Local anaesthetics

Question 1

LO

Answer 1

• Define anaesthesia and its relationship to analgesia.
• Describe the cellular basis for an anaesthetic action (nerve block).
• Describe the features of local anaesthetic in terms of their structure, mode of action.
• and basic pharmacokinetics. These properties act together to ensure the LOCAL action.
• Explain mode of action in terms of structure function relations of their major target voltage gated sodium channels.
• Describe clinical use of local anaesthetics.

Question 2

What is Analgesia?

When is it generally given?

Answer 2

Analgesia refers to the reduction or relief of pain.

This is what commonly happens for example when patients are given morphine after an operation for pain.

Analgesia implies pain relief - but does not imply that all sensation is taken away, analgesia does not mean numbness.

Question 3

Whats anaesthesia?

When is it give and what side effects are often seen when its given?

Answer 3

Anaesthesia refers to lack of sensation.

This can be accomplished with local anaesthetics, for example the injection that your dentist gives you when you have a tooth filled.

Almost always this also results in a lack of pain - therefore analgesia usually accompanies anaesthesia.

Note that when local anaesthetics are used to provide anaesthesia, they also frequently cause muscle weakness or muscle relaxation.

Question 4

What is anaesthesia a general blocker of?

Answer 4

Nerve activity

Question 5

Tell me about 2 past natural ingredients that have been used for anaesthetics and why they were commonly used?

Answer 5

Cocoa leaves have been chewed by South American Indians and numbing effect noted

Cocaine active ingredient isolated and used for “psychic energy”, Freud used it for treatment nervous disorders (early Psychiatry) with little success.

Question 6

Tell me some history of anaesthesia?

Answer 6

1884 Freud’s friend showed good efficacy as anaesthesia in corneal surgery based on local application in form of eye drops.

1905 synthetic substitute Procaine back bone for further development.

Question 7

Tell me about Procaine?

Is it still used as a local anaesthetic?

Answer 7

Procaine has good efficacy but no longer used has key structural features of local anaesthetic.

Question 8

Label these drugs

Answer 8

Question 9

Tell me the chemical features that are the core to these anaesthetics and their localised mode of action…

Answer 9

• In the uncharged form they are intrinsically hydrophobic and partition into membrane
• Tertiary amine group means they have a pKa between 8-9 (vary depending on nature of other chemical moieties (e.g. Bulky or aromatic hydrophobic group).
• This pKa means that at physiological pH (7.2.-7.4) most of molecules will be charged.
• This act against the otherwise hydrophobic nature of the molecule.
• Mode of action requires equilibrium between charged (hydrophilic) and uncharged form (hydrophobic). And their efficacy is reduced in injured tissue which has a more acidic pH.
• The ester are acted upon by plasma esterase’s and rapidly broken down; the amide linked compounds are metabolized by liver N-dealkylation and can retain activity when metabolized.

Question 10

What equation is used to describe the relationship between pH and pKa?

Tell me about the equation

Answer 10

The Henderson- Hasselbalch equation

Question 11

This is the range of structures of anaesthetics based on the core structure, which one is different to the rest and why

Answer 11

Benzocaine is different because it has no nitrogen and it will always be uncharged

Question 12

Tell me the effect of lidocaine on a certain channel?

Answer 12

Question 13

Tell me what the efficacy of inhibition of lidocaine depends on

Answer 13

Question 14

Tell me about the sodium channel structure

What/ where do drugs bind to in the channel

Answer 14

• Sodium Channels made up of one protein sequence that contains 4 domains.
• Each domain has a voltage sensor and ¼ of the pore.

Question 15

What about the Na+ channel explains the different routes taken for local anaesthetic block?

Answer 15

Question 16

Tell me aspects about the structure of the sodium channel that enhance the understanding of the local anaesthetic block

Answer 16

• The drug repels Na+ as it and the charge is positive
• Before that the drug needs to be uncharged so can penetrate inside of the cells and have an effect
• Charged form important for drug to bind to channel which is buried within but also repel the Na+ (plug and repulse)

Question 17

Clinically relevant facts of local anaesthetics

Answer 17

Question 18

Tell me some clinical use and administration for local anaesthetics beyond analgesia and antidysrhythmia

Answer 18

• surface anaesthesia
• Infiltration anaesthesia
• Intravenous regional anaesthesia
• Nerve block anaesthesia
• Spinal/ epidural anaesthesia
• Cardiac antidysrhymic (class 1 drug)

Question 19

Tell me the following about Surface anaesthesia, give some examples and how its applied

Answer 19

Surface anaesthesia. (lidocaine, tetracaine and benzocaine). Application through cream or drops skin, cornea or mucosa. Skin application

Question 20

Tell me the following about infiltration anaesthesia: some examples, how its given, function and how this can be prolonged

Answer 20

Infiltration anaesthesia.

(Most LA) can be effectively injected.

Can prolong mode of action mixing with adrenalin vasoconstriction and reduced blood flow.

Sustains concentration at site of action.

Question 21

Tell me the following about Intravenous regional anaesthesia: some examples, how its given and the effect it causes, when its used and the reason

Answer 21

Intravenous regional anaesthesia

(Mainly lidocaine, prilocaine).

Inject distal to blood flow cuff.

Sustains the LA for as long as blood flow is stopped.

Used in limb surgery.

Question 22

Tell me the following about nerve block anaesthesia: example, how its given and why its used

Answer 22

Nerve block anaesthesia.

(Most LA)

Injection into nerve trunks reduces concentration required (e.g. Dental nerves).

Can be used in surgery but also as an analgesic route.

Question 23

Tell me the following about spinal/ epidural anaesthesia: examples and where its given and why, when its used

Answer 23

Spinal/Epidural anaesthesia.

Sub-arachnoid space (Lidocaine into the CSF) or epidural space to act on spinal cord and/or roots.

Used in sub-abdominal surgery when general anaesthetics cannot be used.

Epidural can be used in childbirth and is the preferred route to anaesthesia for caesarean section.

Procedure where LA and opioid are combined is a route towards pain relief and the combination seems to act synergistically.

Question 24

Tell me the following about cardiac antidysrhymic (class 1 drug): why its given, its effects

Answer 24

Cardiac antidysrhythmic (Class 1 drugs).

Use dependent and membrane stabilization properties.

Particularly ability to preferentially bind open/inactivated channels and show differential unbinding means that fast unbinding LA can be used to act on tachycardia activity while slow unbinding general slow heart.

Question 25

The primary mechanism of action of local anaesthetics involves the blockade of which of the following ion channels?

A. inactivated, voltage-gated, Na+ channels

B. inactivated, ligand-gated, K+ channels

C. Resting, voltage-gated, K+ channels

D. Resting, ligand-gated, Na+ channels

E. activated, ligand-gated Ca2+ channels

Answer 25

A. inactivated, Voltage-gated, Na+ channels

Question 26

Which of the following is NOT a local anaesthetic?

A. cocaine

B. procaine

C. Amethocaine

D. isoflurane

E. procainamide

Answer 26

D. isoflurane

Question 27

The ionised form of local anaesthetics is mainly responsible for which of the following properties of the drug?

A. tissue redistribution

B. Liver biotransformation

C. systemic toxicity

D. plug and repulse

E. Half-life

Answer 27

D. plug and repulse

Question 28

The uncharged form of local anaeshtetics is mainly responsible for which of the following properties of the drug?

A. membrane partition

B. liver biotransformation

C. systemic toxicity

D. receptor binding

E. Half-life

Answer 28

A. membrane partition

Question 29

Which of the following statement best explains why the onset of the therapeutic effect of a local anaesthetic is usually slower in infected tissues?

A. They are very rich in drug-metabolising enzymes

B. They are poorly vascularised, so that the drug slowly reaches the nerve terminals

C. They are rich in extracellular K+ which lowers the drug-receptor binidng

D. They have a low extracellular pH, which hinders drug diffusion into the cell

E. They have a high extracellular pH, which hinders drug diffusion into the cell

Answer 29

D. They have a low extracellular pH, which hinders drug diffusion into the cell

Question 30

Which of the following are the main purposes for adding a vasoconstrictor drug to a local anaesthetic? (choose all that apply)

A. To speed up the onset of the anaesthetic effect

B. To increase the duration of anaesthetic effect

C. To decrease the risk of systemic overdose toxicity of the drug

D. to decrease the risk of allergic reactions of the drug

E. To increase the affinity of the drug for the Na+ channels

Answer 30

B. To increase the duration of anaesthetic effect

C. To decrease the risk of systemic overdose toxicity of the drug

Question 31

Most injectable dental anaesthetics bind to receptor sites at which location?

A. activation gate

B. inactivation gate

C. within the sodium channel

D. on the outer surface of the sodium channel

Answer 31

C. within the sodium channel

Question 32

LA —| VGSC –> Nerve block –> loss of sensation locally

Uncharged/ hydrophobic: partition into membrane

Charged/ hydrophilic: plug and repulse

GA –> ? –> Loss of consciousness