2. Local anaesthetics Med Chem

Name two natural sodium channel blockers.

Tetrodotoxin and Saxitoxin.

How do tetrodotoxin and saxitoxin work?

They bind to the sodium channel and block Na+ entry, preventing nerve signal transmission.

What is a sodium channel gating modulator?

A compound like batrachotoxin that keeps the sodium channel open, leading to continuous nerve firing.

What are the two main classes of local anaesthetics?

Esters and Amides.

Give an example of an ester-type local anaesthetic.

Procaine.

Give an example of an amide-type local anaesthetic.

Lidocaine.

How do pH and pKa influence local anaesthetic effectiveness?

They affect the ionization state of the drug, influencing onset and duration of action.

What are the two mechanisms of action for local anaesthetics?

Hydrophilic and Hydrophobic pathways.

Describe the hydrophilic pathway.

The anaesthetic enters the cell, becomes protonated, and blocks the Na+ channel from the inside when open.

Describe the hydrophobic pathway.

The anaesthetic diffuses through the membrane and directly blocks the closed Na+ channel.

Why does lidocaine have a faster onset than bupivacaine?

Lidocaine has a lower pKa (7.9) compared to bupivacaine (8.4), meaning more of it is in the active form at physiological pH.

How can local anaesthetic activity be modified?

Through electron-donating or withdrawing groups (EDG or EWG) and linker substitutions.

What role does lipophilicity play in local anaesthetic design?

More lipophilic anaesthetics tend to have a longer duration of action.

What is the function of steric shielding in drug design?

It protects the drug from enzymatic degradation, increasing its duration of action.

What are the two classes of muscle relaxants?

Depolarizing and non-depolarizing muscle relaxants.

How do depolarizing muscle relaxants work?

They act as agonists at the nicotinic acetylcholine receptor, causing prolonged depolarization and muscle relaxation.

How do non-depolarizing muscle relaxants work?

They act as antagonists at the nicotinic acetylcholine receptor, preventing acetylcholine from binding and causing muscle paralysis.

What are the essential components of the cholinergic pharmacophore?

A charged nitrogen (N) and a hydrogen bond acceptor (HBA), spaced at an optimal distance (~4.4 Å).

What is Ing's Rule of 5?

A guideline stating that increasing chain length beyond 5 atoms reduces activity.

Give an example of a depolarizing muscle relaxant.

Suxamethonium

How does suxamethonium work?

It mimics acetylcholine but is not rapidly broken down, leading to prolonged receptor activation and muscle relaxation.

What is a natural source of depolarizing muscle relaxants?

Curare (tubocurarine), derived from Chondrodendron tomentosum.

Why can suxamethonium be fatal in some individuals?

Some people lack the enzyme to degrade suxamethonium, leading to prolonged paralysis.

How do non-depolarising muscle relaxants work?

They competitively block acetylcholine at the nicotinic receptor, preventing muscle contraction.

Give examples of non-depolarizing muscle relaxants.

Atracurium, Pancuronium, and Vecuronium.

What is the mechanism of self-degradation for atracurium?

Hoffmann elimination, a process that allows it to break down spontaneously without enzymatic metabolism.

What is laudanosine, and why is it important?

It is an inactive metabolite of atracurium that can accumulate and cause seizures in high doses.