetylcholine which then acts at nicotinic acetylcholine receptors causing the contraction of skeletal muscle.

Nicotinic receptors are also found at the autonomic ganglion in the sympathetic and parasympathetic nervous system and at the adrenal medulla.

Nicotinic receptors are also found in the central nervous system pre-synaptically.

Question 52

What are the three main sub-types of nicotinic receptors?

Answer 52

• Muscle
• Ganglionic
• CNS
• Differing location, structure and pharmacology

Question 53

What are the similarities and differences between the three different types of nicotinic receptors?

Answer 53

They have different locations, structures and pharmacology however they are all ligand gated cation channels, when activated by acetylcholine this produces a fast excitatory response.
Nicotine is an agonist at this receptor mimicking the action of acetylcholine - nicotine won’t stimulate muscarinic receptors.

Question 54

Describe the structure of the nicotinic receptors.

Answer 54

Pentameric structure - made of 5 subunits and there are five different types which is alpha, beta, delta, gamma and epsilon.
Different receptors are made of different combinations of subunits - however all contain 2 alpha subunits and the binding pocket is located here next to the adjacent subunit.

Question 55

Describe the structure of the alpha subunit.

Answer 55

The alpha subunit is composed of four transmembrane domains M1-M4. M2 lines the central pore and due to the presence of negative amino acids this creates a negative charge lining the central pore, only allowing positive ions such as sodium to enter causing depolarisation and then an action potential inducing skeletal muscle contraction.

Question 56

Are nicotinic agonists selective or non-selective?

Answer 56

Most are non-selective for example acetylcholine and nicotine, although they may have a preference.
An example of a selective agonist such as Suxamethonium which is selective for the muscle nicotinic acetylcholine receptors.

Question 57

What are the two mechanisms in which drugs can inhibit the transmission at the neuromuscular junction?

Answer 57

Either by competitive inhibition of the nicotinic receptor (nicotinic acetylcholine antagonists). e.g. Tubocurarine causing a non-depolarising block

Or by a depolarising block by nicotinic receptor agonists.

Question 58

Describe the mechanism of non-depolarising block.

Answer 58

Non-depolarising block is caused by competitive antagonists. An example of this includes Tubocurarine which acts as antagonist at nicotinic receptors at the neuromuscular junction.
Without the presence of Tubocurarine the action potential both at and away from the end plate is present and above threshold meaning that the action potential has been propagated. However when Tubocurarine is present and the alpha motor neuron is stimulated, there is a small depolarisation at the end plate but is not sufficient to cause an action potential, therefore when it is assessed away from end plate no action potential has not been propagated and therefore skeletal muscle contraction will not occur.

Question 59

How can the effect of Tubocurarine be overcome?

Answer 59

It is a competitive agonist and therefore by increasing the concentration of acetylcholine this can overcome the neuromuscular block.

Question 60

How do depolarising agents work?

Answer 60

Depolarizing blocking agents work by depolarizing the plasma membrane of the muscle fiber, similar to acetylcholine. However, these agents are more resistant to degradation by acetylcholinesterase, the enzyme responsible for degrading acetylcholine, and can thus more persistently depolarize the muscle fibers. Voltage gated sodium channels once depolarised are unable to become activated again until hyperpolarisation has occurred and therefore remain in the inactivated state.

Question 61

What are some examples of depolarising muscle relaxants?

Answer 61

Nicotine
ACh (in the presence of cholinesterase inhibitors)
Suxamethonium

Question 62

Are depolarising muscle relaxants competitive or non competitive?

Answer 62

Non-competitive and therefore adding more agonist will only exacerbate this effect.

Question 63

What is phase II depolarising block?

Answer 63

Persistent stimulation leads on to “Phase II
block” due to desensitization of the nAChRs
Repolarization, but still cannot be stimulated due to the desensitisation of the acetylcholine nicotinic receptors.

Question 64

Why is Tubocurarine no longer used clinically?

Answer 64

Due to its side effect profile:
Caused severe hypotension, block the sympathetic ganglion
Release of histamine - unrelated mechanism

Question 65

Which non-depolarising agents are used now during surgery?

Answer 65

Under general anaesthesia patients will be given muscle relaxants to prevent them moving during the surgery, different ones are used depending on the type of surgery but can include:
Pancuronium - long duration of action ( ̴1 hour)
Vencuronium - intermediate duration of action
Atracurium - intermediate duration of action
Mivacurium - short duration of action (15 minutes)

Question 66

What are one of the signs of depolarising muscle agents?

Answer 66

Initially they cause muscle twitching known as fasciculations due to acting as an agonist at the nicotinic receptor and then this is followed by a neuromuscular block caused by the depolarisation of the muscle cells.

Question 67

When is Suxamethomium used?

Answer 67

If fast, brief neuromuscular block is required eg. tracheal intubation prior to surgery. It is very short acting as is hydrolysed by plasma cholinesterases.

Question 68

When should Suxamethomium use be cautioned?

Answer 68

Prolonged paralysis is a potential side effect in neonates, patients with liver disease due to accumulation or genetic variants lacking cholinesterase activity.