General Anaesthetics

Question 1

state the 3 aims of general anaesthesia

Answer 1

1) Loss of consciousness (=hypnosis) linked to amnesia
2) Analgesia
3) Muscle relaxation (immobility)

Question 2

General anaesthetics represent a range of drug classes from gases (e.g. nitrous oxide), halogenated hydrocarbons (e.g. isoflurane) and barbiturates (e.g. thiopental). it was thought that these drugs worked by integrating into the plasma membrane (lipid theory). why was this theory wrong?

Answer 2

the lipid theory is a little too simplistic to account for General anaesthetic effects and molecular drug targets (ion channels and receptors) are now known and accepted

Question 3

Anaesthetic effect is measured in terms of Minimum alveolar concentration (MAC). what is MAC?

Answer 3

1) the concentration of the vapour in the lungs that is needed to prevent movement in 50% of subjects in response to pain stimulus
2) MAC is inversely proportional to potency; thus, a lower MAC value represents a more potent volatile anesthetic

Question 4

outline the actions of general anaesthetic on the CNS

Answer 4

1) CNS: At a cellular level, general anaesthetics act mainly to inhibit synaptic transmission (rather than affect axonal conductance)
- they inhibit excitatory ion channels such as glutamate and acetylcholine ionotropic receptors
- Activate inhibitory ion channels such as GABAa (and glycine) ionotropic receptors and two-pore potassium channels
(i. e general anaesthetics act to reduce excitation or increase inhibition)

Question 5

outline the actions of general anaesthetic at a higher level in the CNS

Answer 5

At a higher level, general anaesthetics act at:

1) Midbrain reticular formation (unconsciousness) and thalamic sensory relay nuclei (analgesia).
- some general anaesthetics e.g. flunitrazepam (Rohypnol) may also act on hippocampus to affect short-term memory (amnesia)
2) Spinal level to cause loss of reflexes (contributes to control of motor function = muscle relaxation)

Question 6

outline the actions of general anaesthetic on the Peripheral nervous system:

• Cardiovascular
• Respiratory
• Muscular

Answer 6

1) Cardiovascular: In general, cause circulatory depression by decreasing cardiac contractility. some general anaesthetics also act on autonomic sympathetic nervous system and/or vascular smooth muscle to affect cardiac output, blood pressure etc.
2) Respiratory: In general, general anaesthetics cause profound respiratory depression.
3) Muscular: General anaesthetic action at the neuromuscular junction (NMJ) causes muscle relaxation

Question 7

list the 5 stages of general anaesthesia

Answer 7

1) Premedication
2) Induction
3) Maintenance
4) Pain relief
5) Muscle relaxation

Question 8

describe the premedication stage of general; anaesthesia and outline its purpose

Answer 8

1) combined drug treatment, typically 1-3 hours prior to anaesthesia
2) Purpose:
- Reduction of anxiety and pain
- Promotion of amnesia
- Reduction of secretions
- Enhancing the hypnotic effects of general anaesthesia
- Reduction of vagal reflexes to intubation
- Reduction of postoperative nausea and vomiting

Question 9

Below is a list of drug classes that can be used in the premedication stage of general anaesthesia. what is the purpose of each of the drugs?

1) Benzodiazepine
2) mAChR antagonist
3) opioid receptor agonist
4) Proton pump inhibitors

Answer 9

1) Benzodiazepine e.g. diazepam - increases inhibitory GABA release for sedative and anxiolytic effect
2) mAChR antagonist e.g. atropine - prevents secretion and vagal reflexes
3) opioid receptor agonist e.g. morphine - reduce pain and sedative
4) Proton pump inhibitors e.g. metoclopramide limits nausea and vomiting

Question 10

the second stage of general anaesthesia is induction. explain what happens during this stage and outline the drugs used.

Answer 10

1) IV bolus agents which induce loss of consciousness and amnesia
2) Propofol or barbiturate e.g. sodium thiopental, activate GABAa receptors and promote inhibition

Question 11

describe the properties that an induction drug, used in the second stage of general anaesthesia must possess

Answer 11

1) small, highly lipophilic compounds with rapid distribution.
2) very fast onset (loss of consciousness typically ~20 s time for blood circulation to reach the brain)
3) action terminated by distribution into large compartments (including muscle)
- given in preference to inhalation agents which are slower (mins) and therefore prone to more dangerous induction

Question 12

below is a list of induction drugs used in general anaesthesia. explain the benefits or problems for each of the drugs

1) Propofol
2) Thiopental
3) Etomidate

Answer 12

1) Propofol- Favoured due to rapid metabolism and lack of hangover effect
2) Thiopental- Only remaining widely used barbiturate potent agent acts within ~20 s and lasts 5-10 mins due to rapid metabolism; however can accumulate in fat which may lead to ‘hangover’ effect. Associated with profound respiratory depression
3) Etomidate- Favoured due to high therapeutic index and therefore lack of respiratory and cardiovascular side effects

Question 13

Whilst thiopental, etomidate and propofol work, at least in part, by activating inhibitory GABAA receptors, in theory block of excitatory glutamate receptors can also induce anaesthesia. The only major drug in this class is ketamine a NMDA glutamate receptor antagonist. outline the use of these drugs in general anaesthesia.

Answer 13

1) Ketamine: Relatively slow onset (2-5 mins)
2) Produces ‘dissociative’ anaesthesia i.e patient experiences sensory loss and analgesia but remains conscious. Can cause dysphoria and hallucination, these are less pronounced in children so ketamine is typically used in pediatric medicine.

Question 14

Describe the maintenance stage of general anaesthesia and state the drugs used.

Answer 14

1) volatile, inhalation agents used to maintain loss of consciousness and amnesia
2) Isoflurane, nitrous oxide, halothane

Question 15

what properties do drugs used in the maintenance stage of general anaesthesia possess and why are they inhaled?

Answer 15

1) inhaled gases with fast onset and offset of action, allowing control of depth of anaesthesia
2) inhaled general anaesthetics freely cross blood-brain barrier so kinetics are determined by rate of transfer from inspired air into blood
3) better for maintenance than IV induction agents due to rapid elimination
4) fewer side-effects than strongly sedative drugs, eg morphine and hyoscine

Question 16

Below is a list of drugs used in the maintenance stage of general anaesthesia. what side effects are associated with some of these drugs and when are they normally used?

1) Halothane
2) Nitrous oxide
3) Isoflurane

Answer 16

1) Halothane- now a widely used, potent agent, but which can lead to adverse cardiovasular and respiratory effects. Can also sensitise cardiac tissue to adrenaline, leading to dysrhythmia. May also cause hepatotoxicity. Hangover effects linked to high accumulation in fat.
2) Nitrous oxide- Low potency so typically used in combination. Use to reduce pain in childbirth
3) Isoflurane- Halogenated ether which replaced flammable ether, together with other members of the flurane drug class are now most commonly used inhalation anaesthetics

Question 17

1) outline the pain relief stage of general anaesthesia
2) state the drugs used
3) what are the side effects of these drugs?

Answer 17

1) IV opioids agents used to provide analgesia
2) Opioids e.g. morphine, fentanyl
- opioids also useful to cause sedation and cardiorespiratory depression
3 side-effects include nausea and vomiting and may also precipitate bronchospasm or anaphylaxis which may outweigh any beneficial effects

Question 18

1) outline the Muscle relaxation stage of general anaesthesia.
2) how do the Neuromuscular blocking agents used in this stage work? (atracurium, pancuronium and vecuronium)

Answer 18

1) Agents acting at the nicotinic acetylcholine receptors at neuromuscular junctions to cause immobility during surgery
2) There are two different types of neuromuscular blocking agents that affect these acetylcholine receptors:
- Competitive antagonists of nAChRs : these competitive blockers bind to the postsynaptic receptors. By binding to these receptors, the channel will not open to allow movement of ions, thus rendering the muscle limp
- Agonists which cause a depolarizing block of the muscle endplate = depolarizing blockers

Question 19

describe how competitive nAChR blockers cause muscle relaxation

Answer 19

1) Act as competitive antagonists at nAChRs
2) non-depolarizing - inhibits the nicotinic acetylcholine receptor at the neuromuscular junction by blocking the binding of acetylcholine
2) Examples: atracurium, pancuronium, vecuronium

Question 20

outline the use of the following competitive nAChR blockers and state their duration of action.

1) atracurium
2) pancuronium
3) vecuronium

Answer 20

1) Widely used as muscle relaxants as an adjunct to anaesthesia; in particular, obstetrics as these drugs do not cross placenta.
2) Given IV and vary in duration of action according to surgery:
- atracurium, vecuronium, rocuronium (< 60 mins)
- pancuronium (> 60 mins)

Question 21

Explain how depolarizing nAChRs blockers cause muscle relaxation

Answer 21

Continually stimulation of the NMJ by agonists causes muscle paralysis: muscle contracts due to maintained depolarization, but cannot repolarize (relax) causing loss of excitability (Na+ channels cannot inactivate)

Question 22

one depolarizing nAChRs blocker is suxamethonium (succinylcholine). why is the duration of action of this drug short?

Answer 22

Used to cause paralysis during anaesthesia:
1) Suxamethonium is short-acting ~ 10 mins (compared to competitive, non-depolarizing blockers) because it is rapidly hydrolysed by cholinesterases

Question 23

For each of the 5 stages of general anaesthesia listed below, specify the drug commonly used during each.

1) Premedication
2) Induction
3) Maintenance
4) Pain relief
5) Muscle relaxation

Answer 23

1) Premedication- benzodiazepines
2) Induction- IV proprofol or thiopental
3) Maintenance- isoflurane
4) Pain relief- IV opioid
5) Muscle relaxation- atracurium
- This procedure ensures a rapid onset and recovery, avoids long, potential dangerous, periods of semi-consciousness without undue disruption of homeostasis.