Parenteral local anesthetics are used for infiltration and nerve block anesthesia. Because of differences in systemic absorption and toxicity, not all of these drugs are indicated for all types of local anesthesia and the concentration of the drug used depends on the anesthetic procedure. For indications of each parenteral local anesthetic and concentrations used for various procedures, see the individual monographs in 72:00.
Infiltration anesthesia, which is frequently used in minor surgical and dental procedures, is achieved by injecting the local anesthetic solution intradermally, subcutaneously, or submucosally across the path of nerves supplying the area to be anesthetized. Field block technique, in which the local anesthetic is infiltrated subcutaneously in a circular pattern around the operative field, is a common type of infiltration anesthesia. Infiltration anesthesia has occasionally been used for cesarean section, but epidural or spinal anesthesia is generally preferred.
Nerve block (regional) anesthesia, used in surgical, dental, and diagnostic procedures and in therapeutic management of pain, is achieved by injecting a local anesthetic solution into or around nerve trunks or ganglia supplying the area to be anesthetized. Nerve block procedures require a high degree of specialization and should be performed only by clinicians experienced in local anesthetic procedures. Peripheral nerve blocks (e.g., paracervical blocks, pudendal blocks, brachial plexus nerve blocks, ulnar nerve blocks, and intercostal blocks) and sympathetic nerve blocks (e.g., stellate ganglion blocks) involve a variety of nerves. Spinal (subarachnoid, intrathecal) and epidural (extradural, peridural) blocks are special forms of nerve block anesthesia. Spinal anesthesia is achieved by injecting local anesthetic solutions intrathecally into the subarachnoid space at the lumbar level, and epidural anesthesia is produced by injecting the drug into the epidural space. Caudal (sacral) anesthesia is a type of epidural anesthesia in which the injection is made through the sacral hiatus.
Several nerve block procedures such as epidural (including caudal), paracervical, pudendal, and low spinal (saddle) blocks are used in obstetrics; high spinal anesthesia using high or medium drug doses should not be used for normal vaginal deliveries because undue ascent of the anesthetic may result from variations in CSF pressure during labor. Local anesthetics should not be given until the cervix is well dilated and labor is progressing normally. In spinal anesthetic procedures, the drugs should not be injected during uterine contractions since undesired ascent of the anesthetic may occur.
Vasoconstrictors (e.g., epinephrine), when added to solutions of some local anesthetics, may decrease the rate of vascular absorption of the anesthetic, thereby localizing anesthesia and prolonging the duration of anesthesia; systemic toxicity of the local anesthetic is also decreased. When infiltration anesthesia is used, vasoconstrictors may also decrease bleeding in the operative field. Epinephrine appears to be the most effective vasoconstrictor. Mepivacaine and prilocaine produce little or no vasodilation and, therefore, administration of a vasoconstrictor with these drugs is usually not necessary. Epinephrine also does not appear to affect time of onset or duration of ropivacaine anesthesia.235 The optimal concentration of vasoconstrictors varies with the vascularity of the injection site and with the individual anesthetic agent. In general, 0.1 mg of epinephrine (20 mL of a 1:200,000 solution) is used and up to 0.2 mg of epinephrine (20 mL of a 1:100,000 solution) is generally well tolerated by normal patients. If the therapeutic benefit of epinephrine administration is considered to outweigh the possible risks in high-risk patients, a lower maximum dose of 0.02-0.05 mg (2-5 mL of a 1:100,000 solution) may be considered.
Local anesthetics should be used as a component of multimodal analgesia (i.e., simultaneous use of a combination of analgesic agents and techniques that target different mechanisms of action in the peripheral and central nervous systems) in the management of postoperative pain.216,220 Studies have demonstrated that multimodal pain management strategies are associated with superior pain relief and decreased need for opiates.220 Experts recommend that clinicians consider the use of local anesthetic infiltration or site-specific regional analgesic techniques as part of a multimodal approach to the management of postoperative pain.220
Parenteral local anesthetics (e.g., lidocaine hydrochloride) have been used to produce regional anesthesia by injecting the drug IV (Bier Block) into a limb in which circulation has been interrupted by application of a tourniquet. However, this route of administration is not recommended with some local anesthetics (e.g., bupivacaine, ropivacaine); cardiac arrest and death have been reported when bupivacaine was administered using this technique.211,213,235 Procaine and lidocaine have also been administered IV as systemic analgesics; however, use of these drugs for analgesia is of doubtful value and may result in serious toxic reactions. Lidocaine hydrochloride is used IV to treat acute ventricular arrhythmias (see 24:04.04.08).
For information on topical local anesthetics, see 52:16 and 84:08.
Administration 
Parenteral local anesthetics may be administered by local infiltration or by epidural (including caudal), spinal (subarachnoid, intrathecal), retrobulbar,211,213 dental,211,213 peripheral, or sympathetic block. The drugs may be given by single injection or continuous block techniques in which repeat injections are given through a catheter inserted into the area being anesthetized. Local anesthetics have been administered by continuous intra-articular infusion† using elastomeric infusion devices (e.g., for control of postoperative pain); however, such use has been associated with chondrolysis.200,201,202,203,204,205,206,207,208,209 (See Cautions: Musculoskeletal Effects.)
Local anesthetic solutions containing preservatives should not be used for spinal or epidural (including caudal) anesthesia. Partially used bottles of solutions which do not contain preservatives should be discarded.
Because of the risk of hypotension, the patient's blood pressure should be monitored during spinal anesthesia.214
Resuscitative equipment, oxygen, drugs, and personnel required for treatment of adverse reactions should be immediately available when local anesthetics are used.211,213,214,216 (See Cautions: Precautions and Contraindications.) Proper positioning of the patient is extremely important in spinal anesthesia. For specific procedures and techniques of administration, specialized references should be consulted.
Local anesthetics should be administered slowly in incremental doses to reduce the risk of adverse effects (e.g., local anesthetic systemic toxicity).211,213,216,234 Frequent aspirations for blood or cerebrospinal fluid (when applicable) should be performed to avoid intravascular administration and to either confirm entry into the subarachnoid space (for spinal anesthesia) or avoid inadvertent subarachnoid injection.211,213,214,216
Dosage
Generally, lower concentrations of local anesthetics are used for infiltration and peripheral or sympathetic nerve block anesthesia than for epidural anesthesia; highest concentrations (but small doses) are used in spinal anesthesia. Dosage varies with the anesthetic procedure, the degree of anesthesia required, and individual patient response. The smallest dose and concentration required to produce the desired effect should be used, especially in obstetrics. Reduced dosage is indicated in debilitated or acutely ill patients, in very young children or geriatric patients, and in patients with liver disease, arteriosclerosis, or occlusive arterial disease.
Adverse effects of local anesthetics usually result from high plasma concentrations of the drug caused by inadvertent intravascular injection, excessive dosage, excessive rate of injection, slow metabolic degradation, or injection into highly vascular tissue. Local anesthetic systemic toxicity occurs rarely, but is associated with serious adverse effects, principally involving the CNS and cardiovascular systems.211,213,216,234
CNS and Cardiovascular Effects
High plasma concentrations of local anesthetics affect the CNS and cardiovascular system. Generally, high plasma concentrations of the drugs initially produce CNS stimulatory effects manifested by anxiety, apprehension, restlessness, nervousness, disorientation, confusion, dizziness, blurred vision, tremors, twitching, shivering, and seizures, followed by CNS depression manifested by drowsiness, unconsciousness, and respiratory arrest. Nausea, vomiting, chills, miosis, and tinnitus also may occur. In some patients, especially those receiving lidocaine or other amides, symptoms of CNS stimulation may be transient or absent, and initial CNS effects are depressant in nature.
Adverse cardiovascular effects are depressant and include myocardial depression, bradycardia, cardiac arrhythmias, hypotension, cardiovascular collapse, and cardiac arrest. Although adverse cardiovascular effects usually occur only with high plasma concentrations of local anesthetic, in rare instances small doses of the drugs used for infiltration have caused cardiovascular collapse. Clinicians should consider that anesthesia itself, especially when the drugs are administered by epidural or subarachnoid routes, can affect the cardiovascular and respiratory systems.
Adverse reactions resulting from administration of epinephrine-containing solutions include anxiety, palpitation, dizziness, headache, restlessness, tremors, tachycardia, anginal pain, and hypertension. In extreme cases, pulmonary edema and ventricular fibrillation may occur. Norepinephrine is less likely to cause cardiac arrhythmias but instead may cause reflex bradycardia.
In the treatment of CNS and cardiovascular reactions, general physiologic supportive measures such as maintenance of adequate airway, oxygen uptake, and carbon dioxide removal should be instituted immediately. Administration of oxygen and assisted respiration may be sufficient to control anoxia in patients with seizures and avoids the hazards associated with administration of CNS depressant drugs. For control of severe seizures, slow IV infusion of diazepam, an ultra-short acting barbiturate, or, if these are not available, a short-acting barbiturate has been recommended. CNS depressants should not be used when asystole, coma, respiratory failure, or hypotension are present. Administration of a short-acting skeletal muscle relaxant (e.g., succinylcholine) in conjunction with artificial respiration has been recommended to block peripheral manifestations of seizures. Some clinicians, however, have questioned the value of skeletal muscle relaxants for treatment of local anesthetic-induced seizures. In the treatment of cardiovascular collapse, assisted respiration is of utmost importance. IV fluids and vasopressor drugs, preferably those that stimulate the myocardium, have been used to treat hypotension and circulatory collapse. The value of vasopressors in the treatment of cardiogenic shock is controversial, however. Cardiac massage should be used if necessary.
Musculoskeletal Effects
Chondrolysis, a condition characterized by necrosis and destruction of articular cartilage, has been reported in patients receiving continuous intra-articular infusions of local anesthetics for treatment of postoperative pain.200,201,202,203,204,205,206,207,208,209 Approximately 35 such cases of chondrolysis were reported to the FDA between 2006 and 2008 and have resulted in substantial injury to otherwise healthy young adults and adolescents.200,201 In most of the reported cases, chondrolysis occurred in the shoulder joint following arthroscopic or other shoulder surgery.200 While most (91%) of the affected patients received bupivacaine with or without epinephrine as the infused drug, several patients received other local anesthetics.200,201 The local anesthetics were infused directly into the intra-articular space using an elastomeric infusion device for periods of 48-72 hours postoperatively.200 Symptoms of cartilage damage (e.g., joint pain, stiffness, loss of motion) were reported as early as 2 months following administration of the infusions.200 It is not known whether the drug, device materials, other factors, or a combination of factors contributed to the development of chondrolysis.200,201 Additional cases of chondrolysis following intra-articular infusions of local anesthetics have been described in the medical literature.202,203,204,205,206,207,208,209 Although a causal relationship could not be established, use of continuous infusion devices to deliver the local anesthetic intra-articularly appeared to be associated with the development of chondrolysis in these cases.202,203,204,205,206,207,209 There currently is no effective treatment for chondrolysis; patients who develop the condition often require additional intervention, including debridement and/or corrective surgical measures (e.g., arthroplasty).200,202,203,204,205,206,209 Neither local anesthetics nor elastomeric infusion devices are approved for use for continuous intra-articular infusion therapy.200,201
Respiratory Effects
Respiratory paralysis or underventilation can occur following spinal anesthesia (due to cephaled extension of the motor level of anesthesia).214
Sensitivity Reactions
Hypersensitivity or allergic reactions occur rarely in patients receiving local anesthetics. These reactions may be manifested by dermatologic reactions, edema, status asthmaticus, or anaphylactoid reactions, which may result in death. There is probably no cross-sensitivity between local anesthetics of the amide type and those of the ester type; however, cross-sensitivity within each type does exist. Although some investigators and manufacturers have recommended skin testing in patients with suspected drug sensitivity, the value of this procedure in predicting sensitivity is controversial.
Other Adverse Effects
A transient burning sensation may occur at the site of injection of local anesthetics. Rarely, prolonged burning, pain, skin discoloration, tissue irritation, swelling, neuritis, neurolysis, tissue necrosis, and sloughing may occur.
Methemoglobinemia may occur in patients receiving some parenteral local anesthetics (e.g., prilocaine hydrochloride). (See Prilocaine Hydrochloride 72:00).
Aseptic meningitis, occasionally resulting in permanent and sometimes fatal paralysis, has occurred in patients undergoing spinal anesthesia and has been attributed to injection of irritating antiseptics or detergents in which the ampuls or syringes may have been stored or cleaned. If stability of the local anesthetic solution permits, ampuls of local anesthetics should be sterilized by autoclaving. Antiseptic or detergent solutions should not be used on the glass surface of ampuls because undetectable cracks may permit leakage of irritants into the local anesthetic solution. If ampuls are stored in antiseptic or detergent solutions, a dye should be added to the solution to facilitate detection of ampul leakage.
Precautions and Contraindications
Accidental intravascular injection of local anesthetics may result in seizures, CNS or cardiorespiratory depression, coma, and/or respiratory arrest. Local anesthetics should be used only by clinicians who are sufficiently knowledgeable in the diagnosis and management of dose-related toxicity and other acute emergencies that might arise from the type of anesthetic block to be used. Patients should be carefully and constantly monitored for possible cardiovascular, respiratory, or CNS complications during and after administration of local anesthetics.211,213,214,216 Resuscitative equipment, oxygen, drugs, and personnel required for treatment of adverse reactions must be immediately available whenever the drugs are used. Delay in appropriate management of dose-related toxicity, underventilation from any cause, and/or altered sensitivity may lead to the development of acidosis, cardiac arrest, and possibly death. For information on the management of severe CNS or cardiovascular reactions, see Cautions: CNS and Cardiovascular Effects.
Proper technique is inherent to safe use of local anesthetics. The drugs should be injected slowly and with frequent aspiration to guard against intravascular injection. The injection should be terminated if toxic effects appear. In intercostal and supraclavicular brachial plexus block, care should be taken to avoid puncture of the pleura. Care should be exercised in performing epidural (including caudal) anesthesia to prevent intravascular or subarachnoid injection of the large dose of local anesthetic. In epidural anesthesia, a test dose of anesthetic solution (usually 2 mL or 20% of the total dose—whichever is less) should be injected at least 5 minutes prior to administering the total dose; whenever clinical conditions permit, use of a test dose solution that contains epinephrine should be considered. If inadvertent subarachnoid injection has occurred, the patient should be resuscitated with oxygen; vasopressor drugs may be administered if necessary for control of blood pressure. In obstetric patients undergoing local anesthetic procedures, care must be taken to prevent accidental injection of the drug directly into the fetus. In spinal anesthesia, proper positioning of the patient and administration techniques are required to minimize spinal fluid leakage and subsequent headaches and to prevent mechanical injury to nerve tissue. Injections into the head and neck area (e.g., retrobulbar, dental, or stellate ganglion blocks) require particular caution since serious adverse effects due to complications of the anesthetic technique (e.g., inadvertent intra-arterial administration with resultant retrograde flow to the cerebral circulation, inadvertent puncture of the dural sheath of the optic nerve) have been reported.211,213
Since p -aminobenzoic acid may antagonize the activity of aminosalicylic acid and sulfonamides, some clinicians have suggested that local anesthetics of the ester type which are hydrolyzed in vivo to aminobenzoic acid derivatives (procaine and tetracaine) should not be given concomitantly with these drugs. In anesthetized individuals, the neuromuscular blocking effect of succinylcholine has been reported to be increased by IV administration of lidocaine or procaine following succinylcholine; however, this effect appears to be important only following high IV doses of the anesthetics.
Some commercially available formulations of articaine, bupivacaine, lidocaine, prilocaine, procaine, and tetracaine contain sulfites that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.
It has been suggested that patients with cardiac disease, hyperthyroidism, or other endocrine diseases may be particularly susceptible to toxic effects of local anesthetics. The drugs should be used with caution in severely debilitated patients and in those with liver disease. Ester-type local anesthetics should be used with extreme caution, if at all, in patients with low plasma pseudocholinesterase concentrations. Local anesthetics are contraindicated in patients with known hypersensitivity to the particular drug or group of local anesthetics (i.e., ester type or amide type) or any ingredient in the formulation (i.e., sulfites) and should be used cautiously in individuals with a history of allergic reactions. Local anesthetics should not be used in patients with myasthenia gravis, severe shock, or impaired cardiac conduction. The drugs are contraindicated by any route when the area or site of injection is infected or inflamed and should be used with extreme caution in patients with skin infections anywhere on the body.
Contraindications to epidural (including caudal) and spinal anesthesia include serious diseases of the CNS or of the spinal cord such as meningitis, spinal fluid block, cranial or spinal hemorrhage, tumors, poliomyelitis, syphilis, tuberculosis, or metastatic lesions of the spinal cord. Although CNS disease is generally a contraindication to spinal or epidural anesthesia, it is not a contraindication to peripheral nerve block. The following conditions are generally considered contraindications to epidural, caudal, or spinal anesthesia, but the therapeutic benefits to the patient should be weighed against the potential risks: spinal deformities that make epidural or spinal puncture inadvisable or difficult; bleeding resulting from traumatic lumbar puncture; arteriosclerosis; occlusive arterial disease; pernicious anemia with spinal cord involvement; severe anemia, cachexia, or moribund condition; septicemia; bowel obstruction; chronic backache; preoperative headaches of long duration or history of migraine; extreme age or youth; high or low blood pressure; and emotional instability, hysteria, or nervous tension. Blood pressure should be closely monitored during spinal anesthesia. Spinal anesthesia is generally contraindicated in patients with septicemia, severe hemorrhage, severe hypotension or shock, and complete heart block or other arrhythmias that severely restrict cardiac output.214 Spinal and epidural anesthesia may be contraindicated in patients with an abnormality of the blood clotting mechanism as in those with a bleeding tendency, those with hypofibrinogenemia, or those receiving anticoagulant therapy. Spinal or epidural puncture in these patients may cause subarachnoid or epidural hemorrhage which could result in neurologic sequelae. Patients on prolonged therapy with chlorpromazine or other antipsychotic agents that interfere with vasomotor control or patients with preexisting vasomotor instability should generally not receive spinal or epidural anesthesia, especially if anesthesia of the upper spinal cord is required. Viral disease, whether local or generalized, is usually a contraindication to spinal anesthesia.
Local anesthetic solutions containing a vasoconstrictor such as epinephrine should be used with caution, if at all, in geriatric patients and in patients with cardiovascular diseases including hypertension, peripheral vascular diseases, diabetes, hyperthyroidism, or Graves' disease. In addition, vasoconstrictors should not be used in conjunction with anesthesia of the digits, ears, nose, or penis. During labor, vasoconstriction of uterine blood vessels may occur and decrease placental circulation and intensity of uterine contractions, thereby prolonging labor. It should be kept in mind that oxytocic drugs of the ergot type may cause severe persistent hypertension and even rupture of a cerebral blood vessel in postpartum patients who have received local anesthetics containing a vasoconstrictor. Vasoconstrictors should not be used when potent inhalation anesthetics are administered, since severe cardiac arrhythmias may occur.211,213 Local anesthetic solutions containing vasoconstrictors should be used with extreme caution, if at all, in patients receiving monoamine oxidase inhibitors or tricyclic antidepressants because prolonged hypertension may result.211,213
Life-threatening adverse effects (e.g., irregular heart beat, seizures, breathing difficulties, coma, death) may occur when topical anesthetics are applied to a large area of skin, when the area of application is covered with an occlusive dressing, if a large amount of topical anesthetic is applied, if the anesthetic is applied to irritated or broken skin, or if the skin temperature increases (from exercise or use of a heating pad). Serious adverse effects (e.g., seizures, coma, irregular heart beat, respiratory depression) have been reported following topical application of local anesthetics to the skin. These events have occurred following application of extemporaneously prepared topical preparations containing high concentrations of anesthetics for cosmetic procedures and following use for indications approved by the FDA. When a topical anesthetic is needed for a procedure, use of a preparation approved by the FDA has been recommended. A preparation containing the lowest concentration of anesthetic likely to be effective should be used; a small amount of topical anesthetic should be applied to the affected area for the shortest period necessary for the desired effect. The patient should apply the topical preparation as directed by a clinician, and should not apply the topical preparation to broken or irritated skin. Patients should speak with their clinician if they are considering using a topical anesthetic before obtaining a mammogram.
Pediatric Precautions
Some local anesthetics are not recommended for use in pediatric patients until more experience is gained. Some manufacturers state that dosage of local anesthetics (e.g., articaine, lidocaine) in pediatric patients should be reduced in proportion to age, weight, and physical condition. For specific recommendations regarding the use of local anesthetics in pediatric patients, see the individual monographs on local anesthetics in 72:00.
Geriatric Precautions
Most manufacturers provide no specific guidance regarding safety and efficacy of local anesthetics in geriatric patients relative to younger adults. Although no overall differences in safety or efficacy were observed between geriatric and younger patients in clinical studies of articaine, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out. The manufacturers generally state that local anesthetics should be used in reduced dosages in geriatric patients.
Mutagenicity and Carcinogenicity
Long-term studies in animals to evaluate the mutagenic and carcinogenic potential of most local anesthetics have not been conducted to date. However, results of standard in vitro and in vivo tests using articaine hydrochloride showed no evidence of mutagenic activity. Limited data from reproductive studies in rats using high doses (approximately 2 times the human dose) of various local anesthetics (i.e., articaine) have not revealed evidence of impaired fertility.
Pregnancy
Pregnancy
Local anesthetics generally cross the placenta rapidly, and when used for epidural, paracervical, pudendal, or caudal block anesthesia, can cause varying degrees of maternal, fetal, and neonatal toxicity. The incidence and degree of toxicity depend on the procedure performed, the type and amount of drug used, and the technique of drug administration. Adverse reactions in the parturient, fetus, and neonate involve alterations of the CNS, peripheral vascular tone, and cardiac function.
Maternal hypotension has resulted from regional anesthesia. Elevating the patient's legs and positioning her on her left side may help prevent hypotension. Fetal heart rate should be monitored continuously, especially during paracervical block, and electronic fetal monitoring is advisable.
Epidural, spinal, paracervical, or pudendal anesthesia may alter the forces of parturition through changes in uterine contractility or maternal expulsive efforts. Use of obstetric anesthesia may increase the need for forceps assistance during delivery.
Administration of local anesthetics by paracervical nerve block during labor has been associated with a high incidence of fetal acidosis and bradycardia and has occasionally resulted in perinatal death. Fetal bradycardia may occur in 20-30% of patients receiving paracervical block anesthesia with the amide-type local anesthetics and may be associated with fetal acidosis. The risk of fetal bradycardia appears to be increased with prematurity, toxemia of pregnancy, and fetal distress. Changes in fetal heart rate and blood pH have been reported following epidural anesthesia. Use of bupivacaine for obstetrical paracervical block anesthesia is contraindicated.211,213,216
Possible inadvertent intracranial injection of local anesthetic solution into the fetus has reportedly occurred following attempted paracervical and/or pudendal block. Such inadvertent injection has resulted in unexplained neonatal depression at birth which was associated with high serum concentration of the anesthetic; seizures usually occurred within 6 hours after birth. Prompt use of supportive measures and forced urinary excretion of the local anesthetic has reportedly been effective for managing this complication.
Systemic absorption of some local anesthetics during paracervical block in early pregnancy (anesthesia for elective abortion) may be rapid, since maternal seizures and cardiovascular collapse have occurred under these conditions. Therefore, the recommended maximum dose of the drug should not be exceeded and injection should be made slowly and with frequent aspiration, allowing a 5-minute interval between sides.
In obstetrics, low spinal (saddle block) and caudal anesthesia are contraindicated in psychologically unsuited patients and in those with pelvic disproportion, abruptio placentae, unengaged or floating fetal head and placenta praevia, unless cesarean section is contemplated after induction of caudal anesthesia. In addition, these anesthetic procedures should not be used when intrauterine manipulations are required.
Safe use of local anesthetics during pregnancy prior to labor has not been established with respect to adverse effects on fetal development. Careful consideration should be given to this fact before administering these drugs in pregnant women.
Pharmacology
Local anesthetics are drugs which reversibly block nerve conduction near their site of application or injection and thus produce temporary loss of feeling or sensation in a limited area of the body. A wide variety of drugs have local anesthetic properties. Many of these drugs, however, are used only as topical anesthetics or antipruritics (see 52:16 and 84:08) or for other therapeutic purposes (e.g., Antihistamines 4:00). Although local anesthetics that are administered parenterally differ in quantitative and even in some qualitative effects, the similarity of their pharmacologic and therapeutic properties permits their discussion as a class.
Local anesthetics block the generation and conduction of impulses through all nerve fibers—sensory, motor, and autonomic. Local anesthetics appear to block conduction of nerve impulses by decreasing permeability of the nerve cell membrane to sodium ions, thereby decreasing the rate of depolarization of the nerve membrane, increasing the threshold for electrical excitability, and preventing propagation of the action potential. A current theory is that local anesthetics reduce nerve cell membrane permeability by competing with calcium for the membrane binding sites that control membrane permeability to sodium.
Small nerve fibers are generally more susceptible to the effects of local anesthetics than are large ones. In general, autonomic activity is affected first, followed by loss of pain and other sensory functions and, finally, loss of motor activity; regression of anesthesia usually occurs in the reverse order.
The various anesthetics produce different degrees of vasoactivity. Sympathetic blockade resulting from spinal anesthesia produces cardiovascular effects, including decreased stroke volume, cardiac output, and peripheral resistance, which may lead to hypotension. Circulatory changes associated with epidural anesthesia also result, in part, from sympathetic blockade. When epinephrine is administered with a local anesthetic, the pharmacologic effects of absorbed epinephrine may also affect the cardiovascular system.
Sympathetic blockade, whether from spinal or epidural anesthesia, results in contraction of the bowel and relaxation of sphincters. The vagus is not blocked, however, and visceral manipulation can cause pain or discomfort and precipitate nausea and vomiting. Spinal and epidural anesthesia, especially high spinal anesthesia, may interfere with normal respiratory function. Medullary depression and death may result from upward diffusion of large doses of local anesthetics. Circulatory and respiratory difficulties from local anesthesia develop more readily in pregnant women than in nonpregnant patients as a result of compression of the vena cava by the gravid uterus.
Tachyphylaxis to local anesthetic agents may develop and occurs most frequently after repeated administration of the drug into areas with limited buffer capacity such as the subarachnoid or epidural space. Although the precise cause of local anesthetic tachyphylaxis has not been determined, it appears that repeated administration of acidic injections lowers pH at the site of injection, thereby decreasing the amount of the free base available for diffusion through the epineurium to the receptor site. It has been suggested that development of tachyphylaxis may be retarded by the following measures: administration of a local anesthetic with a comparatively long duration of action and a high pKa value; addition of epinephrine to the local anesthetic solution to prolong the duration of action; and use of a buffer to increase pH within the epidural or subarachnoid space.
Since local anesthetics exert a generalized effect on all excitable membranes, systemic absorption of these drugs may affect the cardiovascular and central nervous system. High blood concentrations of local anesthetics produce peripheral vasodilatation initially, followed by decreased myocardial contractility which can lead to hypotension and cardiovascular collapse. Toxic blood concentrations of the drugs depress cardiac conduction which can lead to atrioventricular dissociation and ultimately cardiac arrest. High blood concentrations of local anesthetics also produce CNS depression. Initially this is manifested by central excitation, which ultimately leads to seizures resulting from blockade of inhibitory cortical synapses. Generalized CNS depression leading to respiratory depression and finally respiratory arrest may occur.
Other pharmacologic effects including ganglionic blocking activity, neuromuscular blocking activity, anticholinergic activity, antihistaminic activity, and antibacterial action have been attributed to local anesthetics; however, these effects do not appear to be clinically important when the drugs are used alone.
Pharmacokinetics
Absorption
Absorption of local anesthetics into the blood is influenced by the pharmacologic properties of the specific drug including its vasoactivity, the total dose of the drug administered, and the site of injection. Duration of anesthesia depends on the time during which the drug is in contact with nerve tissue. In general, the greater the degree of vasodilation produced by the local anesthetic, the faster the rate of absorption and shorter the duration of action. Procaine and chloroprocaine have relatively short durations of action; articaine, lidocaine, mepivacaine, propoxycaine (no longer commercially available in the US), and prilocaine have intermediate durations of action; and bupivacaine, etidocaine (no longer commercially available in the US), levobupivacaine (no longer commercially available in the US), ropivacaine,235 and tetracaine have long durations of action. Addition of a vasoconstrictor such as epinephrine to solutions of some local anesthetics decreases the rate of absorption and consequently prolongs the duration of action. (See Uses.)
Distribution
Following systemic absorption, local anesthetics are distributed into all body tissues. Individual drugs vary in the rate and degree to which they are distributed into various tissues and organs. Local anesthetics pass the blood-brain barrier in varying degrees. Distribution of local anesthetics in the CSF following epidural administration appears to parallel the degree of vascular absorption. Some direct diffusion across the dura mater may occur. Individual local anesthetics differ in the degree to which they are bound to plasma proteins. Local anesthetics cross the placental barrier in varying degrees. Because they are more rapidly degraded, it has been reported that ester-type local anesthetics are less likely to produce toxic plasma concentrations in the fetus. Drugs with the highest protein-binding capacity (e.g., bupivacaine) appear to have the lowest degree of placental transfer. When used in paracervical block procedures, local anesthetics may reach especially high concentrations in fetal plasma.
To produce anesthesia, local anesthetics must penetrate through surrounding tissue to the nerve cell membrane. The free base form of the local anesthetic has a high oil/water distribution coefficient which produces optimal penetration. Because the relative alkalinity of extracellular fluid favors formation of the free base, penetration in the extracellular space is usually adequate unless inflammation (which results in an unusually low pH) is present. After penetration to the nerve cell membrane, a new equilibrium between the free base and the cation is established. There has been considerable controversy as to whether the cation or the free base of the local anesthetic is active at the nerve membrane. The free base of procaine appears to be its more active form, whereas the cation appears to be essential for activity in most other local anesthetics. Some investigators have suggested, however, that the aromatic lipophilic portion of the molecule is responsible for anesthetic properties and that the cationic portion merely intensifies nerve-blocking effects.
Hyaluronidase has been added to local anesthetic solutions to facilitate penetration of the drug, particularly with nerve block and infiltration anesthesia. Because spread of anesthesia is undesirable in certain blocks and there is an increased incidence of systemic reactions to the local anesthetic when hyaluronidase is used, the enzyme is now used infrequently.
In spinal anesthesia, upward diffusion of the drug in the subarachnoid space depends on many factors including the concentration of the drug, the volume and specific gravity of the solution administered, the rate of injection, the position of the patient, the curvature of the patient's spine, movements of the patient, and the size of the subarachnoid space. In conjunction with appropriate positioning of the patient, hypobaric local anesthetic solutions rise in the subarachnoid space and produce anesthesia at levels higher than the site of injection; isobaric solutions of local anesthetics act at about the level of subarachnoid injection; and hyperbaric local anesthetic solutions exert their effects at levels below the site of injection. Following epidural administration of local anesthetics, leakage of the drug through the intervertegral foramina results in a multiple paravertebral block; uptake of the drug by dura-covered nerve roots within the epidural space results in spinal root blockade, and diffusion of the drug across the dura mater to the subarachnoid nerve roots and the spinal cord produces spinal cord blockade. The relative contribution of each of these factors to epidural anesthesia has not been determined. Since diffusion of the drug through the epidural space and to the above mentioned sites is a slow process, complete onset of action with epidural anesthesia is about 15-30 minutes after administration. Onset of action with spinal anesthesia is considerably shorter (average 5-12 minutes), since the epineurium is the only diffusion barrier in the subarachnoid space.
Elimination
Ester-type local anesthetics are hydrolyzed mainly in plasma by pseudocholinesterases and also by esterases in the liver. Patients with impaired renal function or hepatic disease and neonates with undeveloped renal or hepatic function have decreased serum pseudocholinesterase concentrations and, therefore, hydrolyze ester-type anesthetics more slowly than do other patients. Most local anesthetics with an amide linkage are metabolized principally in the liver by microsomal enzymes. Animal studies suggest that some local anesthetics may undergo enterohepatic circulation. Both ester- and amide-type local anesthetics are excreted mainly in urine as metabolites and small amounts of unchanged drug. Urinary excretion of lidocaine, prilocaine, bupivacaine, and possibly other local anesthetics may be enhanced by acidification of urine; however, the degree of increased urinary excretion is not clinically important.
Chemistry and Stability
Chemistry
Parenteral local anesthetics are synthetic drugs that structurally consist of a secondary or tertiary amino group connected to an aromatic residue by an intermediate group. The aromatic residue is connected to the intermediate group by an ester or amide linkage. Parenteral local anesthetics can be classified by the type of linkage that they possess:
ESTER TYPE
- *benzocaine
- chloroprocaine hydrochloride
- *cocaine
- procaine hydrochloride
- *proparacaine hydrochloride
- tetracaine hydrochloride
- * used only for topical anesthesia (see 52:16 and 84:08)
AMIDE TYPE
- articaine hydrochloride
- bupivacaine hydrochloride
- liposomal bupivacaine
- *dibucaine
- lidocaine hydrochloride
- mepivacaine hydrochloride
- prilocaine hydrochloride
- ropivacaine hydrochloride
- * used only for topical anesthesia (see 52:16 and 84:08)
The type of linkage appears to affect principally the site of metabolism and metabolic pathway of the drug. The aromatic portion of the local anesthetic determines its lipophilic properties, and the amine portion is responsible for its hydrophilic properties. Variations in these portions of the molecule affect the lipid-water distribution coefficient, protein-binding characteristics, and the ability of the drug to penetrate tissues. These and other structural changes in the molecule alter anesthetic potency, duration of action, rate of metabolism, and toxicity.
Because most of the free bases are poorly soluble in water and unstable in solution, parenteral local anesthetics are generally marketed as water-soluble hydrochloride salts. A liposomal formulation of bupivacaine containing the free base drug in an aqueous suspension of multivesicular liposomes is commercially available.216 Local anesthetics are weak bases, and solutions of their hydrochloride salts are usually acidic, a condition that enhances their stability. In solution, the local anesthetic salt is present as the uncharged free amine and as the positively charged ion in a ratio dependent on the pH of the solution and the pKa of the drug. Equilibrium shifts toward the charged cation form as pH decreases or toward the free-base form as pH increases. The pKa of most local anesthetics is in the range of 7.5-9.
Stability
Local anesthetics of the ester type are generally less stable in solution than are the amide-type anesthetics and, therefore, should not be subjected to repeated autoclaving. Chloroprocaine is very unstable, and solutions of this drug should not be autoclaved. Local anesthetic solutions that are cloudy, discolored, or contain crystals should be discarded.
Only references cited for selected revisions after 1984 are available electronically.
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