Basic Pharmacology of Local Anaesthetics
Highlights
- Local anaesthetic agents are amphipathic molecules.
They bind primarily to sodium channels but also to potassium and calcium channels, and G-protein-coupled receptors. (View Highlight)
- Structural modifications alter the physicochemical characteristics of a local anaesthetic (View Highlight)
- Speed of onset, potency, and duration depend on the pKa, lipid solubility and protein binding, respectively (View Highlight)
- Myelinated A fibres are categorised into four groups that have separate functions: Aα fibres supply skeletal muscle; Aβ fibres transmit tactile sensation; Aγ fibres provide innervation to muscle spindles; and Aδ fibres transmit nociception and cold (View Highlight)
- Myelinated B fibres are autonomic preganglionic nerves (View Highlight)
- The voltage-gated Na+ channel is a complex structure composed of a large pore-forming α subunit associated with one or two β subunits. The α subunit is comprised of four domains (I–IV), each containing six segments (S1–S6) that wrap round a bell-shaped central channel (View Highlight)
- The channel is formed by the S5 and S6 segments and the short loops of amino acids that link them. The inactivation gate is formed by a loop connecting domains III and IV. S4 in each domain has positively charged arginine or lysine amino acids and is the voltage-sensitive region of the Na+ channel. (View Highlight)
- In the resting state, the membrane potential is approximately –70 mV and is generated by the outward movement of K+ ions along their concentration gradient, whereas the negatively charged anions (principally proteins) remain within the cell; this gerenates a transmembrane voltage or resting membrane potential. The S4 segments are in the ‘down’ position, making the channel non-conductive (View Highlight)
- The Na+ channels open during depolarisation by outward spiral rotation of the S4 segments allowing rapid influx of Na+ ions, down the electrical and chemical gradients. This exposes the receptor site of the inactivation gate, located between domains III and IV, leading to channel inactivation (View Highlight)
- From the inactivated state, the channel recovers to the resting state only by repolarisation of the cell membrane (View Highlight)
- The molecules dissociate to reach a new equilibrium of ionised and un-ionised moieties, dependent on the intracellular pH and the pKa of the local anaesthetic (View Highlight)
- The binding site for local anaesthetics is located in domain IV, loop S6 and is only accessible when the channel is open (View Highlight)
- The binding of local anaesthetics to open Na+ channels increases with the frequency of nerve depolarisation. This is known as a use-dependent or phasic block (View Highlight)
- Bound local anaesthetic drug stabilises the inactivated receptor state, preventing further neuronal transmission. Local anaesthetic nerve block is concentration-dependent. With increased concentrations of local anaesthetic, the peak of the action potential is reduced, the firing threshold increases, impulse conduction is attenuated, and the refractory period lengthened. Increased concentrations inhibit all nerve conduction. (View Highlight)
- Both lidocaine and bupivacaine block cardiac Na+ channels. However, bupivacaine binds with higher affinity and dissociates more slowly. This causes it to accumulate during diastole, prolong conduction and induce re-entry-induced arrhythmias. (View Highlight)
- Local anaesthetics provide a differential block in a concentration-dependent manner. Aγ spindle efferents and the Aδ nociceptive fibres are most susceptible, whereas non-myelinated C fibres are relatively resistant (View Highlight)
- Sympathetic blockade usually reaches a higher dermatome than other modalities. Temperature (cold) and pain (pinprick), followed by proprioception and finally motor fibres are next most easily blocked, demonstrated by a descending dermatomal level (View Highlight)
- During epidural anaesthesia for Caesarean section, sensation of touch and proprioception (Aβ fibres) may therefore still occur despite adequate sensory block, which can be distressing for patients. (View Highlight)
- Local anaesthetic drugs are water-soluble salts of lipid-soluble alkaloids. The structure of local anaesthetics consists of three components: a lipophilic aromatic group, an intermediary link and a hydrophilic amine group (View Highlight)
- The intermediary link categorises local anaesthetics into esters or amides (View Highlight)
- Compared to bupivacaine, ropivacaine's propyl group gives a lower lipid solubility that causes it to penetrate large myelinated motor fibres to a lesser extent, giving a more selective sensory blockade (View Highlight)
- The discovery of a selective blockade of cardiac Na+ channels by the dextro-enantiomer of bupivacaine led to the creation and widespread use of two levo-enantiomers: levobupivacaine and ropivacaine.5 These exhibit lower potency at myocardial Na+ and K+ channels and have less effect on myocardial electrical conduction and contractility compared to bupivacaine. (View Highlight)
- Enantiomers were historically classified according to their ability to rotate the plane of polarised light. For example, the prefix dextro indicates clockwise rotation and the prefix levo indicates anticlockwise rotation of polarised light. (View Highlight)
- Alternatively, enantiomers may be classified by the order of atoms around the central carbon molecule. For example, in a rectus (R) configuration, atomic mass reduces in a clockwise direction whereas the opposite occurs in the sinister (S) configuration (View Highlight)
- The speed of onset, potency and duration of local anaesthetics is dependant on the pKa, lipid solubility and protein binding, respectively (View Highlight)
- The dissociation of amphipathic local anaesthetics is determined by their pKa and the pH of the tissue into which they are injected (View Highlight)
- The pKa is the pH at which the ionised and un-ionised forms are present in equal amounts. For bases, such as local anaesthetics, the higher the pKa, the greater the ionised fraction in solution. The ratio of the two states is described by the Henderson–Hasselbalch equation (View Highlight)
- As rate of diffusion across the nerve sheath and nerve membrane is related to the proportion of non-ionised drug, local anaesthetics with low pKa have a fast onset of action, and local anaesthetics with a high pKa have a slow onset of action (View Highlight)
- The smaller the molecular weight, the more rapidly molecules diffuse through membranes (View Highlight)
- Lipid solubility and potency are closely related. The lipid solubility of local anaesthetics is expressed as the partition coefficient, which is defined as the ratio of concentrations when local anaesthetic is dissolved in a mixture of lipid and aqueous solvents. Greater lipid solubility enables more rapid diffusion through lipid membranes to reach their site of action, influencing the speed of onset (View Highlight)
- greater lipid solubility gives a greater volume of distribution. (View Highlight)
- Local anaesthetics with high protein binding to α1-acid glycoprotein have a longer duration of action and lower bioavailability (View Highlight)
- Hypoxia, hypercarbia, and acidaemia all decrease protein binding, and increase the risk of toxicity. Children younger than 6 months have less protein binding capacity. (View Highlight)
- The vasoactivity of local anaesthetics influences potency and duration of action (View Highlight)
- Levobupivacaine and ropivacaine have a bimodal vasoactive response. Both vasodilate at clinical doses and vasoconstrict at subclinical doses (View Highlight)
- The absorption of local anaesthetics is dependent on the site of injection, rate of injection, dosage and vasoactivity of the injectate (View Highlight)
- The order of peak plasma concentration after a single dose is intrapleural > intercostal > lumbar epidural > brachial plexus > subcutaneous > sciatic > femoral. (View Highlight)
- Esters local anaesthetic agents are less protein bound than amide local anaesthetics (View Highlight)
- Tissue distribution tends to be proportional to the tissue/blood partition coefficient of the local anaesthetic, and the mass and perfusion of the tissue (View Highlight)
- Esters are hydrolysed rapidly in plasma by pseudocholinesterase to the metabolite para-aminobenzoic acid (PABA), which can cause an allergic reaction. Plasma half-life varies from less than 1 min (chloroprocaine) to 8 min (tetracaine) and is prolonged in the presence of atypical cholinesterase (View Highlight)
- Cocaine, unlike other esters, undergoes hepatic hydrolysis followed by renal excretion (View Highlight)
- In the liver, amide local anaesthetics undergo aromatic hydroxylation, amide hydrolysis and N-dealkylation.3 Amide metabolism is much slower than plasma hydrolysis, and thus amide local anaesthetics are more prone to accumulation in the presence of hepatic dysfunction or reduced hepatic blood flow (View Highlight)
- Prilocaine undergoes metabolism in the lungs (View Highlight)
- Amides have a very low allergic potential themselves, and an observed reaction may be caused by an additive such as the stabilising agent methylparaben (View Highlight)
- Lidocaine has a high hepatic extraction ratio: clearance is dependent on hepatic blood flow and is relatively unaltered by changes in hepatic enzyme activity. Owing to the efficiency of the drug in dissociating from plasma proteins, entering the hepatocyte, and undergoing metabolism, the rate limiting step is hepatic perfusion. This is important in critical illness, particularly in states of low cardiac output and reduced hepatic blood flow. (View Highlight)
- The eutectic mixture of local anaesthetic (EMLA) contains a mixture of crystalline bases of 2.5% lidocaine and 2.5% prilocaine in an oil/water emulsion. The mixture has a lower melting point than separate local anaesthetics and allows for a higher concentration of local anaesthetic to be used (View Highlight)
- The rate and degree of diffusion of local anaesthetic across the placenta depends on protein binding, pKa, and maternal and fetal pH (View Highlight)
- In prolonged labour, acidosis in the fetus can result in accumulation of local anaesthetic in the fetus by ion trapping. However, because of rapid hydrolysis, ester local anaesthetics do not cross the placenta in significant amounts. (View Highlight)
- Ropivacaine and levobupivacaine have lower systemic toxicity than other amides because of their lower affinity for cardiac channels (NaV1.5) (View Highlight)
- Local toxicity caused by local anaesthetics to nerves (and other tissues) and occurs in a time-, concentration-, and drug-dependent manner. (View Highlight)
- O-toluidine, the metabolite of prilocaine, can oxidise haemoglobin causing methaemoglobinaemia. This shifts the oxyhaemoglobin dissociation curve to the left, reducing the ability of haemoglobin to release oxygen to the tissues. (View Highlight)
- Intra-articular local anaesthetics are commonly used as part of multimodal analgesia in arthroscopy. However, they have been demonstrated to cause chondrotoxicity, and at a higher rate in patients with osteoarthritis. Ropivacaine is associated with a lower risk than bupivacaine or mepivacaine (View Highlight)
- Liposomes are amphipathic molecules that form lipid bilayer spherical vesicles when suspended in an aqueous solution. They are used as a sustained release drug delivery system without the need for continuous infusion or risk of toxicity (View Highlight)
- All local anaesthetics target the voltage-gated Na+ channel and carry the risk of toxicity (View Highlight)