Local anaesthetics

Local anaesthetics are drugs that cause a reversible, localised elimination of pain sensation by inhibiting the transmission of impulses along the nerve fibre and in the area of the nerve endings (blocking the voltage-dependent Na+ channels).

Sequence of stimulus elimination: pain pressure-heat motor function. The various local anaesthetics differ in their physicochemical properties (e.g. lipophilia), their potency, the onset of action and the duration of action. In general, lipophilia correlates with the strength and duration of action.

Local anaesthetics are substances with a lipophilic aromatic residue and an amino acid group as the hydrophilic residue, which are connected to each other via an intermediate chain. This contains either an ester bond (-CO-O-C-) or an acid amide bond (-C-NH-CO-C-). Accordingly, a distinction is made between:

• Local anaesthetics of the ester type (prototype = procaine)
• Local anaesthetics of the acid amide type (prototype is lidocaine)

In procaine, the lipophilic part (see figure red) is connected to the hydrophilic part (see figure blue) by an intermediate chain containing an ester part (yellow). In local anaesthetics of the lidocaine type, the intermediate chain contains an acid amide bond (yellow).

Local anaesthetics of the ester type:

• Benzocaine
• Chloroprocaine
• Cocaine
• Oxybuprocaine
• Proxymetacaine
• Procaine
• Tetracaine

Local anaesthetics of the acid amide type:

• Articaine
• Bupivacaine
• Cinchocaine
• Flecainide
• Levobupivacaine
• Lidocaine, Lidocaine patch
• Mepivacaine
• Oxetacaine
• Prilocaine
• Quinisocaine
• Ropivacaine
• Oxybuprocaine

As amines, local anaesthetics (LA) are bases that form easily water-soluble salts with acids, regardless of the type of bond (ester or amide bond). In an acidic environment (e.g. in inflammatory tissue), local anaesthetics are not sufficiently effective because the charged polar form of the local anaesthetics diffuses and penetrates poorly. In the uncharged "penetration form", however, the LA can easily reach its actual destination, the axonal membrane of the peripheral nerves, due to high lipophilicity. For this purpose, the axonal membrane itself, the perineurium and possibly also the myelin sheath as lipophilic barriers must be overcome.

At the channel pore, the LA with their lipophilic aromatic residue bind to the channel protein. The hydrophilic cationic residue protrudes into the channel pore. LA lead to a slowing down of the kinetics of the reactivation of the ion channel. The time constant for channel recovery increases considerably with the increasing concentration of LA. Thus the proportion of channels that can be activated decreases. A peripheral stimulus encounters only a few sodium channels in an activatable resting state. The action potential is not passed on. In contrast to motor nerve fibres, pain-conducting fibres as well as pre- and postganglionic fibres of the sympathetic nervous system consist of thin, slowly conducting fibres. Therefore, pain sensation and sympathetic transmission is more easily blocked than the transmission of excitation in motor fibers (Yanagidate F et al. 2007).

In principle, LA can block the excitation conduction in all nerves. However, thin slow nerve fibres are much more sensitive than thick fast conducting nerve fibres.

Elimination: LA are metabolically eliminated. The degradation is carried out by non-specific esterases at the site of action and in the plasma.

The pharmacologically active form at the sodium channel (blockade of the sodium channel) is the charged quaternary ammonium compound. The lipid solubility of LA scatters considerably. With increasing lipid solubility, the anaesthetic potency of the molecules increases. Acid amides only become active after absorption into the systemic circulation in the liver. They are therefore present at the injection site for longer than the ester type of LA.

The areas of application include:

• Local anaesthesia e.g. in the context of surgical, dental and diagnostic procedures (Eng HC et al. 2014)
• Local treatment of pain of various causes, e.g. nerve pain, sore throat, oral ulcers, etc.
• "delay cream" for ejaculatio praecox (benzocaine)
• Cardiac arrhythmia.

The most common potential adverse effects of parenteral administration include:

• Local reactions at the injection site
• Paresthesia, dizziness
• Bradycardia
• Vegetatively induced hypotension
• Hypertension
• Nausea, vomiting
• In some cases, NW are expression of a toxic plasma level of the LA used, cardiodepression, rhythm disturbances (measure: atropine 0.25-0.5 mg = 1/2-1 amp. s.c.), central excitation with lowering of the cramp threshold (prophylaxis: diazepam premedication 5-10 mg), respiratory depression.
• Incompatibility reactions of LA are reported to occur in 0.1-1% of all submucous or subcutaneous injections, with over 50% of reactions occurring during dental treatment. Follow-up studies on larger collectives show that psychovegative reactions are the most common cause of so-called LA intolerances. Less than 1% of "sensitized" patients showed genuine positive humoral or cellular immune reactions.
• Allergies: Rare; allergies can lead to anaphylactic shock. Local anaesthetics with an amino group in the para position on the benzene ring (ester type) have a proven high allergenic potency.
• Heart: Severe arrhythmias can occur in the heart due to the action of local anaesthetics. Cardiodepressive effects can lead to cardiac arrest. Therefore, correct injection and appropriate measures to prevent the local anaesthetic from flooding into the systemic circulation must be ensured.
• LAA must not be used in cases of AV block II or III degree as well as in heart failure.
• CNS: In rare systemic reactions (<1/1000 pat.) restlessness, nausea and seizures may occur. For prophylaxis, it is recommended to observe the limit dose for the local anaesthetics used. In addition, the correct injection technique and prevention of systemic flooding must be ensured (Wad DL (2017)

Combinations of local anaesthetics with vasoconstrictors (usually adrenaline) are often used to reduce systemic toxicity and extend the duration of action (contraindicated for use in the acras!).

Cocaine: The first local anaesthetic whose basic chemical structure served as the basis for the development of other local anaesthetics was cocaine. It was already used in 1884 by the ophthalmologist Carl Koller as a surface anaesthetic during an eye operation. He had previously tested it in a self-experiment.

The duration of effect of LA depends crucially on the blood circulation. Therefore, vasoconstrictive additives (especially adrenaline) are often chosen to prolong the duration of action.

1. Becker D.E et al (2012) Local anesthetics: review of pharmacological considerations. Anesth Prog 59: 90-101
2. Eggleston ST et al (1996) Understanding allergic reactions to local anesthetics. Ann Pharmacother 30(7-8):851-857. https://pubmed.ncbi.nlm.nih.gov/8826570/
3. Eng HC et al (2014) Practical use of local anesthetics in regional anesthesia. Curr Opin Anaesthesiol 27:382-387.
4. Graefe KH et al. ion channels. In: Graefe KH et al. (Eds) Pharmacology and Toxicology. Georg Thieme Publisher Stuttgart S.148-153
5. Rader S et al (2003) Diagnosis and re-exposure in case of local anaesthetic intolerance. Allergology 10: 423-428
6. Wad DL (2017) Local Anesthetic Systemic Toxicity. AORNJ 106:367-377.
7. Yanagidate F et al. (2007) Local anesthetics. Handb Exp Pharmacol 177:95-127

Overview of the most common local anaesthetics