Increases the threshold for ventricular fibrillation
Mode of Action
In resting neurones a selectively permeable cell membrane and non-diffusible cellular anions leads to a negative membrane potential maintained by the Na+/K+ ATP pump. Transmembrane voltage-gated Na+ channels are closed.
Nerve stimulation starts depolarizing the membrane. If threshold is reached, Na+ channels become activated, and rapid Na+ influx & depolarisation ensues..
The increased membrane potential deactivates the Na+ channels which close as the conductance of K+ out of the cell increases and the membrane repolarises. This action potential is unidirectional as recently open Na+ channels are briefly inactivated (refractory).
LAs are weak bases (pKa ~ 8-9) and the ionised (BH+) and non-ionised (B) forms present in ECF in relative proportions given by the Henderson-Hasselbach Equation:
pH = pKa + log ([B]/[BH+]
At physiological pH, the ratio is 10-100:1 in favour of BH+ and as the pH lowers this ratio and the [BH+] increases.
However it is only the non-ionised form (B) that can diffuse through the lipophilic cell membrane & enter the nerve, but it needs to be ionised again before blocking (stereoscopically or via a receptor) the Na+ channels (preferentially those in an inactivated state) from the inside.
Differential block: Smaller diameter fibres are generally affected first (e.g. C and A-delta pain fibres) before larger (e.g. motor) nerves (except where the motor fibres may surround sensory fibres in large nerve bundles).
If equal size then myelinated fibres more sensitive than unmyelinated
Potency and duration proportional to lipophilicity
At low pH (such as inflamed tissue) less LA penetrates the nerve as most is in the charged form and LAs are less effective.
Action potential conduction brings more sodium channels into the inactivated state and thus increases the rate of the block (use dependency).
Absorption: Depends on site, vascularity, vasoconstrictor use, pH & degree of tissue-binding.
Distribution: Amides – initially in highly perfused organs then redistributed to fat; Esters – not studied as metabolised too quickly
Metabolism: Esters hydrolysed rapidly by pseudocholinesterase (except cocaine) & liver esterases; Amides by liver microsomal dealkylation – variable first pass metabolism.
Excretion: Renal – acidification of the urine promotes excretion (by ion trapping). Protein-binding is proportional to duration of action.
Use With Adrenaline
Adrenaline is a local vasoconstrictor
Reduced blood supply has three advantages:
Less bleeding at the site [local infiltration]
Less systemic absorption, and consequently lower toxicity and opportunity of giving a higher dose
Prolonged duration of action
More useful with short acting agents such as lignocaine
In the past it was always advised that adrenaline should never be used for infiltration around end-arteries i.e. penis, ring block of fingers due to potential risk of severe ischaemia and necrosis. Reviews of the literature have debunked this myth and support the safe use of 1:100,000 or more dilute formulations in these areas if there is no pre-existing circulation impairment and good technique is followed. Caution is still advised if full ring blocks are to be performed.
Also contraindicated in thyrotoxicosis, arrhythmias, CCF, IHD.
NB. Cocaine is a LA with vasoconstrictor properties
Eyes – Amethocaine drops
Skin (for venepuncture, cannulation, LP, etc.)
EMLA: Eutetic mixture1 of local anaesthetics (lignocaine & prilocaine)+emulsifiers
Available as 5% cream or 1g patch. Generally restrict to 1-2 patches per child < 1yr
Need to wait 45mins – 1 hr under occlusive dressing.
Not sterile thus shouldn’t be used on open wounds
Can make veins less visible
Increased risk of methaemoglobinaemia with age<6 months
Amethocaine gel (AnGel)
Available as 4% preparation
Need to wait 30-45mins, remove after maximum of 1 hr
Can cause a dermatitis (metabolises to PABA)
Not sterile thus shouldn’t be used on open wounds
ALA or LET: Adrenaline, lignocaine & amethocaine (tetracaine)
Local pain on injection – warm and buffer with 8.4% bicarbonate in 1:10 ratio & inject slowly with smallest needle.
Systemic effects can occur with intravascular injection or tissue absorption of an excessive dose. The effects are related to site of injection, LA used, abs blood level, rate of change of blood level & pre-existing disease.
Allergic reaction/Dermatitis – Notably with esters as they metabolise to PABA
Initially: circumoral/tongue paraesthesiae or numbness, tinnitus, nystagmus & dizziness
Regarding bupivacaine: less ‘safety margin between first CNS and CVS effects, VF is a major risk, also CVS collapse may be particularly refractory.
Methaemoglobinaemia with prilocaine (esp. foetus/young infants)
Known allergy – can use diphenhydramine (antihistamine with LA properties) instead if infiltration required.
Amide LAs should be avoided in severe liver disease or if patient has inhibition of liver cytochrome P450 3A4 enzyme or is on drugs that compete for this enzyme: e.g. Chloramphenicol, Erythromycin, Fluconazole, Cimetidine, Midazolam. Note that beta blockers can reduce liver blood flow and so slow metabolism
Summary of doses:
Dose with adrenaline
Dunn R. The Emergency Medicine Manual 3rd Ed.
Katung B. Basic & Clinical Pharmacology 8th Ed.
Cameron P. et al. Textbook of Adult Emergency Medicine 2nd Ed.
Mahadevan S. & Garmel G. An Introduction to Clinical Emergency Medicine
Neal M. Medical Pharmacology at a Glance 3rd Ed.
Eutetic Mixture = A mixture whose constituents are in such proportions that it melts and solidifies at a single temperature that is lower than the melting point of the constituents or any other mixture of them.