Local anaesthesia Flashcards
Outline neuronal actin potential
-70mV:
Rapid depolaisation (ie due to pain):
Resting Na+ channels open (VSSC)
Na+ enters cells
Na+ channels close after a couple of ms (inactivation)
K+ channels open, K+ leaves cell
Na+ channels restored to resting state but K+ channels still open therefore cell refractory (greater stimulus would still be required, because some of the depolarisation would be loss due to the open K+ channels)
Na+ and K+ channels restored to resting state therefore cell will respond normally to further depolarizing stimulus
Define local anaesthetics
LAs = Drugs which reversibly block neuronal conduction when applied locally
Differentiate AP and motor end plate potentials
With neuronal, it’s all or nothing
With the motor end plate you can get graded potentials at the nAChR
Improve
Differentiate 2 different LAs
CONSTANT:
1. Aromtic region (benzene)
- Basic amine side-chains
DIFFERENCE:
Linked by bridging ester or amide group
Give example of LAs with ester and an amide bridging group
ESTER: Cocaine
(remember that ester smokes cocaine)
AMIDE: Lidocaine
(lignocaine)
Which LA doesn’t have an amine sidechain
What is the effect on function
Benzocaine
It just has alkly side chain
Weak LA properties, and is lipid soluble (used as a surface anaesthetic). It is useful in throat lozenges.
Why is the 2 structures of LA important
Because it affects their PD and their DOA
Why are LAs denoted by B
They are all weak bases
What is connective tisse sheath
Contains lots of axons
Which form of the LA can gain access to the connective tissue sheath and get into the neurons
Unionised form (there is equilibrium betwen cation and unionised form in the blood, and only the UNionised form is lipid soluble enough to get through the connective tissue sheath AND across the axon membrane of the nociceptive neurone )
What must LAs do to get into the sensory neuron
They must gain access to the inside of the sensory neuron. To do this, they must be in their unionised form.
They cannot work from the outside, they have to get into the axon to work
Outline the hydrophilic pathway
The unionised form of the LA gains access to the neuron by diffusing through the plasma membrane fo the axon.
Then inside, the equilibrium between unionised and ionised form of LA re-establises. And now it is the IONISED form of the LA inside the neuron that can have the action, but stereochemically blocking the VGSC and preventing depolarisation of the sensory neurone
The cationic form of LA blocks the VGSC
Why is there use dependency of LAs
They work better when the sensory neuron is being used more
(the more rapidly they are firing, the more effect they will have)…
this is because, the more active the sensory neuron, the longer the Na+ channels are open, and the higher the chance that the ionised LA (inside the neuron) gains access to and blocks the Na+ channels, from the inside.
This means that the LAs have a degree of selectivity, because of the USE DEPENDENCY, and the fact that the neurons that are transmitting the pain will be firing more, means that these will be more affected by the LA.
Not that the selectivity is not total though, as motor fibres can be blocked by LA and this can cause muscle weakness and relaxation
Compare the hydrophilic and hydrophobic pathway for VGSS
Hydrophilic is the MAJOR pathway.
However, for lipid-soluble LAs (i.e. the ones without the amine side chain, benzocaine), the hydrophobic one is important.
As the unionised form crosses the axonal membrane, some can drop into the ion channel and convert into the cation ionised form to block the ion channel.
This means that, by the hydrophobic route, the LAs can drop into a closed channel AS WELL AS an open channel.
How do LAs affect the resting potential
They don’t
They only affect the generation of the action potential in the nociceptive neurons
How do LAs affect the channel gating
The sodium channels can exist in resting, open and inactivated state.
LAs can bind to VGSC, and some bind preferably to the inactivated state, and hold the channel in the inactivated state. This prolongs the absolute refractory period
Contributes to mechanism of action.
What are LA selective to
Small diameter fibres
Non-myelinated fibres
This good because:
A-Delta and C fibres are both small diameter
C fibres also are unmyelinated
These are the pain fibres which are more selective for the LA
(and neurons which are firing more often because of the use dependent block)
What is the pKa of LA
LAs are weak bases (pKa 8-9)
So they will be largely ionised in physiological pH and not loads will gain access to the neurons
What is the impact of infected tissue for LAs
Infected tissue
There is acidic metabolited produced, so more of the LA will be in its ionised form and less will gain acces
Where is the surface anaesthesia used
Mucosal surface (mouth, bronchial tree)
How is surface anaesthesia used
Spray (or powder)
What shold you be aware of with surface anaesthaesia
Hgh concentations required so beware of systemic toxicity
What is infiltraton of anaesthesia
Directly into tissues → sensory nerve terminals
What is infiltration anaesthesia used for
Minor surgery
What is co-adminstered wth infiltration anaesthesia and why
Adrenaline co-injection
(LA is maintained at site of action for longer due to the vasoconstrictor, so we can use lower dose of the LA and we get less systemic toxicity)
When would you not include adrenaline with infiltration anaesthaesia
In the extremeties (you could cause ischaemic damage)
What is intravenous regional anaestheia
i.v. distal to pressure cuff
When is IV regional anaesthesia used
Limb surgery
What can cause systemic toxicity IV regional anesthesia used?
Systemic toxicity of premature cuff release
When is nerve block anaesthesia
Close to nerve trunks e.g. dental nerves
Advantage and disadvantage of nerve block anaesthesia
Widely used – low doses – slow onset
What can be co-administered with nerve block anaesthesia
Vasoconstrictor co-injection
Where is spinal anaesthesia injected
Sub-arachnoid space – spinal roots =INTRATHECAL
(through the spinous processes, through dura and the arachnoid membranes)…… njected into the CSF
What is spinal anaesthesia used for
Abdominal, pelvic, lower limb surgery
Advantage of spinal anaesthesia
Low doses
Disadvantage of spinal anaesthaesia
- Reduces BP:
pre-ganglionic sympathetic neurons are small dimater and unmyelinted and can be blocked by LA
So you can get reduced sympathetic to the heart and vasculature so you cna get dilatation and reduced HR/contractility
- Headache
How can spinal aeasthesia be manipulated
Glucose (↑ specific gravity)
so you cna control where is sits by tiltin the table
Where is the epidural anaesthesia injected
Fatty tissue of epidural space – spinal roots
What is epidural used for
Abdominal, pelvic, lower limb surgery
+
painless childbirth
Disadvantage of epidural
Slower onset – higher doses
than spinal
Advantage of epidural
More restricted action – less effect on b.p.
Absorption of lidocaine and cocaine?
Both good
Distribution of lidocaine and cocaine
bth highly plasma protein bound (70% for lidocine and 90% for cocaine)
Outline metabolism of lidocaine
Hepatic
N-dealkylation
(reminder, conversion from codeine to morphine is O-dealkylation (=slow))
Outline metabolim of cocaine
Liver and plasma
Non-specific esterases
75%-90% metabolised to inactive metabolite ()
Plasma t1/2 of lidocaine and cocaine. Account for the difference
Lidocaine-2h (as amides more resistant to metabolism, undergoes N-dealkylation instead of cholinesterase)
Cocaine- 1hr
What is used as a long duration of action LA
Bupivacaine (doa ~6hr; epidural anaesthesia)
An amide local anaesthetic
Lidocaine unwanted effects
CNS: (paroxidical)
- Stimulation
- restlessness, confusion
- tremor/seizure
CVS (due to Na+ channel blockade)
- myocardial depression
- vasodilatation
- ↓ b.p.
Why does lidocaine cause excitatory effects on the CNS?
The GABA neurons in the CNS are particularly sensitive to LA,
therefore these neurons are shut down first, increasing excitability
After a while, you get generalised depression of nervous system including respiratory depression
Unwanted effects of cocaine
- CNS
Euphoria/excitation - CVS
- ↑ C.O.
- vasoconstriction
- ↑ b.p.
POTENTIALLY CARDIAC ARYTHMIAS
ALL DUE TO SYMPATHEITC EFFECTS OF COCAINE
Account for the unwanted CNS effects of NA
due to sympathetic effects, not Na+ blockade.
Coaine blocks reuptake of NA being released from central NA neurones
It also acts on the other MA transporters, so increases dopamine and seratonin
