Local anesthetics preparations

Most local anesthetic preparations contain benzo-caine. Because benzocaine is poorly absorbed through the skin, it remains localized for a long time however, its effectiveness is unpredictable. Benzocaine has also been known to produce local hypersensitivity reactions.f ... 

Lidocaine hydrochloride is a topical/local anesthetic preparation. It stabilizes neuronal membranes by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby affecting local anesthetic action. It is indicated as a topical anesthetic for use on normal intact skin for local analgesia or genital mucous membranes for superficial minor surgery and as pretreatment for inhltration anesthesia... 

Describe the interactions of MAOIs with local anesthetic preparations or over-the-counter (OTC) cold medications. 

Local anesthetic preparations often contain a sympathomimetic drug. Cold medications contain pseudoephedrine or ephedrine-type drugs. All of these would synergize with the increased levels of catecholamines produced by a MAOI. 

Some of the vasoconstrictor may be absorbed systemically, occasionally to an extent sufficient to cause untoward reactions (see below). There also may be delayed wound healing, tissue edema, or necrosis after local anesthesia. These effects seem to occur partly because sympathomimetic amines can cause hypoxia and local tissue damage. The use of vasoconstrictors in local-anesthetic preparations for anatomical regions with Umited collateral circulation could produce irreversible hypoxic damage, tissue necrosis, and gangrene, and therefore is contraindicated. 

Since the discovery of cocaine in 1880 as a surgical local anesthetic, several thousand new compounds have been tested and found to produce anesthesia by blocking nerve conductance. Among these agents, oniy approximateiy 20 are ciinicaiiy available in the United States as local anesthetic preparations (Tabie 16.1). Tabie 16.2 contains chemical structures of the different types of agents in current or recent use. 

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. 

To use the port, the overlying skin is prepared using conventional techniques. A local anesthetic is sometimes used to decrease pain of needle insertion, though this is usually not necessary using techniques which utilize small-bore needles. A special point needle is used to puncture the implanted ports as the point of these needles is deflected so it tears the septum rather than coring it, allowing multiple entries. The septum reseals when the needle is removed. 

The NF and reagent grades are employed in the pharmaceutical industry which makes use of benzyl alcohol s local anesthetic, antiseptic, and solvent properties (17—20). It also finds use in cough symps and drops ophthalmic solutions bum, dental (21), and insect repeUant solutions and ointments and dermatological aerosol sprays. It is used in nail lacquers and as a color developer in hair dyes by the cosmetics industry (22), and in acne treatment preparations (23). 

Chlophedianol [791-35-5] (49) is the most potent antitussive ia a series of compounds originally synthesi2ed as potential antispasmodics. It is about one-third as active as codeiae and has weak antispasmodic and local anesthetic activity. Although the onset of antitussive activity is slow, the duration is prolonged. Chlophedianol can be prepared from 2-chlorophenylphenyLmethanone (67). 

Some active 5-pyrazolone derivatives (707) and (708) in which the 1-phenyl substituent of antipyrine was replaced by 2 -, 3 - and 4 -pyridyl groups have been prepared (66HCA272). A series of aminoesters substituted at the nitrogen atom of the ester grouping with an antipyryl residue (709) were found to possess local anesthetic properties (69MI40400). 

The observation that very significant parts of the cocaine molecule could be deleted from synthetic analogs without loss of biologic activity led to the search for the minimal structural feature consistent with activity. This exercise, sometimes referred to as molecular dissection, not only led to great simpli-fi cation of the structure of local anesthetics but resulted fi-tially in the preparation of active molecules that bear only the remotest structural relation to the prototype, cocaine. 

A chance observation made some time prior to the full structural elucidation of cocaine in fact led to one of the more important lasses of local anesthetics. It was found that the simple ethyl e. ter of p-aminobenzoic acid, benzocaine (25), showed activity. 1-. a local anesthetic. It is of interest to note that this drug, I 1rst introduced in 1903, is still in use today. Once the struc-iiire of cocaine was established, the presence of an alkanolamine iiiniety in cocaine prompted medicinal chemists to prepare esters "I aminobenzoic acids with acyclic alkanolamines. Formula 26 11 presents the putative relationship of the target substances with cocaine. 

The low structural specificity in the local anesthetic sell cs is perhaps best illustrated by phenacalne (91), a local an-I -.lhetic that lacks not only the traditional ester or amide func-I ion but the basic aliphatic nitrogen as well. First prepared at I lie turn of the century, a more recent synthesis starts by con-ili iusation of p-ethoxyaniline with ethyl orthoacetate to afford I he imino ether (90), Reaction of that intermediate with a sec-I liil mole of the aniline results in a net displacement of ethanol, iiobably by an addition-elimination scheme. There is thus ob-I.lined the amidine, 91, phenacalne. 

Esters of tropine have a venerable place in medicinal chemistry. One such compound, cocaine, the object of some current interest, was the natural product lead which led eventually to most of today s local anesthetics. A distantly related analogue is prepared by reaction of tropine (132) with 3,5-dimethylbenzoyl chloride. This leads to an ester structurally related to another ]ii ominent natural product, atropine (133). The product, tropanaerin (134), is described as an iinti.serotonergic agent intended for antimigraine use [34]. 

The antiarrhythmic activity of local anesthetics has been noted several times previously. Another such agent is prepared by first alkylating isopropylamine with sulfone 199. Reaction of the ])ioduct (200) with diethylethylenediamine and carbonyldiimidazole results in transfer of the CDI carbonyl group and formation of the urea suricainide (201) [52]. The transform in all likelihood involves stepwise replacement of the imidazole groups by the basic groups in the other reactants. 

It will be recalled that certain local anesthetic amides, such as procainamide and lidocaine, are active antiarrythmic agents. Annelation of a second aromatic ring is consistent with bioactivity. Bunaftine (21) is such an agent, prepared simply from reaction of the acid chloride of 1-naphthoic acid and... 

The triazinoisoquinoline 151 was prepared by cyclocondensation of the diaminoisoquinoline derivative 150 with biacetyl. Treatment of 151 with ethanesulfonic acid in acetonitrile gave the triazinoisoquinolinium salt 152, which is useful as a local anesthetic, antidepressant, tranquilizer, sedative, and muscle relaxant (89GEP3833615). 

Prilocaine (4.138), a chiral local anesthetic, was hydrolyzed stereoselec-tively at its amide bond. Indeed, the plasma concentrations of the (-)-(/ )-enantiomer were lower than those of the (+)-(5 )-enantiomer after i.v. administration in the cat. In vitro studies of liver preparations from various mammals confirmed that the (R)-isomer was hydrolyzed at much higher rates than the (.S )-form [84],... 

The bicyclic tropane ring of cocaine of course presented serious synthetic difficulties. In one attempt to find an appropriate substitute for this structural unit, a piperidine was prepared that contained methyl groups at the point of attachment of the deleted ring. Condensation of acetone with ammonia affords the piperidone, 17. Isophorone (15) may well be an intermediate in this process conjugate addition of ammonia would then give the aminoketone, 16. Further aldol reaction followed by ammonolysis would afford the observed product. Hydrogenation of the piperidone (18) followed then by reaction with benzoyl chloride gives the ester, 19. Ethanolysis of the nitrile (20) affords alpha-eucaine (21), an effective, albeit somewhat toxic, local anesthetic. 

Topically administered local anesthetics are useful in dermatology for preparation of the skin prior to minor surgical procedures, such as skin biopsies, laser treatment of vascular malformations, and curettage of mol-luscum contagiosum lesions, particularly in young children and needle-phobic adults. The topical anesthetic may be used alone or may be applied prior to intrader-mal injection of a local anesthetic to reduce the pain caused by the needle. Two recently approved drugs in... 

Satake et al. reported the use of a coated wire electrode sensitive to procaine and other local anesthetic cations, and their application to potentiometric determination [73]. Electrodes were constructed from a copper wire (0.8 mm diameter), coated with a PVC membrane comprising a mixture of the drug-tetraphenylborate ion-pair, dioctyl phthalate, polyvinyl chloride, and tetrahydrofuran. Potential measurement was made with respect to a Ag-AgCl reference electrode. The electrodes showed linear responses with a Nemstian slope for procaine over the concentration range investigated. The method was used for analyses of the drug in pharmaceutical preparations. 

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