Local Anaesthetic Agents

Action:

Reversible depression of nerve conductance along central and peripheral pathways. The agents diffuse through the lipid cell membrane in the unionised state and interact with a specific receptor-like site on the sodium channel in the ionised state:
  1. The Modulated receptor hypothesis:
    The affinity of the receptor is modulated by the channel state (open, inactivated or resting). The selective binding to the sodium channels in the inactivated-closed state will prevent the channels from changing to the open or resting state and so prevent nerve impulses. The local anaesthetic molecules can only gain access to receptors when the channel is open, when resting some of the drug detaches from the receptor, if the channel is then re-opened an increase in the amount of local anaesthetic occurs leading to a frequency-dependant block - a block that is dependant on the characteristic frequency of activity of the nerve as well as on its anatomical properties (diameter, mylination)
  2. The Guarded receptor hypothesis:
    The affinity is constantly high, but access of the local anaesthetic to the receptor is guarded by channel "gates".

Local anaesthetics prevent the opening of the sodium channels and delay the rate of conduction of action potentials, without changing the resting membrane potential. They can also block certain potasium channels, further modifying the conduction of action potentials. They do inhibit the action of phospholipase A 2 and interfere with prostoglandin synthesis.

Sensory physiology

The sense organs for mechanical stimulation, temperature, proprioception and pain transmit information via various types of primary afferent nerve fibres to the dorsal horn of the spinal cord. Propinospinal neurones, which are totally confined to the spinal cord, transmit the information through the  dorsal horn. Ascending neurones then take the information for interpretation to the appropriate supraspinal destination. A descending pathway from the midbrain modulates the sensory input at different points in the spinal cord, ending at the dorsal horn of the spinal cord.

The primary afferent nerve fibres have been divided into seven different groups depending on their function.

Preferential blockade of a nerve requires a minimal length of fibre exposed to an adequate concentration (Cm) of local anaesthetic. The blocking of three sequential nodes of Ranvier is always sufficient. As thick fibers have an increased distance between nodes of Ranvier this explains the onset of fiber blockade

And the differential blockade seen with different concentrations of local anaesthetics is explained by the Cm (c. f. MAC) which is in itself influenced by nerve fiber diameter, tissue pH and frequency of nerve firing.

  Tetracaine Lignocaine Mepivacaine Bupivacaine Ropivacaine Levobupivacaine
A bsorption            
pKa 8.6 7.9 7.6 8.1 8.07 8.1
% base 5 35 35 20 20 20
          intrinsic vasoconstriction
D istribution            
Protein Binding 75 % 75 % 75 % 95 % 94 % 97 %
Lung extraction   yes   yes (saturated rapidly)
Vd ss L/Kg   1.5 1.25 1 1 1
t 1/2b Hrs   1.5 1.75 3 2 1.3
             
Metabolism Slow Cholinesterase to p-ABA Intermediate
Liver - mono ethyl glycine xylidide to xylidide
Intermediate
Liver
Slow
Liver N-desbutyl bupivacaine
Liver Liver
3-hydroxy levobupivacaine
Excretion Renal Renal Renal Renal Renal Renal
Chemistry Ester Amide Amide Amide Amide Amide
Potency 16 1 1 4 4 4
Dose (mg/Kg)            
Toxic 1-1.5 3-7 7 2 2.5 2.5
Topical         No No
Infiltration         2.5 2.5
Nerve blocks         2.0 2.0
Caudal         0.6 1.5
Epidural         0.6 1.5
Spinal   1.5   0.2 Not approved 0.2
CC:CNS   7   3 5 5
Effect            
Onset min 10 5-15 5-15 10-20 10-15 <15 minutes
Duration Hrs 1-1.5 1-1.5 1.5-2 Dose and technique dependent
Formulation       racemic mixture   S (-) enantiomer
Topical 10 % emla ; 10%        
Infiltration   2%   0.5% 0.5 % 0.75 %
Nerve blocks   1-2%   0.25-0.5 % 0.5 % 0.25-0.5 %
Caudal   2%   0.125-0.5 % 0.2 % 0.125-0.5 %
Epidural   2%   0.125-0.5% 0.2 % 0.085 - 0.5 %
Spinal 1 % 2%   0.5 % Not approved 0.5 %

Adverse Effects:

Local anaesthetics are a safe and effective and highly desirable means for achieving analgesia. However, if you use them enough, despite your best precautions, you will encounter toxicity. If you are not prepared to deal with it, this toxicity may result in serious harm or death. The first step is to recognise toxicity, which takes two major forms:

  1. Neurotoxicity
  2. Cardiotoxicity

Lignocaine, bupivacaine and ropivacaine are all more likely to cause neurotoxicity than cardiac toxicity. This relative risk has been called the cc:cns ratio. The dose in (mg/Kg) that cause cardiovascular collapse vs the dose in  (mg/Kg) that cause central nervous system collapse is the CC/CNS ratio.  It has been estimated that 7 times the dose of lignocaine that caused seizures will cause a cardiac arrest.

Neurotoxicity often starts with a change in mentation, followed by perioral paraesthesia, a feeling that the subject's whole body is flushing, tinnitus and other neurological symptoms culminating in generalised seizures.

  1. Excitation - numbness, tinnitus, nystagmus, dizziness, excitability, restlessness, tremor, convulsions (not cortical in origin. Usually from the Amygdala nucleus of the limbic system - patient experiences symptoms like temporal lobe epilepsy)
  2. Followed by depression - coma, respiratory and cardiac arrest

The initial neurological manifestation is often missed by the incautious doctor, as it may manifest as:

The first and most important rule of local anaesthesia is thus clear: Keep the patient talking at all times!

Cardiotoxicity This is a rightly feared consequence of high blood levels of local anaesthetic.

  1. It starts with peripheral arteriolar and venous dilatation, then
  2. Decreased myocardial contractility (inhibition of Ca 2+ channels).
  3. A decrease in cardiac rate.
  4. Quinidine like action on the action potential with an

Management of toxicity

Most important is to be prepared to resuscitate the patient, and know your 'ABC'. Prolonged cardiopulmonary resuscitation may be required, especially with bupivacaine which has a longer half-life than lignocaine.

  1. Prevent toxicity

Despite the best will in the world, toxic reactions will still occur

  1. Get help now!
  2. Secure and maintain airway and oxygenation - wether you use a mask or endotracheal tube, ventilatory support as necessary.
  3. Ensure intravenous access.
  4. Control convulsions - Thiopentone or a short or long acting benzodiazepine
  5. Haemodynamic support - Know how to use your inotrope of choice
  6. Correct arrhythmias

Allergy

Allergy to amide local anaesthetics is extremely uncommon, if it exists. Ester local anaesthetics, which are infrequently used, are much more often associated with allergy because they are metabolised to para-amino benzoic acid, which acts as a hapten.

Toxicity related to additives

Multi-use vials

These are a cost-saving abomination. They usually contain methyl paraben as a preservative, which is neurotoxic. There are thus several good reasons why you should never use a multi-use vial, including: 

Mixtures

Mistrust doctors who make complex concoctions, especially for epidural or spinal use. Next time you have the opportunity, check the pH of dextrose (a common additive) - you will find it to be surprisingly acidic. This, if added to carefully pH-adjusted solutions like lignocaine or marcaine, will totally muck up the pH balance.

Neurotoxicity

  1. Preservative in the local anaesthetic - Methylparaben, Sodium bisulfite,
  2. High concentrations in close proximity to the nerve root (spinal or epidural) for a long period of time.
  3. Transient Radicular Irritation : Is it a manifestation of nerve damage?

Decreasing latency and prolongation of action of the local anaesthetic agent

  1. Alpha 1 agonists
  2. Alpha 2 agonist (clonidine) cause vasoconstriction and delay systemic absorption.
  3. Combination Alpha 1 and 2 agonist
  4. Addition of NaHCO 3 (1ml per 10ml of lig and 0.1ml per 10ml of bup) raises local pH thus increasing the unionized % and increases transfer across the lipid membrane .
  5. Warming the solution to 37 o C possibly decreases the pKa of the local anaesthetic and hastens the onset
  6. Combining a short onset local anaesthetic with a long duration local anaesthetic should provide the best of both worlds. Mixtures of local anaesthetic show additive toxicities
  7. Combining a local anaesthetic with an opioid will lower the total amount and concentration of local anaesthetic necessary and increase the duration of the block itself.
  8. Addition of low molecular weight dextrans - ? by decreasing systemic absorption
  9. Addition of CO 2 @ 700mmHg (carbonation) increases local CO 2 concentration which passes into cells and decreases intracellular pH therefore increasing the ionized concentration and so promoting receptor binding.
  10. Time release preparations decrease the rate of release and increase the local availability of the local anaesthetic preparationsBiodegradable polyanhydride polymers for regional blockadeLipid depot in neuraxial blockade using iophendylateLiposomal encapsulation with egg yolk phosphatidyl choline and cholesterol in neuraxial blockade
  11. Sodium channel blockers - Veratridine a steroidal alkaloid holds the sodium channel open. It preferentially blocks the unmyelinated C-fibres.
  12. Potasium channel blockers - (Tetraethyl ammonium ion and 3-4-diaminopyridine) potentiate the impulse inhibition caused by the LA.

EMLA = Eutectic Mixture of Local Anaesthetics

Eutectic - two compounds which when mixed behave as a single compound.

Supplied as a 5g or 30g tube with Tegaderm dressings

Dose 1-2g per 10cm 2 of skin.

The serendipitous discovery was that this compund has a melting point of 16 o C and is a liquid at room temperature with the individual components as crystalline solids, with a high base content.

It can penetrate the skin within 15min but takes 50min to maximum effect which can be increased by iontophoresis. Plasma levels for both remain low.

Indications

Complications