Author(s): Michael R.Fettiplace, XiaodongBao
- History: Clinical local anesthetics refer almost exclusively to the ester and amide-linked sodium channel blockers synthesized from the benzoate ring of cocaine isolated from the coca plant of Peru. Other sodium channel blockers exist, but unless otherwise specified (in Chapter 19, Section IV.A) “local anesthetics” refers to the cocaine derivatives.
- Chemistry. Local anesthetics are composed of a terminal amine attached to an aromatic ring via an ester or amide linkage, with both charged (protonated) and uncharged (unprotonated) forms at physiologic pH~7.4). Only uncharged moieties cross the lipid bilayer to block open-state sodium channels with stronger bases (eg, chloroprocaine pKa 9.2) taking longer to take effect than weaker bases (eg, lidocaine pKa 7.2). Amide local anesthetics are preferred given their lower allogenicity and longer half-life.
- Esters.Benzocaine, cocaine, chloroprocaine, procaine, and tetracaine. The ester linkage is cleaved by pseudocholinesterase. The half-life in the circulation is very short (about 1 minute). The degradation product of ester metabolism is p-aminobenzoic acid (PABA).
- Amides.Bupivacaine, etidocaine, lidocaine, mepivacaine, prilocaine, and ropivacaine. The amide linkage is cleaved through initial N-dealkylation followed by hydrolysis, which occurs primarily in the liver. The elimination half-life for most amide local anesthetics is 2 to 3 hours. In particular, the elimination half-life of lidocaine is 90 to 120 minutes and it will remain in circulation for a prolonged period following cessation of intravenous infusions.
- Mechanism of action
- Local anesthetics block nerve conduction by impairing the propagation of the action potentials in axons. They do not alter the resting or threshold potentials but decrease the rate of increase of the action potential so that the threshold potential is not reached.
- Local anesthetics inhibit specific receptors: The therapeutic target of local anesthetics is the voltage-gated Na+ channel (NaV), inhibiting Na+ ion influx. The charged form of the local anesthetic binds the intracellular pore of NaV. To access the intracellular portion, the uncharged molecule must traverse the lipid bilayer through passive nonionic diffusion. Local anesthetics also block other ionic channels (K+, Ca2+, etc.) and metabotropic channels; they also uncouple mitochondrial energy production and prevent excitation-contraction coupling in muscle.
- Physiochemical properties of the local anesthetics affect neural blockade.
- Lipid solubility. Defined by the octanol/water coefficient (LogP) with more lipophilic molecules exhibiting increased potency and prolonged duration of action since they take longer to unbind from channels.
- Protein binding. More protein binding prolongs the duration of the effect.
- pKa. Agents with a lower pKa value will set up faster since a greater fraction of the drug will exist in the uncharged form, ready to diffuse across nerve membranes.
- pH of the drug solution. Higher pH will speed up the onset by increasing the proportion of molecules in the uncharged form.
- Drug concentration. Higher concentrations speed up onset owing to mass effect.
- Differential blockade of nerve fibers
- Peripheral nerves are classified according to size and function (Table 19.1). Local anesthetics block conduction based on the number of NaV channels, with thin and myelinated fibers more susceptible to blockade than thick and unmyelinated fibers.
Table 19-1 Classification of Nerve Fibers
| Class | Myelin | Diameter (μm) | Local Anesthetic Sensitivity | Function |
|---|
| A-α | +++ | 12-20 | ++ | Motor | | A-β | +++ | 5-12 | ++ | Touch/pressure | | A-γ | ++ | 1-4 | +++ | Proprioception/motor tone | | A-δ | ++ | 1-4 | +++ | Pain/temperature | | B | + | 1-3 | ++ | Preganglionic autonomic | | C | – | 0.5-1 | + | Pain/temperature |
|
- Local anesthetics exert a differential blockade, reducing pain and temperature first, followed by fine touch and finally impairing motor function. However, the differential blockade is imperfect (eg, it is nearly impossible to produce a full sensory block without loss of motor function).
- Sequence of block progresses in the following order: Sympathetic ≥ pain and temperature ≥ proprioception ≥ fine touch and pressure ≥ motor.
- Pathophysiologic factors affecting the neural block
- A decrease in the cardiac output reduces the plasma and tissue clearance of local anesthetics, increasing plasma concentration and the potential for toxicity.
- Severe hepatic disease may prolong the duration of action of amides.
- Renal disease has minimal effect.
- Reduced cholinesterase activity. Newborns and pregnant patients and patients with atypical cholinesterase may have decreased clearance of ester-type anesthetics, but this does not usually associate with toxicity.
- Fetal acidosis may cause an ion-trapping phenomenon (eg, accumulation of ionized local anesthetic in the fetal circulation) potentially resulting in fetal toxicity. This is more likely with amide forms not cleared rapidly by maternal liver enzymes.
- Sepsis, malignancy, and cardiac ischemia can increase plasma levels of α1-acid glycoprotein and decrease the plasma concentration of free local anesthetics.
- Commercial preparations: Most commercial preparations are solubilized with ethanol, chloroform, or acetone before dilution in sterile water. The pH is adjusted with hydrochloric acid or sodium hydroxide to a final value of 4 to 6 to maintain stability. Solutions with epinephrine are adjusted to pH 3 to 4 to keep the catecholamine in solution.
- Antimicrobial preservatives: Methylparaben or other paraben derivatives are used as antiseptic agents for multidose vials. Preservative-free solutions are used for neuraxial anesthesia to minimize neurotoxic effects from preservatives.
- Epinephrine: Following preservatives, the most common additive is epinephrine bitartrate to prolong the block and act as a marker for intravascular injection, which requires additional stabilizers (see Chapter 19, Section II.B).
- Antioxidants (sodium metabisulfite, sodium ethylenediaminetetraacetic acid [EDTA]) are added to mixtures containing epinephrine to slow the degradation by oxygen.
- Liposomal bupivacaine: Multivesicular bupivacaine sold under the trade name Exparel was designed for slow release of bupivacaine from liposomes to prolong its local anesthetic effects and reduce toxicity. It is approved by the US Food and Drug Administration (FDA) for TAP block and interscalene block. Data about its clinical benefit over standard bupivacaine are limited, and it holds potential for toxicity, especially when used improperly (eg, mixed with non-bupivacaine local anesthetics, which disrupts the liposomes).