L08 Local Anaesthetics Flashcards
Explain the property of electrical excitability.
To generate propagated action potentials via voltage-gated sodium channels on either nerve cells or muscle cells:
- Nerve cells: Results in communication in the nervous system
- Muscle cells: Results in initiation in mechanical activity in cardiac & striated muscles
Describe the stages of electrical excitability of voltage-gated sodium channels.
Voltage-gated sodium channels open transiently when membrane is depolarised, thus allowing Na+ to always flow from ECF to ICF.
- Inactivated: Ion flow is blocked by gating mechanism (NOT due to closing of channel)
- Deactivated: Ion flow is blocked by closing of channel
- Activated: Ion flow is achieved
Explain the mechanism of action of local anaesthetics (LA).
1) Stop axonal conduction by blocking voltage-gated sodium channels in axonal (intracellular) membrane when applied locally in appropriate concentration.
- Prevents Na+ ion entry from ECF to ICF
- Subsequently slow down or bring electrical conduction to a halt
2) Entry of LA requires them to be initially protonated at physiological pH 7.4, in order to pass thru lipid bilayer from ECF to ICF.
- Due to high pKa of esters/amides (LA)
- Subsequently needs to be changed back to deprotonated form after passing thru lipid bilayer to block Na channels at the gating mechanism
- Thus, many LAs bind most strongly to inactivated & activated states via interaction w/ residues of S6 transmembrane helical domain (i.e. gating mechanism)
3) Passage of train of action potential causes Na channels to cycle thru open & inactivated states
- Depth of LA nerve block increases w/ action potential frequency
- LA gain access to Na channel more readily when channels are open
- LA have higher affinity for inactivated states than resting (closing) states
- More effective during pain (more action potential)
What are some limitations associated with the use of LA? Are there ways to overcome them?
1) Limited use in inflammation
- Acidic pH during inflammation may result in shifting of equilibrium that favours protonated states of LA.
- Protonated LA are unable to pass lipid bilayer membrane as easily, resulting in a drop in effect.
- Avoid use of LA if affected area is inflammed.
2) Non-selective modifiers of neuronal function
- i.e. LA block action potentials in all neurons to which they have access to
- To achieve selectivity, need to deliver LA to limited area to prevent non-nociceptive fibre neurotranmissions to be affected.
- Limit application of LA to topical on skin or limited area via injection
What are some factors influencing LA action?
1) Lipophilicity:
- More lipid-soluble drugs are more potent & act longer.
- Able to pass through lipid bilayer better
2) Type of nerve:
- Size: Smaller nerve > larger nerve
- Freq. of firing: High (sensory) > low (motors) -> since we are trying to modulate pain
- Position: Circumferential (i.e. superficial) > deep (e.g. large trunk nerve)
- Myelination: Myelinated > non-myelinated -> myelinated neurons have higher lipid content
- Size > myelination: Small myelinated axons > Small non-myelinated axons > Large myelinated axons etc.
- Nociceptive and sympathetic transmissions are blocked FIRST!!
3) pH dependency:
- LA molecules are weak bases (pKa 8-9) & are mainly ionised at physiological pH 7.4
- Alkaline pH = increased LA activity since proportion of ionised LA is low
- Acidic pH = decreased LA activity since proportion of ionised LA is high
- pH plays a critical role in LA penetrating nerve sheath & axon membrane in order to reach inner end of Na channel to binding to gating mechanism
Which LAs are considered to be more hydrophobic?
More potent:
Bupivacaine, etidocaine & tetracaine
Which LAs are considered to be less hydrophobic?
Less potent:
Lidocaine, mepivacaine & procaine
Name some examples of ester LA.
Compulsory: Procaine & tetracaine
Optional: Cocaine & benzocaine
Name some examples of amide LA.
Compulsory: Lidocaine, mepivacaine & bupivacaine
Optional: Etidocaine, prilocaine & ropivacaine
Which LA has a short duration of action?
Procaine
Which LA has a medium duration of action?
Lidocaine & mepivacaine
Which LA has a long duration of action?
Tetracaine & bupivacaine
How are ester LAs eliminated from the patient?
Plasma/tissue non-specific esterases
How are amide LAs eliminated from the patient?
Hepatic enzymes
Describe the pharmacokinetic profile of LA.
A: Absorption into systemic circulation determined by blood flow at site of administration
- LA w/ small size, high lipid solubility & low ionisation @ tissue pH (i.e. pKa closer to physiological pH) will end up w/ faster onset.
D: Follows two-compartmental model
M: Ester LA metabolised by plasma/tissue non-specific esterases & amide LA metabolised by hepatic enzymes
