14. Anaesthetics Flashcards
What is an anaesthetic?
drugs used to prevent pain for a limited time for surgical or other procedure
Compare local and general anaesthetic
- local prevent pain/nociception in localised area and prevent tactile sensation
- general includes loss of consciousness
Historical anaesthetics
- pre 1840s used alcohol, cannabis, opium, ice, blow to head
- 1842 - ether for tooth extraction
- 1844 - nitrous oxide dental
- 1847 - chloroform (obstetric)
2 classes of anaesthetics
- inhalation ones
- intravenous ones
List some inhalation anaesthetics
- halothane
- nitrous oxide
- enflurane
- isoflurane
List intravenous anaesthetics
- thiopental
- etomidate
- propofol
2 mechanism of action theories for anaesthetics
- lipid theory/Meyer Overton theory
- ion channel theory
Explain the lipid/Meyer Overton theory
- strong relationship between anaesthetic potency and lipid solubility
- originally thought these agents interacted with lipid bilayer of plasma membrane causing membrane expansion and consequent inability of membrane to facilitate changes in protein configuration and signalling
- largely discredited
Explain ion channel theory
- anaesthetics target number of ligand gated ion channels
- including GABAa, glycine NMDA
Physicochemical properties of inhalation anaesthetics
- depth of anaesthesia determined by concentration in brain and spinal cord
- blood/gas partition coefficient, measure of blood solubility
- oil:gas partition coefficient, measure of lipid solubility
Explain the blood/gas partition coefficient as a measure of blood solubility in inhalation anaesthetics
- low (e.g nitrous oxide) is rapid infuction, recovery
- high (e.g halothane) is slow induction, recovery
- lower the solubility in blood, faster the induction and recovery
- less drug needs to be transferred via lungs to produce equilibrium
Oil:gas partition coefficient as a measure of lipid solubility for inhalation anaesthetics
- main factor to determine potency, since brain high lipophilicity
- lower the oil:gas pc, the less potent the GA
2 reasons pharmacokinetics are important for inhalation anaesthetics
- vascularisation of tissue determines tissue levels of anaesthetics
- ventilation rate
How does vascularisation of tissue determine tissue levels of anaesthetics?
- brain good blood flow - high levels
- body fat has poor blood flow so anaesthetic doesn’t accumulate in body fat
- within reason and obesity causes issues
How does ventilation rate affect inhalation anaesthetics?
- effect rate of removal of anaesthetic
- anaesthetics cause respiratory depression and so require controlled ventilation
Inhaled anaesthetics mainly eliminated via …
lungs
Give the limited hapatic metabolism for
- methoxyflurane
- halothane
- isoflurane
- desflurane
- sevoflurane
- methoxyflurane - extensive (60%) hepatic metabolism resulting in nephrotoxic fluoride ion (no longer used)
- halothane - 15% (hepatotoxic)
- isoflurane 0.5%
- 0.5%
- 3%
List side effects of inhaled anaesthetics
- malignant hyperthermia
- cardiovascular
- respiration
- hepatic toxicity (mainly halothane)
- kidney issues
What is malignant hyperthermia?
- rare but most common with halothane and isoflurane
- hypermetabolism, muscle rigidity, muscle injury and increased sympathetic nervous system activity, hyperthermia
What cardiovascular problems are side effects of inhaled anaesthetics?
- can cause hypotension (except nitrous oxide)
- decreased output and decreased vascular resistance
How is respiration affected by inhaled anaesthetics?
- depressed respiration
- more so with the fluranes, iso then des then sevo
How do inhaled anaesthetics affect the kidneys?
- depressed glomerular filtration and urine output
- not really a problem as decreased cardiac output and vasodilation too
- usually given fluids too
Give 4 intravenous anaesthetics
- thiopental sodium
- etomidate
- ketamine
- propofol
Intravenoud anaesthetics have a … onset of action around … and are used for …
- short, around 20 seconds
- used for induction previously but not maintenance too
Thiopental and etomidate act on …
GABAa receptor (on alpha1/beta3 subunit interface)
Difference between etomidate and thiopental
- etomidate has a wider therapeutic window between anaesthesia and respiratory depression
- has a therapeutic index of 26 compared to 2.5 of thiopental which is rapidly metabolised
Propofol acts on …
GABAa receptor of beta3/beta3 or alpha1/beta3 subunit interface
How quickly is propofol metabolised?
- very rapidly
- extrahepatic, elimination via plasma/esterases and lungs
- rapid recovery, no hangover, TI of 3
- day case surgery
Ketamine is a …
Explain ads and disads
- NMDA receptor antagonist
- less hypotension than the etomidate/propofol
- rarely used due to hallucinations, psychosis
- does have some good analgesic effect
History of local anesthetics
- cocaine first used
- 1860 first isolated
- 1884 used local anaesthetic
- 1905 synthetic analogue procaine developed
Mechanism of action for local anaesthetics
- local anesthetics block electrical signalling in neurones by blocking voltage gated sodium ion channels
What is neuronal signalling?
- transfer of info along and between neurons
- electrical is the action potential
- chemical is neurotransmission
Explain resting potential
- sodium ions and chloride iions concentrated outside
- potassium and A- ions concentrated inside
- ionic charge between inside and outside is uneven
- inside is negative to outside (-60 to -90 mV)
All cells have a membrane potential but …
- neurones are special because they can rapidly alter their membrane potential
- depends on voltage-gated ion channels
Why are voltage gated sodium ion channells essential for action potential?
- crucial to initiate and propagate the action potential and electrical signalling
Voltage gated sodium ion channels are made of … subunits. Give them
- 3
- alpha, beta 1 and beta 2
How are voltage gated ion channels structured?
- the alpha-subunit is a single polypeptide. it contains extracellular domains, 4 transmembrane domains each comprising 6 alpha-helical regions
- beta subunits flank the alpha unit. the beta 2 is covalently linked to alpha, beta 1 is not linked
- two beta-units anchor the alpha subunit into the lipid membrane
Role of the alpha subunit in voltage gated channels
- contains in the hydrophobic domains voltage sensors
- these change their orientation when voltage varies
- this orientation determines the configuration of the entire domain and controls opening and closing of a pore
Effect of local anaesthetics on voltage gated ion channels
- thought to interact with alpha subunit and physically ‘plug’ the transmembrane pore
- anaesthetic binding area located in the inner end of the channel so drug gains access intracellularly
What is the ideal structure of a local anaesthetic to bind and plug voltage gated channel?
- unionised form gains access through nerve sheath and axon membrane
- ionised forms bind in channel
- most anesthetics are weak bases
General structure of local anaesthetic
- aromatic (lipophilic) group on left
- ester or amide bond
- and amine (basic) sidechain/group on right
Why is local anaesthetic structure important to role?
- basic side chain ensures molecules are ionised at physiological pH
- aromatic domain ensures lipid solublity
- duration of action limited by hydrolysis of ester/amide bond and lipid solubility of agent
- allows lipid-soluble base to enter axon
- inside the axon the pH is lower - more acidic environment and ionisation takes place
How are esters metabolised?
- in plasma by esterases
- except cocaine - shorter half life
How are amides metabolised?
- in liver by CYP 3A4, 1A2
- longer half life consequences in those with liver failure
How does an anaesthetic injection lead to no depolarization?
- anaesthetic is a weak base, injected as a hydrochloride salt in acid solution - suitable for injection
- following injection, pH icnreases (as higher pH of tissues) and free base is released (lipid soluble)
- lipid soluble free base enters the axon - inside the axon the pH is lower - environment is more acidic
- re-ionization takes place
- re-ionized portion enters the sodium ion channels and blocks them, preventing depolarization
How can we manipulate local anaesthetics?
- restrict site of action and prolong durations of action - coadminister adrenaline, local vasoconstriction via alpha 1 adrenoreceptors
- accelerate the speed of onset of anaesthetic - use slightly alkaline solution, assists absorption of anaesthetic in nerve tissue
Do all nerves show similar susceptibility to local anaesthetics?
- different axons have different sensitivities
- block conduction in small diatmeter fibres more effectively than large
- small myelinated axons more than non-myelinated axons more than large myelinated axons
- nosciceptive pain fibres are small diameter and particularly sensitive
- motor axons are large and less sensitive
What is the use dependent block?
- the depth of block increases with increase in action potential frequency
- known as ‘use dependent block’
- channels in 3 states (resting, open, inactive)
- use dependent block occurs as anaesthetic gains access to and has higher affinity for channels more readily when open and/or inactive
Unwanted side effects of local anaesthetics
- occur due to local anaesthetic into systemic circulation
- CNS, confusion and agitation
- cardio and hypotension
- inhibition of sympathetic activity and inhibition of sodium conductance in cardiac tissue
Limitation of local anaesthetic
- not very effective in infected or inflamed tissue
- can’t penetrate
