Anesthetics amide-type

The answer is c. (Hardman, p 340. Katzung, p 437.) Of the listed agents, only bupivacaine is an amide. Allergy to amide-type local anesthetics is much less frequent than with ester-type local anesthetics, such as benzo-caine patients who demonstrate an allergy to one such drug will be allergic to all of them... 

The answer is a. (Hardman, p 338. Katzung, pp 438-439.) Ester-type local anesthetics are mainly hydrolyzed by pseudocholinesterases. Amide-type local anesthetics are hydrolyzed by microsomal enzymes in the liver. Of the listed agents, only lidocaine is an amide and can be influenced by liver dysfunction. 

The amide type local anesthetic lidocaine is broken down primarily in the liver by oxidative N-dealkylation. This step can occur only to a restricted extent in prilocaine and articaine because both carry a substituent on the C-atom adjacent to the nitrogen group. Articaine possesses a carboxymethyl group on its thiophen ring. At this position, ester cleavage can occur, resulting in the formation of a polar -COO group, loss of the amphiphilic character, and conversion to an inactive metabolite. 

IM Hypersensitivity to local anesthetics of the amide type and in patients with severe shock or heart block due to the use of lidocaine hydrochloride diluent. 

Local anesthetics are used for topical anesthesia, local infiltration, peripheral nerve block, paravertebral anesthesia, intravenous block also known as regional anesthesia, epidural block, and spinal i.e. subarachnoid blockade. The local anesthetics may be divided into two main groups, the esters and the amide-type agents. 

Amide-type agents include articaine, lidocaine, bupivacaine, prilocaine, mepivacain and ropiva-caine. These are metabolized in the liver by microsomal enzymes with amidase activity. The amide group is preferred for parenteral and local use. If by accident rapidly administered intravascularly these agents, especially bupivacaine but also lidocaine, can produce serious and potentially lethal adverse effects including convulsions and cardiac arrest. They can more easily accumulate after multiple administrations. Intravenous lidocaine is sometimes used for regional anesthesia, for infiltration procedures, for the induction of nerve blockade and for epidural anesthesia. However, it is also used as an antiarrhythmic. Bupivacaine is a long-acting local anesthetic used for peripheral nerve blocks and epidural anesthesia. 

Contraindications include hypersensitivity to local anesthetics of the amide type (a very rare occurrence), severe hepatic dysfunction, a history of grand mal seizures due to lidocaine, and age 70 or older. Lidocaine is contraindicated in the presence of second- or third-degree heart block, since it may increase the degree of block and can abolish the idioventricular pacemaker responsible for maintaining the cardiac rhythm. 

Contraindications History of hypersensitivity to beta-lactams (imipenem and cilas-tin, meropenem), hypersensitivity to amide-type local anesthetics (IM)... 

Contraindications Adams-Stokes syndrome, hypersensitivity to amide-type local anesthetics, septicemia (spinal anesthesia), supraventricular arrhythmias, Wolff-Par-kinson-White syndrome... 

Mechanism of Action An amide-type local anesthetic that shortens the action potential duration and decreases the effective refractory period and automaticity in the His-Purkinje system of the myocardium by blocking sodium transport across myocardial cell membranes. Therapeutic Effect Suppresses ventricular arrhythmias. Pharmacokinetics Very rapidly and completely absorbed following PO administration, Protein binding 10%, Metabolized in liver. Excreted in urine. Half-life 15 hr. 

The local anesthetics are converted in the liver (amide type) or in plasma (ester type) to more water-soluble metabolites, which are excreted in the urine. Since local anesthetics in the uncharged form diffuse readily through lipid membranes, little or no urinary excretion of the neutral form occurs. Acidification of urine promotes ionization of the tertiary amine base to the more water-soluble charged form, leading to more rapid elimination. 

In addition to levobupivacaine, ropivacaine is a new long-lasting amide-type LA that has been produced in order to address the enantioselectivity of the cardiotoxicity of bupivacaine. Ropivacaine, which is an (S)-enantiomer containing an n-propyl instead of the butyl moiety of bupivacaine, was launched in 2000. Clinical data indicate a late onset and long duration of action and the anesthetic potency of ropivacaine is comparable to that of bupivacaine (for review see McClellan and Faulds, 2000 Whiteside and Wildsmith, 2001). In animal models, the... 

Cardiovascular effects due to enhanced sympathetic activity include tachycardia, increased cardiac output, vasoconstriction, and increased arterial pressure. Myocardial infarction is the most common adverse cardiac effect (43), and there is an increased risk of myocardial depression when amide-type local anesthetics, such as bupivacaine, levobupivacaine, lidocaine, or ropivacaine are administered with antidysrhythmic drugs. 

The liver, for the amide-type anesthetics, or plasma esterases, for the ester-type, can eliminate large amoimts of local anesthetics. Within 30 to 60 minutes sufficient elimination of the overdose usually occurs to make the CNS stimulation or depression short-lived. Management objectives should therefore center on temporary respiratory and cardiovascular support. Administration of supplemental oxygen usually rapidly restores normal CNS function. In patients in whom cardiovascular collapse is evident, vasopressor therapy may take the form of metaraminol bitartrate 1% (Aramine) given intramuscularly or intravenously. The effect of this potent short-acting vasopressor lasts 20 to 60 minutes, depending on route of administration. 

The authors concluded that sensitization to lidocaine must have taken place during previous procedures and that cross-reactivity with another amide type local anesthetic, prilocaine, had also occurred. 

Synonyms Dilocaine Lidoderm Lidoject-1 Lignocaine Nervocaine Nulicaine Octocaine Solarcaine Xylocaine Xylocard Chemical/Pharmaceutical/Other Class Amide-type local anesthetic Class IB antiarrhythmic Chemical Structure ... 

Hypersensitivity to amide-type local anesthetics, Adams-Stoke syndrome, supraventricular arrhythmias, Wolf-Parkinson-White syndrome. Spinal anesthesia contraindicated in septicemia. Caution Dosage should be reduced for elderly, debilitated, acutely ill safety in children has not been established. Severe renal/hepatic disease, hypovolemia, CHF, shock, heart block, marked hypoxia, severe respiratory depression, bradycardia, incomplete heart block. Anesthetic solutions containing epinephrine should be used with caution in peripheral or hypertensive vascular disease and during or following potent general anesthesia. Sulfite sensitivity or asthma for some local and topical anesthetic preparations. Tartrazine or aspirin sensitivity with some topical preparations. Anxiety, insomnia, apprehension, blurred vision, loss of hearing acuity, and nausea CNS depression, convulsion and respiratory depression... 

Clinically important, potentially hazardous interactions with amide-type anesthetics, antimalarials, cotrimoxazole, nitric compounds, sulfonamides... 

Amide-type local anesthetics, being hydrolyzed more slowly in the liver by microsomal enzymes, are not dependent upon cholinesterase and have therefore become the preferred... 

In contrast, allergic reactions to local anesthetics, although rare, are known to occur exclusively with p-aminobenzoic ester-type local anesthetics (18). Whether the formation of PABA on ester hydrolysis is solely responsible for this hypersensitivity remains to be investigated. However, the preservative compounds, such as methyparaben, used in the preparation of amide-type local anesthetics are metabolized to PABA-like substance, p-hydroxybenzoic acid. Thus, patients who are allergic to amino ester-type local anesthetics should be treated with a preservative-free amino amide-type local anesthetic. 

Amide-type local anesthetics (e.g., procainamide and lidocaine) also possess antiarrhythmic activity when given parenterally and at a subanesthetic dosage. Although this action can be attributed to their actions on sodium channels in cardiac tissues, current evidence suggests a distinctly different mechanism of action with respect to the modulation of channel receptors and the location of binding sites for these compounds (19,20). 

In the lidocaine series, lengthening of the alkylene chain from one to two or three increases the pKa of the terminal tertiary amino group from 7.7 to 9.0 or 9.5, respectively. Thus, lengthening of the intermediate chain effectively reduces local anesthetic potency as a result of a reduction of onium ions under physiological conditions. As mentioned earlier, the onium ions are required for effective binding of the amino amide-type local anesthetics to the channel receptors. 

The amino amide-type local anesthetics, however, are metabolized primarily in the liver, involving CYP1A2 isozymes (49). A general metabolic scheme for lidocaine is shown in Figure 16.10. 

Articaine [4-methyl-3-(2-propylaminopropionamido) thiophene-2-carboxylic acid methyl ester hydrochloride] has been widely used in dentistry since its approval by the U.S. FDA in the year 2000 because of its quick onset and short duration of action. The structure of articaine differs from those of all other amino amide-type local anesthetics in that it contains a thiophene ring instead of a benzene ring and a carbomethoxy group. This renders the molecule more lipophilic and, thus, easier to cross any lipoidal membranes. 

Articaine, a dental anesthetic, is said to lack the CNS and cardiovascular toxicity associated with lidocaine and other amide-type local anesthetics. Explain. 

Lidocaine [2-(diethylamino)-N-(2, 6-dimethylphenyl) acetamide monohydrochloride] is the most commonly used amino amide-type local anesthetic. Lidocaine is very lipid soluble and, thus, has a more rapid onset and a longer duration of action than most amino ester-type local anesthetics, such as procaine and tetracaine. It can be administered parenterally (with or without epinephrine) or topically either by itself or in combination with prilocaine or etidocaine as a eutectic mixture that is very popular with pediatric patients. The use of lidocaine-epinephrine mixtures should be avoided, however, in areas with limited vascular supply to prevent tissue necrosis. Lidocaine also frequently is used as a class IB antiarrhythmic agent for the treatment of ventricular arrhythmias, both because it binds and inhibits sodium channels in the cardiac muscle and because of its longer duration of action than amino ester-type local anesthetics. 

Mepivacaine hydrochloride [N-(2, 6-dimethylphenyl)-1-methyl 2-piperidinecarboxamide monohydrochloride] is an amino amide-type local anesthetic agent widely used to provide regional analgesia and anesthesia by local infiltration, peripheral nerve block, and epidural and caudal blocks. The pharmacological and toxicological profile of mepivacaine is quite similar to that of lidocaine, except that mepivacaine has a slightly longer duration of action and lacks the vasodilator activity of lidocaine. For this reason, it serves as an alternate choice for lidocaine when addition of epinephrine is not recommended in patients with hypertensive vascular disease. 

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