1. Fern White & Hamish Auld
Anaesthesia
Fern White & Hamish Auld

2. If GA then drug induced and predictably reversible coma.
Define sedation.
Allows patients to tolerate unpleasant diagnostic or surgical procedures and to relieve anxiety and discomfort. Verbal contact can be maintained.
Define coma.
A state of extreme unresponsiveness, in which an individual exhibits no voluntary movement or behaviour.
Learning Outcome: Describe the characteristic behaviours of different levels of arousal and sedation
Define anaesthesia.
If GA then drug induced and predictably reversible coma.

3. Regional (e.g. spinal, brachial plexus block, femoral nerve block)
What is anaesthesia?
General
Regional (e.g. spinal, brachial plexus block, femoral nerve block)
Local
Amnesia
Muscle relaxation
Amnesia induced by intra-venous anaesthetic agents and then maintained by using inhalational anaesthetic agents.
Analgesia provided by various analgesic drugs or by regional/peripheral nerve blocks.
Muscle relaxation not required in all patients or surgical procedures. Muscle relaxants are used to facilitate tracheal intubation, mechanical ventilation or surgical procedure.
Analgesia

4. Principle side effects
GA: Inhalational vs. IV?
Volatile
Intravenous
Onset
Offset
Specific Drugs
Metabolism
Principle side effects
Notes
Rapid Dependent on Cardiac Output One ‘arm-brain’ circulation time
Slow Alveolar gas exchange
Alveolar gas exchange
Redistribution/metabolism
Nitrous Oxide Isoflurane Sevoflurane
Thiopentone Propofol Ketamine
Learning Outcome: Name the drug classes (and give examples of the most common pharmacological agents) available for use in sedation and anaesthesia; Describe the mechanisms of action of the most common general and local anaesthetic agents.
Thiopentone: Rapid, no pain on injection. Decreases cerebral metabolic rate and ICP. Hypotension (vasodilation) and reflex tachycardia. Barbiturate: binds at a distinct binding site associated with a Cl- ionopore at the GABAA receptor, increasing the duration of time for which the Cl- ionopore is open. The post-synaptic inhibitory effect of GABA in the thalamus is, therefore, prolonged.
Propofol: Most commonly used. Rapid, and recovery of consciousness is quick. Pain on injection, but better suppression of laryngeal reflexes > LMA without coughing or spasms. Hypotension (vasodilation). Positive modulation of the inhibitory function of GABA through GABA-A receptors – reducing neuron excitability in CNS.
Isoflurane: Pungeant odour so not used as induction, rather just maintains GA following injection. Depression of ventilation.  Induces a reduction in junctional conductance by decreasing gap junction channel opening times and increasing gap junction channel closing times. Also activates calcium dependent ATPase in the sarcoplasmic reticulum by increasing the fluidity of the lipid membrane and  binds to the GABA receptor.
Sevoflurane: If inhalation is used for induction, this is the one they use – better smell and less of an irritant to URT. Dose dependent depression of ventilation. Same MoA as isoflurane.
Nitrous oxide: Sweet smelling and non-irritant; delivered with oxygen in order to achieve ~33% O2. Good analgesic, weak anaesthetic agent. Also associated with post-op nausea and vomiting. Relaxes vascular smooth muscle (think of your GTN spray in angina!) and therefore = pulmonary vasodilation.
Almost none
Liver
Cardiac suppression Respiratory depression
Cardiac suppression Respiratory Depression
Malignant Hyperpyrexia (ethers) Bone marrow suppression (N2O)
Anaphylaxis (any)

5. GA Scoring systems
What is the difference between general anaesthesia and moderate sedation? (American Society of anaesthesiologists)
General anaesthesia: Unrousable even with painful stimulus.
Moderate sedation: Purposeful response to verbal/tactile stimulation. (usually referred to as conscious sedation)
RICHMOND AGITATION SCALE
Learning Outcome: Describe the characteristic behaviours of different levels of arousal and sedation; Name and describe TWO scales used to measure levels of sedation and anaesthesia.
RAMSAY

6. General anaesthesia: muscle relaxation
Ach diffuses across the synaptic cleft and binds to nAChR on postsynaptic 
membrane. nAChR is a Na+/K+ channel – it opens and there is Na+ influx
To understand muscle relaxants, we need to understand the neuromuscular junction.
Order these steps at the NMJ…
Na+ influx generates action potential in the motor endplate called an endplate potential (EPP)
Increase in intracellular [Ca2+] causes fusion of presynaptic vesicles to cell membrane and release of Acetylcholine by exocytosis
Acetylchloinesterase hydrolyses Ach to choline and acetate, which are recycled
Upon reaching threshold an AP occurs in the muscle
Voltage-gated Ca2+ channels open allowing Ca2+ influx
Action potential arrives at motor nerve terminal

7. General anaesthesia: muscle relaxation
1. Action potential arrives at motor nerve terminal
2. Voltage-gated Ca2+ channels open allowing Ca2+ influx
3. Increase in intracellular [Ca2+] causes fusion of presynaptic vesicles to cell membrane and release of ACh by exocytosis
4. ACh diffuses across the synaptic cleft and binds to nAChR on postsynaptic membrane. nAChR is a Na+/K+ channel. It opens and there is Na+ influx
5. Na+ influx generates action potential in the motor endplate called an endplate potential (EPP)
6. Upon reaching threshold an AP occurs in the muscle
7. Acetylchloinesterase hydrolyses ACh to choline and acetate, which are recycled

8. General anaesthesia: muscle relaxation
When would you need to give drugs for muscle relaxation?
Intubation (insertion of tube into trachea)
Surgery requires muscles relaxed e.g. abdominal surgery
What are the TWO categories of muscle relaxant?
Depolarising
Non-depolarising
How does a depolarising muscle relaxant work?
Similar structure to Ach so binds to nAChR at NMJ
Example?
Side-effects
Fasciculations
K+ efflux can lead to hyperkalemia
Learning Outcome: Outline the pharmacological actions of drugs used as adjuncts to anaesthesia.
Suxamethonium
Important points about suxamethonium:
Cannot be reversed – wait for it to wear off in 3-5mins
Wears off as broken down by pseudocholinesterase. People deficient in this enzyme get suxamethonium apnoea and stop breathing for up to 2hrs

9. General anaesthesia: muscle relaxation
How does a non-depolarising muscle relaxant work?
Competes with ACh and blocks nAChR
THREE examples?
Atracurium
Rocuronium
Vecuronium
Hoffman degradation – not dependent on liver/kidneys pH and temperature dependent.
Why might you need to ‘reverse’ muscle relaxation?
End of operation to allow patient to breathe on their own
Failed intubation – wake patient up, let them breathe on their own
Learning Outcome: Outline the pharmacological actions of drugs used as adjuncts to anaesthesia.
Reversal agents:
Atracurium: anticholinesterases e.g. neostigmine and pyridostigmine. Inhibit acetylecholinesterase which breaksdown Ach, thus more Ach available to compete with muscle relaxant
Rocuronium and vecuronium: drug called sugammadex (expensive)

10. Local anaesthetics How do local anaesthetics work? Block Na channels
Examples?
Lidocaine (still pronounced “lig-no-caine”)
Bupivicaine – slower onset, longer lasting
What 3 factors can determine the effect of LA?
Diffusion gradient
Fibre size
Myelination
Learning Outcome: Outline the pharmacological actions of drugs used as adjuncts to anaesthesia.
Why can local anaesthetics give a ‘mobile block’ (loss of sensation, motor function retained)?
Larger diameter, myelinated motor fibres less sensitive to anaesthetic than sensory fibres

11. Local anaesthetics How can local anaesthetic toxicity occur?
Intravascular injection
Remember! Local anaesthetic is less effective in acidic tissues (becomes ionised), so will not be used for certain procedures, such as abcess I&D.
Signs and symptoms?
Paraesthesia of tongue and lips
CNS
Drowsiness
Seizures
Muscle twitching
CVS
Hypotension
Bradycardia
Cardiac arrest
Related to Na channel blocking action
Learning Outcome: Outline the pharmacological actions of drugs used as adjuncts to anaesthesia.

12. Thank-you! Any questions: f.white@warwick.ac.uk h.auld@warwick.ac.uk