Pharmacology 3 LA Flashcards
What is LA? how does it work?
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
How is LA administered?
- 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)
Lipophilic aromatic terminal function?
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
Hydrophilic amino terminal function?
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
pKA
pKa indicates the pH at which the ionized and non-ionized (unionized) forms are equal
Mechanism of action
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
Determinants of diffusion of LA in to nerve fibres:
- Site of administration
- Drug
- — pKa
- — lipid solubility
- — whether its affected by pathophysiological factors – inflammation
Concentration of LA given?
Has to be high since only a small fraction of LA molecules actually reach the target site.
How LA affects sodium channels?
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
What is a sodium channel?
Integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell’s plasma membrane
Sodium channel binding site location
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
Biochemical mechanism of action of LA and affect on AP
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
The order of sensitivity to LA inhibition is:
autonomic > warmth > pain > touch > pressure
first to last
Sodium channel affinity for LA
- 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)
Acidosis effect on LA
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
Factors affecting neuron blocking
- Critical lengths of axons
- – short - Frequency dependence
- – resting nerve is less sensitive - Nerve fibre size
- – small diameter
- – myelination, nodes of Ranvier - Arrangement of fibres bundles in nerve sheath
- – motor nerve block occurs before sensory block in large mixed nerves and analgesia first develops proximally
Frequency dependance
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
Tonic Blockade
When there are long intervals between impulses, the level of inhibition of each impulse is the same
Phasic blockade
When intervals between impulses is short, the level of inhibition increase with each impulse
Hierarchy of LA effects onsensory function
Sensory function lost in the following general order
- Cold
- Warmth
- Pain (‘first pain’ (Ad fibres), then ‘second pain’ (C 4. fibres)
- Touch
- Deep pressure
- Motor function (relatively resistant, possible for LAs to block nociception with little effect on motor function)
Site of administration from fastest to slowest
- intravenous
- mucous membrane
- intercostal block
- caudal block
- epidural block
- brachial plexus block
- peripheral nerve block
- subcutaneous infiltratio
LA toxicity- Hypersensitivity
(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
LA CNS toxicity
initial effects are excitatory with involuntary muscle activity; later effect is depressant, which may lead to unconsciousness and respiratory arrest
Cardiac LA toxicity
possible reduction in cardiac output may lead to circulatory collapse (lidocaine used in treatment of ventricular dysrhythmias). Bupivacaine most cardiotoxic LA
Methaemoglobinaemia LA toxicity
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
Vasoconstrictors purpose with LA
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
Why are vasoconstrictors give with LA
- prolong action
- reduce plasma levels (less risk of CNS effects?)
- ‘greater anaesthesia’ or reduced dose
- reduced operative haemorrhage
What vasoconstrictors are commonly used?
- 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
How does adrenaline work as a vasoconstrictor?
- 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
