Local Anaesthetics Notes

Local anaesthetics

Lidocaine

-Rapid onset, medium duration, Good tissue penetration

Structure

-most of the local anaesthetics are tertiary amines that are connected to a hydrophobic group, often a aromatic compound such as a benzene ring by an amide or an ester bond

-the amine side chains weakly basic- pKa of 8-9, mainly but not completely ionised at physiological pH- important in their ability to penetrate nerve sheath and axon membrane

-inflammed tissue resistant to LA as it is often acidic leading to increased drug ionisation and reduced cellular penetration

- Quaternary comoupnds, QX-314, fully ionised irrespective of pH- are not able to cross the lipid membranes- instead they enter the nerves through open Na channels

-Local anaesthetics are rapidly hydrolysed by enzymes in the blood- LA with ester bonds are rapidly metabolised by esterase enzymes and have a plasma half life of less than 1hour, amides are more stable and are hydrolysed by liver, half life of around 2h.

Mechanism of action

-Local anaesthetics- block initiation and propogation of AP, preventing voltage dependent increase in Na+ conductance

-tertiary amines that are linked to a hydrophobic group enter through the nerve sheath, the perineuronal tissue and axonal membrane where they enter the axoplasm and are protonated. The protonated LA enter the open sodium channel and interact with amino acid residues in the S6 pore- bind to the channel blocking the transmembrane pore. It aslo electrostatically repels sodium ions entering

-low concentration of local anaesthetics blocks some of the voltage gated ion channels, results in a decrease in the rate of increase in depolarisation, longer lasting action potential and decreasing the firing rate of another action potential

-high concentration of local anaesthetics completely blocks the voltage gated ion channels and prevents an action potential from forming.

-some local anaesthetics have use dependent block- their action increases when more channels are open-ionisied form of the drug is able to enter open channels to reach its binding site

-Many local anaesthetics bind most strongly to the inactivated state of the channel-equilibrium shifted in favour to the inactivated state

Duration of action

1. Dependence on lipid solubility

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