Question 22

Describe the factors that increase the risk of systemic toxicity of the amide local anaesthetics. 

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College Answer

The amide group oflocal anaesthetics consist of lignocaine, prilocaine, ropivacaine and bupivacaine. The systemic toxicity primarily relates to toxic plasma levels and the factors that influence this. The main factors expected can be categorized under drug factors (including kinetics), patient factors, site of injection and external factors. Many candidates omitted important details such as pKA, lipid solubility and addition of vasoconstrictors. For  example, absorption is affected by drug pKA, (thecloser to physiological pH themore rapid the absorption), use of vasoconstrictors and the drugs own vasoactive properties, site of injection (intercostal>epidural>brachial plexus>subcutaneous infiltration). Distribution is dependent on physicochemical properties of the amide. The rate of metabolism, mechanism of action (bupivacaine, in comparison to lignocaine has stronger binding to inactivated 
resting sodium channels and a slower rate of dissociation) and external factors (e.g. systemic acidosis) are other factors that should have been mentioned, and expanded upon with relevant detail.

Discussion

Drug factors:

  • Choice of agent matters; bupivacaine is thought to have greater potential for cardiotoxicity. CNS toxicity usually requires about three times less local anaesthetic than cardiovascular toxicity. This empirically derived ratio is as high as 7.1 for lignocaine, and as low as 2.4 for bupivacaine (Garg et al, 2020).
  • Dose of the drug:  overdose could happen accidentally if dose calculations to an actual body weight are performed in obese or pregnant patients
  • Site of administration: 
    • Increased risk of direct intravascular injection:
      • Interscalene block
      • Brachial plexus block
      • Stellate ganglion block
      • Intercostal nerve block
    • Increased risk of rapid absorption:
      • Scalp
      • Bronchial mucosa
      • Interpleural cavity
      • Epidural
  • Drug interactions can increase or decrease the risk of local anaesthetic toxicity:
    • Adrenaline: decreased systemic absorption
    • GTN infusion: increase systemic absoprtion
    • Compete for protein binding with local anaesthetics: eg. phenytoin, quinidine and desipramine can displace bupivacaine from plasma proteins.
    • Interference with hepatic metabolism of amide anaesthetics (eg. by cimetidine) or with hydrolysis of esters (eg. ecothiopate) could result in delayed clearance.
    • Pharmacodynamic interactions (eg. where flumazenil lowers the seizure threshold and potentiates the CNS toxicity)

Patient factors:

  • Acidosis: changes the protein binding and makes more of the agent available
  • Old age: the elderly have slower clearance
  • Young age: lower α1-acid glycoprotein level, thus greater free fraction
  • Pregnant patients also have a lower α1-acid glycoprotein level
  • Hyperkalemia potentiates the cardiotoxic effects of local anaesthetics

References

Finucane, Brendan T. Complications of regional anesthesia. New York: Springer, 2007.

Scott, D. B. "Toxic effects of local anaesthetic agents on the central nervous system." BJA: British Journal of Anaesthesia 58.7 (1986): 732-735.

Shibata, Masatoshi, et al. "Tetraphasic actions of local anesthetics on central nervous system electrical activities in cats." Regional Anesthesia and Pain Medicine 19.4 (1994): 255-263.

Ladd, Leigh A., et al. "Effects of CNS site-directed carotid arterial infusions of bupivacaine, levobupivacaine, and ropivacaine in sheep." The Journal of the American Society of Anesthesiologists 97.2 (2002): 418-428.

Blair, M. R. "Cardiovascular pharmacology of local anaesthetics." BJA: British Journal of Anaesthesia 47 (1975): 247-252.

Newton, D. J., et al. "Mechanisms influencing the vasoactive effects of lidocaine in human skin." Anaesthesia 62.2 (2007): 146-150.

Christie, Linsey E., John Picard, and Guy L. Weinberg. "Local anaesthetic systemic toxicity." Bja Education 15.3 (2015): 136-142.

Mauch, J., et al. "Electrocardiographic changes during continuous intravenous application of bupivacaine in neonatal pigs." British journal of anaesthesia 105.4 (2010): 437-441.

Nancarrow, C., et al. "The influence of acidosis on the distribution of lidocaine and bupivacaine into the myocardium and brain of the sheep." Anesthesia and analgesia 66.10 (1987): 925-935.

Avery, Pamela, et al. "The influence of serum potassium on the cerebral and cardiac toxicity of bupivacaine and lidocaine." Anesthesiology 61.2 (1984): 134-138.

Dillane, Derek, and Brendan T. Finucane. "Local anesthetic systemic toxicity." Canadian Journal of Anesthesia/Journal canadien d'anesthésie 57.4 (2010): 368-380.

Garg, Divya, Shikha Soni, and Rakesh Karnawat. "Local Anesthetic Systemic Toxicity." Topics in Local Anesthetics. IntechOpen, 2020.

Naguib, Mohamed, et al. "Adverse effects and drug interactions associated with local and regional anaesthesia." Drug safety 18.4 (1998): 221-250.