Pharmacology 3 LA

Question 1

What is LA? how does it work?

Answer 1

A drug that causes reversible local anesthesia and a loss of nociception (the neural processes of encoding and processing noxious stimuli)
LAs reversibly block impulse conduction along nerve axons and other excitable membranes that utilise sodium channels as the primary means of action potential (nerve impulse) generation

Question 2

How is LA administered?

Answer 2

• Topical (surface) application (gums, cornea, skin prior to venepuncture)
• Subcutaneous injection (infiltration anaesthesia, one or more injections)
• Nerve block (around nerve)
• Epidural (into epidural space; child birth)
• Intrathecal (into subarachnoid space; spinal anesthesia)

Question 3

Lipophilic aromatic terminal function?

Answer 3

The aromatic terminal is essential for the local anaesthetic to penetrate fatty tissue such as the lipid sheath of nerves in order to gain access to the nerve cell membrane to reach its site of action

Question 4

Hydrophilic amino terminal function?

Answer 4

At certain pHs, it can gain a charge that will enhance its solubility in water and prohibit its solubility in lipids

Solubility in water is essential for two reasons:

• to allow for the dissolution in a solvent to permit injection
• to allow penetration through interstitial fluid following administration

Question 5

pKA

Answer 5

pKa indicates the pH at which the ionized and non-ionized (unionized) forms are equal

Question 6

Mechanism of action

Answer 6

LA receptor of the voltage-gated Na+ channel is not accessible from the external side of the cell membrane so the non-ionized form is important for rapid penetration of cell membrane
but once the local anaesthetic has diffused into the nerve trunk the ionized form binds to the Na+ channel

Question 7

Determinants of diffusion of LA in to nerve fibres:

Answer 7

• Site of administration
• Drug
• — pKa
• — lipid solubility
• — whether its affected by pathophysiological factors – inflammation

Question 8

Concentration of LA given?

Answer 8

Has to be high since only a small fraction of LA molecules actually reach the target site.

Question 9

How LA affects sodium channels?

Answer 9

The trigger for voltage-gated sodium channels to open the channel for Na+ ions is a voltage-change.
LA act mainly by inhibiting Na+ influx through voltage-gated sodium channels
- When the influx of Na+ is interrupted, an action potential (nerve impulse) cannot arise and signal conduction is inhibited
An AP is a self-regenerating wave of electrochemical activity that allows excitable cells (e.g. nerve cells) to carry a signal over a distance

Question 10

What is a sodium channel?

Answer 10

Integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell’s plasma membrane

Question 11

Sodium channel binding site location

Answer 11

The binding site is located at the cytoplasmic (intracellular) portion of the sodium channel
Once inside the cell, the LA will be in equilibrium, with the formation of the ionized form, which binds to the local anaesthetic binding site on the inside of the ion channel

Question 12

Biochemical mechanism of action of LA and affect on AP

Answer 12

With increasing concentrations of local anaesthetic agent applied to the nerve fibre.

• Threshold for excitation increases
• impulse conduction slows
• the rate of the rise of the action potential declines
• the action potential amplitude decreases
• the ability to generate an action potential is abolished
• If sodium current is blocked over a critical length of the nerve, propagation across the blocked area is no longer possible

Question 13

The order of sensitivity to LA inhibition is:

Answer 13

autonomic > warmth > pain > touch > pressure

first to last

Question 14

Sodium channel affinity for LA

Answer 14

• Channels in the rested state (more negative transmembrane potentials) have less affinity for local anaesthetics than activated (open) state and inactivated channels (more positive transmembrane potentials)
• Except for benzocaine which blocks the resting channel
• The effect of local anaesthetic at a given concentration is more marked in rapidly firing axons than in resting fibres (frequency-dependent block)

Question 15

Acidosis effect on LA

Answer 15

Acidosis = increased blood acidity below pH 7.35
Acidosis can occur in a wound with inflammation and can partly reduce the action of LA
Higher pH = more non-ionised versions of LA
Low pH= more ionised versions= acidosis prevent transmission of LA over the cell membrane

Question 16

Factors affecting neuron blocking

Answer 16

1. Critical lengths of axons
   - – short
2. Frequency dependence
   - – resting nerve is less sensitive
3. Nerve fibre size
   - – small diameter
   - – myelination, nodes of Ranvier
4. Arrangement of fibres bundles in nerve sheath
   - – motor nerve block occurs before sensory block in large mixed nerves and analgesia first develops proximally

Question 17

Frequency dependance

Answer 17

Degree to which a nerve is blocked is dependent on the recent frequency of nerve stimulation or use.

• Resting nerve is far less sensitive due to the requirement for the inner gates of the sodium channel to be open for the local anaesthetic to gain access to the binding site
• Small diameter C and A(delta) pain fibres that participate in high frequency pain transmission, are blocked earlier and sooner with low concentrations of local anaesthetic than are the A(alpha) fibres

Question 18

Tonic Blockade

Answer 18

When there are long intervals between impulses, the level of inhibition of each impulse is the same

Question 19

Phasic blockade

Answer 19

When intervals between impulses is short, the level of inhibition increase with each impulse

Question 20

Hierarchy of LA effects onsensory function

Answer 20

Sensory function lost in the following general order

1. Cold
2. Warmth
3. Pain (‘first pain’ (Ad fibres), then ‘second pain’ (C 4. fibres)
4. Touch
5. Deep pressure
6. Motor function (relatively resistant, possible for LAs to block nociception with little effect on motor function)

Question 21

Site of administration from fastest to slowest

Answer 21

• intravenous
• mucous membrane
• intercostal block
• caudal block
• epidural block
• brachial plexus block
• peripheral nerve block
• subcutaneous infiltratio

Question 22

LA toxicity- Hypersensitivity

Answer 22

(allergic response) – resulting anaphylactic reaction can range from skin rash to full anaphylactic shock. A problem with ester LAs but very rare with amides. May be a reaction to preservatives

Question 23

LA CNS toxicity

Answer 23

initial effects are excitatory with involuntary muscle activity; later effect is depressant, which may lead to unconsciousness and respiratory arrest

Question 24

Cardiac LA toxicity

Answer 24

possible reduction in cardiac output may lead to circulatory collapse (lidocaine used in treatment of ventricular dysrhythmias). Bupivacaine most cardiotoxic LA

Question 25

Methaemoglobinaemia LA toxicity

Answer 25

Main toxic effect of prilocaine (due to its metabolite orthotoluidine) and articaine when administered in high doses.
Symptoms are cyanosis, lethargy and respiratory distress which does not respond to oxygen. Treatment - i.v. methylene blue 1-2 mg/kg

Methaemoglobinemia is not a concern in the dental practice, due to the small volumes of LA drug used

Question 26

Vasoconstrictors purpose with LA

Answer 26

Vasoconstrictors restrict the diffusion of the local anaesthetic away from the site of injection and thus allows the local anaesthetic to stay at the site longer, producing a longer duration of action
A) reduced local anaesthetic systemic absorption away from active site
B) increased anaesthetic concentration near nerve fibres
C) decreases the peak serum concentration and toxic effect and allows metabolism to keep pace with absorption
D) greatly intensifies and prolongs the duration of action

Question 27

Why are vasoconstrictors give with LA

Answer 27

• prolong action
• reduce plasma levels (less risk of CNS effects?)
• ‘greater anaesthesia’ or reduced dose
• reduced operative haemorrhage

Question 28

What vasoconstrictors are commonly used?

Answer 28

• Preparations with vasoconstrictors usually contain epinephrine (adrenaline) 1:200,000, or norepinephrine (noradrenaline) 1:100,000
• Agents with vasoconstriction activity
• – cocaine and bupivacaine constrict blood vessels

Question 29

How does adrenaline work as a vasoconstrictor?

Answer 29

• Stimulation of a adrenoceptors constrict blood vessels (also stimulates cardiac b1 adrenoreceptors)
• Most common dental LA in UK is 2% lidocaine + 1:80,000 adrenaline. Other countries use 1:100,000 or 1:200,000
• Dose equivalent to 28 mg; plasma concentration in patients awaiting dental surgery 0.027 mg/ml