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As was first demonstrated by Gasser and Erlanger in , all LAs will block smaller diameter fibers at lower concentrations than are required to block larger fibers of the same type.

Local anesthetic agents

Bupivacaine and ropivacaine are relatively selective for sensory fibers. Bupivacaine produces more rapid onset of sensory than motor block, whereas the closely related chemical mepivacaine demonstrates no differential onset during median nerve blocks Figure True differential anesthesia may be possible when Nav isoform-selective antagonists become available. Certain Nav isoforms have been found to be prevalent in dorsal root ganglia, and as previously noted the relative populations of various Nav isoforms can change in response to various pain states.

Many factors influence the ability of a given LA to produce adequate regional anesthesia, including the dose, site of administration, additives, temperature, and pregnancy. As the LA dose increases, the likelihood of success and the duration of anesthesia increase, while the delay of onset and tendency for differential block decrease. In general, the fastest onset and shortest duration of anesthesia occur with spinal or subcutaneous injections; a slower onset and longer duration are obtained with plexus blocks. Epinephrine is frequently added to LA solutions to cause vasoconstriction and to serve as a marker for intravascular injection.

Uncharged local anesthetics have greater apparent potency at basic pH, where an increased fraction of LA molecules is uncharged, than at more acidic pH Figure Uncharged LA bases diffuse across nerve sheaths and membranes more readily than charged LAs, hastening onset of anesthesia. Some clinical studies showed that the addition of sodium bicarbonate had an inconsistent action during clinical nerve block; however, not all studies demonstrated a faster onset of anesthesia.

One might anticipate that bicarbonate would have its greatest effect when added to LA solutions to which epinephrine was added by the manufacturer. Bicarbonate shortens the duration of lidocaine in animals. Marked prolongation of local anesthesia can be achieved by incorporating LAs into liposomes, as has been done with bupivacaine in the some formulation. Pregnant women and pregnant animals demonstrate increased neural susceptibility to LAs. Peak LA concentrations vary by the site of injection Figure With the same LA dose, intercostal blocks consistently produce greater peak LA concentrations than epidural or plexus blocks.

Both protein binding and protein concentration decline during pregnancy. During longer-term infusion of LA and LA-opioid combinations, concentrations of LA-binding proteins progressively increase There is considerable first-pass uptake of LAs by the lungs, and animal studies suggest that patients with right-to-left cardiac shunting may be expected to demonstrate LA toxicity after smaller intravenous bolus doses.

Esters undergo rapid hydrolysis in blood, catalyzed by non-specific esterases.

List of Local Anesthesia Medications (91 Compared) - iqegumybiwyf.ml

Procaine and benzocaine are metabolized to para-aminobenzoic acid PABA , the species underlying anaphylaxis to these agents. Higher doses of benzocaine, typically for topical anesthesia for endoscopy, can lead to life threatening levels of methemoglobinemia. The amides undergo metabolism in the liver. Bupivacaine, ropivacaine, mepivacaine, and etidocaine also undergo N-dealkylation and hydroxylation. Prilocaine is hydrolyzed to o-toluidine, the agent that causes methemoglobinemia. Prilocaine doses of as little as mg in fit adults may be expected to produce methemoglobinemia concentrations great enough to cause clinical cyanosis.

Disposition of amide LAs is altered in pregnancy due to increased cardiac output, hepatic blood flow, and clearance, as well as the previously mentioned decline in protein binding. Renal failure tends to increase volume of distribution of amide LAs and to increase the accumulation of metabolic by-products of ester and amide LAs. Theoretically, cholinesterase deficiency and cholinesterase inhibitors should increase the risk of systemic toxicity from ester LAs; however, there are no confirmatory clinical reports.

Some drugs inhibit various cytochromes responsible for LA metabolism; however, the importance of cytochrome inhibitors varies depending on the specific LA species. On the other hand, coadministration with strong inhibitors of CYP 3A4 ketoconazole, itraconazole has only a small effect on ropivacaine clearance.

It is a common, but misguided, assumption that all LA actions, including toxic side effects, arise from interaction with voltage-gated Na channels. LA binding to any one or all of these other sites could underlie LA production of spinal or epidural analgesia and could contribute to toxic side effects. Local anesthetic CNS toxicity arises from selectively blocking the inhibition of excitatory pathways in the CNS, producing a stereotypical sequence of signs and symptoms as the LA concentration in blood gradually increases Table 3.

With increased LA doses, seizures may arise in the amygdala. More potent at nerve block LAs produce seizures at lower blood concentrations and at lower doses than less-potent LAs. Cardiovascular Toxicity. In laboratory experiments, most LAs will not produce cardiovascular CV toxicity until the blood concentration exceeds three times that necessary to produce seizures; however, there are clinical reports of simultaneous CNS and CV toxicity with bupivacaine Table 4.

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In dogs, supraconvulsant doses of bupivacaine more commonly produce arrhythmias than supraconvulsant doses of ropivacaine and lidocaine. LAs produce CV signs of CNS excitation increased heart rate, arterial blood pressure, and cardiac output at lower concentrations than those associated with cardiac depression.

Hypocapnia reduces ropivacaine-induced changes in ST segments and left ventricular contractility. TABLE 4. Convulsive versus lethal doses of local anesthetics in dogs. Bupivacaine binds more avidly and longer than lidocaine to cardiac Na channels. These laboratory observations led to the clinical development of levobupivacaine and ropivacaine.


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Local anesthetics inhibit conduction in the heart with the same rank order of potency as for nerve block. Local anesthetics produce dose-dependent myocardial depression, possibly from interference with Ca signaling mech-anisms within cardiac muscle. These anesthetics bind and inhibit cardiac voltage-gated Ca and K channels at concentrations greater than those at which binding to Na channels is maximal.

In dogs, lidocaine was the least potent, and bupivacaine and levobupivacaine were more potent than ropivacaine at inhibiting left ventricular function as assessed by echocardiography Table 5. In dogs, both programmed electrical stimulation and epinephrine resuscitation elicited more arrhythmias after bupivacaine and levobupivacaine than after lidocaine or ropivacaine administration.

The mechanism by which CV toxicity is produced may depend on which LA has been administered. When LAs were given to the point of extreme hypotension, dogs receiving lidocaine could be resuscitated but required continuing infusion of epinephrine to counteract LA-induced myocardial depression. Conversely, many dogs receiving bupivacaine or levobupivacaine to the point of extreme hypotension could not be resuscitated. After bupivacaine, levobupivacaine, or ropivacaine, dogs that could be defibrillated often required no additional therapy.

Similarly, in pigs, comparing lidocaine with bupivacaine, the ratio of potency for myocardial depression was , whereas it was for arrhythmogenesis.

How does Local Anesthesia Work? Mechanisms - ESTER VS AMIDE LOCAL ANESTHETICS

The LAs produce dilation of vascular smooth muscle at clinical concentrations. Cocaine is the only LA that consistently produces local vasoconstriction. True immunologic reactions to LAs are rare. Accidental intravenous injections of LAs are sometimes misdiagnosed as allergic reactions. Some patients may react to preservatives, such as methyl-paraben, included with LAs. Several studies have shown that patients referred for evaluation of apparent LA allergy, even after exhibiting signs or symptoms of anaphylaxis, almost never demonstrate true allergy to the LA that was administered.

On the other hand, LA skin testing has an excellent negative predictive value. During the s, 2-chloroprocaine at that time formulated with sodium metabisulfite at a relatively acidic pH occasion-ally produced cauda equina syndrome following accidental large-dose intrathecal injection during attempted epidural administration. At the same time, other investigators have linked neurotoxic reactions in animals to large doses of 2-chlo-roprocaine rather than to metabisulfite. There is also contro-versy about transient neurologic symptoms and persistent sacral deficits after lidocaine spinal anesthesia.

The reports and the controversy have persuaded many physicians to abandon lidocaine spinal anesthesia. This may be the result of lidocaine-induced increases in intracellular calcium and does not appear to involve Na channel blockade. Treatment of adverse LA reactions depends on their severity. Minor reactions can be allowed to terminate spontaneously.

Seizures induced by LAs should be managed by maintaining a patent airway and by providing oxygen. Seizures may be ter-minated with intravenous midazolam 0. LA CV depression manifested by moderate hypotension, may be treated by infusion of intravenous fluids and vasopressors phenylephrine 0. When toxicity progresses to cardiac arrest, the guidelines for treatment of LA toxicity as developed by the American Society of Regional Anesthesia and Pain Medicine ASRA are reasonable, and certainly preferable to the chaotic resuscitation schemes identified in a national survey prior to publication of the guideline.

It makes sense that amiodarone be substituted for lidocaine and, based on multi-ple animal experiments, that smaller, incremental doses of epinephrine be used initially rather than 1-mg boluses. Animal experiments and clinical reports demonstrate the remarkable ability of lipid infusion to resuscitate from bupivacaine-induced cardiac arrest Figure Given the nearly nontoxic status of lipid infusion, one cannot make a convincing argument to withhold this therapy from a patient requiring resuscitation from LA intoxication.

With unresponsive bupivacaine cardiac toxicity cardiopulmonary bypass should be considered. It appears that the threat from severe local anesthetic systemic toxicity may be on the decline, whether from better treatment or from changes in techniques. Many practitioners believe that ultrasound guidance during peripheral nerve blocks has led to safer practices and less risk.

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While this view remains controversial, there are studies that support this belief. After more than a century of use in Western medicine, LAs remain important tools for the twenty-first-century physician. Peripheral nerve blocks are almost certainly the result of LA inhibition of voltage-gated Na channels in neuronal membranes.

The mechanisms of spinal and epidural anesthesia remain incompletely defined. The appropriate and safe dose of LAs varies with specific nerve block procedure.

The mechanisms by which differing LAs produce CV toxicity likely vary: The more potent agents eg, bupivacaine may produce arrhythmias through a Na channel action, whereas the less-potent agents eg, lidocaine may produce myocardial depression through other pathways.

Fears about LA systemic toxicity have abated with safer LAs, safer regional anesthesia practices, and improved treatments. There is renewed effort to produce clinically applicable delayed-release local anesthetic formulations to extend the duration of the currently available LAs. It is important to note that patients under general anesthesia will typically present with cardiotoxicity as the first sign of local anesthetic toxicity.

Low doses of local anesthetics may cause vasoconstriction, where as, moderate or high doses result in vasodilation and decreased SVR. Cocaine is the only local anesthetic that causes vasoconstriction at all doses. This order parallels the vascular supply of each tissue. See Keyword below.

JADA examines effectiveness of local anesthetics

A side effect unique to prilocaine is methemoglobinemia at doses of at least mg. The liver metabolizes prilocaine to O-toluidine which oxidizes hemoglobin to methemoglobin. Methemoglobinemia is readily treated with methylene blue. Cancel Join.

Definition Local anesthetic toxicity can be seen in organs of the body that depend upon sodium channels for proper functioning. Pharmacologic Data Effects on Organ Systems Central nervous system The initial CNS symptoms are tinnitus, blurred vision, dizziness, tongue parathesias, and circumoral numbness. The effects on the CNS depend on various clinical factors including: Hypercarbia — Increased PaCO2 lowers the seizure threshold with local anesthetic administration.

Cardiovascular system Local anesthetics have directs effects on the heart and peripheral blood vessels. Local Anesthetic Relative Potency Procaine 1 Chloroprocaine 1 Cocaine 2 Lidocaine 2 Prilocaine 2 Mepivacaine 2 Etidocaine 6 Bupivacaine 8 Tetracaine 8 Peripheral vascular effects Low doses of local anesthetics may cause vasoconstriction, where as, moderate or high doses result in vasodilation and decreased SVR.

Methemoglobinemia A side effect unique to prilocaine is methemoglobinemia at doses of at least mg. Methemoglobinemia is readily treated with methylene blue Lidocaine: A Focus. Connect with Us.