Local Anaesthetics Flashcards
What is the site of action of local anaesthetics and what does this tell us about the drug
The site of action is inside the sodium channel, so the drug has to get through several layers of lipid to get to the site of action. It also need to be in its ionised form to have the best action, so drug must be both hydrophilic and lipophilic.
What is local anesthetic?
Something that causes loss of feeling/sensation in a localised area.
The size of the area anaesthetised can vary and be large or small.
This is something that is interfering with action potential propagation, specifically voltage gated sodium channels.
Specifically it interferes with impulse transmitting in peripheral or spinal cord nerves.
There is no loss of consciousness.
How do local anaesthetics work?
Normally the resting membrane is stable in an inactive neuron.When a local anesthetic blocks the sodium channel, the threshold potential increases, so the recovery from the block is slower, and the duration of the refractory period period increases, meaning the frequency of impulse conduction decreases. This means that as well as removing the ability to generate an action potential, it takes longer for the nerve to recover after the block is removed.
Local anaesthetic is reversible, so once the block dissociates from the channel, all function returns to normal.
Describe the process of action potential activation.
A stimulus is received, which affect the dendrites of a neuron.
There is small changes in sodium or calcium permeability, or an inhibition of potassium permeability.
This depolarises the membrane, which then stimulates large numbers of voltages gated sodium channels which are located on the axonal hillock.
There is then a large influx of sodium, and then the sodium channels inactivate, and during the inactivated phase there is no influx of sodium.
At the same time potassium channels open, and there is an effluent of potassium, causing the membrane to start to repolarise.
This is the refractory period, when there is no influx of sodium, however the channel is not yet reset to closed, so it is not possible for another AP to be generated yet.
Because of this process, the AP is propagated down the length of the axon, where the are further channels that are activated. The distribution of these channels depend on whether it is a myelinated or unmyelinated nerve.
Local anesthetic works by blocking these channels and preventing the signal from spreading down the nerve to the CNS
What are the types of nerve and their myelination that are most affected by local anaethetics?
The nerves responsible for pain and sympathetic transmission are blocked first. These tend to be small myelinated or non-myelinated axons. The larger myelinated axons are the last to be blocked, and this normally only occurs when in large concentration or applied in a site specific manner.
What is the non specific mode of action of local anaesthetics?
It is believed that increased pressure caused by dissolution of the molecules into the membrane causes the channel to distort so it cannot function.
What is use dependence?
It crosses the channel more readily when the channel is already open( activated)
It has higher affinity for the inactivated state than the resting state, as it cannot easily bind to the channel when it is closed.
This is termed use dependence, as the local anaesthetic will act quicker on nevers that are in use, than ones that are in the resting position.
What pharmokinetic factors affects the rate of action of local anaesthetics?
Rate of tissue penetration, which is dependant on molecular weight, lipid solubility, length of side chains etc
What are the two classes of local anesthetics and what is the difference?
Ester type - require plasma esterases which are found all through the body.
Amide type - require amidases which are associated with liver function. Because of this, changes in liver function can alter duration of action in these anesthetics
The difference is in the mechanism by which they are metabolised.
What parts make up a local anesthetic
A lipophilic group - aromatic ring
Link chain - the amide or ester
An ionisable group- a tertiary amine
The hydrophobic group give lipid solubility, the hydrophilic groupd give water solubility, so both parts are important for function.
Remember it must be in its ionized state to work, but it must first cross the membrane to get to the area which require it to be in the unionized form.
What are the expected half lives of the two types of local anaesthetic?
Ester types are hydrolysed in the plasma very quickly, so have short half lives.
Amide Types are metabolised in the liver so have longer half lives, but is still variable.
How can the duration of action be increased in local anaesthetics?
In casing the dose.
Adding a vasoconstrictor agent ie noradrenaline.
Why is it beneficial to add a vascoconstrictor to local anaesthetics?
It increases the duration of action.
It reduces wash out - when injecting the LA to a blood vessel, this will naturally cause dilation. This increases perfusion, which increases the chances that the anaesthetic will be washed away, which reduces the effectiveness at the desired location, but could also cause problems elsewhere in the body.
What determines the rate of onset in local anaesthetics?
The concentration - higher means faster action
Is hit use dependent or not - faster on areas Being used if so.
Protein binding - is any anaesthetic lost by binding to proteins, therefore not in its active form. This also causes problems as if conc is increased to overcome this binding, if the extra then gets released there is a higher risk of side effects.
What is an example of a rapid action local anaesthetic?
Lignocaine has a rapid onset, and a moderate duration, with a half lif of 2 hours.
It is the most commonly used local anaesthetic, and can be used with adrenaline as an epidural and spinal anaesthesia.
Not recommended in third degree heart block as it can slow if not stop heart.
It can also be used for surface anaesthesia in creams or gels.
