Local Anesthetics 💉 Flashcards
Which sites of the neuron have lots of voltaged gated sodium channels?
Note of Ranvier
Gaps in the myelin sheath
Important site for Local anaesthetics
Is the nerve bi-layer filled with lipids?
Yes, therefore drugs need to ve lipophilic
How do local anaesthetics work?
Reversibly block the never conductance that transmits nociception to the brain
Binds to selective site INSIDE of the voltage gated sodium channel in the excitable membranes of nerve cells
Stops sodium from passing through channels.
What type of conformation do Local Anaesthetics prefer?
Activated (open) and inactivated (closed) channels
Pharmacophore of LA?
3 major components
- lipophilic aromatic head
- linked by either an ESTER or AMIDE chain to the
-Terminal hydrophobic amine tail
Can the ionised form of LAs penetrate the gate?
No. Ionised forms of LA are +ve charged, can’t penetrative the gate but CAN BLOCK THE VOLTAHE GATED NA CHANNEL FROM THE INSIDE
How many carbon atoms in the linkage region of LA provided the ideal banalnce between potency and toxicity?
1 to 3 carbons.
= longer/more branched chains have increased potency and increases toxicity
What determines the onset of action of LAs?
pH or pKa?
pKa(dissocation factor)
pKa = the pH at whi h 50% of the drug is in the lipid soluble unionised form and 50% are in the water soluble ionised form
Structure- activity relationship:
Does the ionised (BH+) drug or unionised (B+) penetrate the membrane?
Unionised (B+) drug penetrates the membrane
Structure activity relationship
Does the ionised BH+ or the unionised B+ block the Voltage gated sodium channel?
Unionised B+ penetrated the membrane, it gets converted to ionised inside.
= The ionised BH+ blocks the gate, preventing the influx of Na entering the cell = no action potential = no message of pain
How is the cation-to-base ratio critical to conduction block?
Too little base = too few local anaesthetics molecules will reach the neural target
Too little cation to bind to Na channel Receptor sites = Too few Na channels will.be closed to ion traffic
Why are local anaesthetics less effective in infected or inflamed tissues?
Infection = acidic environment = greater portion of ionised drug and less local anaesthetic base
= less unionised drug availabile to cross the nerve membrane.
Local anaesthetics with a lower pKa have a:
FASTER OR SLOWER
ONSET OF ACTION?
Lower pKa = faster onset of action
What 2 factors are associated with greater potency of LAs?
- Lipid solubility:
More lipophilic = greater permiability and affinity
- lipid solubility determined by aromatic ring, its substituants + substitutions to tertiary amine
- Molecular Weight:
Larger molecule = greater lipid solubility
Eg.
Bupivacaine and Ropivacaine are more lipid soluble than Lidnocaine.
What are concentrations of LAs expressed in (units)?
% or mg/mL
Speed of onset
If a LA has a pKa closer to 7.4, does this increase or decrease its onset of action?
PKa closervto 7.4 = increases portion of unionised La = more rapid onset
Eg. Lidnocaine (pka 7.8) has a more rapid onset than Bupivacaine (pka 8.1)
Does a INCREASE OR DECREASE concentration of solution increase rapid onset?
Increase concentration of solution
Do smaller or larger molecular Weight increase onset pf action?
Smaller mW = faster onset
Does High lipid solubility result in sequestration of neighbouring adipose tissue and slower onset?
Yes
How does site of injection effect speed of action?
- SUBCUT = IMMEDIATE
- SPINAL = MINUTES
- PERIPHERAL NERVE BLOCK = longest
Metabolism of ESTERS
Hydrolysed rapidly in plasma by
PSEUDOcholinesterase OR
PABA (which can cause allergic reactions)
Metabolism of AMIDEs
Metabolised by liver
Is there any cross reactivity between AMIDE AND ESTER groups?
No cross-reactivity between the 2 groups
Does lipid solubility increase or decrease DURATION of ACTION?
LA with higher lipid solubility remains bound to nerve membranes longer snd have higher binding affinity to AAG = LONGER DURATION OF ACTION
