LOCAL ANAESTHETICS

Question 1

Describe the process of generation of neuronal action potential

Answer 1

1) depolarization occurs –> Resting Na+ channels open –> Na+ enters cells
(sharp upward stroke)

2) Na+ channels close (inactivation), K+ channels open –> K+ leaves cell
3) Na+ channels = inactivated –> restored to resting state but K+ channels = still open therefore cell refractory
4) Na+ and K+ channels BOTH = restored to resting state –> so cell will respond normally to further depolarizing stimulus (post refractory phase)

Question 2

define what is meant by Local Anesthetics

Answer 2

Drugs which reversibly block neuronal conduction when applied locally

Question 3

what are common features of structure of LA

Answer 3

COMMON FEATURES:

• all have aromatic region
• all have basic amine side chain
• bridging groups = either ESTER (e.g cocaine) or AMIDE (e.g Lidocaine) bond

“Ester smokes cocaine”

exceptions: Benzocaine = weak LA –> no basic side chain
(good surface local anesthetic)

Question 4

Describe the MoA of LA

Answer 4

a) Hydrophilic Pathway (use dependent) - MOST LA
- only unionized LA –> can pass through lipid memb –> and outer memb of sensory neurone –> to pass into inside of neurone
- LA needs access to inside of neurone to work

• unionised form blocks multi- sensitive NA+ channel
  binds to site iside channel and blocks na+ influx
• reduce propagation of Na+ channels

more rapidly neurones are firing –> more Na+ channels = in open state –> increase in effect of LA

b) hydrophobic pathway (e.g benzocaine)
- unionized drug drops into (closed) ion channel
- channel don’t need to be open

Question 5

note: ALL LA = WEAK BASES

Answer 5

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Question 6

What re the main effects of LAs

Answer 6

They:

• Prevent generation and conduction of APs
• Do NOT influence resting membrane potential
  ( only affect generation of AP)
• May also influence channel gating

Selectively block

a) small diameter fibres (great preference for LA)
b) non myelinated fibres

Question 7

multi-sensitive sodium channel = in 3 states

what are the 3 states?

Answer 7

• resting
• open state
• inactivate state
• -> goes back to resting state

–> some LA binds preferentially to inactivated state
(prolong refractory period) –> contribute to action of LA effects

Question 8

LA –> shows PH dependency –> because they are weak bases

PKa 8-9

Answer 8

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Question 9

What are some routes of administration of LAs ?

Answer 9

1. Surface anaesthesia
   - Mucosal surface (mouth, bronchial tree)
   - Spray
   - High concentrations → can cause systemic toxicity
2. Infiltration anaesthesia
   - LA Directly into tissues → sensory nerve terminals
   - (subcutaneous application)
   - Minor surgery
   - Adrenaline co-injected
   –> Adrenaline = vasoconstrictor –> so lower dose of LA can be used
   –> also reduced risk of systemic toxicity
   (not extremities –> as it can cause ischemia of digits)
3. Intravenous regional anaesthesia
   - i.v. distal to pressure cuff
   - Limb surgery
   - Systemic toxicity of premature cuff release (keep cuff on for at least 20 mins)
4. Nerve block anaesthesia
   - LA injected close to nerve trunks e.g. dental nerves
   - Widely used – low doses – slow onset
   - Vasoconstrictor co-injection (e.g adrenaline)
5. Spinal anaesthesia
   - injected into Sub-arachnoid space – spinal roots
   - (between L4 + L5)
   - Abdominal, pelvic, lower limb surgery
   - Low doses
   - keep aware of any ↓ b.p.; prolonged headache
   - can mix w Glucose (↑ specific gravity) –> increase density of solution –> manipulate LA target area (tilt bed to meet target site)
6. Epidural anaesthesia
   - inject into Fatty tissue of epidural space – spinal roots
   - similar uses as spinal anaesthesia and painless childbirth
   - DSAVTG = Slower onset – higher doses –> more risk for systemic toxicity
   - But allows more restricted action w less effect on b.p.

Question 10

Describe pharmacokinetic properties of

a) Lidocaine
b) Cocaine

Answer 10

Describe pharmacokinetic properties of

BOTH –> good absorption –> can be used as surface anesthetics

a) Lidocaine
absorption = good 
PPB = 70%  
Metabolism = Hepatic N-dealkylation 
Plasma T1/2 = 2h 

b) Cocaine
absorption = good
PPB = 90%
Metabolism = Liver + Plasma + non-specific Esterases 
Plasma T1/2 = 1h

Question 11

NOTE Bupivacaine = more resistant to metabolism

–> DoA = 6 hr
epidural anaesthesia

Answer 11

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Question 12

What are SE of Lidocaine

Answer 12

CNS (paradoxical)

• stimulation
• restlessness, confusion
• tremor

CVS (Na+ Channel Blockade)

• myocardial depression
• vasodilatation
• ↓ b.p.

Question 13

What are SE of Cocaine

Answer 13

(Sympathetic action stimulation)

CNS
- euphoria, excitation

CVS

• ↑ C.O.
• vasoconstriction
• ↑ b.p.

Question 14

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 14

ANS: D: Is a weak base

Question 15

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 15

ANS: C: Enhance action potential propagation