Local anesthetic

The alkaloid cocaine was discovered in coca leaves in 1860 (1). It had long been known that the South American Indians were in the habit of chewing these leaves as a stimulant to enable them to stand great exertion without fatigue. The first use of cocaine in this country was for a similar purpose, but its great importance among alkaloids at the present time is due chiefly to Roller s important discovery that cocaine is a powerful and rapid local anesthetic. 

By hydrolysis with alkalies, cocaine yields ecgonine, benzoic acid, and methyl alcohol. Ecgonine was shown by Willstatter to be a carboxylic acid of tropine— 

It is found that the free carboxylic acid, benzoyl-eegonine itself, has no local anesthetic action, but that any of its alkyl esters, such as ethyl, propyl, etc., resemble its methyl ester, cocaine, in having this action (2). This applies only to the aliphatic esters, as the aromatic do not appear 

Benzoyl-eegonine (type of first series of esters) 

Ecgonine methyl ester (type of second series of esters) 

Other subtypes of Na+ channels such as the tetrodotoxin (TTX)-resistant Na+ channels are also expressed by airway afferent nerves. Capsaicin-sensitive neurones are sensitized by inflammatory mediators, such as PGE2, an effect partly mediated by an increase in TTX-resistant Na+ currents (Kwong and Lee 2005). These neurones are inactivated in the normal airways, but are recruited in inflamed airways to contribute to cough sensitization (Mazzone et al. 2005). Therefore, selective inhibitors of TTX-resistant Na+ channels may be useful as cough suppressants in chronic cough. 

Adverse reactions to dextran 1 were investigated in trials involving over 70,000 patients. The following reactions and incidences were recorded cutaneous reactions 0.016 % moderate hypotension 0.014 % severe hypotension 0.001 % bradycardia and moderate hypotension 0.013 % bradycardia and severe hypotension 0.001 % bradycardia alone 0.004 % and mild symptoms (nausea, pallor, shivering) 0.011 %. 

For skin test diagnostic investigation, dextran (6-10 mg/ml) is used undiluted in prick tests and at a maximum concentration of a 1 in 100 dilution of the prick test concentration for intrader-mal testing. 

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Yohimbine (104), also from the bark of C.johimbe K Schum. and from the roots of R. serpentina (1. ) Benth. has a folk history (unsubstantiated) of use as an aphrodisiac. Its use has been confirmed experimentally as a local anesthetic, with occasional employment for rehef ia angiaa pectoris and arteriosclerosis, but is frequently contraindicated by its undesired renal effects. Yohimbine and some of its derivatives have been reported as hahuciaogenic (70). In addition, its pattern of pharmacological activities ia a variety of animal models is so broad that its general use is avoided. All ten carbon atoms of secologanin (102) as well as the entire skeleton of tryptamine (98, R = H) are clearly seen as iatact portions of this alkaloid. 

Each of the endoscopic imaging procedures is relatively risk free and painless when performed by competent and weU-trained individuals using a local anesthetic. Eetoscopy has the highest risk. There is a 10% increased probabiUty of premature deUvery and 10% higher fetal loss rate. 

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). 

The onset of action is fast (within 60 seconds) for the intravenous anesthetic agents and somewhat slower for inhalation and local anesthetics. The induction time for inhalation agents is a function of the equiUbrium estabUshed between the alveolar concentration relative to the inspired concentration of the gas. Onset of anesthesia can be enhanced by increasing the inspired concentration to approximately twice the desired alveolar concentration, then reducing the concentration once induction is achieved (3). The onset of local anesthetic action is influenced by the site, route, dosage (volume and concentration), and pH at the injection site. 

Local anesthetics produce anesthesia by blocking nerve impulse conduction in sensory, as well as motor nerve, fibers. Nerve impulses are initiated by membrane depolarization, effected by the opening of a sodium ion channel and an influx of sodium ions. Local anesthetics act by inhibiting the channel s opening they bind to a receptor located in the channel s interior. The degree of blockage on an isolated nerve depends not only on the amount of dmg, but also on the rate of nerve stimulation (153—156). 

Table 4. In Vitro Conduction Blocking and Physiochemical Properties of Local Anesthetic Agents ...

The rate of removal of the local anesthetic from the site of injection also affects its profile. AH local anesthetic agents possess some vasodilatory activity at clinically useful concentrations. Agents which are more potent in this regard tend to be absorbed more rapidly by the vasculature. They are less potent anesthetics and have shorter durations than those having lower vasodilatory activity. A comparison of potency, onset, and duration as a function of physiochemical properties is presented in Table 4. 

Another clinical consideration is the abiUty of local anesthetic agents to effect differential blockade of sensory and motor fibers. In surgical procedures such as obstetrics or postoperative pain rehef, an agent which produces profound sensory block accompanied by minimal motor block is desirable. On the other hand some procedures such as limb surgery require both deep sensory and motor blockade. In clinical practice, bupivacaine ( 22,... 

Specific Local Anesthetic Agents. Clinically used local anesthetics and the methods of appHcation are summarized in Table 5. Procaine hydrochloride [51-05-8] (Novocain), introduced in 1905, is a relatively weak anesthetic having along onset and short duration of action. Its primary use is in infiltration anesthesia and differential spinal blocks. The low potency and low systemic toxicity result from rapid hydrolysis. The 4-arninobenzoic acid... 

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. 

B. G. Coviao and H. G. VasaHo, Local Anesthetics Mechanism of Action and Clinical Use, Grune and Stratton, New York, 1976. 

Medical Usage. Isopropyl alcohol is also used as an antiseptic and disinfectant for home, hospital, and industry (see Disinfectants and antiseptics). It is about twice as effective as ethyl alcohol in these appHcations (153,154). Rubbing alcohol, a popular 70 vol % isopropyl alcohol-in-water mixture, exemplifies the medicinal use of isopropyl alcohol. Other examples include 30 vol % isopropyl alcohol solutions for medicinal liniments, tinctures of green soap, scalp tonics, and tincture of mercurophen. It is contained in pharmaceuticals, eg, local anesthetics, tincture of iodine, and bathing solutions for surgical sutures and dressings. Over 200 uses of isopropyl alcohol have been tabulated (2). 

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. 

Sorbitan sesquioleate emulsions of petrolatum and wax are used as ointment vehicles in skin treatment. In topical appHcations, the inclusion of both sorbitan fatty esters and their poly(oxyethylene) derivatives modifies the rate of release and promotes the absorption of antibiotics, antiseptics, local anesthetics, vasoconstrictors, and other medications from suppositories, ointments, and lotions. Poly(oxyethylene(20)) sorbitan monooleate, also known as Polysorbate 80 (USP 23), has been used to promote absorption of ingested fats from the intestine (245). 

These agents are often combined with a vasoconstrictant such as epinephrine [51-43-4]. By using such a combination, the local anesthetic is held in the area for a longer period of time and its effect extended hemorrhage is minimized, blood loss prevented, and a better surgical repair obtained. 

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). 

Appllca.tlons. Various A/-derivatives of amino acids (qv) are resolvable on BSA columns. These /V-amino acid derivatives include ben2enesulfonyl-, phthalimido-, S-dimethylarnino-l-naphthalenesulfonyl- (DANSYL-), 2,4-dinitrophenyl- (DNP-), and 2,3,6-trinitrophenyl- (TNP-) derivatives (30). Amines such as Prilocain, ( )-2-(prop5lamino)-(9-propiono-toluidide, a local anesthetic (Astra Pharm. Co.), are also resolved on BSA. The aromatic amino acids DL-tryptophan, 5-hydroxy-DL-tryptophan, DL-kynurenine [343-65-7] C qH 2N 2 3 3-hydroxy-DT.-kynurenine [484-78-6] and dmgs... 

Carbamates derived from chloroformates are used to manufacture pharmaceuticals, including tranquili2ers (58), antihypotensives, and local anesthetics, pesticides, and insecticides (see Carbamic acid). 

The Class I antiarrhythmic agents inactivate the fast sodium channel, thereby slowing the movement of Na" across the cell membrane (1,2). This is reflected as a decrease in the rate of development of phase 0 (upstroke) depolarization of the action potential (1,2). The Class I agents have potent local anesthetic effects. These compounds have been further subdivided into Classes lA, IB, and IC based on recovery time from blockade of sodium channels (11). Class IB agents have the shortest recovery times (t1 ) Class lA compounds have moderate recovery times (t 2 usually <9 s) and Class IC have the longest recovery times (t 2 usually >9 s). 

Procainamide. Procainamide hydrochloride is a ben2amide, synthesized to prolong the therapeutic effects of the local anesthetic procaine [59-46-1] (13) (see Anesthetics). The dmg is effective in a wide range of supraventricular and ventricular arrhythmias (14). 

Lldoc ine. Lidocaine hydrochloride, an anilide, was originally introduced as a local anesthetic in 1943 and found to be a potent antiarrhythmic in 1960. The compound is a reverse amide of procainamide. Lidocaine is generally considered to be the dmg of choice in the treatment of ventricular arrhythmias and those originating from digitalis glycoside toxicity (1,2,15—17). 

Glass IG Antiarrhythmic Agents. Class IC antiarrhythmic agents have marked local anesthetic effects. They slow the rapid inward sodium current producing marked phase 0 depression and slow conduction. Action potential duration of ventricular muscle is increased, ie, prolonged repolarization, but decreased in the His-Purkinie system by these agents. The effects on the ECG are increased PR interval, marked prolongation of the... 

Propranolol. Propranolol hydrochloride, considered the prototype of the P-adrenoceptor blocking agents, has been in use since 1964. It is a nonselective, highly Hpid-soluble P-adrenoceptor blocker having no ISA. It is a mixture of (+) and (—) enantiomers, and the (—) enantiomer is the active moiety. The local anesthetic effects of propranolol are equipotent to those of Hdocaine [137-58-6] C 4H22N20, (see Anesthetics). Therapeutic effects include termination of catecholamine-induced arrhythmias, conversion of SA nodal tachycardias (including flutter and fibrillation) and AV nodal tachyarrhythmias to normal sinus rhythm, digitahs-induced arrhythmias, and ventricular arrhythmias (1,2). The dmg also has cardioprotective properties (37,39). 

Verapamil. Verapamil hydrochloride (see Table 1) is a synthetic papaverine [58-74-2] C2qH2 N04, derivative that was originally studied as a smooth muscle relaxant. It was later found to have properties of a new class of dmgs that inhibited transmembrane calcium movements. It is a (+),(—) racemic mixture. The (+)-isomer has local anesthetic properties and may exert effects on the fast sodium channel and slow phase 0 depolarization of the action potential. The (—)-isomer affects the slow calcium channel. Verapamil is an effective antiarrhythmic agent for supraventricular AV nodal reentrant arrhythmias (V1-2) and for controlling the ventricular response to atrial fibrillation (1,2,71—73). 

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