Local anaesthetics and ion channel inhibitors Flashcards
What blocks sodium channels?
TTX
What blocks K+ channels?
TEA
What is the overall structure of a local anaesthetic?
They consist of a hydrophobic group linked by ester or amide to an ionisable group (often amine)
What is the effect of a local anaesthetic drug?
Cause the absence of pain sensation.
Membrane-stabilizing drugs (decrease the rate of depolarization and repolarization of excitable membranes (like nociceptors))
What inhibits the NaKATPase?
Ouabain (cardiac glycoside)
What are pain receptors called?
Nociceptors
What is the main action of LA?
Inhibiting sodium influx through voltage-gated sodium channels
Where is the receptor site for LA on the VGNC?
On the cytoplasmic (inner) portion
What must LA be to act on a cell?
Lipid soluble
What two features of a drug does its lipid solubility effect?
Potency and duration of action
Compare hydrolysis of different LA?
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
Are LA basic or acidic? How strongly?
Weak basic
Describe state of ionisation of most LA, what is the pKa?
pKa of 8-9 so almost entirely ionised at physiological pH
At a pH = pKa what is the ratio of protonated and non-protonated?
1:1 (equimolar)
In what state can LA diffuse across the cell membrane?
Unprotonated
Describe the state of most LA molecules in alkali and acidic conditions
Alkali conditions - most molecule of LA in uncharged form (lipid soluble)
Acidic conditions - most molecules of LA are in charged form
What is the mechanism for most LA (hydrophilic pathway)?
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
What is hydrophobic pathway for LA?
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.
What is meant by use dependent block by Lidocaine?
Lidocaine blocks more effectively when nerve stimulated more frequently as more Na+ open and more can be blocked.
What is difference between TTX and LA?
TTX more specific and potent, blocks extracellularly and irreversibly
What is sequence of blockade by LA?
Pain, general sensory, motor
Why does LA result in loss of motor control?
LA binds Na+ non selectively
How does varying pKa affect action of LA?
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.
What is pKa?
The pH at which ionised and non-ionised fractions of the drug is in equilibrium.
How does pH affect action of LA?
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.
How does lipid solubility affect LA activity?
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.
How does length of the intermediate chain affect LA potency?
The longer the molecular intermediate chain (between amine and ester/amide) the more potent.
How does protein binding ability affect duration of LA?
The duration of action is much longer if the drug is a better protein binder.
What is often injected along with LA, why?
Treated with vasoconstrictors such as adrenaline or felypressin. This reduces the loss of drug as a result of circulation.
Where can LA be injected to have more widespread effects?
Epidural space or subarachnoid space
Where are spinal anaesthetics administered and why?
L2-L5 where no longer spinal cord, corda equina far harder to hit
What increases sensitivity of LA block?
Increases as diameter of nerve decreases (smaller nerves fire more frequently)
Increases as myelination decreases
