Local Anaesthetics (La)

Front 1

three structural requirements of LAs

Back 1

Liphophillic group
Intermediate bond
hydrophillic group

Front 2

procaine (novocaine)

Back 2

first synthetic LA that is an ester with a very long time of onset of anaesthetic, wore off too quickly and was not nearly as potent as cocaine. Because it is an ester it has very high potential to cause allergic reactions

Front 3

lignocaine

Back 3

amide, which are hypoallergenic, anaesthetic effects occur quickly and when combined with a small amout of adrenaline, produces anaethesia for several hours

Front 4

Problem with procaine and lignocaine

Back 4

These LAs analogs cause vasodilation of the local blood vessels, increasing blood flow in the area. Therefore, the anaesthetic is absorbed into the circulation before it takes local effect. That is why they are mixed with adrenaline so vasoconstriction occurs, which slows blood flow through the area.

Front 5

Why is sodium bicarbonate added to a LA solution

Back 5

maximises the % of drug in un-ionised lipid soluble form, as un-ionised molecules can passively move across the membrane

Front 6

why doesn't LAs word in infected tissue

Back 6

Because the environment is more acidic and as the pH is reduced, the fraction of ionised LA is greatly increased, which results in a delayed and reduced effect. Another explanation is that infected tissue also have an increased blood supply hence more anaesthetic may be removed from the area before it can affect the neurons

Front 7

How does pKa affect LAs

Back 7

the lower the pKa the greater % of unionised drug, which leads to a rapid onset of action. vice versa with a higher pKa

Front 8

What do LAs target

Back 8

LAs target voltage-dependent sodium channels and have a greater affinity for inactivated channels, and by binding to them, they prevent channels from re-opening. Thus, there appears to be a loss of ion channels (and ion current) during a train of pulses.

Front 9

Main mode of access of LAs

Back 9

LA can block via the hydrophillic pathway, but only if the charged form of the LA can enter sodium ion channels when they open. If a neuron is actively firing APs, these channels will open frequently, allowing greater access of the LA molecule to the inner pore region. This is known as use-dependent pathway. (90%)

Front 10

Secondary mode of access of LAs

Back 10

The hydrophobic pathway. The blocking site within the sodium channel is thought to be reached directly from the membrane by the uncharged B, and the molecule will become charged upon arriving in the cytoplasm. (10%)

Front 11

Which nerve fibres are affected by LAs

Back 11

LAs have the greatest effect on small diameter afferent neurons of the peripheral nerves (Delta fibres), which are coincidentally are involved in pain transmission

Front 12

Side effects of LAs

Back 12

temporary weakness or paralysis. At high concentrations in the CNS, LAs can cause tremor, agitation and convulsions. Should LA concentrations increase, CNS depression may result. In the cardiovascular system, a reduction in myocardial contractility and force of contraction can occur. Toxicity can occur where the pharmacokinetics of the drug are altered by comorbidity, alterations in plasma protein binding, or interactions with other drugs

Front 13

QX-314

Back 13

a charged LA that can only pass the membrane through TRPV1, an ion channel that is opened by capsaicin, the 'hot' component in chilli peppers. Once inside it can bind to the inner pore of sodium channels. However, the access route for QX-314 exists only on nociceptors and pain-sensing neurons. Thus, QX-314 and capsaicin acts as an analgesic

Front 14

QAQ

Back 14

A novel LA that can be "switched on and off", the molecule resembles lignocaine that has cis- and trans- forms. A novel LA that can be "switched on and off". When exposed to light (380 nm), switches to the cis- form (LA); if treated with 500 nm light, it slowly reverts back to the trans-. QAQ can penetrate active TRPV1 receptors, which allows for targeted treatment