This module covers the major drug classes that are used as anaesthetics; from topical and locally acting drugs, to general anaesthetics that are used in surgical procedures.
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Local anaesthetics (LAs) are applied to block nociception (pain perception) that is transmitted via peripheral Aδ and C nerve fibres to the brain. Chemically, LAs are amphiphilic molecules with a hydrophobic aromatic group and a basic amine group. They are weak bases that act in their ionised form, but which can only diffuse across the cell membrane to their site of action (at the intracellular face of voltage-gated sodium channels) in their un-ionised form. Docking to the channel blocks Na+ from entering nerve cells, and thereby prevents depolarisation and propagation of the action potential along the axon. Efficacy (potency and duration of action) is determined by both the hydrophobicity and pKa of ionisation of the LA compound. LAs are ineffective in inflamed tissue due to tissue acidosis.
Two main subfamilies of LAs are used clinically:
Ester-linked LAs e.g. procaine- rapidly metabolised by tissue and plasma cholinesterases (half-life <3 minutes)
Amide-linked LAs e.g. lidocaine- primarily metabolised slowly by liver p450 enzymes (half-life 1-3 hours)
Administration:
Topical- high concentration of LA in an oily vehicle > slow penetration through skin or mucous membrane.
Infiltration- the LA is injected intradermally or subcutaneously > effective more quickly than via topical application. Lidocaine is the most widely used injected LA.
Peripheral nerve block- the LA is injected around the nerve trunk, to produce anaesthesia distal to the injection site e.g. brachial plexus block anaesthesia can be used the numb the whole arm.
Central nerve block- the LA is injected near the spinal cord, to produce anaesthesia above and below the injection site e.g. epidural anaesthesia used during labour.
Intravenous regional anaesthesia- a tourniquet is used to restrict diffusion of the LA beyond the target area, for example in the arm. This procedure can be used to manipulate bones in limb fractures, or for minor surgical procedures.
Local anaesthetics (LAs) are applied to block nociception (pain perception) that is transmitted via peripheral Aδ and C nerve fibres to the brain. Chemically, LAs are amphiphilic molecules with a hydrophobic aromatic group and a basic amine group. They are weak bases that act in their ionised form, but which can only diffuse across the cell membrane to their site of action (at the intracellular face of voltage-gated sodium channels) in their un-ionised form. Docking to the channel blocks Na+ from entering nerve cells, and thereby prevents depolarisation and propagation of the action potential along the axon. Efficacy (potency and duration of action) is determined by both the hydrophobicity and pKa of ionisation of the LA compound. LAs are ineffective in inflamed tissue due to tissue acidosis.
Two main subfamilies of LAs are used clinically:
Ester-linked LAs e.g. procaine- rapidly metabolised by tissue and plasma cholinesterases (half-life <3 minutes)
Amide-linked LAs e.g. lidocaine- primarily metabolised slowly by liver p450 enzymes (half-life 1-3 hours)
Administration:
Topical- high concentration of LA in an oily vehicle > slow penetration through skin or mucous membrane.
Infiltration- the LA is injected intradermally or subcutaneously > effective more quickly than via topical application. Lidocaine is the most widely used injected LA.
Peripheral nerve block- the LA is injected around the nerve trunk, to produce anaesthesia distal to the injection site e.g. brachial plexus block anaesthesia can be used the numb the whole arm.
Central nerve block- the LA is injected near the spinal cord, to produce anaesthesia above and below the injection site e.g. epidural anaesthesia used during labour.
Intravenous regional anaesthesia- a tourniquet is used to restrict diffusion of the LA beyond the target area, for example in the arm. This procedure can be used to manipulate bones in limb fractures, or for minor surgical procedures.
This is a 10 minute long hand drawn tutorial by Armando Hasudungan, which explains the concept and mechanism of action of local anaesthetics. It is suitable for beginners.
General anaesthetics (GAs) cause a controlled and reversible loss of consciousness, analgesia and amnesia, but despite having been in use for over 150 years, the precise mechanism of action of commonplace GAs is still not fully understood. A variety of compounds with widely different chemical structures can act as GAs. Central nervous system (CNS) areas affected by GAs include the cerebral cortex, thalamus, reticular activating system and spinal cord, and potential molecular targets include GABA, NMDA, serotonin (5-HT) and glycine receptors, as well as voltage-gated ion channels. GAs are delivered intravenously (IV) or are inhaled, by specially trained anaesthesiologists who must closely monitor the patient's vital signs during the procedure. Muscle relaxants (neuromuscular blockers) such as pancuronium, rocuronium, vecuronium, atracurium, mivacurium, and succinylcholine are used alongside the GA agents. The effect of these neuromuscular blockers can be reversed at the end of surgery by administration of anticholinesterase drugs (e.g. neostigmine).
Following a premedication step, general anaesthesia is described as a four stage process: Stages 1-3 represent the safe clinical window during which surgery can proceed, stage 4 must be avoided.
Several different types of drug are given together during general anaesthesia.
Stage 1: induction - is the time between administration of the drug and loss of consciousness. Administered IV or by inhalation.
Stage 2: excitement - this stage is characterised by erratic breathing and heart rate, and is associated with a vomiting risk. Modern, fast-acting drugs have been designed to limit the time spent in stage 2.
Stage 3: surgical anesthesia - during this stage muscles relax, motor reflexes are blunted, vomiting stops, breathing is depressed and eye movements cease. Anaesthesia is then maintained for the duration of the procedure using IV or inhalational anaesthetics.
Stage 4- overdose- administration of medication overdose causes brain stem or medullary suppression and leads to respiratory and cardiovascular collapse.
Malignant hyperthermia is a rare but potentially lethal complication of anaesthesia, most commonly associated with use of the volatile anaesthetics. This condition is characterised by a rapid rise in temperature, increased muscle rigidity, tachycardia, and acidosis. Dantrolene sodium is used in the treatment of malignant hyperthermia.
This session is a basic introduction to the pharmacodynamics and pharmacokinetics of inhalation and intravenous anaesthetics. It is aimed at preclinical medical or dental students, or students in the early years of a pharmacology degree.
Contributed by Dr Clare Guilding, Newcastle University Medicine Malaysia
Propofol is the most widely used intravenous anaesthetic. It can be used for induction or maintenance of anaesthesia.
Thiopental sodium is used for induction, but has no analgesic action. As metabolism is slow repeated doses have a cumulative effect and recovery is much slower.
Recovery from etomidate anaesthesia is rapid, and it benefits from reduced risk of hypotension compared to propofol and thiopental sodium, but its propensity to produce a high incidence of extraneous muscle movements, requires co-administration of an opioid analgesic or a short-acting benzodiazepine just before induction.
Inhalational anaesthetics include gases and volatile liquids.
Isoflurane is the preferred inhalational anaesthetic for use in obstetrics. It causes muscle relaxation in its own right and potentiates the effects of muscle relaxant drugs.
Desflurane is less potent than isoflurane, but benefits from rapid onset and recovery from anaesthesia. Its propensity to irritate the airway precludes its use as an induction anaesthetic. Use of desflurane is being minimised in some countries because of its negative impact on the environment (it has global warming potential >2000 times greater than carbon dioxide).
Sevoflurane is more potent than desflurane, is moderately slower acting, and is non-irritant. It has little effect on heart rhythm compared with other volatile liquid anaesthetics.
Malignant hyperthermia is a rare but potentially lethal complication of anaesthesia, most commonly associated with use of the volatile anaesthetics. This condition is characterised by a rapid rise in temperature, increased muscle rigidity, tachycardia, and acidosis. Dantrolene sodium is used to combat malignant hyperthermia.
Nitrous oxide (N2O) is used for maintenance of anaesthesia (at a concentration of 50 to 66% in oxygen) in combination with other inhaled or intravenous agents. It is not recommended as a sole anaesthetic agent. A 50:50 N2O/oxygen mixture is used for analgesia without loss of consciousness.
A teaching slide set (29 in total) describing the mechanisms of action and clinical use of local anaesthetics. This session is a basic introduction to the pharmacodynamics and pharmacokinetics of local anaesthetics. It is aimed at preclinical medical or dental students, or students in the early years of a pharmacology degree. Contributed by Clare Guilding, Newcastle University Medicine Malaysia.