Local anaesthetics and ion channel inhibitors

Question 1

What blocks sodium channels?

Answer 1

TTX

Question 2

What blocks K+ channels?

Answer 2

TEA

Question 3

What is the overall structure of a local anaesthetic?

Answer 3

They consist of a hydrophobic group linked by ester or amide to an ionisable group (often amine)

Question 4

What is the effect of a local anaesthetic drug?

Answer 4

Cause the absence of pain sensation.

Membrane-stabilizing drugs (decrease the rate of depolarization and repolarization of excitable membranes (like nociceptors))

Question 5

What inhibits the NaKATPase?

Answer 5

Ouabain (cardiac glycoside)

Question 6

What are pain receptors called?

Answer 6

Nociceptors

Question 7

What is the main action of LA?

Answer 7

Inhibiting sodium influx through voltage-gated sodium channels

Question 8

Where is the receptor site for LA on the VGNC?

Answer 8

On the cytoplasmic (inner) portion

Question 9

What must LA be to act on a cell?

Answer 9

Lipid soluble

Question 10

What two features of a drug does its lipid solubility effect?

Answer 10

Potency and duration of action

Question 11

Compare hydrolysis of different LA?

Answer 11

Ones with ester bonds hydrolysed by esterases in blood and liver but those with amide bonds only broken down in liver so longer half life

Question 12

Are LA basic or acidic? How strongly?

Answer 12

Weak basic

Question 13

Describe state of ionisation of most LA, what is the pKa?

Answer 13

pKa of 8-9 so almost entirely ionised at physiological pH

Question 14

At a pH = pKa what is the ratio of protonated and non-protonated?

Answer 14

1:1 (equimolar)

Question 15

In what state can LA diffuse across the cell membrane?

Answer 15

Unprotonated

Question 16

Describe the state of most LA molecules in alkali and acidic conditions

Answer 16

Alkali conditions - most molecule of LA in uncharged form (lipid soluble)

Acidic conditions - most molecules of LA are in charged form

Question 17

What is the mechanism for most LA (hydrophilic pathway)?

Answer 17

Move across cell membrane in non-ionised form

At low pH (cell) change to charged/ionised form.

Ion-trapping as cannot leave across membrane in ionized form

Bind to open Na+ channel have high affinity for inactivated state of channel so difficult for Na+ to enter

Question 18

What is hydrophobic pathway for LA?

Answer 18

LA in uncharged form can access the channel interior via hydrophobic pathways in the channel. The uncharged LA is then protonated inside the channel leading to its blockade.

Question 19

What is meant by use dependent block by Lidocaine?

Answer 19

Lidocaine blocks more effectively when nerve stimulated more frequently as more Na+ open and more can be blocked.

Question 20

What is difference between TTX and LA?

Answer 20

TTX more specific and potent, blocks extracellularly and irreversibly

Question 21

What is sequence of blockade by LA?

Answer 21

Pain, general sensory, motor

Question 22

Why does LA result in loss of motor control?

Answer 22

LA binds Na+ non selectively

Question 23

How does varying pKa affect action of LA?

Answer 23

The lower the pKA, the more unionised fraction is present for any pH and hence the faster the onset of action as more can diffuse in.

Question 24

What is pKa?

Answer 24

The pH at which ionised and non-ionised fractions of the drug is in equilibrium.

Question 25

How does pH affect action of LA?

Answer 25

The lower the pH the less the potency as the ionised fraction is in greater amounts so there is less unionised to cross the membrane and block the sodium ion channels.

Question 26

How does lipid solubility affect LA activity?

Answer 26

The greater the lipid solubility the greater the potency, immediacy and duration of action, more drug can cross the membrane and create a depot in the cell.

Question 27

How does length of the intermediate chain affect LA potency?

Answer 27

The longer the molecular intermediate chain (between amine and ester/amide) the more potent.

Question 28

How does protein binding ability affect duration of LA?

Answer 28

The duration of action is much longer if the drug is a better protein binder.

Question 29

What is often injected along with LA, why?

Answer 29

Treated with vasoconstrictors such as adrenaline or felypressin. This reduces the loss of drug as a result of circulation.

Question 30

Where can LA be injected to have more widespread effects?

Answer 30

Epidural space or subarachnoid space

Question 31

Where are spinal anaesthetics administered and why?

Answer 31

L2-L5 where no longer spinal cord, corda equina far harder to hit

Question 32

What increases sensitivity of LA block?

Answer 32

Increases as diameter of nerve decreases (smaller nerves fire more frequently) Increases as myelination decreases