Local Anaesthetics

Question 1

What is the structure of LAs important for

Answer 1

Pharmacodynamics and pharmacokinetics

Question 2

Define what is meant by a local anaesthetic

Answer 2

LAs = Drugs which reversibly block neuronal conduction when applied locally

Question 3

Outline the stages involved in generating the action potential

Answer 3

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).

1. Depolarising stimulus – Na+ channels open, Na+ enters cell- VGSCs open- rapid depolarisation
2. Inactivation – Na+ channels close (inactivated state), K+ channels open, K+ leaves cell.
3. 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)
4. Resting state – Na+ and K+ channels restored to resting state.

Question 4

What is important to remember when Na+ and K+ channels return to their resting state

Answer 4

Na+ and K+ channels restored to resting state therefore cell will respond normally to further depolarizing stimulus

Question 5

What are the key properties of action potentials

Answer 5

 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

Question 6

What are the basic components of local anaesthetics

Answer 6

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.

Question 7

Compare an ester to an amide bond

Answer 7

Ester- C=O, -O

Amide = C-NH,=O

Question 8

List the LAs with an ester bond

Answer 8

Procaine
Cocaine
Tetraqcaine (amethocaine)
Clinchocaine (dibucaine)

Question 9

List all the LAs with an amide bond

Answer 9

Lidocaine (lignocaine/xylocaine)
Prilocaine
Bupivacaine

Question 10

5. Name a local anaesthetic that doesn’t fit the structure of all other local anaesthetics.

Answer 10

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)

Question 11

What type of chemical do all LAs belong to

Answer 11

Weak bases

Question 12

What is the most important pathway for the MoA of LAs

Answer 12

The hydrophilic pathway.

Question 13

Describe the hydrophilic pathway

Answer 13

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.

Question 14

Describe the use-dependency of the hydrophilic pathway

Answer 14

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.

Question 15

Describe the hydrophobic pathway

Answer 15

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.

Question 16

Differentiate between the properties of the ionised and unionised forms of LAs

Answer 16

2. Unionised form – can pass across membranes but CANNOT have any action.
3. Ionised form – is needed to have an action but CANNOT pass across membranes.

Question 17

Summarise the effects of LAs

Answer 17

1. Prevent generation and conduction of APs.
2. Do not influence resting membrane potentials.
3. May influence:
   a. Channel gating – e.g. hold an inactivated state in a channel.
   b. Surface tension – lower surface tension.
4. 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

Question 18

Describe the effects of LAs on channel gating

Answer 18

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

Question 19

Describe the effects of LAs on surface tension

Answer 19

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

Question 20

What are the 6 routes of administration for LAs

Answer 20

Surface anaesthesia 
Infiltration anaesthesia 
Intravenous regional anaesthesia 
Nerve block anaesthesia 
Spinal anaesthesia 
Epidural anaesthesia

Question 21

Describe surface anaesthesia

Answer 21

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

Question 22

Describe infiltration anaesthesia

Answer 22

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.

Question 23

Why is adrenaline co-injected with local anaesthetic in infiltration anaesthesia

Answer 23

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

Question 24

Suggest a use for infiltration anaesthesia

Answer 24

Post-surgery sutra LA analgesia.

Question 25

Describe intravenous regional anaesthesia

Answer 25

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)

Question 26

Describe the purpose of a cuff in intravenous regional anaesthesia

Answer 26

i.v. distal to pressure cuff
Limb surgery
Systemic toxicity of premature cuff release
Wait for LA to diffuse into the tissues.

Question 27

Suggest a use of intravenous regional anaesthesia and when it would be used over infiltration anaesthesia

Answer 27

Trigger finger repair., repairing fractured bones in forearm

Used when the area is larger

Question 28

Describe nerve block anaesthesia

Answer 28

§ 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.

Question 29

What are the two centrally acting routes of LA

Answer 29

Spinal and epidural anaesthesia.

Question 30

Describe spinal anaesthesia

Answer 30

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)

Question 31

Why does spinal anaesthesia decrease BP

Answer 31

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

Question 32

Describe the purpose of adding glucose to spinal anaesthesia

Answer 32

Increase the specific gravity

The anaesthetist can then tilt the patient to move the bolus to a more localised area of the spinal cord.

Question 33

Why may spinal anaesthesia cause headaches

Answer 33

CSF containing LA going to the brain

Leakage of CSF from the penetration site.

Question 34

Describe spinal anaesthesia

Answer 34

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.

Question 35

Describe the pros and cons of epidural anaesthesia compared to spinal (intrathecal) anaesthesia

Answer 35

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

Question 36

Suggest a use for spinal anaesthesia

Answer 36

Hip replacement.

Question 37

Compare the absorption of lidocaine and cocaine across mucous membranes

Answer 37

Both good

Hence both good for surface anaesthesia

Question 38

Compare the plasma protein binding of lidocaine and cocaine

Answer 38

Lidocaine- 70%

Cocaine- 90%

Question 39

Describe the metabolism and half-life of lidocaine

Answer 39

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.

Question 40

Describe the metabolism and half life of cocaine

Answer 40

Metabolism- Liver and plasma non-specific esterases - split through bridging bond of ester
Half-life- 1 hour

Question 41

Describe the uses of Bupivacaine

Answer 41

Bupivacaine (doa ~6hr; epidural anaesthesia) - also spinal anaesthesia.

Question 42

Describe the paradoxical effects of Lidocaine on the CNS seen at low doses

Answer 42

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.

Question 43

Describe the unwanted effects of Lidocaine on the CVS

Answer 43

Due to Na+ channel blockade on cardiac myocytes and VSMC
myocardial depression
vasodilatation
↓ b.p.

Question 44

Describe the unwanted effects of cocaine

Answer 44

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