Toxicity of local anesthetic

Denson DD and Mazoit JX. Physiology, pharmacology and toxicity of local anesthetics Adult and pediatric considerations. In P Prithvi Raj P (ed.). Clinical Practice of Regional Anesthesia. New York Churchill Livingstone, 1991. 

Hagiwara Ozawa (1985) investigated toxicity of local anesthetics on chick myogenic cells (mononu-... 

Burns RR Forster RK, Laibson P, Gibson IK. Chronic toxicity of local anesthetics on the cornea. In Leopold IH, Burns RP, eds. Symposium on ocular therapy. NewYork John Wiley Sons, 1977 31-44. 

Hurley R, Feldman H. Toxicity of local anesthetics in obstetrics. I. Bupivacaine. Clin Anaesthesiol 1986 4 93. 

Heavner JE. Cardiac toxicity of local anesthetics in the intact isolated heart model a review. Reg Anesth Pain Med 2002 27(6) 545-55. 

Chauvin M. Toxicite aigue des anesthesiques locaux en fonction du terrain. [Acute toxicity of local anesthetics as a function of the patient s condition.] Ann Fr Anesth Reanim 1988 7(3) 216-23... 

The endothelial toxicity of local anesthetics has been assessed in pigs, as this might be relevant to the safety of agents given by intracameral injection (335). Lidocaine, mepivacaine, and prilocaine were safe, while bupivacaine in clinically effective concentrations resulted in significant cell reduction. 

Covino BG. Toxicity of local anesthetic agents. Acta Anaesthesiol Belg 1988 39(3 Suppl 2) 159-64. 

MuUanu Ch, Gaillat F, Scemama F, Thibault S, Lavand homme P, Auffray JP. Acute toxicity of local anesthetic ropivacaine and mepivacaine during a combined lumbar plexus and sciatic block for hip surgery. Acta Anaesthesiol Belg 2002 53(3) 221-3. 

The toxicity of local anesthetics is related to their potency which is directly related to their hydrop-hobicity. The more hydrophobic drugs such as bupivacaine produce toxicities at concentrations lower than the less potent anesthetics such as lido-caine and mepivacaine. 

Skill Keeper Cardiac Toxicity of Local Anesthetics (see Chapter 14)... 

Explain how hyperkalemia facilitates the cardiac toxicity of local anesthetics. The Skill Keeper Answer appears at the end of the chapter. 

Which one of the following statements about the toxicity of local anesthetics is most correct lA) Serious cardiovascular reactions are more likely to occur with tetracaine than with bupiv-... 

The side effects and toxicity of local anesthetics seem to be related to their actions on other excitable membrane proteins, such as in the sodium and potassium channels in the heart, the nicotinic acetylcholine receptors in the neuromuscular junctions, and the nerve cells in the CNS. In general, neuromuscular junctions and the CNS are more susceptible than the cardiovascular system to the toxic effects of local anesthetics. 

Table 64.4. Factors affecting systemic toxicity of local anesthetics...

Mather LE, Copeland SE, Ladd LA. Acute toxicity of local anesthetics underlying pharmacokinetic and pharmacodynamic concepts. Reg Anesth Pain Med 2005 30 553-566. 

The metabolic degradation of local anesthetics depends on whether the compound has an ester or an amide linkage. Esters are extensively and rapidly metabolized in plasma by pseudochoUnesterase, whereas the amide linkage is resistant to hydrolysis. The rate of local anesthetic hydrolysis is important, since slow biotransformation may lead to drug accumulation and toxicity. In patients with atypical plasma cholinesterase, the use of ester-linked compounds, such as chloroprocaine, procaine and tetracaine, has an increased potential for toxicity. The hydrolysis of all ester-linked local anesthetics leads to the formation of paraaminobenzoic acid (PABA), which is known to be allergenic. Therefore, some people have allergic reactions to the ester class of local anesthetics. 

Infiltration (i.e., the injection of local anesthetics under the skin) of the surgical site provides adequate anesthesia if contiguous structures are not stimulated. Since the onset of local anesthesia is rapid, the surgical procedures can proceed with little delay. Minimally effective concentrations should be used, especially in extensive procedures, to avoid toxicity from overdosage. 

Excellent and rapid anesthetization of an extremity can be obtained easily. Following insertion of an intravenous catheter in the limb of interest, a rubber bandage is used to force blood out of the limb, and a tourniquet is applied to prevent the blood from reentering a dilute solution of local anesthetic, most commonly lido-caine, is then injected intravenously. This technique fills the limb s vasculature and carries the anesthetic solution to the nerve by means of the blood supply. Because of the pain produced by a tourniquet after some time, this procedure usually is limited to less than 1 hour. The systemic blood levels of drug achieved after tourniquet release generally remain below toxic levels. 

Depression or cardiac excitability and contractility may cause AV block, ventricular arrhythmias, or cardiac arrest. Symptoms of local anesthetic CNS toxicity, such as dizziness, tongue numbness, visual impairment or disturbances, and muscular twitching appear to occur before cardiotoxiceffects. Cardiotoxic effects include angina, QT prolongation, PR prolongation, atrial fibrillation, sinus bradycardia, hypotension, palpitations, and cardiovascular collapse. 

Combining agonists with some local anesthetics greatly prolongs the duration of infiltration nerve block the total dose of local anesthetic (and the probability of toxicity) can therefore be reduced. Epinephrine, 1 200,000, is the favored agent for this application, but norepinephrine, phenylephrine, and other agonists have also been used. Systemic effects on the heart and peripheral vasculature may occur even with local drug administration but are usually minimal. 

The development of newer agents continues because it is relatively easy to synthesize chemicals with local anesthetic properties. Unfortunately, it is difficult to reduce the toxicity of these compounds because the common side effects of local anesthetics represent extensions of their therapeutic effects. New research into the mechanisms of local anesthetic-induced cardiac and spinal toxicity and identification of alternative drug targets for spinal analgesia (eg, opioid receptors, [Pg.560]

Some pharmacokinetic properties of the commonly used amide local anesthetics are summarized in Table 26-2. The pharmacokinetics of the ester-based local anesthetics have not been extensively studied owing to their rapid breakdown in plasma (elimination half-life < 1 minute). Local anesthetics are usually administered by injection into dermis and soft tissues around nerves. Thus, absorption and distribution are not as important in controlling the onset of effect as in determining the rate of offset of local analgesia and the likelihood of CNS and cardiac toxicity. Topical application of local anesthetics (eg, transmucosal or transdermal) requires drug diffusion for both onset and offset of anesthetic effect. However, intracavitary (eg, intra-articular, intraperitoneal) administration is associated with a more rapid onset and shorter duration of local anesthetic effect. 

Local anesthetics have poorly understood effects on inflammation at sites of injury, and these anti-inflammatory effects may contribute to improved pain control in some chronic pain syndromes. At the concentrations used in spinal anesthesia, local anesthetics can inhibit transmission via substance P (neurokinin-1), NMDA, and AMPA receptors in the secondary afferent neurons (Figure 26-1). These effects may contribute to the analgesia achieved by subarachnoid administration. Local anesthetics can also be shown to block a variety of other ion channels, including nicotinic acetylcholine channels in the spinal cord. However, there is no convincing evidence that this mechanism is important in the acute clinical effects of these drugs. High concentrations of local anesthetics in the subarachnoid space can interfere with intra-axonal transport and calcium homeostasis, contributing to potential spinal toxicity. 

The two major forms of local anesthetic toxicity are (1) systemic effects following absorption of the local anesthetic from their site of administration and (2) direct neurotoxicity from the local effects of these drugs when high concentrations are administered in close proximity to the spinal cord and other major nerve trunks. When blood levels of local anesthetics rise rapidly, adverse effects on several major organ systems may be observed. 

All local anesthetics have the ability to produce sleepiness, light-headedness, visual and auditory disturbances, and restlessness when high plasma concentrations are produced after rapid absorption or inadvertent intravascular administration. An early symptom of local anesthetic toxicity is circumoral and tongue numbness and a metallic taste. At higher concentrations, nystagmus and muscular twitching occur, followed by tonic-clonic convulsions. Local anesthetics... 

Systemic effects are more likely to occur with long-acting anesthetics if an excessive dose is used, if absorption into the blood stream is accelerated for some reason, or if the drug is accidentally injected into the systemic circulation rather than into extravascular tissues.17 40 Other factors that can predispose a patient to systemic effects include the type of local anesthetic administered, as well as the route and method of administration.3 Therapists and other health care professionals should always be alert for signs of the systemic effects of local anesthetics in patients. Early symptoms of CNS toxicity include ringing/buzzing... 

Two major forms of local anesthetic toxicity are recognized direct neurotoxicity from the local effects of certain agents administered around the cord or other major nerve trunks, and systemic... 

Because of cocaine s toxicity and addictive properties, a search began for synthetic substitutes for cocaine. In 1905, procaine was synthesized and became the prototypic local anesthetic for half a century. Newer derivatives include mepivacaine and tetracaine (Figure 13.1). Briefly, the SAR of local anesthetics revolves around their hydrophobicity. Association of the drug at hydrophobic sites, such as the sodium channel, is believed to prevent the generation and conductance of a nerve impulse by interfering with sodium permeability (i.e., elevating the threshold for electrical excitability). 

A healthy 17-year-old man received an interscalene brachial plexus block using mepivacaine 600 mg and bupivacaine 150 mg. He became disorientated and showed signs of local anesthetic toxicity, for which he was given midazolam 5 mg. Flumazenil 0.5 mg was given 23 minutes after the end of the procedure, causing opisthotonos. 

Tetracaine causes rapid surfece anesthesia, but even repeated applications to the conjiuictival surface may fail to achieve effective scleral anesthesia. Preparations of local anesthetics for topical use that include tetracaine should never be injected. Practitioners are cautioned to consider tetracaine a potent and potentially toxic local anesthetic. Dangerous overdoses may occur if it is administered in doses higher than 1.5 mg/kg of body weight. 

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