PED1003/L14 Local Anaesthetics Flashcards
What are anaesthetics?
Drugs used to prevent pain for a limited period of time for surgical or other procedures
What is the difference between local and general anaesthetics?
Local - prevent localised pain or nociception and prevent tactile sensation
General - also induce loss of consciousness
What is the mechanism of action in local anaesthetics?
Block electrical signalling in neurones by blocking VG Na+ channels
What 3 subunits make up voltage-gated ion channels?
Alpha, beta1 and beta2
Describe the structure of the alpha subunit in VG ion channels. (2)
One single polypeptide chain with extracellular domains
4 transmembrane domains each with 6 a-helical regions
Where are the voltage sensors located on the VG ion channel?
Hydrophobic domain of a subunit
Describe the linkage of the beta subunits to the alpha subunit in VG ion channels. (3)
B2 subunit linked covalently to a subunit
B1 not linked
2 B-units anchor a-subunit into lipid membrane
How do local anaesthetics interact with the voltage-gated ion channel?
Plug the transmembrane pore
What form do local anaesthetics bind in?
Ionised (hydrophilic) form
How do local anaesthetics cross membranes if they can only bind to the site of action in an ionised form?
Exploit difference in pH outside and inside cell
Describe the general structure of a local anaesthetic. (2)
Aromatic domain ensures lipid solubility
Basic side chain ensures molecules are ionised at physiological pH
What is the duration of local anaesthetic action limited by?
Hydrolysis of ester/amide bond and lipid solubility of agent
Describe the movement of local anaesthetic from outside to inside a cell. (3)
Lipid soluble base enters axon
pH lower inside axon
Ionisation occurs
What is the difference between the esters and the amides?
Esters metabolised in plasma by esterases with shorter T1/2
Amides metabolised in liver by CYP3A4,1A2
How can local anaesthetics be manipulated? (2)
Restrict site of action and prolong durations of action by coadministering adrenaline
Accelerate speed on onset of anaesthetic by using slightly alkaline solution
Do all nerves show similar susceptibility to local anaesthetics?
Different types of axons show different sensitivity
Block conduction in small diameter fibres more than large
Give an example of small and large diameter nerve fibres.
Nosciceptive (pain fibres) small
Motor axons large
What is use-dependent block and why does it occur?
Depth of block increases with an increase in action potential frequency
Occurs because anaesthetic gains access to and has higher affinity for channels more readily when open and/or inactive
Give a CNS and cardiovascular side effect of local anaesthetics.
CNS - confusion, agitation
CVS - hypotension
Why do local anaesthetics cause cardiovascular side effects? (2)
Inhibition of sympathetic activity
Inhibition of sodium conductance in cardiac tissue
Why is local anaesthetic not very effective in inflamed tissue?
Change in pH (more acidic) causes ionisation of drug before it crosses membrane
Name 3 drug targets for chemical transmission.
G-protein coupled receptors
Ligand gated ion channels
Synthesis
Release
Uptake
Give a drug target for electrical transmission.
Voltage-gated ion channels
Give an example of other drugs targeting ion channels.
Anticonvulsant/antiepileptic drugs
How do anticonvulsant/antiepileptic drugs exploit use dependent block?
Block high frequency discharge that occurs during a seizure without effects the low frequency firing of neurones in normal state
Give an example of an anticonvulsant/antiepileptic drug.
Phenytoin
Carbamazepine
