Local anaesthetics

Question 1

What are the unwanted effects of cocaine overdose?

Answer 1

CNS - excitation, euphoria CVS - increased CO, hypertension, vasoconstriction (all sympathetic actions)

Question 2

What are the unwanted effects of lidocaine overdose?

Answer 2

CNS - restlessness, confusion, tremor (paradoxical) CVS - myocardial depression, vasodilation, hypotension (caused by Na channel blockade)

Question 3

How can local anaesthetics be administered?

Answer 3

1. Surface - mucosal (mouth, bronchial tree), spray/powder 2. Infiltration = directly into tissues - sensory nerve terminal 3. IV regional - distal to pressure cuff 4. Nerve block 5. Spinal 6. Epidural

Question 4

When would LAs be administered by infiltration?

Answer 4

Minor surgery

Question 5

Why are LAs by infiltration co-administered with adrenaline?

Answer 5

Adrenaline causes vasoconstriction So LA doesn’t spread (decreases systemic toxicity) And increases duration of action

Question 6

What is a local anaesthetic?

Answer 6

A drug which reversibly blocks neuronal conduction when applied locally

Question 7

What is a problem with surface LAs?

Answer 7

Have to use a high concentration Can cause systemic toxicity

Question 8

When would LAs be administered by regional IV?

Answer 8

Limb surgery

Question 9

If the pressure cuff is released prematurely when LAs are administered by regional IV, what issue could arise?

Answer 9

Systemic toxicity

Question 10

Where are epidural LAs injected?

Answer 10

Into fatty tissue of epidural space Spinal roots

Question 11

When may an epidural LA be used?

Answer 11

Childbirth Abdominal, pelvic, lower limb surgery

Question 12

When may a spinal LA be used?

Answer 12

Abdominal, pelvic, lower limb surgery

Question 13

Where are spinal LAs injected?

Answer 13

Sub-arachnoid space Spinal roots

Question 14

Why are spinal LAs injected with glucose

Answer 14

To increase specific gravity

Question 15

What are the disadvantages of epidural LA over spinal LA?

Answer 15

Slower onset Higher doses need to be used More restricted action - less effect on BP

Question 16

When may nerve block LA be used?

Answer 16

Dental work

Question 17

What is co-injected with nerve block LA?

Answer 17

A vasoconstrictor

Question 18

Where is nerve block LA injected?

Answer 18

Close to target nerve trunks

Question 19

Are LAs acids or bases?

Answer 19

Weak bases PKa 8-9

Question 20

What are the effects of local anaesthetics?

Answer 20

• Prevent generation and conduction of action potentials - May influence channel gating - Selectively block nociceptive pain fibres - small diameter fibres (A-delta and C-neurones have small diameter axons), non-myelinated fibres (pain C fibres)

Question 21

Do LAs influence resting membrane potential?

Answer 21

No

Question 22

Why is infected tissue harder to anaesthetise?

Answer 22

Infected tissue tends to be acidic Larger proportion of LA in ionised state (BH+)

Question 23

What are the side effects of spinal anaesthesia?

Answer 23

Decreased BP Prolonged headache

Question 24

What are the pharmacokinetics of lidocaine?

Answer 24

• Good absorption at mucous membranes - 70% plasma protein binding - Hepatic metabolism by N-dealkylation - Plasma half life = 2 hours

Question 25

What are the pharmacokinetics of cocaine?

Answer 25

- Good absorption at mucous membranes - 90% plasma protein binding - Hepatic and plasma metabolism by non-specific esterases - Plasma half life = 1 hour

Question 26

Compare the plasma half lives of lidocaine and cocaine

Answer 26

Lidocaine = 2 hours Cocaine = 1 hour

Question 27

Compare the absorption at mucous membranes of lidocaine and cocaine

Answer 27

Both good

Question 28

Compare the plasma protein binding of lidocaine and cocaine

Answer 28

Lidocaine = 70% Cocaine = 90%

Question 29

Compare the metabolism of lidocaine and cocaine

Answer 29

Lidocaine = hepatic, N-dealkylation Cocaine = hepatic and plasma, non-specific esterases

Question 30

Are LAs largely unionised or ionised at physiological pH?

Answer 30

Largely ionised

Question 31

What is the general structure of a LA?

Answer 31

Aromatic region + basic amine side-chain Linked by either an ESTER or AMIDE bond.Benzocaine, relatively weak but a useful surface local anaesthetic(NOTE: it is the exception to the whole general strucure rule). Bupivacaine is an important one.

Question 32

How do the structures of lidocaine and cocaine differ?

Answer 32

Cocaine has an ester bond Lidocaine has an amide bond

Question 33

Explain the hydrophilic pathway of LA action

Answer 33

- Only unionised (lipid soluble) LA (B) can pass through connective tissue sheath and thr axon membrane - LA can only work from inside the neurone (as ionised form - BH+) 1. Unionised LA (B) passes across connective tissue sheath + axon membrane into neurone 2. Equilibrium established btwn B + BH+ 3. Cationic form (BH+) of LA is formed inside 4. BH+ can only bind w/Na channel when channel is open bc binding site is inside channel 5. Once inside channel, it stereochemically inhibits passage of Na ions from outside to inside of cell = HYDROPHILIC PATHWAY = main MOA = gives rise to use-dependency of LA

Question 34

Summarise an action potential

Answer 34

1. Depolarisation 2. Resting Na channels open, Na enters cells 3. Na channels close (inactivation), K channels open, K leaves cell 4. Na channels restored to resting state but K channels still open tf cell refractory 5. Na and K channels restored to resting state tf cell will respond normally to further depolarising stimulus

Question 35

What is use dependency of LAs?

Answer 35

The more active the cell is, the more frequently its Na channels will be open and the more it will be blocked bc the binding site for cationic LA (BH+) is INSIDE the channel

Question 36

Why is use dependency a useful feature of LAs?

Answer 36

Gives LAs a greater degree of selectivity for nociceptive neurones When conducting pain, nociceptive neurones fire rapidly

Question 37

You would think that something that blocks nerve transmission would be a CNS depressant. Why is the CNS stimulated by lidocaine?

Answer 37

- GABA system is very sensitive to LAs - GABA signalling is reduced - Causes CNS excitation - GABA is main inhibitory NT

Question 38

Why does spinal anaesthesia cause a prolonged headache?

Answer 38

LA mixes in with CSF Can diffuse towards brain

Question 39

How can you control the level of spinal anaesthesia?

Answer 39

- Add some glucose w/LA - Increases specific gravity - LA stays more or less in one place - Can be moved by tilting patient rather than freely diffusing through CSF

Question 40

Why does spinal anaesthesia cause a drop in blood pressure?

Answer 40

- Inject into CSF - Preganglionic sympathetic neurones are v susceptible to block by LA - Reduced sympathetic outflow to heart and vasculature - Drop in BP

Question 41

Explain the hydrophobic pathway of LA action

Answer 41

- Only unionised LA can pass through connective tissue sheath and thr axon membrane - LA can only work from inside the neurone 1. LA can also pass into neuronal membrane in unionised form (B) 2. Some highly lipid soluble LAs can drop straight into Na channel 3. They then become ionised in Na channel and block channel = HYDROPHOBIC PATHWAY