Local anaesthesia

Question 1

What are local anaethetics?

Answer 1

Drugs that reversibly block neuronal conduction when applied locally. All local anaesthetics are weak bases. They are sodium ion channel blockers.

Question 2

Are local anaesthetics bases or acids?

Answer 2

bases

Question 3

How is an action potential normally generated?

Answer 3

• When neurones are depolarised the VGSCs open
• Sodium rushes into the neurone -> generates a rapid depolarisation phase
• Within a millisecond, the sodium channels close
• The VGKCs open -> potassium leaves the neuronal cell
• This allows the neurone to enter a repolarisation phase
• At the third phase, the sodium channels have been restored to their resting state, however potassium channels remain open (therefore the cell is in its refractory period – we could generate another AP, but it is harder)
• In phase IV, both sodium and potassium channels have restored to their resting state

Question 4

What do all local anaesthetics have in common in terms of their structures?

Answer 4

• Aromatic region
• Basic amine side chain
• Linked by an ester or amide bond

Question 5

What does the ester or amide bond determine?

Answer 5

Two groups of local anaesthetics:

• esters
• amides

Question 6

Give an example of a ester and an amide LA

Answer 6

cocaine - ester

lidocaine - amide

Question 7

Benzocaine - what is special about it?

What are its properties and where is it used?

Answer 7

Benzocaine doesn’t have the basic amine side chain – it is the only LA that doesn’t have it (it just has an alkyl group on the side). It still has weak LA properties, and is lipid soluble (used as a surface anaesthetic). It is useful in throat lozenges.

Question 8

What is the hydrophilic pathway for local anaesthetics?

Answer 8

• We can inject a local anaesthetic close to sensory, pain-conducting neurones
• The unionised form of the LA is lipid soluble and is able to pass through the connective tissue sheath, to gain access to the sensory axons inside the neurone
• Once the lipid-soluble form of the LA is inside the axon, the equilibrium is established (unionised and ionised versions of the LA)
• It is the ionised form of the LA has the anaesthetic property (blocks VGSCs)
• The ionised form binds to the inside of the VGSCs and stereochemically hinders the influx of Na ions
• In order for the ionised form of the LA to be able to bind to its target site, the VGSCs must be open
• This is the hydrophilic pathway: single most important mechanism of action for local anaesthetics – it uses use dependency

Question 9

What is use dependency of local anaesthetics?

Answer 9

The more the neurones are active, the more the VGSCs will be opening and closing (the more time they are spending in the open state). This means that the LAs can bind to their target sites more effectively. This gives LAs a degree of selectively – pain neurones are firing rapidly so these will be blocked

Question 10

When injecting LA what do we want to target and what do we want to avoid?

Answer 10

We want to get it close to the nociceptive neurones but away from motor neurones or we will see weakness and relaxation of skeletal muscles

Question 11

What is the hydrophobic pathway for local anaesthesia action?

Answer 11

• This is more important for the more lipid-soluble LAs
• As the unionised form crosses the axonal membrane, some can drop into the ion channel and convert into the cation ionised form to block the ion channel
• This means that, by the hydrophobic route, the LAs can drop into a closed channel as well as an open channel

Question 12

What are the effects of local anaesthetics?

Answer 12

• Prevent the generation and conduction of action potentials (because they block the VGSCs)
• They do not influence the resting membrane potential
• They may also influence channel gating
• Local anaesthetics have higher affinity for the inactivated state of the channel, than any other state
• Selectively block small diameter fibres (rather than larger ones) and non-myelinated fibres
• Pain impulses are conducted by narrow fibres – so this allows us to selectively inhibit pain
• Pain C fibres are non-myelinated

Question 13

Why are infected tissues more hard to anaesthetise?

Answer 13

Infected tissues tend to be acidic – larger portion is ionised

Question 14

What is the pKa of LAs?

Answer 14

8-9

Question 15

What are the different ways that LA can be administered?

Answer 15

• surface
• infiltration
• intravenous regional
• nerve block
• spinal
• epidural

Question 16

What is surface anaesthesia?

What are the problems with it?

Answer 16

• Mucosal surface (mouth, bronchial tree, eyes, nose and throat)
• Spray form (or powder form)
• Problem: we need high concentrations of the LA to gain an effective anaesthetic action, however, high concentrations can lead to systemic toxicity

Question 17

What is infiltration anaesthesia?

What is co-administered and why?

Answer 17

• LA is directly injected into tissues → accesses the sensory nerve terminals directly
• The injection is given subcutaneously
• This has applications in minor surgery (suturing and stitching)

Adrenaline co-injection because adrenaline causes vasoconstriction (not extremities). This increases the duration of action of the local anaesthetic. This reduces the incidence of systemic side effects (thus limits toxicity). If we are affecting the extremities, we do not give adrenaline (could lead to ischaemic damage)

Question 18

What is intravenous regional anaesthesia, how is it given?

Answer 18

• Intravenous injection is given distal to a pressure cuff – shuts off the blood supply
• This has applications in limb surgery (more major surgery)
• Systemic toxicity may occur if there is premature cuff release
• We should keep the cuff on for 20 minutes minimum

Question 19

What is nerve block anaesthesia?

What is co-injected?

How long is onset?
When can it be used?

Answer 19

• Local anaesthetic is injected close to the nerve trunks e.g. dental nerves
• Widely used – we can use low doses – however there is a relatively slow onset (minutes)
• Vasoconstrictor co-injection with nerve block anaesthesia

Question 20

What is spinal anaesthesia?
Where is it injected?

What may be an effect of this anaesthesia and why?

What can be mixed with the LA and why?

Answer 20

• LA is injected into the sub-arachnoid space -> has an action on the spinal roots
• Abdominal, pelvic and lower limb surgery – anaesthetic mixes with the CSF (injected at L3/L4)
• This decreases blood pressure, and may produce a prolonged headache (accesses brain). Decreased BP: LA acting on small-diameter pre-ganglionic sympathetic ANS neurones
• Some glucose can be mixed with the LA ->
  increase in specific gravity (allows level of control)

Question 21

Where is epidural anaesthesia administered?
When?
Onset time?
What happens at higher doses?
What is an advantage?

Answer 21

• Injected into fatty tissue of epidural space – action on the spinal roots
• Uses as for spinal anaesthesia, but also for painless childbirth
• It has a slower onset, and higher doses are required compared to spinal anaesthesia
• Higher doses -> more likely to experience systemic side effects
• Advantage: more restricted action and less effects on blood pressure

Question 22

Compare the pharmacokinetic properties of lidocaine and cocaine: absorption, plasma protein binding, metabolism and plasma half life

Answer 22

• Absorption (mucous membranes): both good
• Plasma protein binding: lidocaine (70%), cocaine (90%)
• Metabolism: lidocaine (hepatic, N-dealkylation), cocaine (liver, plasma and non specific esterases)
• Plasma half life: lidocaine (2h), cocaine (1h)

Question 23

…

Answer 23

Lidocaine is very widely used as a local anaesthetic – it can be used for any of the routes of administration. It is not always the drug of choice, however it is widely used.

Cocaine was the original local anaesthetic used in the 1870s. Both lidocaine and cocaine show good absorption, so they can both be used as surface anaesthetics.

Question 24

What are the unwanted effects of cocaine? (CVS, CNS)

Answer 24

• CNS: euphoria and excitation – due to the sympathomimetic action of cocaine
• CVS: increased cardiac output, vasoconstriction and increased BP

These are both sympathetic actions

Question 25

What are the unwanted effects of lidocaine? (CVS, CNS)

Answer 25

• CNS: stimulation, restlessness, confusion and tremor (PARADOXICAL EFFECTS)

This is because the inhibitory GABAergic neurones in the CNS are more sensitive to local anaesthetics

• CVS: myocardial depression, vasodilatation, decreased BP (NA CHANNEL BLOCKADE

Question 26

Why do amides have longer durations of action?

Answer 26

They are more resistant to metabolism