4. Local Anaesthetics: Actions

a local anaesthetic agent is defined as a compound which produces temporary blockade of neuronal transmission when applied to a nerve axon.

Numerous drugs share this characteristic with conventional local anaesthetics. They include anticonvulsants, many antiarrhythmics, including bretylium and β-adrenoceptor blockers, some phenothiazines and some antihistamines, as well as drugs such as pethidine and ketamine. None is used as a local anaesthetic but all have a similar mechanism of action. lidocaine, bupivacaine, prilocaine and, ropivacaine.

lipophilic aromatic portion, which is joined via an ester or amide linkage to a hydrophilic tertiary amine chain Esters are hydrolyzed by nonspecific plasma cholinesterase, and amides are metabolized in the liver

The axon maintains a voltage differential of 60–90 mV across the nerve membrane. At rest the membrane is relatively impermeable to the influx of sodium (Na+) ions and is selectively permeable to potassium (K+) ions. In the resting cell membrane, this selective permeability allows a small net efflux of K+ ions, which leaves the axoplasm electrically negative (polarized). At rest, Na+ ions tend to flow into the axon, both because the inside is electrically negative and because of the concentration gradient. This resting membrane potential is maintained by the Na+/K+ pump which continually extrudes Na+ from within the cell in exchange for K+, using ATP as an energy source. When specific sodium channels in the axonal membrane are opened, there is a selective permeability to Na+ ions, and the membrane depolarizes. Repolarization takes place when voltage-dependent K+ channels open to permit a large efflux of K+. As the membrane becomes less negative, more Na+ channels open, and open more rapidly; more Na+ ions enter the cell, and depolarization is further accelerated.

the impulse is propagated by the spread of inward current through the conducting medium of the axoplasm to adjacent inactive regions. Inward currents from all the active nodes integrate as they spread, ensuring that impulse propagation will continue.

these mainly block the function of the sodium channels, which exist in ‘open’, ‘resting’ and ‘inactivated’ conformational states. Local anaesthetic affinity is higher when the channel is in the open or inactivated state. The drugs exert no effect on cellular integrity or metabolism, but when a sufficient concentration is reached in the perfusing solution, depolarization does not occur in response to an electrical stimulus. Na+ influx is blocked, although repolarization associated with K+ efflux is unaffected. The agents in their cationic ionized form block the sodium channels on the inside of the axoplasm. External perfusion has no effect; the uncharged form must penetrate the cell wall before dissociating. The nerve blockade is concentration-dependent and ends when the local anaesthetic concentration falls below a critical minimum level. Local anaesthetics work by stabilizing the axonal membrane will stabilize all excitable membranes, including those of skeletal, smooth and cardiac muscle. Local anaesthetics also block some potassium ion channels, broaden the action potential and enhance binding by maintaining the sodium channel in the open or inactivated state.

Local anaesthetics exist in equilibrium between ionized and non-ionized forms. The ratio of the two states is given by the Henderson–Hasselbalch equation (originally derived to describe the pH changes resulting from the addition of H+ or OH− ions to any buffer system). The Ka is the dissociation constant which governs the position of equilibrium between the charged and uncharged forms. By analogy to pH, the pKa is the negative logarithm of that constant. Rearranging the equation pH = pKa + log [HCO3 −] / [H2CO3] gives: pKa = pH – log [base] / [conjugate acid]. This is the same as saying [base] / [conjugate acid] = 1.0, so the dissociation constant, or pKa, is the pH at which equal amounts of drug are present in the charged and uncharged state.

pKa of 7.4 indicates that, at body pH, there are equal numbers of molecules in the charged and uncharged forms. Most local anaesthetics have pKa values higher than body pH, and the more distant the dissociation constant from body pH, the more molecules that exist in the ionized form pKa of 8.4, it is 1 pH unit (i.e. a tenfold H+ concentration) away from body pH. At 7.4 there is a 10:1 ratio, that is, the drug is 90% ionized and 10% non-ionized. At pKa 9.4 the difference is 100-fold, so at body pH of 7.4, 99% of the drug will be charged

Uncharged base is necessary for tissue penetration, and so drugs with lower pKa usually have a more rapid onset of action Thus, lidocaine and prilocaine (pKa 7.7) have a shorter latency than bupivacaine (pKa 8.1). This dominance of the non-diffusible cation also explains the reason why local anaesthetics are much less effective in the presence of inflamed and acidotic tissue.

Note, however, that pKa is not the only factor involved. Concentration and intrinsic potency are also important. Drugs also have to penetrate a perineural membrane of connective tissue, and this property has not been well quantified, thus chloroprocaine (popular in the USA although not used in the UK) has one of the fastest onsets of action of all local anaesthetics, despite having a pKa of 9.1

peripheral nerves contain both afferent and efferent axons which are enclosed in a fine matrix of connective tissue which embeds the axons – the endoneurium The fascicles of axons are enclosed within a squamous cellular layer, the perineurium, effective semi-permeable barrier to local anaesthetics whole structure is surrounded by a sheath of collagen fibres, the epineurium, which permits easy diffusion of local anaesthetic myelinated sensory nerve, the local anaesthetic molecule may have to traverse four or five connective-tissue and lipid-membrane barriers. The most important of these is the perineurium, and this squamous cell layer, connected by tight junctions, is one of the main reasons why, under clinical conditions, only about 5% of the injected anaesthetic dose will actually penetrate the nerve.

The affinity of the drug to the channel, which determines its duration of action, is related to the length of the aliphatic (open carbon) chains on the compound Small structural changes also influence factors such as lipid solubility and protein binding. Increase protein binding = increased duration

Lidocaine Duration: 100 minutes Protein binding: 64% Lipid solubility: ’1’ Bupivacaine Duration: 175 minutes Protein binding: 96% Lipid solubility: ‘20 Ropivacaine Duration: 150 minutes Protein binding: 95% Lipid solubility: ‘7’

prime determinant of potency, which is increased by the substitution of longer side chains bupivacaine has three times the lipid solubility of ropivacaine and twenty times that of mepivacaine From least to most lipid-soluble, therefore, the local anaesthetics are ranked as follows: prilocaine, lidocaine, ropivacaine, bupivacaine and etidocaine lipid solubility and potency is not linear

affected by structural differences in the molecule. Longer aliphatic substituents increase affinity for the sodium channel and prolong the duration of action Bupivacaine and ropivacaine are both ~96% protein-bound. Lidocaine and prilocaine are much more weakly protein-bound (65% and 55%, respectively), with actions lasting for around 100 minutes. High protein binding decreases toxicity by reducing the proportion of free drug in the plasma

rare possibility of both acquired and innate resistance to local anaesthetics antigen/antibody complex that is formed following envenomation clinical experience reveals the very occasional patient in whom local anaesthesia is only partially effective or completely ineffective

Cochrane review published in July 2015 concluded that there was ‘low to moderate’ evidence that intravenous lidocaine reduced early post-operative pain scores the review did report that intravenous infusions of lidocaine reduced pain scores at up to 4 hours after laparoscopic and open abdominal surgery It also appeared to have a beneficial effect on the recovery of bowel function. A lower incidence of post-operative nausea was attributed to its opioid-sparing actions

stress of surgery is immunomodulating. The details are complex, but in addition to factors such as the suppression of natural killer (NK) cell function and a global reduction in the reactivity of the immune system, surgery may enhance the release of substances such as the polypeptide transforming growth factor-β1 (TGF-β1) Anaesthesia also modulates immune function, including that mediated by neutrophils, NK and T-cells. is postulated that some of these effects, in particular the endocrine stress response and the adverse effects of opioids, may be attenuated by effective regional and neuraxial anaesthesiaRegional Anaesthesia and Tumour Recurrence

Regional anaesthesia and cancer surgery. The evidence is drawn largely from retrospective reviews, in which inevitably there are numerous uncontrolled variables. Breast cancer, for example, is not a homogenous entity but includes several tumour types; equally heterogeneous are general anaesthetic techniques. These are invariably multimodal, and together with opioid analgesia, may well suppress immune surveillance of tumour cells had either paravertebral blocks or patient-controlled anaesthesia, there was a four times greater rate of recurrence-free survival in the block group (6% vs 24%).