13 - Local Anaesthetics Flashcards
Anaesthetics are drugs that…
Prevent pain for a limited period of time
Anaesthetics are divided into two main categories…
- Local (prevents local pain/ nociception)
- General (induces a loss of consciousness)
Analgesics are drugs that…
Reduce (rather than prevent) pain
Local anaethetics work by blocking…
Electrical signalling in neurones
How do local anaesthetics block electrical signalling in neurons?
By blocking voltage gated sodium channels
Sodium Channels are made up of 3 subunits, namely…
α, β1 & β2
The α subunit of the sodium channel is a ______ polypeptide with ___________ domains and 4 _________ domains and 6 _-_____ regions.
The α subunit of the sodium channel is a single polypeptide with extracellular domains and 4 transmembrane domains and 6 α-helical regions.
The beta subunits of the sodium channel anchor the…
Alpha subunit within the phospholipid membrane
The ( beta 1 / beta 2 ) subunit is ( covalently / ionically) bonded to the alpha subunit.
The beta 2 subunit is covalently bonded to the alpha subunit.
The voltage gate sodium channel has voltage sensors located in the…
Hydrophobic domains of the alpha subunit
It is thought that local anaesthetics exert their effect by…
Physically plugging the transmembrane pore of the sodium channel
Ionised molecules can’t cross lipid membranes. Why is this a problem for a local anaesthetic?
Local anaesthetic molecules bind in an ionised form. But the binding site in at the inner end of the ion channel, which requires intracellular access!
The ideal local anaesthetic enters in an (ionised / un-ionised) form through the axon membrane. This converts to an (ionised / un-ionised) form which binds to the channel.
The ideal local anaesthetic enters in an un-ionised form through the axon membrane. This converts to an ionised form which binds to the channel.
Describe the general structure of anaesthetic molecules…
- Aromatic group (ensures lipid solubility)
- Ester or amide group
- Basic amine side-chain (ensures ionisation at lower pH)
The duration of action of local anaesthetics is limited by which two factors?
- Lipid solubility
- Hydrolysis of the ester/amide bond
Esters are metabolised by ________ (with the exception of _________ )
Esters are metabolised by esterases (with the exception of cocaine )
Amides are metabolised by ________ in the ______* . This gives anaesthetics linked by an amide group a longer half life, but poses consequences for those with _____ *________.
*same word
Amides are metabolised by CYP3A4, 1A2 in the liver. This gives anaesthetics linked by an amide group a longer half life, but poses consequences for those with liver failure.
Process of local anaesthesia…
- Anaesthetic injected as hydrochloride salt in acid solution
- Drug dissociates releasing lipid-soluble free base (due to higher pH)
- Lipid soluble free base enters axon
- Re-ionisation in the axon (due to lower pH)
- Re-ionised molecule enters and blocks sodium channels
- Depolarisation prevented
Coadministration of adrenaline with a local anaesthetic can be used to achieve which 2 effects?
- Restrict the site of action
- Prolong duration of action
(due to local vasoconstriction via α1 adrenoreceptors)
What method can be used to accelerate the speed of onset of a local anaesthetic?
Using a slightly alkaline solution to improve absorption into nerve tissue
Different axon types show different sensitivities to local anaesthetics.
Local anaesthetics are more effective in which of the following fibres (and why?):
Nosciceptive fibres
Motor axons
Nosciceptive fibres as they are small, whereas motor axons are larger and less sensitive
Use-dependent block
Depth of block increases with the frequency of action potentials (as access and affinity are improved when the channel is open)
Unwanted side effects of local anaesthetic are generally caused by…
The drug escaping into systemic circulation
Unwanted CNS side effects of local anaesthetics include…
Confusion and agitation
Unwanted cardiovascular side effects of local anaesthetics include…
Hypotension (due to inhibition of sympathetic activity, inhibition of sodium conductance in cardiac tissue)
A limitation of local anaesthetics is that they are not very effective in ________ or _________ tissue
A limitation of local anaesthetics is that they are not very effective in infected or inflammed tissue
Tetrodotoxin is produced by marine bacteria and is utilised by frogs, newts and pufferfish. It works by…
Blocking voltage-gate sodium channels
The nervous system comprises of sensory neurons detecting input, interneurones in the CNS responsible for _________ and finally output via the PNS and glands
The nervous system comprises of sensory neurons detecting input, interneurones in the CNS responsible for integration and finally output via the PNS and glands
List the chemical drug targets in the nervous system (6)…
- G-protein coupled receptors
- Ligand gated ion channels (ionotropic receptors)
- Enzyme linked (kinase) receptors
- Synthesis of NT
Reuptake of NT - Release of NT
Other than local anaesthetics, give 2 examples of drug types that target voltage-gated ion channels…
- Antihypertensive and antiarrythmic drugs (L-type calcium channels)
- Anticonvulsant/ antiepileptic drugs (Sodium channels)
Give two examples of anticonvulsant/antiepileptic drugs and state how they exploit use-dependent block…
Phenytoin and carbomazepine
Use-dependent block allows these drugs to block high frequency discharges (corresponding to seizures) while allowing normal frequency firing.
