CPTP 3.22 Neuropharmacology 7 Local Anaesthetics

Question 1

Recall the three possible confirmations of sodium channels

Answer 1

• Open
  
  • Inactivated
  • Resting

There is also a number of intermediate states

Question 2

Why are sodium channels impermeable in the resting confirmation?

Answer 2

The S4 regions (which are positive) are aligned along the middle of the channel by the ‘lumen’ when in the resting confirmation, repelling Na+ ions

Question 3

How do sodium ion channels become inactivated?

Answer 3

Once sodium travels through, it induces a change in confirmation whereby a ‘linker region’ moves to block the lumen of the sodium channel (IMG 18)

Question 4

Where do local anaesthetics target? How do they work

Answer 4

They REVERSIBLY bind to the intracellular side of the Na+ channels thus preventing sodium influx. Can do this by either:
• Physically blocking the lumen
• Stabilising the channel in the inactive confirmations

Question 5

In which confirmations do local anaesthetics bind to sodium channels?

Answer 5

• Open
  
  • Inactivates

(NB: NOT resting)

Question 6

What is needed for local anaesthetics to be effective?

Answer 6

• They must be able to diffuse across the nerve cell membrane to the intracellular side
  
  • Bind to the LA target site

Question 7

Describe the chemical structure of lidocaine. Which properties does each component influence?

Answer 7

IMG 19
• Aromatic group - affects hydrophobicity of the drug
• Linker region (ester or amide bond) - affects metabolism of drug
• Amine group - influences the charge of the drug

Question 8

What are the central ‘linker regions’ in older and newer local anaesthetics structure?

Answer 8

(IMG 19)
Older: ester
Newer: amide

Question 9

Describe the metabolism of anaesthetics with different linker regions.

Answer 9

Affects how the drug is metabolised:
• Ester: Short half life - 3 mins, rapidly metabolised by plasma cholinesterases
• Amide: 3 hour half life, metabolised by liver P450 enzymes

Question 10

Describe the hydrophobicity of anaesthetics with different aromatic groups.

Answer 10

Adding functional groups onto the aromatic ring INCREASES hydrophobicity

Question 11

Describe the how hydrophobicity affects the drug pharmacology of local anaesthetics

Answer 11

PHARMACOKINETICS:
The drug needs to be hydrophobic enough to be able to enter the lipid bi-layer and therefore cross into the neurone, but cannot be too hydrophobic or it will become trapped in the lipid bilayer (IMG 20)

PHARMACODYNAMICS:
The LA binding sire on Na+ channels contains hydrophobic residues, so more hydrophobic LAs bind more tightly to it and thus have greater potency

Therefore for an effective drug which can still get into the neurone = MODERATELY hydrophobic is ideal

Question 12

Describe the pH of local anaesthetics

Answer 12

• Weak bases (proton acceptors)

Question 13

What does the proportion of the drug which is ionised depend on?

What conditions are needed for 50% of the drug to be ionised?

Answer 13

• pH of the solution
  
  • pKa of the drug

pH = pKa

Question 14

What range of pKa’s of local anaesthetics lie within?

Recall physiological pH?

Thus, determine if there are more ionised or unionised forms of local anaesthetics in the equilibrium at physiological pH

Answer 14

7. 6 to 9
8. 4

More in the ionised form (IMG 21)

Question 15

How does increasing or decreasing the pKa of a weak base drug affect the amount of that drug which is ionised?

Answer 15

Increasing pKa: more is ionised

Decreasing pKa: less is ionised (more is in its neutral form)

Question 16

What form of the local anaesthetic:

1) Passes through the hydrophobic lipid bi-layer?
2) Binds to the sodium ion channel?

Answer 16

1) Un-ionised form

2) Ionised form

Question 17

Describe how the hydrophobicity of local anaesthetics is distributed within their molecule

Answer 17

They are amphiphilic

Question 18

How does the pKa affect the onset time of a local anaesthetic?

Answer 18

Lower pKa = faster onset

• Lower pKa means more un-ionised drug
• More can cross the lipid bi-layer
• Therefore faster action

Question 19

Recall the effect of hydrophobicity on:

1) Potency
2) Duration of action

Answer 19

1) More hydrophobic = greater potency

2) More hydrophobic = longer duration of action

Question 20

How does hydrophobicity affect the duration of action?

Answer 20

Hydrophobic drugs are more likely to be sequested in fat and therefore
• Are less available for metabolisation
• Are less available to be removed by the blood stream

Question 21

How is duration of action of local anaesthetics boosted in clinical practise?

What second benefit does this have

Answer 21

They are administered with a vasoconstrictor such as epinephrine to localise the anaesthetic

This reduces toxicity as it inhibits absorption into the systemic circulation

Question 22

In which cases should a vasoconstrictor not be used in conjunction with local anaesthetics?

Answer 22

In terminal vasculature (e.g. fingers)

Question 23

In which case will local anaesthetics not be effective and why?

What must be done to compensate for this?

Answer 23

In inflamed tissue
• Inflammation causes tissue acidosis
• Lower pH causes an increased proportion of the weak acid LA drug to be ionised
• Therefore the ionised drug cannot enter the neurones and inhibit the Na+ channels from inside

Increase the dose

Question 24

What effect does the nerve type have on local anaesthetics? Why?

Answer 24

Small diameter fibres with little myelination are most readily blocked (A-δ, B and C-fibres)

This is because the local anaesthetic needs to diffuse into the neurone through the cell membrane. Increased thickness hinders this diffusion

Question 25

Why can patients often still feel touch sensations regardless of local anaesthesia?

Answer 25

A-α, A-β and A-Ɣ fibres all have myelination and so hinder diffusion of LA into the neurone

Question 26

What effect does ionisation have on water solubility?

How does this affect injection-able preparations?

Answer 26

Ionised drug is more water soluble

They are formulated as HCl salts, to ionise the weak base as much as possible

Question 27

In which ways can LAs be administered?

Answer 27

Topical anaesthesia
• An oily vehicle is used
• Slow onset

Infiltration anaesthesia
• LA is injected intra-dermally or subcutaneously
• Fast onset

Peripheral nerve block anaesthesia
• Injection of LA around a nerve trunk
• Blocks all inputs which would be passing through this nerve trunk
• (e.g. brachial plexus block will anaesthetise a whole arm)

Central nerve block anaesthesia, can be:
• SPINAL ANAESTHESIA -Anaesthesia is injected into the subarachnoid space
• EPIDURAL ANAESTHESIA - Anaesthesia is injected into the epidural space
• Produces anaesthesia above AND below the site of injection

Intravenous regional anaesthesia:
• LA is injected into a limb after application of a tourniquet

Question 28

What level must spinal anaesthesia be used below to avoid damage to the spinal cord?

Answer 28

L2

Question 29

What is intravenous regional anaesthesia used for?

What is the risk of this administration method?

Answer 29

Manipulation of fractures and minor surgical procedures

Toxicity - you must wait 20 mins before removing the tourniquet

Question 30

What administration method of LA is used before:

1) venipuncture?
2) dentistry?

Answer 30

1) Topical

2) Infiltration

Question 31

What are the side effects of LA when it gets into the systemic circulation?

Answer 31

• Numbness or paraesthesia of mouth
  
  • Light headedness
  • Tinnitus
  • Spasms
  • Grand mal convulsions

Question 32

What effects do LAs have on the cardiovascular system? Describe this with reference to the selectivity of LAs.

Answer 32

Blocks sodium, potassium and calcium channels due to its non-selectivity, effects on the heart include:
• At low doses they slow the conduction of impulses through myocardial tissues
• At higher doses can cause arrhythmias
• Eventually they can cause cardiac arrest

Question 33

What is the potential therapeutic use of LAs due to the slowing effects it has on conduction in the myocardium?

Answer 33

Can be used as anti-arrhythmia drugs

Recall first year FIRST CLASS ANTI-ARRHYTHMIC drugs