Local anaesthetics :p3

Question 1

Compare the metabolism of lidocaine and cocaine

Answer 1

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

Question 2

Are LAs largely unionised or ionised at physiological pH?

Answer 2

Largely ionised

Question 3

What is the general structure of a LA?

Answer 3

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 4

How do the structures of lidocaine and cocaine differ?

Answer 4

Cocaine has an ester bond Lidocaine has an amide bond

Question 5

Explain the hydrophilic pathway of LA action

Answer 5

• 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 6

Summarise an action potential

Answer 6

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 7

What is use dependency of LAs?

Answer 7

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 8

Why is use dependency a useful feature of LAs?

Answer 8

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

Question 9

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

Answer 9

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

Question 10

Why does spinal anaesthesia cause a prolonged headache?

Answer 10

LA mixes in with CSF Can diffuse towards brain

Question 11

How can you control the level of spinal anaesthesia?

Answer 11

• 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 12

Why does spinal anaesthesia cause a drop in blood pressure?

Answer 12

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

Question 13

Explain the hydrophobic pathway of LA action

Answer 13

• 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