Local anaesthetics L13 Flashcards
what are anaesthetics
drugs that prevent localised pain and sensation for limited period of time during surgery
general anaesthetics induce loss of consciousness
how do LA work
they block electrical activity in neurones
what is the composition of ions in neurones
inside: K+ and A-
outside: Na+ and Cl-
outside is more positive than outside (-60mv to -90mv)
what is an action potential and what causes it
rapid change in membrane potential
dependant on voltage gated ion channels
describe an action potential
In response to depolarisation above (approx. -55mV)
Voltage gated Na channels open at -55 mV Na+ goes into the cell (concn gradient) Membrane potential rises and polarity changes
Na channels close and Na+/K+ATPase moves Na+ out
K+ pours out of the cell (concn gradient) via voltage gate K channels
Membrane potential falls again
what do LA block in the action potential
voltage gated Na channels
describe the composition of VG Na channels
it has 3 subunits
- Alpha: contains the ion channel
- single polypeptide. It contains extracellular domains, 4 transmembrane domains each comprising 6 A-helical regions
- Beta 1 and 2: anchor alpha to the membrane
- Beta 2 is covalently attached to alpha, beta 1 is not
what does the alpha subunit contain in the hydrophobic domain
voltage sensors that change their orientation when voltage varies. Their orientation determines the configuration of the entire domain and controls the opening and closing of a pore.
what do LA interact with
interact with the A subunit and physically ‘plug’ the transmembrane pore
what form do LA have to be in to bind to binding site and where is the binding site
- why is this an issue
have to be in ionised/ hydrophilic form
the binding site is normally closer to intracellular domain in membrane
hydrophilic ions can not cross the membrane
how do we deal with the ionisation issue
intra and extra cellular domains have slightly different pH’s
this property is exploited
Unionised form gains access through nerve sheath and axon membrane
Ionised form binds in channel
what is the general structure of LA
aromatic group (left), ester or amide group (middle) and basic amine group (right).
what does the basic amine group ensure
the molecules are ionised at physiological pH
what does the aromatic group ensure
ensures lipid solubility.
what does the ester or amide group determine
Duration of action is limited by the hydrolysis of the ester/amide bond and by the lipid solubility of the agent.
esters: Metabolised in plasma by esterases (except cocaine) Shorter T1/2
amide: Metabolised in liver by CYP3A4,1A2 -longer T1/2 consequences in individuals with liver failure
describe the action of LA
The anaesthetic, a weak base, is injected as hydrochloride salt in an acid solution - suitable for injection (i.e. dissolves in solution).
Following injection, the pH increases (due to the higher pH of the tissues, which is usually 7.4) and the drug dissociates, the degree of which depends on pKa, and free base is released (lipid soluble).
Lipid soluble free base enters the axon. Inside the axon the pH is lower (the environment is more acidic, pH7), and re-ionization takes place.
The re-ionized portion enters the Na+ channels and blocks them, preventing depolarization
how can we manipulate LA
- Restrict site of action and prolong durations of action
Coadmininster adrenaline (local vasocontriction via A1 adrenoreceptors - Accelerate the speed of onset of the anaesthetic
Use slightly alkaline solution, this will assist in absorption of the anaesthetic into the nerve tissue
how do all nerves respond to LA
they all have VG Na+ channels
describe why some nerves may respond differently to LA
Block conduction in small diameter fibres more effectively than in large diameter fibres
Nosciceptive (pain) fibres are small diameter and particularly sensitive
Motor axons have a large diameter and are less sensitive
what is use dependant block
depth of block increases with an increase in action potential frequency
Channels is in three states
Resting, open, inactive
Use dependent block occurs because the anaesthetic gains access to, and has higher affinity for the channels more readily when it is open and/or inactive
what are the side effects of LA
occur due to escape of the local anaesthetic into the systemic circulation
- CNS, confusion and agitation
- Cardiovascular, hypotension
- Inhibition of sympathetic activity
- Inhibition of sodium conductance in cardiac tissue
doesnt work well on inflamed or infected tissue as this disrupts pH
what would a drug target if it wanted to target chemical neurotransmission
G-protein coupled receptors
Ligand gated ion channels
Synthesis
Release
Uptake
what would a drug target if it wanted to target electrical transmission
voltage gated channels
what do antihypertensive and antiarrhythmic drugs target
L-type calcium channels
what do antiepileptic or Anticonvulsant target
target voltage gated sodium channels
Exploit use dependence block
Block high frequency discharge that occurs during a siezure without effects the low frequency firing of neurones in their normal state
what is Tetrodotoxin
produced by marine bacteria and defensively by a number of animals such as tropical rain forest frogs and newts and by puffer fish block voltage gated Na+ channels.
(different binding site to LAs)
