Local Anaesthetics Notes

Lecture 8

Local anaesthetics

• General

  • Local anaesthesia: local, reversible loss of sensation without loss of consciousness

    • (morphine and heroin give general loss of sensation and consciousness),

  • Mechanism: block nerve conduction

  • Many drugs have LA properties at high conc. (e.g. Propranolol & morphine)

    • Have amine and aromatic moieties

    • But interact with specific receptors at lower conc.

    • LA drugs have NO other activities

• Local anaesthetic nerve block

  • Small-diameter nerve fibres blocked more readily (lower doses) than large fibres

  • Nociceptive impulses (pain info) carried by A(delta) and C fibres

  • Higher concentrations- other ‘nerve’ fibres blocked

    • E.g. cardiac cells (Lidnocaine; “big nerve cell” that contracts)

• Susceptibility to block of types of nerve fibres

  • A(delta)

    • Function: PAIN, prickling, touch, temperature

    • High sensitivity to block

  • C fibres

    • Function: PAIN (slow, burning), temperature, touch

    • High sensitivity to block

  • Some other small diameter fibres also blocked, so not absolutely selective

• Effects of Las on events in nerve excitation

  • Block and inactivate (also enhance) certain parts of AP cycle

  • LA block the Na channels opening following depolarisation

  • LA enhance Na channels inactivation

• Na channel subunits

  • 4 repeat units

  • a-units mainly form (B sit on side, not as much function)

  • Each unit has 6 transmembrane domains with a loop between two of these domains

  • Subunits 5 & 6 of each unit contribute to the pore of the channel

  • Tyrosine and phenylamine (AAs of units) are important binding sites for LA

    • Phenylalanine= No charge but has benzene ring with electron on either side. Nitrogen attracts electron charge from ring, pulls down arm of (F) by attaching to ring, causing conformational shape change (structure in book)

• LAs- chemical structure

  • All anaesthetics (bar 1) have 3 groups

    • Aromatic group (lipophilic, hydrophobic)

    • Ester/Amide (intermediate chain variable length)

    • Amino group (secondary or tertiary; water soluble when protonated)

  • Can be in both charged or uncharged state (find both in blood)

  • Examples

    • Procaine

      • Out of use, but simplest structure

      • Ester part (very quickly broken down in blood by plasma esterases)

      • Tertiary nitrogen

      • Short plasma life- readily hydrolysed by plasma esterases

      • Tissue penetration poor

    • Lignocaine (Lidocaine)

      • Amide part (metabolised by liver)

      • Tertiary nitrogen

      • 2h plasma t

      • Most widely used LA

      • Rapid onset, moderate duration of action, extremely stable (long shelf life)

• Uncharged and charged forms of LAs

  • Uncharged important

    • Penetrate neural sheath (get drug to site; rate of onset of action)

    • Crossing plasma membrane (get inside nerve cell; access site of action)

  • Charged important for

    • Interacting with Na channel (only not the case for one LA)

• What percentage of LA molecules are ionised?

  • Determined by pH

  • Determined by pKa of LA (most weak bases, pKa=8-9)

  • pKa=pH at which: LA + H LAH

50% (unionised) 50% (ionised)

• Since pKA for LAs= 8-9, at physiological pH of 7.4

  • Approx. 20%= [LA] & 80% [LAH]

• pH INCREASES [LA] DECREASES [LAH] INCREASES

  • Inflamed tissue, pH quite low which means more charged and so drug won’t be able to get to site

• Henderson-Hasselbalch equation

  • % of ionised/unionised LA molecules at given pH can be calculated with this

  • pKa-pH = log [LAH]/[LA]

• Atypical LAs

  • Benzocaine

    • Only LA without nitrogen (not very important)

    • Can’t be charged

    • Condoms

  • QX-314

    • Permanently charged- 100% ionised

    • Blocks Na channels only if introduced into cells

    • Quaternary nitrogen

• Most LAs show some degree of use-dependence

  • Need Na channels to open so can get to site of action

  • I.e. more often neurone fires AP the greater the greater degree of block

  • Not of major...

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