3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.3. Pharmacology
                  3.1.3.4. Local anaesthetics
 3.1.3.4.1. Pharmacodynamics of local anaesthetics 

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