Anaesthesia Flashcards
Explain, from the perspective of the patient and of the surgeon, why we need anaesthetics
• For the patient: o No pain o No traumatic memory of surgery • For the surgeon: o Patient is immobile; can perform complex procedures more easily
What are the 3 key components of anaesthesia? Are there other effects - if so, what are they? Are these effects reversible?
• 3 key components: o Hypnosis – loss of consciousness o Amnesia – no memory formation o Immobility – no response to a painful stimulus • Other effects: o Analgesia o Sedation o EEG slows o Heart rate stabilises • Effects are reversible • Not just one state; it’s the culmination of multiple effects
Describe the theory of the 4 stages of anaesthesia
4 stages:
- Analgesia – dream-like state
- Excitement – increased muscle tone, heart rate, and blood pressure
- Anaesthesia – loss of consciousness; immobility; no memory formation
- Cessation of breathing – can be fatal, is avoided based on dosage alterations
Describe the stages of anaesthesia in practise
In practice:
1. Induction – normally via propofol
2. Maintenance – via N2O (a volatile anaesthetic)
3. Recovery
• Induction gets you to stage 3; may not notice stage 1-2
List the ideal qualities of an anaesthetic from the patient’s perspective
• Unconscious; no pain, memory, or anxiety • Fast induction with fast recovery • No undesirable side effects, e.g.: o Airway irritation o Nausea o Vomiting o Acidity
List the ideal qualities of an anaesthetic from the surgeon’s perspective
• Immobility
• Relaxed muscles
o Easy to slice into and operate on
• Non-inflammable and non-explosive
List the ideal qualities of an anaesthetic from the anaesthesiologist’s perspective
- Potent
- Can quickly adjust the depth of anaesthesia
- Regular breathing and heart rate
- High safety margin – no deaths
- Cheap, stable, easily stored
List the types of intravenous anaesthetics
- Etomidate
- Alphaxalone
- Propofol
- Ketamine
- Pentobarbital
- Thiopental
List the types of inhalant anaesthetics
- Nitrous oxide
- Halothane
- Xenon
- Isoflurane
- Desflurane
- Sevoflurane
- Enflurane
Why is classifying anaesthetic by administration route not ideal?
- Not the best way to classify them
- Large structure diversity and no obvious relationship between structure and function
- Neurosteroids are the only known endogenous anaesthetics
Explain the history and use of inhalational anaesthetics
• N2O – first in use; still used today
• Ether had side-effects and chloroform was worse
• Cyclopropane was highly unstable
• 1950s-now:
o Fluorine-based inhalants
o Halothane not used much anymore – causes liver toxicity
Explain the history and use of intravenous anaesthetics
• Barbiturates: have been used, even for death penalty and as a sedative/anxiolytic
o Mostly replaced as anaesthetic by propofol
• Benzodiazepines: sedative, anxiolytic
• Short duration of action – good for anaesthetics
o Notably etomidate, propofol
• Long duration of action – good as sedatives
Define and explain MAC and the applications of MAC
• MAC = minimum alveolar concentration
o Minimum concentration of vapour in the lungs which produces immobility/hypnosis in 50% of subjects
High MAC50 = low potency
Low MAC50 = high potency
o MAC for inhaled anaesthetics producing immobility (MAC-immobility) is considered a standard measure of anaesthetic potency
Plasma concentrations (Cp50-immobility) for intravenous agents can be evaluated in a similar manner
• Analogous potency measurements for hypnosis (MAC-awake or Cp50-awake) have been documented for many anaesthetics
• 1 atmosphere is the maximum alveolar concentration you can get; anything above 1 can never reach MAC
Describe the unitary theory of anaesthesia
• Meyer-Overton correlation shows that all anaesthetics have a hydrophobic site of action
o Suggests:
Anaesthetics act on hydrophobic sites of proteins or on lipid membranes
o Together with the diversity of anaesthetic structures, it suggests that:
All anaesthetics act through a common molecular mechanism
The assumption was that anaesthetics dissolve in the lipid membrane of neurons, and affect neuronal activity by perturbing their membrane
List the issues with the unitary theory of anaesthesia
- Recently discovered anaesthetics are less potent than predicted by their lipid solubility
- Anaesthetics can bind to proteins (in a way consistent with Meyer-Overton correlation)
- Mutations in some proteins impair anaesthetic effects
- Enantiomers (S- and R-) pairs of chiral anaesthetic molecules have different potencies
Explain why there has been a movement towards mechanISMS of action for anaesthesia
Anaesthesia is not a simple all-or-nothing change in the state of the nervous system
Each component of anaesthesia:
Hypnosis – no perceptive awareness
Amnesia – no memory formation
Immobility – no movement in response to a painful stimulus
Analgesia – no pain sensation
and all other effects of anaesthetics are not achieved at the same time – they depend on the drug used and the concentration of the drug used
∴ for each anaesthetic agent it is important to determine the molecular target(s) through which it produces a specific component of anaesthesia
Establishing the mechanism of action is very recent
Depends on relatively new techniques:
Binding studies
Electrophysiology
Transgenic animals with targeted mutations
Protein structure
Write the ratio which shows how variation in drug concentration causes variable effects, and state the implications of this
• Ratio of the drug concentration producing immobility:drug concentration producing amnesia/sedation varies with anaesthetics
o –> multiple components of anaesthetic effects; each of these is mediated by different molecular target(s)
Explain the pharmacology of propofol
Propofol is routinely used for induction – has a rapid effect and is rapidly eliminated from the body
Anaesthetic potency of propofol correlates with its ability to potentiate GABAAR-mediated Cl- currents
R- and S- enantiomers have >10 ratio in GABAA current modulation and anaesthetic potency
Immobility and hypnotic effects are induced at different subunits than amnestic effects
Which volatile anaesthetics are currently used? What does their mechanism of action involve? Are there any other targets?
Currently used:
Isoflurane
Desflurane
Sevoflurane
These are often used with N2O and O2 during maintenance of anaesthesia
strong immobilisation, amnesic, and hypnotic effects
Mechanism of action involves GABAARs and other targets
S270H mutation – serine replaced by histidine
HA mice have S270H mutation + another mutation to make sure that control condition currents are identical to WT
Other targets:
Mutation on GABAAR α subunit resistance to hypnosis by enflurane
Mutation on GABAAR β3 subunit mild resistance to immobilisation by halothane and enflurane
Effects are not as strong as for propofol/etomidate ∴ volatile anaesthetics may act on other targets:
GlyR potentiation (Cl- current like GABAAR; predominant in spinal cord) contributes to immobilisation
nAChR inhibition?
2-pore-domain potassium channels (K2p) activation
‘leak’, not voltage-gated
GluR inhibition
Depression of neurotransmitter release
Inhibition of Na+ channels
Explain K2P channels and name the anaesthetic which targets them
• Are leaky K+ channels; not voltage-gated
• Halothane increases TREK1 and TASK1 currents
• TREK1 KO mouse is:
o Weakly resistant to hypnotic effects
o Strongly resistant to immobilisation
Explain the use and mechanism of action of N2O and ketamine
• N2O = nitrous oxide, not nitric
o Used with volatile anaesthetics and O2 during maintenance of anaesthesia
o Is an analgesic with weak anaesthetic effects (MAC: >100%)
o In mammals:
Activates K2p channels
Weakly inhibits nAChR channels
• Ketamine can induce general anaesthesia by itself
• Inhibit NMDA-R channels – this is the only target in C. elegans
o NMDA blockers don’t produce immobilisation
List the effects of anaesthetics on putative targets
Table here: https://www.google.com/url?sa=i&url=https%3A%2F%2Fwww.cambridge.org%2Fcore%2Fbooks%2Fanesthetic-pharmacology%2Fmechanisms-of-anesthetic-action%2FFB87CE46FC0A2CA6D0FCF5D89AD503BC%2Fcore-reader&psig=AOvVaw1yOIKRBpCMT-GNUrWtagsQ&ust=1577222559881000&source=images&cd=vfe&ved=0CAIQjRxqFwoTCMCRjIbazOYCFQAAAAAdAAAAABAD
Where are the targets responsible for the immobilisation effect of anaesthetics located?
Spinal cord, specifically the dorsal root ganglia
Which arousal systems are targeted by anaesthetics? What effect does this have?
- LC = locus corelus; does arousal
- TMN = tuberomammillary; promotes wakefulness
- VLPO = ventrolateral preoptic nucleus; promotes sleep - inhibitory
- ORX = orexin - stimulatory
