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level: local anaesthetics

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level questions: local anaesthetics

Question	Answer
Local anesthetics abolish sensation and, in higher concentrations, motor activity in a limited area of the body. They are applied or injected to block nerve conduction of sensory impulses from the periphery to the CNS.	local anaesthetics
Local anesthesia is induced when propagation of action potentials is prevented, so that sensation cannot be transmitted from the source of stimulation to the brain. Local anesthetics work by blocking sodium ion channels to prevent the transient increase in permeability of the nerve membrane to sodium that is required for an action potential to occur. They cause depolarization Local anesthetics gain access to their receptors from the cytoplasm or the membrane. Because the drug molecule must cross the lipid membrane to reach the cytoplasm, the more lipid soluble (nonionized, uncharged) form reaches effective intracellular concentrations more rapidly than does the ionized form. On the other hand, once inside the axon, the ionized (charged) form of the drug is the more effective blocking entity. Thus, both the nonionized and the ionized forms of the drug play important roles—the first in reaching the receptor site and the second in causing the effect. The affinity of the receptor site within the sodium channel for the local anesthetic is a function of the state of the channel, whether it is resting, open, or inactivated. In particular, if other factors are equal, rapidly firing fibers are usually blocked before slowly firing fibers. High concentrations of extracellular K+ may enhance local anesthetic activity, whereas elevated extracellular Ca2+ may antagonize it.	local anaesthetics moa
Delivery techniques include topical administration, infiltration, ring blocks, peripheral nerve blocks, and neuraxial (spinal, epidural, or caudal) blocks. The small, unmyelinated nerve fibers that conduct impulses for pain, temperature, and autonomic activity are most sensitive to the action of local anesthetics. Structurally, local anesthetics have fundamental features in common. These include a lipophilic group, joined by an amide or ester linkage to a carbon chain, which in turn, is joined to a hydrophilic group. The most widely used of the local anesthetic compounds are bupivacaine, lidocaine, mepivacaine, procaine , ropivacaine, and tetracaine. Of these, lidocaine is probably the most commonly used. Bupivacaine is noted for its cardiotoxicity. Mepivacaine should not be used in obstetric anesthesia due to its increased toxicity to the neonate.	delivery techniques
Biotransformation of amides occurs primarily in the liver. Prilocaine is also metabolized in the plasma and kidney, and one of its metabolites may lead to methemoglobinemia. Esters are biotransformed by plasma cholinesterase (pseudocholinesterase). Patients with pseudocholinesterase deficiency may be expected to metabolize ester local anesthetics more slowly. However, at normal doses, this has little clinical effect. Reduced hepatic function predisposes the patient to toxic effects but should not significantly increase the duration of action of local anesthetics.	A. Metabolism
Onset and duration of action of local anesthetics are influenced by several factors. These include tissue pH, pKa of the drug, nerve morphology, concentration, and lipid solubility of the drug. Of these, the most important are pH of the tissue and pKa of the drug. At physiologic pH, these compounds are charged. The ionized form interacts with the protein receptor of the sodium channel to inhibit its function and, thereby, achieve local anesthesia. The pH may drop in sites of infection, which causes onset to be delayed or even prevented. Within limits, higher concentration and greater lipid solubility improve onset to some degree. Duration of action depends on the length of time the drug can stay in the nerve to block sodium channels.	B. Onset and duration of action
Local anesthetics cause vasodilation, which leads to rapid diffusion away from the site of action and results in a short duration of action when these drugs are administered alone. By adding the vasoconstrictor epinephrine to the local anesthetic, the rate of local anesthetic diffusion and absorption is decreased. This both minimizes systemic toxicity and increases the duration of action. Hepatic function does not affect the duration of action of local anesthesia, which is determined by redistribution and not biotransformation. Some of these local anesthetics agents confer additional benefits such as the antiarrhythmic effect of lidocaine when administered intravenously.	C. Actions
Patient reports of allergic reactions to local anesthetics are fairly common, but investigation shows that most of these are of psychogenic origin. Psychogenic reactions are often misdiagnosed as allergic reactions and may also mimic them, with signs such as urticaria, edema, and bronchospasm. True allergy to an amide is exceedingly rare, whereas the ester procaine is somewhat more allergenic. An allergy to one ester rules out use of another ester, because the allergenic component is the breakdown product para-aminobenzoic acid, and metabolism of all esters yields this compound. In contrast, an allergy to one amide does not rule out use of another amide. A patient may be allergic to other compounds in the local anesthetic, such as preservatives in multidose vials.	D. Allergic reactions
Before administering local anesthetic to a child, the maximum dose based on the child’s weight should be calculated to help prevent inadvertent overdose. There are no significant differences in the response to local anesthetics between younger and older adults, and the doses required for each block are the same regardless of patient age. However, it is prudent to stay well below the maximum recommended doses in elderly patients who often have some compromise in liver function. Because some degree of cardiovascular compromise may also be expected in elderly patients, reducing the dose of epinephrine may be prudent. Previous recommendations, now known to be wrong, precluded the use of specific local anesthetics in patients who are susceptible to MH. Today, it is well accepted that all local anesthetics are safe for these patients.	E. Administration to children and the elderly
Toxic blood levels of the drug may be due to repeated injections or could result from a single inadvertent IV injection. Aspiration before every injection is paramount to safety. The signs, symptoms, and timing of local anesthetic systemic toxicity are unpredictable. The most important step in treating local anesthetic toxicity is to consider the diagnosis in any patient with altered mental status or cardiovascular instability following injection of local anesthetic. CNS symptoms (either excitation or depression of the CNS) may be apparent but may also be subtle, nonspecific, or absent. Treatment for systemic local anesthetic. toxicity includes airway management, support of breathing and circulation, seizure suppression, and, if needed, cardiopulmonary resuscitation. Administering a 20-percent lipid emulsion infusion (lipid rescue therapy) is a promising asset in treating local anesthetic toxicity.	F. Systemic local anesthetic toxicity
The local anesthetics constitute a group of chemically similar agents (esters and amides). Most local anesthetic drugs are esters or amides of simple benzene derivatives. Subgroups within the local anesthetics are based on this chemical characteristic and on duration of action. The commonly used local anesthetics are weak bases with at least 1 ionizable amine function that can become charged through t he gain of a proton (H+). Because the pH of tissue may differ from the physiologic 7.4 (eg, it may be as low as 6.4 in infected tissue), the degree of ionization of the drug will vary. Because the pKa of most local anesthetics is between 8.0 and 9.0 (benzocaine is an exception), variations in pH associated with infection can have significant effects on the proportion of ionized to nonionized drug.	chemistry
Many shorter acting local anesthetics are readily absorbed into the blood from the injection site after administration. The duration of local action is therefore limited unless blood flow to the area is reduced. This can be accomplished by administration of a vasoconstrictor (usually an α-agonist sympathomimetic) with the local anesthetic agent. Cocaine is an important exception because it has intrinsic sympathomimetic action due to its inhibition of norepinephrine reuptake into nerve terminals.	shorter acting local anesthetics
The longer-acting agents (eg, bupivacaine, ropivacaine, tetracain) are also less dependent on the coadministration of vasoconstrictors. Surface activity (ability to reach superficial nerves when applied to the surface of mucous membranes) is a property of certain local anesthetics, especially cocaine and benzocaine (both only available as topical forms), lidocaine, and tetracaine.	longer-acting agents
Metabolism of ester local anesthetics is carried out by plasma cholinesterases (pseudocholinesterases) and is very rapid for procaine (half-life, 1–2 min), slower for cocaine, and very slow for tetracaine). The amides are metabolized in the liver, in part by cytochrome P450 isozymes. The half-lives of lidocaine and prilocaine are approximately 1.5 h. Bupivacaine and ropivacaine are the longest-acting amide local anesthetics with half-lives of 3.5 and 4.2 h, respectively. Liver dysfunction may increase the elimination half-life of amide local anesthetics (and increase the risk of toxicity). Acidification of the urine promotes ionization of local anesthetics; the charged forms of such drugs are more rapidly excreted than nonionized forms.	metabolism and half lifes
Differential sensitivity of various types of nerve fibers to local anesthetics depends on fiber diameter, myelination, physiologic firing rate, and anatomic location. In general, smaller fibers are blocked more easily than larger fibers, and myelinated fibers are blocked more easily than unmyelinated fibers. Activated pain fibers fire rapidly; thus, pain sensation appears to be selectively blocked by local anesthetics. Fibers located in the periphery of a thick nerve bundle are blocked sooner than those in the core because they are exposed earlier to higher concentrations of the anesthetic.	PHARMACOLOGIC EFFECTS on nerves
Most local anesthetics also have weak blocking effects on skeletal muscle neuromuscular transmission, but these actions have no clinical application. The mood elevation induced by cocaine reflects actions on dopamine or other amine-mediated synaptic transmission in the CNS rather than a local anesthetic action on membranes.	B. Other Tissues
The local anesthetics are commonly used for minor surgical procedures often in combination with vasoconstrictors such as epinephrine. Onset of action may be accelerated by the addition of sodium bicarbonate, which enhances intracellular access of these weakly basic compounds. Articaine has the fastest onset of action. Local anesthetics are also used in spinal anesthesia and to produce autonomic blockade in ischemic conditions. Slow epidural infusion at low concentrations has been used successfully for postoperative analgesia. Repeated epidural injection in anesthetic doses may lead to tachyphylaxis, however. Intravenous local anesthetics may be used for reducing pain in the perioperative period. Oral and parenteral forms of local anesthetics are sometimes used adjunctively in neuropathic pain states.	CLINICAL USE
The important toxic effects of most local anesthetics are in the CNS. All local anesthetics are capable of producing a spectrum of central effects, including light-headedness or sedation, restlessness, nystagmus, and tonic-clonic convulsions. Severe convulsions may be followed by coma with respiratory and cardiovascular depression.	toxicity cns effects
With the exception of cocaine, all local anesthetics are vasodilators. Patients with preexisting cardiovascular disease may develop heart block and other disturbances of cardiac electrical function at high plasma levels of local anesthetics. Bupivacaine, a racemic mixture of two isomers may produce severe cardiovascular toxicity, including arrhythmias and hypotension. The (S) isomer, levobupivacaine, is less cardiotoxic. Cardiotoxicity has also been reported for ropivacaine when used for peripheral nerve block. The ability of cocaine to block norepinephrine reuptake at sympathetic neuroeffector junctions and the drug's vasoconstricting actions contribute to cardiovascular toxicity. When cocaine is used as a drug of abuse, its cardiovascular toxicity includes severe hypertension with cerebral hemorrhage, cardiac arrhythmias, and myocardial infarction.	toxicity cardiovascular effects
Prilocaine is metabolized to products that include o-toluidine, an agent capable of converting hemoglobin to methemoglobin. Though tolerated in healthy persons, even moderate methemoglobinemia can cause decompensation in patients with cardiac or pulmonary disease. The ester-type local anesthetics are metabolized to products that can cause antibody formation in some patients. Allergic responses to local anesthetics are rare and can usually be prevented by using an agent from the amide subclass. In high concentrations, local anesthetics may cause a local neurotoxic action (especially important in the spinal cord) that includes histologic damage and permanent impairment of function.	C. Other Toxic Effects
Severe toxicity is treated symptomatically; there are no antidotes. Convulsions are usually managed with intravenous diazepam or a short-acting barbiturate such as thiopental. Hyperventilation with oxygen is helpful. Occasionally, a neuromuscular blocking drug may be used to control violent convulsive activity. The cardiovascular toxicity of bupivacaine overdose is difficult to treat and has caused fatalities in young adults; intravenous administration of lipid has been reported to be of benefit.	D. Treatment of Toxicity