Fern White & Hamish Auld Anaesthesia Fern White & Hamish Auld

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.

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

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)

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

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

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

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

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)

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

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.

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