Local Anaesthetics Flashcards
What is the structure of LAs important for
Pharmacodynamics and pharmacokinetics
Define what is meant by a local anaesthetic
LAs = Drugs which reversibly block neuronal conduction when applied locally
Outline the stages involved in generating the action potential
Depolarising stimulus will cause small depolarisation (stimulus could be injury or application of excitatory NT)- will trigger opening of VGSCs if threshold potential reached (-55mV).
- Depolarising stimulus – Na+ channels open, Na+ enters cell- VGSCs open- rapid depolarisation
- Inactivation – Na+ channels close (inactivated state), K+ channels open, K+ leaves cell.
- Cell refractory state – Na+ channels restored to resting state but K+ channels still open so cell is refractory.- need a larger than normal stimulus to cause an action potential (due to ongoing K+ efflux)
- Resting state – Na+ and K+ channels restored to resting state.
What is important to remember when Na+ and K+ channels return to their resting state
Na+ and K+ channels restored to resting state therefore cell will respond normally to further depolarizing stimulus
What are the key properties of action potentials
These are all-or-nothing events, not like end-plate potentials which are graded potentials (which depend on numbers of Ach and nicotinc receptors)
Very fast- 10-15 msecs
What are the basic components of local anaesthetics
o Aromatic region – very lipid-soluble/hydrophobic.
o Amine side-chain – hydrophilic (tertiary amine)
o Ester or Amide bond.
Cocaine – ester – Ester smokes cocaine.
Lidocaine – amide.
Compare an ester to an amide bond
Ester- C=O, -O
Amide = C-NH,=O
List the LAs with an ester bond
Procaine
Cocaine
Tetraqcaine (amethocaine)
Clinchocaine (dibucaine)
List all the LAs with an amide bond
Lidocaine (lignocaine/xylocaine)
Prilocaine
Bupivacaine
- Name a local anaesthetic that doesn’t fit the structure of all other local anaesthetics.
Benzocaine – it has an alkyl group rather than the basic amine side chain
NOTE: this means that it is relatively weak but highly lipid soluble (good for surface anaesthesia)
What type of chemical do all LAs belong to
Weak bases
What is the most important pathway for the MoA of LAs
The hydrophilic pathway.
Describe the hydrophilic pathway
sodium channels allow propagation of impulses during regenerative processes (transmit painful stimuli through a series of action potentials along the noiciceptive nerve fibres to the thalamus and sensory cortex).
Injected LA reaches equilibrium of B (unionised) and BH+ (ionised) forms
Unionised forms need to cross over the connective tissue sheath, and then over the membrane of the axon to the inside of the neurone
LA inside neurone needs to reach equilibrium again
BH+ cationic ionised form then binds to inside of voltage sensitive sodium channels
BH+ blocking stops propagation of action potentials (stereochemically hinders the influx of Na+)- no action potential generated.
Describe the use-dependency of the hydrophilic pathway
The VGSC needs to be open for the LA to bind to the channel and prevent the influx of Na+
This makes it selective for the nociceptive nerve fibres which will be rapidly firing to transmit painful stimuli.
This (and also the myelin sheath) makes LAs less likely to bind to and block motor neurones- which would otherwise cause paralysis or muscle weakness.
Describe the hydrophobic pathway
Important for more lipid soluble LAs (benzocaine)
Dissolves in membrane of axon
Form ionised form (BH+)- once it has bound to the VGSC.
Blocks VGSC this way
Channel doesn’t need to be open- hence no use-dependence.
Differentiate between the properties of the ionised and unionised forms of LAs
- Unionised form – can pass across membranes but CANNOT have any action.
- Ionised form – is needed to have an action but CANNOT pass across membranes.
Summarise 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. - Selectively block:
a. Small diameter fibres – e.g. nociceptive pain fibres.
b. Non-myelinated fibres – pain fibres are often small (Ad-fibres) and unmyelinated (C-Fibres).
§ LAs are 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 (due to metabolites released by bacteria) and so the LA is less effective as more will be ionised
Describe the effects of LAs on channel gating
There is some suggestion that local anaesthetics bind more strongly to the sodium channels in their inactive state
Once bound to the sodium channel, it then holds it in the inactive stage for longer thus increasing the refractory period and reducing the frequency of action potentials
Describe the effects of LAs on surface tension
They lodge into the plasma membrane and reduce surface tension of the membrane
This leads to non-selective expansion of the lipid membrane and leads to non-specific inhibition of ion channels
What are the 6 routes of administration for LAs
Surface anaesthesia Infiltration anaesthesia Intravenous regional anaesthesia Nerve block anaesthesia Spinal anaesthesia Epidural anaesthesia
Describe surface anaesthesia
Mucosal surface (mouth, bronchial tree, throat, nose, eyes)- can be used for sore throat relief Spray (or powder)- or ointment for wounds High concentrations → systemic toxicity- can travel as bolus to heart or brain
Describe infiltration anaesthesia
Directly into tissues → sensory nerve terminals Minor surgery (sport injuries, suturing, draining cysts, removing abscesses). Adrenaline co-injection (NOT extremities- don't want ischaemic damage) Injected subcutaneously.
Why is adrenaline co-injected with local anaesthetic in infiltration anaesthesia
Adrenaline – this causes vasoconstriction and increases the duration of action of the anaesthetic meaning that a lower dose can be used
It also slows bleeding at the site of injection and reduces the amount of local anaesthetic going into the systemic circulation- thus reducing the toxicity that it can cause.
NOTE: felypressin (V1 agonist) can also be used
Suggest a use for infiltration anaesthesia
Post-surgery sutra LA analgesia.
Describe intravenous regional anaesthesia
i.v. distal to pressure cuff
Limb surgery
Systemic toxicity of premature cuff release
Should keep on cuff for 20 minutes (but no more than 45 minutes as not to cause ischaemic limb damage)
Describe the purpose of a cuff in intravenous regional anaesthesia
i.v. distal to pressure cuff
Limb surgery
Systemic toxicity of premature cuff release
Wait for LA to diffuse into the tissues.
Suggest a use of intravenous regional anaesthesia and when it would be used over infiltration anaesthesia
Trigger finger repair., repairing fractured bones in forearm
Used when the area is larger
Describe nerve block anaesthesia
§ Nerve block anaesthesia – injection: Tooth extraction.
o Injection close to nerve TRUNKS – e.g. dental nerves.
o Widely used – low doses (close to nerve trunks) and slow onset of action (needs to cross connective tissue of nerve fibre and then axonal membranes of sensory neurones).
o Vasoconstrictor co-administration often (often adrenaline).
Can also inject into brachial plexus, intercostal nerves etc.
What are the two centrally acting routes of LA
Spinal and epidural anaesthesia.
Describe spinal anaesthesia
Sub-arachnoid space – spinal roots Abdominal, pelvic, lower limb surgery Low doses (because its circulated in the CSF). ↓ b.p.; prolonged headache Glucose (↑ specific gravity)
Why does spinal anaesthesia decrease BP
It can cause a drop in blood pressure because it anaesthetises the nerve roots and the preganglionic sympathetic nerves are particularly sensitive to blockade by local anaesthetics (they have a small diameter)
This leads to reduced sympathetic output and hence a drop in blood pressure
Give shot of ephedrine to increase BP again
Describe the purpose of adding glucose to spinal anaesthesia
Increase the specific gravity
The anaesthetist can then tilt the patient to move the bolus to a more localised area of the spinal cord.
Why may spinal anaesthesia cause headaches
CSF containing LA going to the brain
Leakage of CSF from the penetration site.
Describe spinal anaesthesia
Fatty tissue of epidural space – spinal roots
Uses as for 5) and painless childbirth
Slower onset – higher doses (as we are injecting into fatty tissue space- more chance of systemic toxicity as higher doses needed)
More restricted action – less effect on b.p.
Describe the pros and cons of epidural anaesthesia compared to spinal (intrathecal) anaesthesia
o Cons – slower onset and higher doses required.
o Pros – more restricted action, less effect on BP.- Unwanted effects similar to those of spinal anaesthesia but less probable, because longitudinal spread of LA is reduced
Suggest a use for spinal anaesthesia
Hip replacement.
Compare the absorption of lidocaine and cocaine across mucous membranes
Both good
Hence both good for surface anaesthesia
Compare the plasma protein binding of lidocaine and cocaine
Lidocaine- 70%
Cocaine- 90%
Describe the metabolism and half-life of lidocaine
Metabolism- Liver microsomal enzymes- hepatic N-dealkylation (alkyl side chain split off)
Half-life- 2 hours
Amides tend to be more stable (broken down less readily) than the esters, meaning that they have a longer duration of action.
Describe the metabolism and half life of cocaine
Metabolism- Liver and plasma non-specific esterases - split through bridging bond of ester
Half-life- 1 hour
Describe the uses of Bupivacaine
Bupivacaine (doa ~6hr; epidural anaesthesia) - also spinal anaesthesia.
Describe the paradoxical effects of Lidocaine on the CNS seen at low doses
CNS
stimulation
restlessness, confusion
tremor- may become a convulsion.
GABA neurones are most sensitive-so these effects are observed first (low doses)
However, CNS depression (which may lead to respiratory depression) will be seen at higher doses.
Describe the unwanted effects of Lidocaine on the CVS
Due to Na+ channel blockade on cardiac myocytes and VSMC
myocardial depression
vasodilatation
↓ b.p.
Describe the unwanted effects of cocaine
CNS
euphoria, excitation (inhibits reuptake of dopamine)
CVS (inhibits reuptake of NA)
↑ C.O.
vasoconstriction
↑ b.p.
Cocaine has sympathomimetic actions.
CVS drive Due to increased sympathetic drive caused by blockade of monoamine transporters
