Local Anaesthetics

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Basic structure of a Local Anaesthetic

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LIPOPHILIC--HYDROCARBON CHAIN--HYDROPHILIC

Aromatic portion
Ester or Amide
Amine portion

Now only Amides - due to allergic reactions

All have same pharmacodynamics (same effect) but different pharmacokinetics (different metabolism)

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Mechanism of Action

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LAs are Sodium Channel Blockers
- blocking the formation of an action potential
-reversible and limited

Does not change threshold or resting membrane potential - just makes sodium influx impossible to reach threshold

(anaesthetics are NOT analgesics - provide total nerve block, not just pain sensation)

1) Generation Block - at side of generation
2) Conduction Block - conducting pathway (eg. radial nerve) (need to block more than one myelin sheath; 3-4)
- generally, more central - better

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pKa of LAs

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They act on the INtracellular portion of the Na channel in the IONISED form.

However, to cross the lipid bilayer to it's site of action, it needs to be UNIONISED.

LAs need to be 50/50 ionised/unioinsed
Therefore, pKa of LAs = physiological pH

Two important implications:
1) LAs are LESS effective in inflammed tissue
(acidity -> lowers pH -> more ionised, can't cross cell membrane)
2) LAs have a faster onset if combined with a buffer (but unoften used clinically)

(for these 2 conditions - we're changing pH of ECF but not ICF - alkalosis works better, acidity works less)

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Adverse Effects of LA

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1) Psychogenic Reactions (needles)
2) Allergic Reactions

3) Toxic Reactions

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1) Psychogenic Reactions to LA

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Syncope (most common)

hyperventilation
nausea, vomiting
alterations in HR or BP
mimics an allergic reaction
- If Sx during 1st mL of injection - usually psychogenic
- If Sx after 40-50mL of injection - usually allergic

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2) Allergic reactions to LA

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Two reasons for being "allergic" to LA

1) Ester-type agents were used
(Due to metabolite PABA - cocaine, procaine, tetracaine, articaine)
- Extremely rare for amide-type agents
(lidocaine, bupivacaine, prilocaine)

2) Additives in multidose vials of LA (to prolong life after opening)
- now abolished in developed countries
- metabisulfite or methylparaben

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3) Toxic reactions to LA

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Usually due to rapid attainment of high systemic blood concentrations

Affects: CNS and CVS (brain & heart)
CNS toxicity comes first (also easier to Rx)

opposite of most drugs - for LAs want as little as possible in the blood (or else it's no longer local)

TO AVOID TOXIC REACTIONS:
1) do not inject IV (aspirate first)
2) stay away from highly vascularised areas
3) don't inject in excessive amounts
(rarely due to impaired P450s)

"While you're injecting - talk to the patient" any sign of 'drunkness' then STOP ASAP

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Addition of Adrenaline

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Vasoconstrictor:
1) Prolongs duration of action of LA
2) Reduces potential systemic toxicity - by decreasing rate of absorption
(less plasma concentration when adrenaline added)

eg. Lignocaine + Adrenaline (all amide ones)

Caution:
1) can result in tachycardia/hypertension - very small amounts if systemically (frightening if injected IV)
2) ABSOLUTELY CONTRADICTED IN TISSUES SUPPLIED BY END-ARTERIES (eg. fingers, toes, penis -> tissue necrosis)

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Factors affecting Time of onset and Duration of action

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Time of onset - pH(tissue), pKa(drug), anatomy knowledge, merve morphology, drug conc, lipid solubility of drug

Duration of action
1) Site of injection (blocks last longer than infiltrations)
2) Type of LA
3) addition of vasoconstrictor

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1) Lidocaine (lignocaine)

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"mother"
Short duration
Best agent for infiltration

Max dose: 200mg, 500mg (with adr)
Duration with adrenaline > 6h

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2) Prilocaine

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"safest"
'when you don't know exactly where the nerve is'
Best agent for IV regional anaesthesia
Very good diffusion -> good for peripheral nerve blocks

Max dose: 400mg, 600mg (with adr)

BUT: methaemaglobinaemia

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Methaemoglobinaemia

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Occurs with Prilocaine (also articaine & topical benzocaine)
Due to their metabolites
reducing Hb -> meth Hb, less Hb available for O2 transport

requires excessive doses
leads to cyanosis -> later potentially serious complications

Therefore, don't use Prilocaine to anaesthetise large areas - as will require large doses (eg. bronchoscopy requires while URT)

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3) Bupivacaine

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"no pain, but can't move"
old, long lasting - good for post. op analgesia
"fast in, slow out" (cf. to lignocaine - fast out)

Lowest margin of safety (max dose 150mg)
Bupivacaine Cardiotoxicity:
Cardiac arrest more likely without premionitory CNS symptoms
Cardiac arrest difficult to resuscitate

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1) Ropivacaine (l-bupivacaine)

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Safe alternative to bupivacaine
L enantiomer: less significant CVS toxicity
behaves more like lidocaine (premonitory CNS toxicity first before CVS toxicity)
No fatal outcome reported until now!

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Golden Rules For LA Use

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1) Use amide-type agents
2) Use the weakest concentration necessary
3) Maintain constant observation
4) Cease injecting immediately when early signs of toxicity occur
5) Do not overmedicate early toxicity
6) Have IV access and O2 available when using larger doses

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Patient Management After LA Use

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1) Do not discharge earlier than 1 hour after injection of larger doses
2) Instruct to be aware of correct position and dangers of anaesthesia to tissues
3) Mention temporary duration of block
4) Organise for appropriate analgesia after block worn off