Vasodilators local anesthetics

Many 1,2,3,5-benzenetetrol derivatives are used mediciaaHy. For example, khellin [82-02-0] (65), which is a naturally occurring benzopyranone, is used as a coronary vasodilator and bronchodilator (233). Derivatives of khellin are effective local anesthetics and antiarrythmics (234). Similarly, amine derivatives (68) that are prepared from khellinone oxime (66) exhibit hypnotic, sedative, anticonvulsant, antiinflammatory, cardiac analeptic, diuretic, and antiulcerous activity (235) (see Analgesics, antipyretics, and antiinflammatory agents). 

Lidocaine hydrochloride [73-78-9] (Xylocaine), is the most versatile local anesthetic agent because of its moderate potency and duration of action, rapid onset, topical activity, and low toxicity. Its main indications are for infiltration, peripheral nerve blocks, extradural anesthesia, and in spinal anesthesia where a duration of 30 to 60 min is desirable. Because of its vasodilator activity, addition of the vasoconstrictor, epinephrine, increases the duration of action of Hdocaine markedly. It is also available in ointment or aerosol preparations for a variety of topical appHcations. 

Prilocaine hydrochloride [1786-81-8] is also similar in profile to Hdocaine, although prilocaine has significantly less vasodilator activity. Prilocaine is the least toxic of the amino amide local anesthetics. However, its tendency to cause methemoglobinemia, especially in newborns, has eliminated its use in obstetric surgery. 

Shifting the side chain to the 4 position (with the necessary tautomeric change) affords an agent with local anesthetic and coronary vasodilator activity. Cycllzation of compound 147 by means of phosphorus oxychloride gives the amino-l,2,4-oxodiazole (148). Alkylation of that compound with 2-chlorotriethylamine in the presence of sodium hydroxide proceeds via the tautomer,... 

The answer is d. (Hardman, p T36J The addition of a vasoconstrictor, such as epinephrine or phenylephrine, to certain short-acting, local anesthetics is a common practice in order to prevent the rapid systemic absorption of the local anesthetics, to prolong the local action, and to decrease the potential systemic reactions. Some local anesthetics cause vasodilation, which allows more compound to escape the tissue and enter the blood. Procaine is an ester-type local anesthetic with a short duration of action due to rather rapid biotransformation in the plasma by cholinesterases. The duration of action of the drug during infiltration anesthesia is greatly increased by the addition of epinephrine, which reduces the vasodilation caused by procaine. 

Since autonomic postganglionic fibers lack a myelin sheath, they are particularly susceptible to blockade by local anesthetics. As a result, vasodilation ensues in the anesthetized region, because sympathetically driven vasomotor tone decreases. This local vasodilation is undesirable (see below). 

Hydralazine is a vasodilating drug and inhibition of DNA methyltransferases in the range of 10-20 pM have been reported in vitro [83]. In addition, hypomethylation in cell culture has also been shovm [84]. Also the local anesthetic procaine [85] and its amide analog procainamide [84] have been identified as DNA methyltransferase inhibitors. Synthetic analogs of procaine have shown activity only around 500 pM [86] (Figure 8.10). 

Labetalol produces equilibrium-competitive antagonism at p-receptors but does not exhibit selectivity for Pi- or P2-receptors. Like certain other p-blockers (e.g., pindolol and timolol), labetalol possesses some degree of intrinsic activity. This intrinsic activity, or partial ago-nism, especially at P2-receptors in the vasculature, has been suggested to contribute to the vasodilator effect of the drug. The membrane-stabilizing effect, or local anesthetic action, of propranolol and several other p-blockers, is also possessed by labetalol, and in fact the drug is a reasonably potent local anesthetic. 

Cocaine and other local anesthetics abolish not only the sensation of pain, but other special sensations, if they are suitably applied. Here also there is some selection. In the skin, they paralyze first the vasoconstrictor reaction, then progressively the sensations of cold, warmth, touch, tickling, pressure, pain, and joint sense. In the nose, they abolish the olfactory sense. On the tongue, they destroy the taste for bitter substances but have less effect on sweet and sour taste and none on salty taste. When cocaine is applied to the appropriate nerves, it is found that the centrifugal vagus fibers are paralyzed before the centripetal, vasoconstrictor fibers before vasodilator, bronchial constrictors before the dilators, etc. (Sollmann, 1944). 

Masters and Domb [250] reported on an injectable drug delivery system that uses liposomes [251] to release the local anesthetic, bupivacaine, from a liposomal matrix that is both biodegradable and biocompatible to produce SLAB. Bupivacaine due to its minimum vasodilating properties was preferred to other local anesthetics (e.g., lidocaine) allowing the released drug to remain at the site of injection longer [252]. Lipospheres are an aqueous microdispersion of water insoluble, spherical microparticles (0.2 to 100 pm in diameter), each consisting... 

Most local anesthetics are vasodilators therefore they increase blood flow to the area of administration and increase their own absorption. To decrease absorption, epinephrine (1 200,000 to 1 50,000) or other vasoconstrictors are often added to local anesthetic solutions. Block action by blocking Na+ channels... 

LS have been used for the controlled delivery of various types of drugs, including vasodilator and antiplatelet drugs, antiinflammatory compounds, local anesthetics, antibiotics, and anticancer agents they have also been used successfully as carriers of vaccines and adjuvants [18]. 

A) All local anesthetics with ester bonds are vasodilators... 

Vasoconstriction (a1). Vasodilation (p2). Injected with local anesthetics a 1-mediated vasoconstriction delays distribution of anesthetic away from the site of injection. 

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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