Anesthetic agents

Question 1

Mechanism of action of anesthetic drugs

Answer 1

• They potentiate effects of cys-loop ligand-gated ion channels such as GABA/glycine receptors (also receptors for acetylcholine and 5-HT). They bind to hydrophobic pockets and act as agonist. GABA and glycine receptors allow influx of Cl ions, which leads to hyperpolarization of neurons.
• Allows for opening of K channels, so K will move out of the cell – hyperpolarization -> reduce membrane excitability.
• Inhibit ligand-gated NMDA/glutamate ion channels. Glutamate is excitatory, when blocking NMDA channel, it reduces excitation by preventing release of glutamate in the presynaptic neuron.

Question 2

Local anaesthetics

Answer 2

MOA: they produce a local nerve block by blocking the voltage-gated Na channels from the inside.
Two ways local anesthetic enters:
1. Action potential arrives -> opens voltage-gated Na channels ->local anesthetic comes in though the open Na channel (prefers to bind to the inactivated form).
2. Local anesthetic needs to be un-ionized to get through the lipid membrane -> once bound intracellularly its ionized.

High activity at alkaline pH, where ionized molecule concentration is low. Low activity at acidic pH, where ionized molecule concentration is high.

The more the channels are opened, the greater the block. Block mainly occurs at high frequencies of action potential.

An active nerve is more sensitive to local anesthetics. This is because local anesthetics in their charged form gain access to the binding site only when Na+ channels are in the open state. Also, because local anesthetics bind with the highest affinity to inactivated Na+ channels.

Adverse effects:
Mainly due to escape in systemic circulation: CNS (restlessness, tremor, confusion, death due to respiratory depression), Cardiovascular (partial or complete heart block, dysrhythmias).