Local anaesthetic agents

Mechanism of action of local anaesthetics

The VASC is one of many membrane proteins in the phospholipid bilayers that encapsulate neurons ( Fig. 5.1 ). Voltage-activated Na ⁺ channels provide selective permeability to Na ⁺ when the cell becomes depolarised from the resting potential (approximately –70 mV), which is maintained in quiescent neurons by the tonic activity of potassium ion (K ⁺ ) channels.

Pain transmission begins as a depolarisation in the nerve ending of the primary afferent neuron initiated by the activation of cation channels. When the depolarisation reaches the threshold for activation of VASCs (approximately −45 mV), an action potential is generated, resulting in rapid depolarisation to approximately +20 mV ( Fig. 5.2 ). Each action potential is brief (approximately 2 ms) because VASCs rapidly inactivate, leading to closure of their inactivation gates and halting of Na ⁺ influx, while at the same time VASCs activate, leading to an increase in the permeability of the cell membrane to K ⁺ . As a result, the membrane potential travels rapidly back towards the K ⁺ equilibrium potential, and this period is known as the afterhyperpolarisation; this phenomenon contributes to the refractory period during which generation of another action potential is unlikely (see Fig. 5.2 ).

Mechanism of local anaesthetic inhibition of the voltage-activated Na ⁺ channel

Local anaesthetics inhibit action potentials in primary afferent nociceptive neurons: the pain-sensing neurons that transmit to the dorsal horn of the spinal cord (see Chapter 6 ). Their mechanism of action is that they access the open VASC from the inside of the cell and bind to specific amino acids lining the channel lumen to inhibit VASC activity (see Fig. 5.1 ). They bind preferentially to the open channel and are therefore said to be use-dependent (or open channel) blockers. First the local anaesthetic must cross the cell membrane, which requires it to be lipid soluble. The molecule must then diffuse into the aqueous environment within the ion channel. Amide and ester local anaesthetics possess both lipophilic and hydrophilic properties and are described as amphipathic ( Fig. 5.3 ). They exist in basic (uncharged) and cationic (charged) forms, and the relative proportion of each (determined using the Henderson–Hasselbalch equation) depends on the pH of the solution and the p K a of the local anaesthetic (see also Chapter 1 ):

$pKa=\text{pH}+\log \frac{\left[\text{Cationic LA}\right]}{\left[\text{Uncharged LA}\right]}$

$\log \frac{\left[\text{Cationic LA}\right]}{\left[\text{Uncharged LA}\right]}=p{K}_a-\text{pH}$

Local anaesthetics are weak bases, and most have a p K a between 7.7 and 8.5 (see Table 5.1 ). Therefore they exist predominantly in the charged form of the molecule compared with the uncharged molecule at physiological pH:

$\log \frac{\left[\text{Cationic LA}\right]}{\left[\text{Uncharged LA}\right]}=1$

$\frac{\left[\text{Cationic LA}\right]}{\left[\text{Uncharged LA}\right]}=10$

An alkaline solution speeds the onset of analgesia by increasing the proportion of uncharged local anaesthetic on the outside of the nerve, resulting in more rapid passage through the cell membrane to the inside of the cell. Once inside, the balance of isoforms is re-established by the intracellular pH. In contrast, infected and inflamed tissue has a relatively low (acidic) pH, leading to a further increase in the proportion of the charged cationic local anaesthetic component, and higher doses are needed to achieve analgesia.

The voltage-activated Na ⁺ channel

Local anaesthetics gain access to their binding site within the inner lumen of the VASC when the activation gate opens in response to depolarisation. The VASC is formed by a large protein (the α subunit) consisting of 24 membrane-spanning segments arranged in four repetitive motifs (see Fig. 5.1 ). The fourth segment of each motif is a voltage sensor: a series of positively charged amino acids (arginine and lysine residues) lying within the membrane. Depolarisation causes electrostatic repulsion of the voltage sensors, providing the energy required to open the activation gate (see Fig. 5.2 ). Na ⁺ ions, selected by the filter formed by the four pore loops (between the fifth and sixth segments) lining the outer vestibule of the channel, are then free to pass down their concentration gradient into the cell, generating a depolarising electrical current. However, Na ⁺ current is inhibited by local anaesthetic bound within the inner vestibule of the channel. The inactivation gate, formed by intracellular components of the channel, closes rapidly after depolarisation (see Fig. 5.2 ) and local anaesthetics stabilise the inactivated state.

There are multiple subtypes of VASCs, named after the identity of their α subunit (Na _V 1.1–Na _V 1.9) encoded by one of nine different genes (SCN1A–SCN5A, SCN8A–SCN11A) which are differentially expressed in tissues throughout the body and have differing pharmacological and biophysical properties. This heterogeneity provides the potential (to date unmet) for selectively targeting VASCs in pain-sensing neurons. Nociceptive neurons predominantly express Na _V 1.7, Na _V 1.8 and/or Na _V 1.9 α subunits. Mutations in the SCN9A gene, which encodes Na _V 1.7, are associated with several pathological pain conditions. Aspects of systemic toxicity relate to the ability of local anaesthetics to block VASCs outside the pain pathway. Cardiac VASCs are of the Na _V 1.5 subtype, and local anaesthetics such as ropivacaine and levobupivacaine are thought to have less systemic toxicity because of their lower affinity for cardiac channels. Additional VASC heterogeneity is conferred by four genes that encode ancillary β subunits.

Pain fibres

Different peripheral nerve fibres have differing sensitivities to blockade by local anaesthetics and are classified as A, B and C according to their conduction velocities, A being the fastest conductors and C the slowest. Aδ and C fibres both conduct pain (see Chapter 6 ). Other subtypes of A fibre supply skeletal muscles (α and γ) and conduct tactile sensation (β), whereas type B are preganglionic autonomic fibres. Aδ fibres are heavily myelinated and rapidly conduct acute stabbing pain. Myelination enables a remarkably high velocity of transmission (approximately 20 m s ⁻¹ ) through a mechanism known as saltatory conduction. VASCs are segregated within the neuronal membrane of Aδ fibres at gaps in the myelin sheaths (nodes of Ranvier), enabling action potentials effectively to ‘jump’ from one node to the next. Aδ fibres are of small diameter and therefore have little ability to conduct changes in membrane potential once VASC activity has been inhibited. This makes them particularly sensitive to local anaesthetic block. Unlike Aδ fibres, C fibres are unmyelinated and their velocity of conduction from the skin to the spinal cord is relatively slow (approximately 1 m s ⁻¹ ). Local anaesthetics block the transmission of dull, aching pain, mediated by C fibres very effectively. The fibre diameter is very small (approximately 1 µm) and therefore there is little passive conduction, making transmission reliant on the activity of VASCs. C fibres are activated by inflammatory mediators, and therefore the pain resulting from their stimulation can also be treated by anti-inflammatory agents.

Local anaesthetic structure

Local anaesthetics of the amide and ester classes share three structural moieties: an aromatic portion, an intermediate chain and an amine group (see Fig. 5.3 ). The aromatic portion is lipophilic, and lipid solubility is further enhanced in local anaesthetics that have longer intermediate chains. The amine group is a proton acceptor, providing the potential for both charged and uncharged isoforms. This means that local anaesthetics are amphipathic – that is, the molecule contains both polar (water soluble) and non-polar (water insoluble) parts. Amide and ester anaesthetics are so named because of their distinctive bonds within the intermediate chain. A convenient mnemonic is that the names of esters contain one letter i whereas those of amides contain two letter i s. The presence of either an amide or an ester bond determines its metabolic pathway. This has important implications regarding allergy potential and pharmacokinetic profile. For example, replacement of the tertiary amine by a piperidine ring increases lipid solubility and duration of action; addition of an ethyl group to lidocaine on the α carbon of the amide link created etidocaine; and addition of a propyl or butyl group to the amine end of mepivacaine results in [p]ropivacaine and bupivacaine, respectively. Halogenation of the aromatic ring of procaine produces chloroprocaine, an ester with faster hydrolysis and shorter duration of action.

Pharmacological properties of local anaesthetics

Several factors influence the pharmacological properties of local anaesthetic drugs (see Table 5.1 ), in particular p K a, lipid solubility, protein binding and vasodilator activity. Speed of onset is related to the concentration of unionised (lipid soluble) drug at the site of action, which relates mainly to the p K a, but also the lipid solubility, initial dose and the pH of the tissues. Potency is closely related to lipid solubility; duration of action is proportional to the degree of protein binding. Both potency and duration of action may also be affected by the addition of vasoconstrictors.

• p K a is the pH at which the ionised and unionised forms of a compound are present in equal amounts and is an important determinant of the speed of onset of a drug. For basic drugs such as local anaesthetics, the greater the p K a, the greater the ionised fraction. As diffusion across the nerve sheath and nerve membrane requires unionised drug, a local anaesthetic with a low p K a has a fast onset of action, whereas one with a high p K a has a slow onset of action. For example, lidocaine (p K a 7.9) has a fast onset compared with bupivacaine (p K a 8.1), because, at pH 7.4, 25% of lidocaine exists in the unionised base form compared with only 15% of bupivacaine.

• Lipid solubility is the ratio of aqueous and lipid concentrations when a local anaesthetic is introduced into a mixture of oil- and water-based solvents; it is commonly expressed as the octanol/water partition coefficient. Drugs with a higher lipid solubility are more potent but also have greater toxicity.

• Molecular weight influences the rate of transfer of drug across nerve membranes, including into the CNS. In theory, drugs with a lower molecular weight should transfer more quickly. However, drug mass increases with the length of side chains, which tend to be more lipid soluble.

• Protein binding, including local anaesthetic attachment to protein components of the nerve membrane, increases the duration of action of a local anaesthetic. In plasma, amide anaesthetics bind predominantly to α-acid glycoprotein (AAG), a high-affinity limited capacity protein, and albumin, a low-affinity large capacity protein. The bioavailability of anaesthetic is determined by the availability of plasma proteins; high plasma AAG concentrations permit greater binding of anaesthetic, and so plasma concentrations of free drug are lower. After surgery, trauma or malignancy, AAG concentrations increase significantly and serve to decrease the potential for toxicity in patients receiving local anaesthetic epidural or perineural infusions.

• Vasodilator activity influences potency and duration of action. Most local anaesthetics cause vasoconstriction at lower doses and vasodilatation at higher doses. Intrinsic vasodilator properties are in the order lidocaine > bupivacaine > levobupivacaine > ropivacaine. Vasodilatation reduces the amount of drug at the site of injection, increasing systemic absorption and potential toxicity. In practice, a vasoconstrictor may be added to prolong the duration of effect and reduce systemic effects (e.g. adrenaline 1 : 80,000 to 1 : 200,000 with lidocaine, bupivacaine or mepivacaine). This is more relevant for infiltration or nerve/plexus blocks than for neuraxial blockade. Felypressin, an octapeptide derivative of vasopressin, is a potent vasoconstrictor and is added to a formulation of prilocaine for dental use.

Differential sensory and motor blockade

Local anaesthetics provide differential sensory and motor block, dependent on fibre size. Smaller pain fibres are more sensitive to the effects of local anaesthetics; this is most apparent with lower drug concentrations. For example, epidural administration of 0.5% bupivacaine provides excellent sensory and motor block for Caesarean section, yet administration of 0.1% bupivacaine, often combined with fentanyl 2 µg ml ⁻¹ , can provide analgesia during labour but with full lower limb movement.

Pharmacokinetics