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Pharmacokinetics and toxicity of local anaesthetics

Created: 19/7/2009
Updated: 17/11/2009



The absorption of local anaesthetics into the systemic circulation varies depending on the site of injection. This will be influenced by the characteristics of the agent used and presence of added vasoconstrictor. If local anaesthetic is inadvertently injected into a vein or artery, very high systemic levels will result and possibly cause central nervous system or cardiovascular toxicity.


The distribution of the drug is influenced by the degree of tissue and plasma protein binding of the drug. Ester local anaesthetics are minimally bound, while amides are more extensively bound in the plasma. Alpha–acid glycoprotein binds local anaesthetic with high affinity, although albumin binds a greater quantity due to its relative abundance. When protein binding is decreased, the free fraction of drug is increased. 

The degree of protein binding will affect the amount of placental transfer. Bupivacaine is more highly bound than lidocaine, so less crosses the placenta. If the foetus becomes acidotic, there will be an increase in the ionised fraction and local anaesthetic will accumulate in the foetus (ion trapping). Ester local anaesthetics do not cross the placenta in significant amounts due to their rapid metabolism.

Metabolism and excretion

Ester and amide anaesthetics differ in their metabolism. 

Esters (except cocaine) are broken down rapidly by plasma esterases to inactive compounds and consequently have a short half-life. Para-aminobenzoate is one of the main metabolites and has been associated with hypersensitivity reactions, especially in the atopic patient. Cocaine is hydrolysed in the liver. Ester metabolite excretion is renal.

Amides are metabolised hepatically by amidases. Amidase metabolism is much slower than plasma hydrolysis and so amides are more prone to accumulation when administered by continuous infusion. Reduced hepatic blood flow or hepatic dysfunction can decrease amide metabolism.

Local anaesthetic toxicity

Local anaesthetic toxicity can be discussed under a number of headings. View the table below for a suggested framework.


Additive toxicity
• Vasopressors
• Preservatives

Local toxicity
• Intraneural injection
• Neural ischaemia due to local pressure
• High-dose lidocaine radicular irritation
 Systemic toxicity

• Dose injected
• Weight of patient
• Concentration of drug
• Rate of administration
• Site of injection
• Addition of a vasoconstrictor          
• Degree of protein binding

Local anaesthetics may be toxic if sufficient amounts are absorbed into the systemic circulation. Of these, bupivacaine appears to be the most dangerous, although all can be harmful. Clinical toxicity appears to relate to the effects of the drug on other excitable membranes in the CNS and cardiovascular systems. CNS effects may include tingling of the lips, slurred speech, reduced level of consciousness and seizures. Cardiac effects on a variety of ion channels may cause arrhythmias and reduced myocardial contractility. In the case of bupivacaine, the cardiac effects are particularly difficult to treat, since its strong protein binding makes it difficult to displace from the myocardium. By contrast, lidocaine may be used clinically for its cardiac effects as an antiarrhythmic. 

Unexpected local anaesthetic toxicity can occur, where the pharmacokinetics of the drug are altered by co-morbidity such as cardiac or hepatic failure (reducing the metabolism of the drug), alterations in plasma protein binding or interactions with other drugs.

Other clinical problems are more specific to particular drugs. The incidence of allergy to PABA, a metabolite of many esters, has been mentioned. Prilocaine is metabolised to O-toluidine, which can cause methaemoglobinaemia in susceptible individuals. Cocaine is a potent vasoconstrictor and may cause problems in patients already on vasoconstricting drugs such as monoamine oxidase inhibitors.

Treatment of local anaesthetic toxicity

Standard resuscitation guidelines apply in the event of severe toxicity. In the event of local anesthetic-induced cardiac arrest that is unresponsive to standard therapy, in addition to standard cardiopulmonary resuscitation, Intralipid 20% should be given intravenously.

Weinberg et al. have published data indicating that Intralipid is effective in treating experimental models of severe cardiotoxicity secondary to intravenous overdose of local anaesthetic drugs such as bupivacaine (Picard and Meek, 2006; Weinberg et al., 1998, 2003 and 2004). Recent case reports have been published of the successful use of lipid emulsion in this way (Rosenblatt, 2006; Litz, 2006; Foxall, 2007) to save patients who were unresponsive to the usual resuscitation methods. All patients recovered completely shortly after intravenous injections of lipid.

Video 1: A video outlining the technique of basic cardiopulmonary resuscitation.


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