Medical Pharmacology Topics   

Local Anesthesia

Local anesthetics prevent or relief pain by reversibly blocking nerve conduction (i.e. preventing action potential) through inhibition of Na channel activity. The use of these drugs at clinically relevant concentrations is followed by complete recovery of nerve function. In general, the onset, duration and effectiveness of local anesthetics is dependent on route of administration, concentration and volume of drug administered and characteristics of the drug.

The chemical structure of local anesthetics has three domains: hydrophobic domain (aromatic), intermediatre linkage and hydrophilic domain (tertiary or secondary amine). The hydrophobic domain increases partition into the plasma membrane, where the sodium channel is, thus increasing potency and duration of action. The hydrophilic domain plays a role in anesthetic binding to the Na channel.

The intermediate linkage may be either an amide or an ester. Amide linkages only broken down in the liver, while esters are hydrolazed by plasma esterases. Ester linkages may also lead to hypersensitivity reactions.

Commonly used amide local anesthetics include lidocaine, mepivacaine, bupivacaine, etidocaine and pilocaine. Commonly used ester local anesthetics include procaine, tetracaine, benzocaine and cocaine.

Mechanism of Action

Local anesthetics block nerve conduction by decreasing or preventing the large transient increase in permeability of Na that depolarizes nerve cells. They bind to the hydrophobic region of the alpha subunit of the channel inside the cell. Unionized drug preferentially enters the epineurium (connective tissue around nerve fiber) and the cell membrane, while ionized drug preferentially binds to the channel.

The degree of channel blockade depends on the activity of the nerves. A resting nerve is less sensitive to local anesthetics than one that is being stimulated repetitively. This occurs because local anesthetics gain access to the channel in its open state and binds more tightly in the inactivated state, whereas they dissociate in the resting state.

In general, the small diameter nerve fibers are more susceptible to blockade by local anesthetics than larger fibers:

This is clinically important because pain-transmitting fibers (C and A-d) are the first to be blocked.

Pharmacokinetics

Local anesthetics are applied by intradermal or subcutaneous injection. Absorption is determined by the site of injection, dosage, and the potential co-administration of a vasoconstrictor. Different drugs vary in rate of absorption and onset of action. The ionized drug is effective, but the unionized drug preferentially gets to the site of action inside the cell. This is clinically relevant when the drug is given into an abscess: the lower the pH the more ionized and absorption is prevented.

Distribution from the site of injection into the systemic circulation will decease local action of the anesthetic and increase the possibility of side effects. Many amide local anesthetics will bind higly with plasma proteins (so?). In clinical practice, local anesthetics are often administered with the vasoconstrictior epinephrine in order to decrease the rate of absorption and decrease distribution to the systemic circulation. Cocaine is the only local anesthetic with vasoconstriction action.

Since there is little esterase activity in cerebrospinal fluid, ester anesthetics are slowly metabolized after spinal injection. Since amides ae metabolized by hepatic enzymes, caution must be taken in patients with hepatic disease (i.e. reduce dosage). A metabolite of prilocaine can cause methemoglobinemia.

Usage

Local anesthetics can be used by infiltration, intravenous infusion, regional peripheral blockade, central neural blockde, or topicaly.

Infiltration anesthesia is done by intradermal or subcutaneous injection. Epinephrine is normally used to prolong action, but is contraindicated in tissuessupplied by end arteries as it may led to gangrene. Patients may experience momentary pain immediatelly after injection. Procaine is a short duration ester anesthetic used for infiltration anesthesia. Lidocaine, mepivacaine and prilocaine are amide anesthetics of intermediate duration used for infiltration anesthesia, while bupivacaine and etidocaine are amides of long duration.

Intravenous regional anesthesia is rarely performed because of the high systemic toxicity risk. It may be done into tourniquet-occluded limb, using lidocaine without epinephrine.

Peripheral nerve blockade can be done as a minor block (single nerve) or as a major block (multiple nerves. Branchial plexus blockade is the most common major block. Duration of drug action is similar to infiltration. Determinants of block onset include proximity of injection to nerve (NEVER inject into nerve), concentration and volume injected, degree of ionization and time. 

To achieve a central neural block, local anesthetic is injected into either the epidural or subdural (intrathecal) space. The amides lidocaine and mepivacaine are used for shorter duration of ation, bupivacaine for longer. One major side effect is loss of autonomic tone. The baricity of the solution (the pressure under which the drug is given, ?) dictates the direction f migration of the drug. If the patient is siting up, an hyperbaric solution will probably stay at the injection site. Epidural injection is associated with greater incidence of systemic toxicity because more drug is needed (to get through the duramater into the nerves) for longer periods of time. Complications include infection, hematoma, trauma to the spinal cord, and postural headache.

Topical anesthesia is the least dangerous method but systemic absorption may still occur. Cocaine is used in eyes, nose and throat procedures because of its vasoconstrictive properties. This sites are very vascular and the vasoconstrictive effect of cocaine decreases bleeding during surgery. For other topical sites, an eutectic (?) mixture of lidocaine and prilocaine is available that produces anesthetic action 5 mm into the tissue after topical application.

Side Effects

Local anesthetics may have undesirable effects in the CNS, cardiovascular system, smooth muscle, neuromuscular junction, autonomic ganglia and immune system. Anesthetics cause CNS stimulation (restlessness), tremor, clonic convulsions), followed by depression (drowsiness, sedation, respiratory failure). They can ause either euphoria or disphoria.

Although bupivicane (amide) is more toxic to the cardiovascular system, all local anesthetics may decrease electrical excitability, conduction rate and force of contraction of the heart, as well as induce vasodilation and decrease vascular tone. Rarely, low concentration cause cardiovascular collapse.

By affecting smooth muscle, anesthetics may decrese contraction of the bowel and tone/contraction of uterine muscle. At the neuromuscular junction, toxic concentration can decrease muscle activation. Central administration can decrease sympathetic nerve activity. At toxic concentrations local anesthetics block K channels. Reactions in hypersensitive individuals may include allergic dermatitis and asthma attacks.

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