Principles of Local Anaesthesia Flashcards
what are the steps of action potential generation?
- Depolarising stimulus
– Na+ channels open, Na+ enters cell. - Inactivation
– Na+ channels close, K+ channels open, K+ leaves cell. - Cell refractory state (TARGET to prolong)
– 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.
all or nothing events
(EPPs are graded however)
what are local anaesthetics?
they induce reversible neuronal conduction block when applied locally
what are the 3 components of LAs?
o Aromatic region (ring) – very lipid-soluble/hydrophobic. o Amine side-chain – hydrophilic. o Ester or Amide bond
how do the two types of LA differ in structure?
ester or amide linkage
example of LA with ester linkage
cocaine
example of LA with amide linkage
lidocaine
what LA is an exception in terms of structure?
benzocoaine
has no basic amine group therefore weaker potency
what are two main pathways of action of LAs?
1) hydrophilic (channel open)
2) hydrophobic
describe the hydrophilic pathway of LA action
- The drug remains in equilibrium between ionised and unionised forms (as all LAs are weak bases).
- Unionised form passes into axonal membrane
– can pass across membranes but CANNOT have any action once inside (need to be ionised) - when equilibrium is reached in the axon, Ionised form can bind to Na+ channel from the inside
– is needed to have an ACTION but can’t pass across membranes. - This pathway is use-dependent as the channels need to be open for the cation drug to access the VGSCs.
describe the hydrophobic pathway LA action
Lipid-soluble drugs can access the hydrophobic pathway and drop into the sodium channel at axonal membrane level even when the channel is closed (they are NOT use-dependent).
how do the hydrophilic and hydrophobic pathways differ?
the hydrophilic pathway is use dependent and needs the sodium channel to be open
the hydrophobic pathway is not use dependent and does not need an open sodium channel
what does use-dependency mean for the effect of the LA?
the more rapidly a neurone fires (i.e. spends a lot of time in the open state) , the better it can be blocked
important for the hydrophilic pathway using an open channel
what kind of neurones are targeted by LAs?
why do they target VGSCs?
sensory neurones with small diameter fibres or non-myelinated fibres (tend to be pain neurones)
preferably to sodium channels in the inactivated stage to increase the refractory period
what are the effects of LAs?
- Prevent generation and conduction of APs.
- Do not influence resting membrane potentials.
- May influence:
a. Channel gating – e.g. hold an inactivated state in a channel.
b. Surface tension – lower surface tension.
what fibres do LAs selectively block?
the slower conduction fibres a. Small diameter fibres – e.g. nociceptive pain fibres. b. Non-myelinated fibres – pain fibres are often small (Adelta-fibres) and unmyelinated (C-Fibres).
what kind of substances are LAs? what pKa do they have?
weak bases (therefore pKa 8-9)
what effect does the high pKa have on state of the LAs in acidic condition?
mostly ionised (when pH is low)
what effect will infected tissues have on the infiltration of LAs?
infected tissues are slightly acidic so LA is less effective as more of it will be ionised
NB LAs are weak bases
what are the main routes of LA administration?
- surface anaesthesia (spray or powder form)–> sore throat relief
- infiltration anaesthesia (SC injection) –> post-surgery suture LA analgesia
- IV regional anaesthesia (IV injection distal to pressure cuff)–> trigger finger repair
- nerve block anaesthesia (injection)–> tooth extraction
- spinal anaesthesia (intrathecal/subarachnoid injection) –> hip replacement
- epidural anaesthesia (epidural injection)–> child birth
describe Surface anaesthesia
- formulation
- admin sites
- toxicity
o Powder or spray form
o Mucosal surfaces – e.g. mouth, bronchial tree.
o High concentrations can lead to systemic toxicity e.g. cardiac
describe infiltration anaesthesia
- uses
- admin site
- technique
o Used in minor surgeries and SC injection directly into tissues (the sensory nerve terminals)
o Adrenaline is co-administered to vasoconstrict to:
1. Slow down diffusion of LA away from the site of injection
– lower concentration of LA needed.
2. Reduce systemic toxicity.
what must be co-administered with LAs in minor surgeries? why is this given?
why is it not given in extremities?
adrenaline :
- vasoconstrictor so the LA can be restricted to a local area without spreading systemically
- this reduced the dosage of the LA and also reduces the toxicity risk
! not in the extremities due ischaemic tissue damage risk,
NE is not given
describe IV regional anaesthesia
- uses
- admin
- technique
o Used in limb surgery and extensive wounds
- injected directly into the bloodstream
o Systemic toxicity if the cuff is released prematurely (leave cuff on for 20 minutes)
describe nerve block anaesthesia
- admin site
- onset
- technique
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.
describe spinal anaesthesia
- admin site
- uses
- effect on BP
- technique
o Injection close to spinal roots into subarachnoid space
– e.g. lower limb surgery, abdominal,
o Reduces BP due to blockage of preganglionic sympathetic neurones and so can cause prolonged headache.
o Glucose can be added to increase specific gravity so the LA doesn’t travel up the CSF to the brain.
what is added to spinal anaesthesia to avoid it reaching the brain?
Glucose:
added to increase specific gravity so the LA doesn’t travel up the CSF to the brain.
describe epidural anaesthesia
- admin site
- uses
- cons
- pros
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 (limited effect on the pregangSNS neurones)
describe the pharmacokinetics of lidocaine (amide)
T1/2= 2 hours
o Good absorption.
o 70% PPB (less than cocaine)
o Hepatic metabolism – N-dealkylation
describe the pharmacokinetics of cocaine (ester)
T1/2= 1 hour
o Good absorption.
o 90% PPB.
o Hepatic and plasma metabolism – non-specific esterases.
what are the 2 types of characteristic unwanted effects of most LAs?
CNS and CVS effects
what are the unwanted CNS effects of Lidocaine? what is significant about them?
Stimulation.
Restlessness, confusion.
Tremor.
this is paradoxical (as GABA transmission is inhibited at first, at higher concs everything falls)
what are the CVS side effects of lidocaine?
what facilitates these effects?
due to Na+-channel blockade leading to reduced intracellular calcium (less contraction)
Myocardial depression.
Vasodilation.
Reduction in BP
NB cocaine has the opposite effects on the CVS (increased SNS do to amine re-uptake blockage)
what are the CNS side effects of cocaine?
Euphoria, excitation
due to blocking effects in re-uptake of NA.
what are the CVS side effects of cocaine?
Increased CO.
Vasoconstriction.
Increased BP.
what is the difference in CVS side effects of lidocaine and cocaine?
lidocaine has depressive effects on the CVS
cocaine has stimulating effects on the CVS
what is the principle target of LAs?
Voltage Gated Na+ channels involved in AP propagation
what is cocaine a unique local anaesthetic in terms of unwanted effects?
cocaine is an exception when it comes to side effects:
has the opposite effects on the CVS and CNS of what is expected from local anaesthetics
this is due to the ability to block monoamine reuptake (which other LAs don’t do) enhancing the CNS effects
therefore causes euphoria (CNS) and raised BP (CVS) etc
how does plasma conc of LA determine the side effects of local anaesthetics?
Most LAs produce a mixture of stimulant and depressive effects
Low concs of plasma LA give depressant effects
while high concs give stimulant effects
