Local Anaesthetics (09.03.2020)

Question 1

What are LAs?

Answer 1

Drugs which reversibly block neuronal conduction when applied locally

Question 2

Generation of an AP

Answer 2

1. Depolarisation (Resting Na+ channels open Na+ enters cells)
2. Na+ channels close (inactivation) K+ channels open, K+ leaves cell
3. Refractory phase (Na+ channels restored to resting state but K+ channels still open therefore cell refractory)
4. 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

Question 3

Name some local anaesthetics

Answer 3

• Procaine
• cocaine -> ester
• tetraqcaine (amethocaine)
• cinchocaine (dibucaine)
• lidocaine (lignocaine) -> amide
• prilocaine
• bupivacaine
• benzocaine

Question 4

LAs - structure

Answer 4

• aromatic region, region with benzene like properties
• basic amine side chain
• ester or amide bond

Question 5

What are the 2 main groups of LAs?

Answer 5

Esters or amines
-> depending on the bridging group

(they all have aromatic region and basic amine side chain)

Question 6

Benzocaine

Answer 6

• relatively weak
• lipid soluble
• doesn’t have a basic amine side chain but a Ch2CH3

Question 7

MoA of LAs

Answer 7

• 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.

Question 8

Effects of LAs

Answer 8

1. Prevent generation and conduction of APs
2. Do NOT influence resting membrane potential
3. May also influence (channel gating)
4. 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

Question 9

RoA of LAs

Answer 9

1. Surface anaesthesia
2. Infiltration anaesthesia
3. Intravenous regional anaesthesia
4. Nerve block anaesthesia
5. Spinal anaesthesia
6. Epidural anaesthesia

Question 10

Surface anaesthesia

Answer 10

• Mucosal surface (mouth, bronchial tree)
• Spray (or powder)
• High concentrations needed → can give rise to systemic toxicity

Question 11

Infiltration anaesthesia

Answer 11

• 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!

Question 12

I.v. regional anaesthesia

Answer 12

• 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

Question 13

Nerve block anaesthesia

Answer 13

• Close to nerve trunks e.g. dental nerves
• Widely used – low doses – slow onset
• Vasoconstrictor co-injection
• you need very accurate injection

Question 14

Spinal Anaesthesia

Answer 14

• 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.

Question 15

Epidural anaesthesia

Answer 15

• 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.

Question 16

Pharmacokinetics of Lidocaine

Answer 16

• 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.

Question 17

Pharmacokinetics of Cocaine

Answer 17

• ester
• good absorption
• PPB: 90%
• Metabolism: Liver and plasm; non-specific esterase
• plasma t 1/2 = 1h

Question 18

Pharmacokinetics of Bupivacaine

Answer 18

• DoA 6h (much longer)
• ## epidural anaesthesia

Question 19

Unwanted effects of Lidocaine

Answer 19

CNS

• stimulation
• restlessness, confusion
• tremor

=> paradoxical

CVS

• myocardial depression
• vasodilatation
• ↓ b.p.

=> Na+ channel blockade

Question 20

Unwanted effects of cocaine as a LA

Answer 20

=> 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.

Question 21

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

Answer 21

D

Question 22

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

Answer 22

C

Question 23

Where do LAs work?

Answer 23

From inside the neurone

Question 24

What accounts for the use dependency of LAs?

Answer 24

• 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.

Question 25

What kind of chemical are all LAs?

Answer 25

weak bases

due to basic amine side chain