Local Anaesthetics Flashcards
Quick brief outline of generation of APs •
- Depolarising stimulus
– Na+ channels open, Na+ enters cell - Inactivation
– Na+ channels close, K+ channels open, K+ leaves cell - Cell refractory state
– Na+ channels restored to resting state but K+ channels still open so cell is refractory - Resting state
– Na+ and K+ channels restored to resting state
Difference between normal potentials & end-plate potentials
These are all-or-nothing events
not like end-plate potentials which are GRADED POTENTIALS
Explain the structures of LAs, using specific examples
There are 3 components to a LA:
o Aromatic region – very lipid-soluble/hydrophobic
o Amine side-chain – hydrophilic
o Ester or Amide bond.
COCAINE – ester – Ester smokes cocaine.
LIDOCAINE – amide.
One LA doesn’t obey the above structure law – Benzocaine:
• No basic amine group so WEAKER POTENCY
MoA of LAs of VGSCs?
Hydrophilic pathway (top pathway – channel open):
• gives rise to the use-dependency of LAs
- The drug remains in equilibrium between ionised and unionised forms (as all LAs are weak bases).
- Unionised form (B) – can pass across membranes but CANNOT have any action.
- Ionised form (BH+) – is needed to have an action but CANNOT pass across membranes.
- This pathway is use-dependent as the channels need to be open for the CATIONIC DRUG (BH+) to access the VGSCs.
Once inside the channel, it stereochemically inhibits the passage of Na+ from the outside to the inside of the cell
Hydrophobic pathway (bottom pathway, much less important):
- Lipid-soluble drugs can access the hydrophobic pathway and drop into the channel even when the channel is closed (they are NOT use-dependent).
(Ludleys!!)
Important facts about ALL LAs?
They are ALL WEAK BASES (pKa 8-9)
AND so are mostly ionised and so LESS pass into the axons of neurones
• as they have a high pKa, this means they are use-pH-dependent
o INFECTED TISSUES are normally slightly acidic and so the LA is less effective as more will be ionised
Explain the use-dependency of LAs
Use-‐dependency
• the more active the cell is, the more frequently its sodium channel will be open and the more it will be blocked
• this is a useful feature of LAs because it gives a greater degree of selectivity for nociceptive neurones
• when conducting pain, the nociceptive neurones fire rapidly
Explain the general effects of LAs
- Prevent generation and conduction of APs
- Do NOT influence resting membrane potentials
- May influence: (LAZ)
(a) Channel gating – e.g. hold an inactivated state in a channel
(b) Surface tension – lower surface tension - Selectively block:
(a) Small diameter fibres – e.g. nociceptive pain fibres.
(b) Non-myelinated fibres – pain fibres are often small (Adelta-fibres) and unmyelinated (C-Fibres)
6 RoA for LAs?
(1) Surface anaesthesia
(2) Inflitration anaesthesia
(3) IV regional anaesthesia
(4) Nerve block anaesthesia
(5) Spinal anaesthesia
(6) Epidural anaesthesia
Explain the FIRST 2 RoA of LAs
(1) Surface anaesthesia – spray or powder form:
• Sore throat relief
o Mucosal surfaces – e.g. mouth, bronchial tree
o High [conc] can lead to systemic toxicity
(2) Infiltration anaesthesia – SC injection:
• Post-surgery sutra LA analgesia
o Used in minor surgeries and SC injection directly into tissues (the sensory nerve terminals)
o Adrenaline is co-administered to vasoconstrict to:
(a) Slow down diffusion of LA away from the site of injection – lower concentration of LA needed.
(b) Reduce systemic toxicity
Explain the NEXT 2 RoA of LAs
(3) IV regional anaesthesia – IV injection distal to a pressure cuff:
• Trigger finger repair
o Used in limb surgery.
o Systemic toxicity if the cuff is released prematurely (needed to cut off blood flow so the LA does NOT move beyond area where it is meant to be)
(4) Nerve block anaesthesia – injection:
• Tooth extraction
o Injection close to nerve TRUNKS – e.g. dental nerves.
o Widely used – low doses and slow onset of action.
o Vasoconstrictor co-administration often
Explain the LAST 2 RoA of LAs?
(5) Spinal anaesthesia – intrathecal (sub-arachnoid space injection):
• Hip replacement:
o Injection close to spinal ROOTS – e.g. lower limb surgery
o Reduces BP (due to preganglionic SNs) and so can cause prolonged headache
(1) Glucose can be added to increase specific gravity so the LA doesn’t travel up the CSF to the brain
(6) Epidural anaesthesia – injection into epidural space:
o Injection close to spinal ROOTS – e.g. lower limb surgery, painless childbirth
o Cons – slower onset and higher doses required
o Pros – more restricted action, less effect on BP
Explain the pharmokinetics of lidocaine vs. cocaine Absorption PPB Metabolism Plasma t1/2
Lidocaine (amide) • T1/2 = 2h • Good absorption • 70% PPB • Hepatic metabolism – N-dealkylation
Cocaine (ester) • T1/2 = 1h • Good absorption • 90% PPB • Hepatic and plasma metabolism – non-specific esterases
What are some unwanted effects of Lidocaine
CNS – paradoxical effects:
Stimulation (?)
Restlessness, confusion
Tremor
(?) = would think something that blocks nerve transmission would be a depressant BUT the GABA system is sensitive to LA so its signalling is reduced = excitation of CNS
CVS – due to Na+-channel blockade:
Myocardial depression
Vasodilation
Reduction in BP
What are some unwanted effects of Cocaine?
Cocaine – SNS actions (blocks monoamine transporters):
CNS:
Euphoria, excitation – due to blocking effects in re-uptake of NA
CVS:
Increased CO
Vasoconstriction
Increased BP
All CVS effects due to increased sympathetic output!!
Bupivacaine?
Has a half-life/duration of action lasting 6 hours so is used in epidural anaesthesia (injected into fatty epidural space and affects spinal roots)
Slower onset as given OUTSIDE of SC
