Which Anaesthesia Should I Use? A Brief Review of Pharmacological Considerations for the Onset and Duration of Action of Local Anaesthetics

Mechanism of Action  

Local anaesthetics block the transmission of pain signals to the brain by binding voltage-gated sodium channels and inhibiting the influx of sodium into the cell.3 This prevents cell depolarisation and action potential propagation.4  

In order to reach the voltage-gated sodium channels, the un-ionised anaesthetic molecules must cross a phospholipid neuronal membrane. In the neuron, the anaesthetic molecules dissociate to reach a new equilibrium of ionised and un-ionised molecules. The equilibrium depends on the intracellular pH and the ionisation constant (pKa) of the anaesthetic.3  

The ionised anaesthetic molecule binds to open voltage-gated sodium channels in a reversible and concentration-dependent manner. With the local anaesthetic bound, the sodium channel becomes stabilised in the inactive state and blocks neuronal transmission.3  

 While local anaesthetics have the same mechanism of action, unique properties of each drug result in differing onsets and duration of actions.  

Onset of Action 

The onset of action of local anaesthetics depends on two factors — the lipid solubility and the pKa.2   

Lipid Solubility 

Anaesthetics are water-soluble salts of lipid-soluble drugs. The more lipid-soluble the drug, the more potent it is. A more lipid-soluble drug is able to more rapidly diffuse across lipophilic membranes to reach the site of action.2,4  

 The lipid solubility of a drug is defined as the partition coefficient — the ratio of concentrations when the drug is dissolved in a mixture of lipid and aqueous solvents. A greater partition coefficient is associated with greater lipid solubility and a more potent local anaesthetic.3  

Ionisation Constant (pKa) 

The pKa measures the extent to which the anaesthetic dissociates from the salt it is formulated with. The pKa is equal to the pH where the ionised and un-ionised forms of the anaesthetic are present in the same amount. Therefore, the onset of action also depends on the pH of the tissue it is injected into.3 

Overall, anaesthetics with a lower pKa have a more rapid onset of action because there is more of the ionised form of the drug present in normal tissue.2 

Infected tissue typically has a more acidic environment and, therefore, can be more difficult to anaesthetise because it favours the un-ionised form of the drug.2 

Duration of Action 

A local anaesthetic’s duration of action depends on two different factors — protein binding and tissue distribution. The amount of time it takes for the concentration of the local anaesthetic to decrease by half — known as the elimination half-life — is a good indication of the drug’s duration of action. A longer half-life is associated with a longer duration of action.5  

Protein Binding 

Local anaesthetics vary in their affinity to bind alpha-1-acid glycoprotein. In general, the more protein-bound a local anaesthetic is, the longer the duration of action.5  

 The extent of protein binding is associated with the anaesthetic’s affinity for the sodium channel. This can be used to predict how long the anaesthetic will continue to stabilise the sodium channel and block depolarisation.3,5  

 Factors that may decrease protein binding, therefore increasing the risk of toxicity, include hypoxia, hypercarbia, acidemia, and age younger than 6 months.3  

Tissue Distribution 

To be effective, the local anaesthetic must remain in close proximity to the nerve fibres requiring anaesthesia. When the drug is acting in a highly vascular area, it will be absorbed into the systemic circulatory system and away from the target area more rapidly than in less vascular areas.4  

 Some local anaesthetics, like lidocaine, also dilate surrounding blood vessels, further decreasing its duration of action. The addition of a vasopressor (such as epinephrine) to the local anaesthetic can increase the duration of action by delaying systemic absorption.4  

Putting It All Together 

The choice of local anaesthetic should consider specific factors about the procedure and the patient, including: 

• Type of procedure 
• Location of the procedure 
• Length of the procedure 
• Patient’s infection status 
• Patient’s overall health 

Table 1 summarises the physicochemical characteristics of four commonly used local anaesthetics in dentistry. The onset and duration of action of the specific product used should be referenced before selection. However, a general understanding of the pharmacology of these agents can help in the selection process.  

Table 1. Physicochemical Characteristics of Select Local Anaesthetics  

References: 

1. Su N, Liu Y, Yang X, Shi Z, Huang Y. Efficacy and safety of mepivacaine compared with lidocaine in local anaesthesia in dentistry: a meta-analysis of randomised controlled trials. Int Dent J. 2014 Apr;64(2):96-107. doi: 10.1111/idj.12087. Epub 2014 Jan 16. PMID: 24428507; PMCID: PMC9376404.
2. Decloux D, Ouanounou A. Local anaesthesia in dentistry: a review. Int Dent J. 2020 Sep 17;71(2):87-95. doi: 10.1111/idj.12615. Epub ahead of print. PMID: 32944974; PMCID: PMC9275172.
3. Taylor A, McLeod G. Basic pharmacology of local anaesthetics. BJA Educ. 2020 Feb;20(2):34-41. doi: 10.1016/j.bjae.2019.10.002. Epub 2019 Dec 4. Erratum in: BJA Educ. 2020 Apr;20(4):140. PMID: 33456928; PMCID: PMC7808030.
4. Becker DE, Reed KL. Local anesthetics: review of pharmacological considerations. Anesth Prog. 2012 Summer;59(2):90-101; quiz 102-3. doi: 10.2344/0003-3006-59.2.90. PMID: 22822998; PMCID: PMC3403589.
5. Becker DE, Reed KL. Essentials of local anesthetic pharmacology. Anesth Prog. 2006 Fall;53(3):98-108; quiz 109-10. doi: 10.2344/0003-3006(2006)53[98:EOLAP]2.0.CO;2. PMID: 17175824; PMCID: PMC1693664.
6. Snoeck M. Articaine: a review of its use for local and regional anesthesia. Local Reg Anesth. 2012;5:23-33. doi: 10.2147/LRA.S16682. Epub 2012 Jun 5. PMID: 22915899; PMCID: PMC3417979.