Local Anaesthetics (09.03.2020) Flashcards
What are LAs?
Drugs which reversibly block neuronal conduction when applied locally
Generation of an AP
- Depolarisation (Resting Na+ channels open Na+ enters cells)
- Na+ channels close (inactivation) K+ channels open, K+ leaves cell
- Refractory phase (Na+ channels restored to resting state but K+ channels still open therefore cell refractory)
- Back to RP: Na+ and K+ channels restored to resting state therefore cell will respond normally to further depolarizing stimulus
- Painful stimulus from site to primary somatosensory cortex.
- ion fluxes
- all or nothing (not graded responses like at the NMJ)
- msecs
Name some local anaesthetics
- Procaine
- cocaine -> ester
- tetraqcaine (amethocaine)
- cinchocaine (dibucaine)
- lidocaine (lignocaine) -> amide
- prilocaine
- bupivacaine
- benzocaine
LAs - structure
- aromatic region, region with benzene like properties
- basic amine side chain
- ester or amide bond
What are the 2 main groups of LAs?
Esters or amines
-> depending on the bridging group
(they all have aromatic region and basic amine side chain)
Benzocaine
- relatively weak
- lipid soluble
- doesn’t have a basic amine side chain but a Ch2CH3
MoA of LAs
- interact with sodium channels
- work inside the neurone
Hydrophilic pathway: Single most important MoA of all LAs
- unionised form passes the connective tissue sheath and the axonal membranes)
- once inside the axon it is found in both the ionised and unionised form
- cationic form (BH+) can gain access into the sodium channels (they have to be OPEN for this) and bind to its binding site there.
- this stereochemically hinders the flow of Na+ inside the cell
- decreased generation and propagation of action potentials
Hydrohobic pathway:
- tend to dissolve in the membrane
- turn into BH+ first
- can block the channel
- stop Na+ influx
- the LA can drop into aa closed channel
- less important but also a MoA of LAs.
Effects of LAs
- Prevent generation and conduction of APs
- Do NOT influence resting membrane potential
- May also influence (channel gating)
- Selectively block (small diameter fibres a-delta and C-fibres; non-myelinated fibres rather than myelinated - get into neurone more effectively)
- LAs are weak bases (pKa 8-9)
- action of LAs is pH dependent (changes the amount that is ionised)
- Infected tissue tends to be acidic so a higher proportion will be ionised??/ so you have to give a higher concentration
RoA of LAs
- Surface anaesthesia
- Infiltration anaesthesia
- Intravenous regional anaesthesia
- Nerve block anaesthesia
- Spinal anaesthesia
- Epidural anaesthesia
Surface anaesthesia
- Mucosal surface (mouth, bronchial tree)
- Spray (or powder)
- High concentrations needed → can give rise to systemic toxicity
Infiltration anaesthesia
- Directly into tissues (s.c.) → sensory nerve terminals
- Minor surgery
- Adrenaline co-injection (NOT extremities b/c of danger of ischaemic tissue damage) often in the same tube, A is a vasoconstrictor, also less bleeding -> low levels fo adrenaline!
I.v. regional anaesthesia
- i.v. distal to pressure cuff
- Limb surgery
- Systemic toxicity of premature cuff release (leave on for at least 20 minutes but not more than 40)
- regional for a bigger region e.g. forearm
- can be used for resetting a broken bone
Nerve block anaesthesia
- Close to nerve trunks e.g. dental nerves
- Widely used – low doses – slow onset
- Vasoconstrictor co-injection
- you need very accurate injection
Spinal Anaesthesia
- central RoA
- Sub-arachnoid space – spinal roots
- Abdominal, pelvic, lower limb surgery
- Low doses
- ↓ b.p.; prolonged headache after spinal anaesthesia
- Glucose (↑ specific gravity)
- intrathecal also means subarachnoid
- by tilting the table you can control the localisation of the anaesthesia and move the bolus around.
Epidural anaesthesia
- Fatty tissue of epidural space – spinal roots
- abdominal, pelvis, lower limb surgery and painless childbirth
- Slower onset – higher doses
- More restricted action – less effect on b.p.
Pharmacokinetics of Lidocaine
- amide
- good absorption
- PPB: 70%
- Metabolism: hepatic N-dealkylation
- plasma t 1/2 = 2h
amines tend to be more stable than the esters, longer half life.
Pharmacokinetics of Cocaine
- ester
- good absorption
- PPB: 90%
- Metabolism: Liver and plasm; non-specific esterase
- plasma t 1/2 = 1h
Pharmacokinetics of Bupivacaine
- DoA 6h (much longer)
- ## epidural anaesthesia
Unwanted effects of Lidocaine
CNS
- stimulation
- restlessness, confusion
- tremor
=> paradoxical
CVS
- myocardial depression
- vasodilatation
- ↓ b.p.
=> Na+ channel blockade
Unwanted effects of cocaine as a LA
=> sympathetic actions (because of blocking the re-uptake of monamines; slowing the actions of NA in the CVS)
CNS
- euphoria, excitation
CVS
- ↑ C.O.
- vasoconstriction
- ↑ b.p.
SBA 1: Lidocaine:
A: Inhibits reuptake of 5-hydroxytryptamine
B: Blocks voltage-gated K+ channels
C: Is a competitive muscarinic cholinoceptor antagonist
D: Is a weak base
E: Is a general anaesthetic
D
SBA 2:
Which ONE of the following statements about local anaesthetics is INCORRECT? They:
A: Cause blockade of voltage-sensitive sodium channels
B: Block rapidly firing neurones more readily than more slowly firing neurones
C: Enhance action potential propagation
D: Are largely ionised at physiological pH
E: Have their durations of action increased if injected with adrenaline
C
Where do LAs work?
From inside the neurone
What accounts for the use dependency of LAs?
- the hydrophilic pathway as a MoA
- the more a tissue is used the more it is targeted
- the more rapidly the neurone fires the more effectively it can be blocked (quicker and more fully)
- this is because Na+ channels spend more time in the open state and it is more likely for the LA to get in.
- this is advantagous: selectivity to nociseptive sensory neurones
- If there is damage there is more rapid firing of Ads to the thalamus and somatosensory cortex
Could also block motor neurones but not as intensive as sensory neurones. not as much because of the myelination and less rapid firing.
What kind of chemical are all LAs?
weak bases
due to basic amine side chain
