Molecular weight

Molecular weight itself does not affect the pharmacological properties. However, increases in molecular weight tend to be indicative of increased side-chain size and therefore increased lipid solubility.

Lipid solubility

The higher the lipid solubility, the greater the penetration of the nerve membrane by the drug, so that higher lipid solubility results in greater potency. It also results in more toxicity and local irritancy. High lipid solubility also increases the rate of onset and duration of action of local anaesthetic agents.

pK_a

The lower the pK_a, the lower the degree of ionisation for any given pH and so the more rapid the speed of onset of the block. Increasing pK_a increases the ionised proportion of the drug so that intracellularly a higher proportion is in the active state. However, this also means that less is in the non-ionised, diffusible state, so the onset and offset of action are also slower. Figure 33.4 shows the effect of differences in pH and pK_a on the proportion of ionised and non-ionised local anaesthetic agents.

Figure 33.4

Effect of pH on the ionisation of local anaesthetic agents

pH

Acidosis (low pH) increases the proportion of ionised drug in the interstitium, and therefore reduces the amount of drug able to cross the neuronal membrane. The local anaesthetic is therefore reduced in potency. Manipulation of the pH of the local anaesthetic solution by addition of alkali, buffers or carbonation may be used to alter the proportion of non-ionised drug.

Protein binding

The degree of protein binding reflects the ability of the drug to bind to membrane proteins: the greater the binding, the longer the duration of action. Increased binding to tissue protein correlates with an increase in the duration of action and probably indicates a higher affinity for membrane proteins (for example, the fast sodium ionophore).

Amethocaine

Amethocaine (tetracaine) is an ester local anaesthetic agent used for topical anaesthesia. It is available as a gel (4%) for local anaesthesia of the skin before intravascular cannulation. Applied to the skin, it is effective within 45 minutes. It can then be removed, and remains active for 4–6 hours. The preparation should not be applied to inflamed or damaged skin or highly vascular tissues, as it is rapidly absorbed through mucosal surfaces. More dilute solutions (0.5% and 1%) are available for topical anaesthesia of the conjunctiva. Amethocaine is potent and readily absorbed, but in common with other ester local anaesthetics it may cause hypersensitivity.

Benzocaine

Benzocaine is an unusual ester local anaesthetic agent in that the side chain is an ethyl group with no amine component, and therefore remains un-ionised. Benzocaine has a low potency but it may cause methaemoglobinaemia. It is a component of some throat lozenges, and may be applied directly to painful skin ulcers.

Cocaine

Cocaine is a naturally occurring ester derived from benzoic acid, and extracted from the leaves of Erythroxylum coca. It is available in solution and pastes in concentrations ranging from 1% to 10%. It is mainly used for topical anaesthesia and to reduce bleeding during nasal surgery. Cocaine is rapidly taken up into mucous membranes to provide anaesthesia and intense vasoconstriction. This vasoconstriction limits systemic absorption, resulting in a bioavailability by this route of 0.5%. It is well known as a drug of abuse with high addictive potential, and in this role is taken by chewing, inhaling nasally, smoking or intravenously. It causes marked sympathomimetic activity, and arrhythmias are a definite risk. Systemic injection must be avoided. Systemically absorbed cocaine has a volume of distribution of 2 L kg^–1, with 98% being protein-bound. It is eliminated by plasma and liver esterases, having a clearance of 35 mL kg^–1 min^–1 and a half-life of 45 minutes.

Cocaine shares the same mechanism of action as the other local anaesthetic agents (pK_a = 8.7), and also inhibits catecholamine neuronal uptake-1. Synaptic levels of dopamine and noradrenaline increase, resulting in the central stimulation and euphoria, and vasoconstriction. Cocaine initially blocks the inhibitory pathways, resulting in euphoria, hyperthermia, altered vision and hearing, nausea and eventually convulsions. Higher levels of cocaine also block the excitatory pathways, resulting in central nervous depression leading to sedation and unconsciousness, with respiratory depression. Cocaine causes mydriasis and raised intraocular pressure. It is no longer used for local anaesthesia of the eye. The central stimulation increases respiratory rate and volume. A rise in sympathetic tone leads to tachycardia and hypertension, the latter being exacerbated by peripherally mediated vasoconstriction. High doses depress the myocardium. The general excitation also increases metabolic rate, which contributes to the hyperthermia and raises oxygen consumption and CO₂ production. The recommended maximum dose is 1.5 mg kg^–1. Cocaine should be avoided in porphyria.