Pharmacodynamics of local anaesthetics

[SH4:p181-p183, p188-p194]

Mechanism of action

[SH4:p182]

• Binds selectively to sodium channels in inactivated-closed state
  --> Stabilize the channels (which are kept in the inactivated-closed state)
  --> No change to rested-closed state
  --> No sodium influx in response to action potential
  --> Threshold potential not reached
  --> Action potential not propagated
• No change in resting transmembrane potential or threshold potential

NB:

• Ionised form of LA has access to Na+ channels [???]
• ??? Na+ channels in resting state have lower affinity for LA [???]
  * Lower affinity (so binding still happen), or binding does NOT happen at all ???

Frequency-dependent blockade

• LA gains access to sodium channels ONLY when they are in activated-open state
  --> Conduction blockade deepens each time sodium channels open
  --> Greater blockade when the nerve is repetitively stimulated

NB:

• Sodium channels tend to recover from LA blockade between action potentials
  * [SH4:p182]

Sodium channels

• Has 3 states
  * Activated-open
  * Inactivated-closed
  * Rested-closed
• 4 subunits
  * Alpha subunit is the one forming the channel

Other sites of action

LA may also block:

• Voltage-dependent potassium channel
  --> May explain broadening of action potential
• Voltage-gated calcium channels (especially the L-type)
• May also act on G-protein-coupled receptors

Minimal concentration (Cm)

• ... is the minimal concentration of local anaesthetic necessary to produce the conduction blockade of nerve impulses
  --> Similar to minimal alveolar concentration (MAC)
• Cm is higher for:
  * Motor nerves (twice that of sensory nerve)
  * Larger nerve fibres
• Cm is decreased when:
  * Increased tissue pH
  * High frequency of nerve stimulation

NB:

• Peripheral nerves are comprised of:
  * Myelinated A and B fibres
  * Unmyelinated C fibres
  * Pain is conducted by myelinated A-delta fibre and unmyelinated C fibres
• A minimal length of myelinated nerve fibre must be exposed to an adequate concentration of local anaesthetics before conduction blockade in the peripheral nerve occurs

 

Differential conduction blockade

• Preganglionic B fibres are blocked first
  * Even though they are myelinated
  * Sympathetic nerve
• Pain conducting nerve fibres are blocked next
  * i.e. Myelinated A-delta nerve fibre and unmyelinated C nerve fibre
  * Blocked at approximately the same concentration
• During pregnancy, there may be increased sensitivity to local anaesthetics
  --> Onset of action of LA is more rapid
  * May be due to changes in protein-binding --> Higher unbound fraction
  * Increased progesterone may also increase sensitivity per se??? [???]

Side effects

[SH4:p188-p194]

• Main side effects relating to LA are:
  * Allergic reactions
  * Systemic toxicity
• Other side effects include:
  * Methaemoglobinaemia

NB:

• Toxicity of local anaesthetic drug mixture is additive, not synergistic

Allergic reactions

• Actually rare
  * <1% of adverse reactions to LA are due to allergic mechanism
  * Most adverse reactions to LA are related to systemic toxicity
• Allergic reaction is more likely with ester LA
  * Due to metabolites such as para-aminobenzoic acid
  * Metabolism of amide LA does not produce para-aminobenzoic acid
• Allergic reaction could be due to preservatives instead of the LA
  * e.g. methylparaben, which is structurally similar to para-aminobenzoic acid

Cross-sensitivity

• Cross-sensitivity between LA reflects the common metabolite para-aminobenzoic acid
• There is NO cross-sensitivity between classes of LA
  * i.e. allergy to ester LA does not react with amide LA
  * Provided the "allergy" is not due to preservative 

Documentation of allergy

• Occurrence of rash, urticaria, and laryngeal oedema (with or without hypotension and bronchospasm)
  --> Highly suggestive of allergic reaction
• Testing with preservative-free preparations could eliminate possibility of cause other than the LA itself

Systemic toxicity

• Systemic toxicity is due to an excess plasma concentration of the drug
• Plasma concentration is determined by:
  * Rate of drug entrance into the systemic circulation
  * Redistribution to inactive tissue
  * Clearance by metabolism
• Most often caused by accidental intravascular injection
• Occasionally caused by absorption from injection site
• Systemic toxicity of LA involves:
  * CNS
  * CVS

Central nervous system

• Earliest signs of LA toxicity are:
  * Numbness of tongue and circumoral tissues (probably due to high blood flow)
  * Not due to central effect (i.e. not CNS mediated)

Pattern of CNS changes

• As plasma concentration increases
  --> Predictable pattern of CNS changes
• Initially:
  * Restlessness
  * Vertigo
  * Tinnitus
  * Difficulty in focusing
• Then:
  * Slurred speech
  * Skeletal muscle twitching (first in the face and extremity)
• Then:
  * Seizures, followed by CNS depression

NB:

• CNS depression may be accompanied by hypotension and apnoea

Mechanisms of CNS change

• Exact aetiology unknown
• Probably due to selective depression of inhibitory cortical neurons

Toxic plasma level

• CNS changes are seen when
  * Lignocaine, mepivacaine, and prilocaine = 5 - 10 microgram/mL
• Bupivacaine is associated with seizure at 4.5 - 5.5 microgram/mL
  * c.f. Cardiotoxicity occurs at bupivacaine 8-10 micrgram/mL

Factors affecting toxicity

• Inverse relationship between PaCO2 and seizure threshold
  --> High PaCO2 is associated with low seizure threshold
  * Possibly via increased CBF and thus greater delivery of LA to brain
• Serotonin level
  --> Serotonin accumulation decreases seizure threshold
• Hyperkalaemia
  --> Facilitate depolarisation
  --> Increases LA toxicity
• Hypokalaemia
  --> Decreases LA toxicity
• Rapid rate of increase in plasma level of LA may also be important

Dose-dependent effects of lidocaine:

• 1-5 microgram/mL
  * Analgesia
• 5-10 microgram/mL
  * Tongue and circumoral numbness
  * Tinnitus
  * Skeletal muscle twitching
  * Systemic hypotension (due to both decreased SVR and depressed myocardium)
• 10-15 microgram/mL
  * Seizures
  * Unconsciousness
• 15-25 microgram/mL
  * Apnoea
  * Coma
• >25 microgram/mL
  * Cardiovascular depression

NB:

• The order of toxic S&S should apply to other LA as well

Treatment of seizures

• Ventilation
  --> Prevention of hypoxaemia and acidosis
• IV benzodiazepine
  --> Suppression of LA-induced seizures

Neurotoxicity

• LA (especially lidocaine) into epidural or subarachnoid space can cause neurotoxicity
  --> Transient neurologic symptoms

Transient neurologic symptoms

• S&S:
  * Moderate to severe pain in the lower back, buttocks, and posterior thighs
  * Appears within 6-36 hrs after complete recovery of spinal anaesthesia
• Unknown aetiology
• Full recovery usually occurs within 1-7 days
• Incidence:
  * The same for different concentrations of lidocaine solution used (from 0.5% to 5%)
  * Incidence is higher with lignocaine

Cauda equina syndrome

Occurs when diffuse injury across the lumbrosacral plexus produces varying degrees of:

• Sensory anaesthesia
• Bowel and bladder sphincter dysfunction
• Paraplegia

Anterior spinal artery syndrome

• Consists of:
  * Lower extremity paresis
  * Variable sensory deficiency
  * i.e. Motor deficiency is more pronounced than sensory
• Usually diagnosed as the blockade resolves
• Etiology uncertain
  * Possibly due to thrombosis or spasm of the anterior spinal artery
• May be difficult to distinguish symptoms due to anterior spinal artery syndrome and those due to spinal cord compression from an epidural abscess or haematoma

Cardiovascular system

• CVS system is more resistant to the toxic effects of high plasma level of LA
  --> CVS toxicity occurs at higher plasma level than CNS toxicity
• Cardiotoxicity are increased with:
  * Concurrent drugs which inhibit myocardial impulse conduction (beta-blocker, digoxin, Ca2+ blocker)
  * Epinephrine, phenylephrine
  * Hypoxaemia, acidosis, and hypercapnia (in animal)
• All LA inhbits Na+ influx through Na+ channel
  --> depresses the maximal depolarisation rate of cardiac AP (Vmax)

S&S of cardiac toxicity

• At lower plasma concentration
  --> Hypotension
  * Due to arteriolar vascular smooth muscle relaxation and direct myocardial depression
• At higher plasma concentration
  --> Sufficient cardiac Na+ channels are blocked
  --> Conduction and automaticity become depressed
  --> Prolonged P-R interval and QRS complex, reentry venticular arrhythmia

Comparison between lignocaine, bupivacaine, and ropivacaine

• Order of cardiac depressant action (from strong to mild):
  * Bupivacaine > Ropivacine > Lidocaine
• Bupivacaine is highly lipid soluble
  --> Dissociates from Na+ channel more slowly
  --> Stronger effect on Vmax
  --> Greater cardiac toxicity
• Lidocaine is less lipid soluble
  --> Dissociates from Na+ channel more quickly
  --> Low cardiac toxicity
• Ropivacaine is a pure S-enantiomer
  --> Less lipid soluble than bupivacaine
  --> Cardiac toxicity in between lidocaine and bupivacaine

NB:

• Pregnancy may increase sensitivity to the cardiotoxic effects of bupivacaine, but not ropivacaine
• [MCQ:Q75] Ropivacaine is 8 times less lipid soluble than bupivacaine [???]
• [MCQ:Q74-76] Ropivacaine produces same or less motor block than bupivacaine [???]

Frequency-dependent blockade

• LA bind to cardiac Na+ channels during systole
• LA dissociate from cardiac Na+ channels during diastole
• Bupivacaine dissociate slowly
  --> Intensity of cardiotoxicity increases with heart rate

CC:CNS ratio

[???] [James]

Lignocaine = 7.1

Bupivacaine = 3.7

 

Treatment of systemic toxicity

??? Bretylium
* Bretylium blocks release of NE from peripheral sympathetic nervous system
* Not sure how it would help

Lipid emulsion (e.g. intralipid)
--> Soaks up LAs in plasma
* [???]

Methaemoglobinaemia

• Rare but potentially life-threatening complication
  * Caused by oxidation of iron in Hb
• Neonates may be at increased risk
  * Foetal haemoglobin more readily oxidised
  * Less methaemoglobin reductase available

Known oxidants

... which may cause methaemoglobinaemia include:

• Topical LA (prilocaine, benzocaine, Cetacaine, lidocaine)
• Nitroglycerin
• Phenytoin
• Sulfonamides

Treatment of methaemoglobinaemia

Reversed by methylene blue

• 1-2mg/kg IV over 5min
• No more than 7-8mg/kg in total
• May require repeated dosing

 

NB:

• Cetacaine is a topical LA made from:
  * 14% benzocaine
  * 2% tetracaine
  * 2% butamben
  * [SH(H)2:p192]

Other side effects

• Lidocaine at clinically useful plasma concentration
  --> Causes depression of hypoxic ventilatory response
• Bupivacaine
  --> Stimulates ventilatory response to CO2
• Hepatotoxicity can occur after bupivacaine, possibly due to allergic reaction
• Dysphoria (and fear of imminent death) has been described in some cases

Toxic doses

[SH4:p181]

Maximum single dose for infiltration

	Maximum single dose	Dosage recommendation [PI on MIMs]
Ester LA
Procaine	500mg
Chloroprocaine	600mg
Amethocaine	100mg (topical)
Amide LA
Lignocaine	300mg	200mg 3mg/kg in children
Etidocaine	300mg
Prilocaine	400mg
Mepivacaine	300mg
Bupivacaine	175mg
Levobupivacaine	175mg	150mg (single dose) 400mg (over 24 hours) 1.25-2.5 mg/kg <12 y.o.
Ropivacaine	200mg	2mg/kg <12 y.o. 28mg/hr in epidural