LA Flashcards
Define LA
Loss of sensation ins specific area of the body by depression of excitation in nerve endings or an inhibitor of the conduction process in peripheral nerves
List some qualities of the ideal LA (12)
Specific and reversible Non-irritant produces no permeant damage no systemic toxicity high therapeutic ratio active topically and by injection Rapid onset suitable duration of action Chemically stable and sterilisable Combine with other agents Non-allergic Non-additive
Of the 12 qualities of an ideal LA, what is the hardest to achieve?
Specificity
What is the consequence of the lack of specificity of LAs?
It will affect transmission of any excitable tissue they come into contact with e.g. CNS, cardiac, motor system
List 4 uses of LA in dentistry?
Operative pain management
Post-operative pain management
Diagnosis
Haemostasis
How can LA be used in diagnosis?
If tooth ache cannot be localised can give infiltrations adjacent to each tooth and see which one gets rid of the pain
Why is LA not commonly used for diagnosis of tooth ache anymore?
Pulp sensibility testing is available (EPT, ethyl chloride)
How is LA used for haemostasis?
Uses the adrenaline within the LA to cause vasoconstriction of the BV in that area - reduce bleeding
Name the 2 theories of LA action?
Membrane expasnion therory
Specific receptor theory
Describe generally how LA works?
Blocks/inhibits sensory signals from tooth to brain
Describe an action potential
Resting potential - the inside of the cell is negative compared to the outside fo the cell. 3K+ out for 1Na+ in
Depolarisation - voltage gated sodium ion channels open due to electronic stimulus - Na+ move into the cell and the inside of the cell becomes positive compared to the outside of the cell. If the membrane potential reaches the threshold potential the maximum response will be elicited.
Repolarisation - once the action potential has occurred voltage gated Na+ channels close. the positive charge in the cell causes voltage gated K+ channel to open, K+ move down electrochemical gradient out of the cell. Membrane returns to resting potential. depolarisation tends to overshoot - making the inside of the cell more negative = hyperpolarisation = refractory period where another AP cannot occur
What part of an action potential is targeted by LA?
Voltage gated NA+ channels
Name the gates within voltage gated Na+ channels?
M gate and H gate
Make and halt
Describe the membrane potential and positioning of the voltage gated Na+ channel at rest
Inside of the cell -ve compared to outside
M gate closed, H gate open
How does the voltage gated Na+ channel change during depolarisation?
M gate opens, Na+ flood in - inside of cell = +ve
How does voltage gated Na+ channel change during repolarisation?
H gate closes
This stops Na+ moving into the cell
The inside fo the cell is +ve - this opens voltage gated K+ channels and K+ moves out of the cell making the inside -ve
Describe membrane expansion theory
La enters the nerve cell membrane, this causes the membrane to expand, this blocks the Na+ channels and stops Na+ entering the cells, this stops depolarisation = no AP
Describe specific receptor theory
Specific receipt int he H gate of the VG Na+ channel.
LA bind to this receptor
Stops the H gate opening - keeps Na+ channel closed - hold the cell in the refractory period - no AP can be fired
In what subunit does NA pass through the VG Na+ channel?
alpha
Describe the position of the M gate on the VG Na+ channel
Alpha subunit split into 4 domains, each contains 6 subunits
M gate is the 4th subunit
Describe the position of the H gate on the VG Na+ channel
Link of protein between domain 3 and 4 within the alpha subunit
Name the 3 parts fo an LA molecule
Aromatic group, intermediate chain, substituted amino terminal
Function of the aromatic group on LA?
Makes it lipophilic
Function of substituted amino terminal on LA?
Makes it hydrophilic
Function of intermediate chain on LA?
Allows optimal separation of lipid and water soluble components
Allows classification of LA = ester or amides depending on what chain it is
Why does LA need to lipophilic and uncharged?
LA binding is intracellular so needs to cross the membrane.
Why does LA need to be charged when in the cell?
Specific binding requires charged molecules
LA needs to be lipophilic and uncharges to cross the membrane but charged to bind to the receptor - how is this achieved?
LAs are weak bases:
in solution LA exists as uncharges base and charged cation –> lipid soluble and enter the cell, but when is gets there becomes charged
Describe how weak bases allow for passing the membrane and binding to receptor.
In solution the LA will be a mix of uncharged base and charged cation. So when injected into the body, the uncharged base portion will cross the membrane. The weak base will always want to be in equilibrium so when in the cell half of the uncharged base will dissociate into charged cations. These charged cations will bind to specific receptors on the H gate
Why is it important for LA to have a high proportion of uncharged molecules soon after injection?
Makes the LA more effective because more can pass through the membrane - enters the cell quicker = acts quicker
What term describes the ratio of uncharged to charged molecules? What 2 factors govern this?
Ionisation
pH and PKa
What is pKA?
Dissociation constant
How do pH and pKa relate to ionisation?
Lower pH = less uncharged molecules present
Lower pKa = more uncharged molecules present
Why does LA not tend to work in areas of infection?
Infected tissues have lower pH = makes the weak base have less uncharged molecules = does not enter the cell as quickly
List 4 chemico-phsycial properties that influence LA action. How do they effect the action
Ionisation (pH and pKa) - onset
Partition coefficient - onset
Protein binding - duration of action
Vasodilatror ability - duration of action
Describe partition coefficient. How does this effect LA
Measures lipid solubility
Higher partition coefficient = more lipid soluble = crosses the lipid bilayer quicker.
Higher partition coefficient = faster onset
How does protein binding effect LA?
Degree of protein binding related to duration of action.
Bound portion of drug acts as a reservoir that cannot be used until the free drug has been used up. Higher protein binding = longer action
How does vasodilator ability effect LA?
More vasodilation = LA washes away quicker so short duration
Are most LAs vasodilators or vasoconstrictors?
Vasodilators
What is in an LA cartridge?
Anaesthetic agent Vasoconstrictor Reducing agent (stop vasoconstrictor breaking down) Ringers solution (solvent the drugs are dissolved in) No longer have preservatives because of allergies
