Local Anaesthetic Agents
- Local anaesthetic drugs deliver a use-dependent, temporary blockade of neuronal transmission
- Unionised drug passes through the cell membrane, and then becomes ionised intracellularly
- The ionised drug is then able to bind to the ion channel, and prevent conduction of sodium and therefore generation of an action potential
- All local anaesthetics consist of:
- A hydrophilic component
- A lipophilic aromatic ring
- An amide or ester link connecting the two
Common Features of Local Anaesthetics
| Property | Action |
|---|---|
| Class | Amide (-NHCO-) or Ester (-COOH-) |
| Pharmaceutics | Amides are stable in solution, esters are unstable in solution. All are formulated as a hydrochloride salt to ensure water solubility. |
| pKa | All are weak bases, and have a pKa > 7.4 |
| Onset | Onset is related to dose (Fick's Law) and pKa, with a low pKa giving a faster onset as there is more unionised drug present and therefore more drug able to cross the cell membrane. This is why local anaesthetics are poor at anaesthetising infected tissues, as the tissue pH is low resulting in a greater proportion of ionised drug, and less drug reaching the effect site. |
| Duration of Action | Duration of action is related to protein binding, with greater protein binding giving a longer duration of action |
| Potency | Potency is related to lipid solubility (higher lipid solubility increases potency) and vasodilator properties (weaker vasodilators having greater potency) |
| Absorption | Systemic absorption varies with site of entry (from highest absorption to lowest: IV, intercostal, caudal epidural, lumbar epidural, brachial plexus, subcutaneous), dose, and presence of vasoconstrictors |
| Distribution | Amides are extensively protein bound, esters are minimally bound |
| Metabolism | Amides are hepatically metabolised, esters are hydrolysed by plasma cholinesterases (giving a much shorter t1/2) |
| CVS | Vasodilatation at low concentrations, vasoconstriction at high concentrations. Inhibition of cardiac Na+ channels, inhibiting maximum rate of rise of phase 0 of the cardiac action potential. Negative inotropy proportional to potency. |
| CNS | Does-dependent CNS effects: circumoral tingling, visual disturbances, tinnitus, tremors, dizziness, slurred speech, convulsions, coma, apnoea. Potentiated by other CNS depressants and hypercarbia (due to ↑ CBF and ↓ seizure threshold). |
| Toxic Effects | Esters have a higher incidence of allergy due to their metabolite para-amino benzoic acid (PABA). Local anaesthetic toxicity is predominantly CNS and CVS. |
Comparison of Local Anaesthetics
| Property | Lignocaine | Bupivacaine | Ropivacaine | Cocaine | |
|---|---|---|---|---|---|
| Class | Amide | Amide | Amide | Ester | |
| Uses | Local/regional/epidural, ventricular dysrhythmia | Local/regional/epidural | Local/regional/epidural | Topical anaesthesia and vasoconstriction | |
| Presentation | Clear, colourless solution at 0.5/1/2% with or without adrenaline. Spray. Ointment. 4% solution. | Clear, colourless solution at 0.25/0.5% | Clear, colourless solution | 1-4% solution, Moffat's solution (8% cocaine, 1% NaCO3, 1:2 000 adrenaline) | |
| pKa | 7.9 | 8.1 | 8.1 | 8.6 | |
| Route of Administration | SC, epidural, IV | SC, epidural | SC, epidural | Topical | |
| Onset/Duration | Rapid onset, short duration | Intermediate onset, long duration | Intermediate onset, long duration | 20-30 minutes | |
| Maximum Dose | Analgesia: 4mg.kg-1 without adrenaline, 7mg.kg-1 with adrenaline | 2mg.kg-1 | 3mg.kg-1 | 3mg.kg-1 | |
| Distribution | 70% protein bound | Highly protein bound | Lower lipid solubility reduces motor block compared to bupivacaine | Highly protein bound | |
| Metabolism | Hepatic with some active metabolites | Hepatic to inactive metabolites | Hepatic to active metabolites | Plasma esterases, some hepatic metabolism (unlike other esters) | |
| Elimination | Reduced in hepatic or cardiac failure | Elimination of active drug and inactive metabolites | |||
| CC/CNS ratio | 7 | 3 | 5 | ||
| Other | Most toxic of LA agents as it takes longer to dissociate from the myocardial Na+ channel. Levobupivacaine is less cardiotoxic the racemic mixture, possibly as it has more intrinsic vasoconstrictive properties. | May cause ↑ BP, ↑ HR, coronary vasoconstriction, myocardial depression, VF, ↑ temperature due to ↑ serotonin, dopamine, and noradrenaline reuptake |
Lignocaine Toxicity
| Serum concentration (µg.ml-1) | Phase | Effect |
|---|---|---|
| 2 | Safe | Antiarrhythmic. May begin to have lightheadedness, circumoral tingling, numbness |
| 5 | Excitatory | Dysarthria |
| 8 | Excitatory | Visual changes |
| 10 | Excitatory | Seizures |
| 12 | Depressive | Loss of consciousness |
| 20 | Depressive | Respiratory depression |
| 25 | Depressive | CVS depression |
Pharmaceutics of Topical Local Anaesthetics
Effect of topical local anaesthetics is governed by Fick's Law.
| Characteristic | Effect |
|---|---|
| Pharmaceutic Factors | |
| Presentation | Aerosol improves speed of onset by moisturising skin |
| Concentration of active component | Increase speed of onset |
| Stability | |
| pH | ↑ pH ensures more local anaesthetic is in the unionised form, ↑ absorption. |
| Additives | Affect pH and vasoconstrictor activity |
| Drug Factors | |
| Molecular weight | Small molecules will diffuse more easily |
| pKa | Affects ionisation and therefore lipid solubility |
| Lipid solubility | ↑ lipid solubility improves speed of onset. |
| Potency | Determines amount of drug needed to produce an effect |
| Vasoconstrictor activity | Will affect both speed of onset and degree of systemic absorption |
| Patient Factors | |
| Site | Degree of vascularity of site |
| Skin | Skin thickness and area will affect onset |
References
- CICM March/May 2009
- Peck TE, Hill SA. Pharmacology for Anaesthesia and Intensive Care. 4th Ed. Cambridge University Press. 2014.
- Smith S, Scarth E, Sasada M. Drugs in Anaesthesia and Intensive Care. 4th Ed. Oxford University Press. 2011.
- Open Anaesthesia. Local Anaesthetics Systemic Toxicity
- Gadsden J. Local Anaesthetics: Clinical Pharmacology and Rational Selection. NYSORA.
- Leslie RA, Johnson EK, Goodwin APL. Dr Podcast Scripts for the Primary FRCA. Cambridge University Press. 2011.
- Christie LE, Picard J, Weinberg GL. Local anaesthetic systemic toxicity. Continuing Education in Anaesthesia Critical Care & Pain, Volume 15, Issue 3, 1 June 2015, Pages 136–142.