Antihistamines doxylamine

Alkylation of these as their sodium salts with the ubiquitous N-C2-chloroethyl)dimethylamine affords the desired antihistamines. There are thus obtained, respectively, mephenhydramine (23a) chlorphenoxamine (23b), and mebrophenhydramine (23c)Alkylation of the tertiary alcohol, 22b, with the pyrrolidine derivative, 24, affords meclastine (25). In much the same vein, reaction of 2-acetylpyridine with phenyImagnesium bromide gives the tertiary alcohol, 27. Alkylation in the usual way leads to the potent antihistamine, doxylamine (28). " ... 

In this chapter, the voltammetric study of local anesthetics (procaine and related compounds) [14—16], antihistamines (doxylamine and related compounds) [17,22], and uncouplers (2,4-dinitrophenol and related compounds) [18] at nitrobenzene (NB]Uwater (W) and 1,2-dichloroethane (DCE)-water (W) interfaces is discussed. Potential step voltammetry (chronoamperometry) or normal pulse voltammetry (NPV) and potential sweep voltammetry or cyclic voltammetry (CV) have been employed. Theoretical equations of the half-wave potential vs. pH diagram are derived and applied to interpret the midpoint potential or half-wave potential vs. pH plots to evaluate physicochemical properties, including the partition coefficients and dissociation constants of the drugs. Voltammetric study of the kinetics of protonation of base (procaine) in aqueous solution is also discussed. Finally, application to structure-activity relationship and mode of action study will be discussed briefly. 

Nonpharmacologic therapy such as dietary, physical, and behavioral approaches should be considered first. Pyridoxine (vitamin B6) 10 to 25 mg three to four times daily alone or in combination with an antihistamine such as doxylamine is often used for NVP.9,11,12 This combination was previously marketed as Bendectin or Debendox but was withdrawn due to concerns over possible teratogenic effects, although the literature did not support this claim.11,12 Pyridoxine is well tolerated, but doxylamine and other antihistamines commonly cause drowsiness. For more severe NVP, promethazine, meto-clopramide, and trimethobenzamide may be effective and have not been associated with teratogenic effects.9... 

Antihistamines are popular as nonprescription (over-the-counter) sleep remedies (e.g., diphenhydramine, doxylamine, p. 114), in which case their sedative side effect is used as the principal effect. 

Doxylamine succinate etc. Details are given in chapter Antihistaminic agents . 

Sleep aids Diphenhydramine, 25-50 mg at bedtime Nytol, Simply Sleep, Sominex, various generic Diphenhydramine and doxylamine are antihistamines with well-documented CNS depressant effects. Because insomnia may be indicative of a serious underlying condition requiring medical attention, patients should consult a physician if insomnia persists continuously for longer than 2 weeks. 

The most popular OTC sleep aids are those that contain antihistamines such as diphenhydramine or doxylamine (Table 3.1). As noted in Chapter 1, nerve cells in the brain communicate with each other by secreting chemicals called neurotransmitters. One such neurotransmitter that regulates sleep is histamine. When histamine is released by a nerve cell, it diffuses over to the target nerve cell and binds to specialized proteins called receptors located on the outer surface of the nerve cell. These receptors are specially designed to bind only histamine, and when they do, the target nerve cell will become either activated or deactivated. In the brain, histamine serves the function of keeping us awake, and when drugs such as antihistamines are taken, they block the ability of histamine receptors to bind histamine. 

Very simple liquid-liquid partitioning systems have been employed to isolate many drugs from biological media. Alkaloids, antihistamines, barbiturates, and tranquilizers from blood, can be extracted from urine, stomach juices, and tissue, using acetone diethyl ether, 1 1, and aqueous phases of varying pH (3-6). Typical drugs include caffeine, cocaine, atropine, codeine, heroin, morphine, quinine, doxylamine, chlorpheniramine, diphenyl-pyraline, amobarbital, pentobarbitol, secobarbitol, and pheno-barbitol (2-5). 

Pharmaceuticals. A wide variety of pyridine compounds, with varying, and often multiple, drug action are used commercially. A few examples are given. A number of antihistamines contain the pyridine moiety in their structure, as exemplified by chlorpheniramine maleate (2-[p-chloro-a-(2-dunethylaminoethyl)benzyl] pyridine acid maleate) doxylamine succinate (2-[cM2-dimethylamino)ethoxy- -methylbenzyl]-pyridine add succinate) and pyrilamine maleate (2-(2-dimethyl-aminoethyl-2-p-methoxybenzyl) aminopyndine acid maleate). These products are synthesized, e.g., from... 

Nonprescription antihistamines with sedating properties, such as diphenhydramine and doxylamine (see p. 422), are effective in treating mild types of insomnia. However, these drugs are usually ineffective for all but the milder form of situational insomnia. Further, they have numerous undesirable side effects that make them less useful than the benzodiazepines. These sedative antihistamines are marketed in numerous over-the-counter products. 

Teratogenic activity has been attributed to doxylamine, a constituent of many combinations with vitamin B6 and antispasmodic agents, and used in the treatment of hyperemesis gravidarum. However, extensive studies and reviews have suggested that the incidence of malformations is not higher in children whose mothers have taken formulations containing antihistamines as a group, and in particular the combination of doxylamine/pyridoxine with or without dicycloverine (100-102). 

Doxylamine is an antihistamine, a monoethanolamine derivative, with antimuscarinic and pronounced sedative effects. 

Some analgesic preparations also contain sedating antihistamines, such as diphenhydramine and doxylamine, for their claimed sedative and muscle-relaxant effects. 

Capella-Peiro et al. (28) used a 3 full factorial design to optimize the capillary zone electrophoresis (CZE) separation of a group of seven antihistamines (brompheniramine, chlorpheniramine, cyproheptadine, diphenhydramine, doxylamine, hydroxyzine, and loratadine). In this case, critical parameters such as pH (a concentration of 20 mM phosphate was kept constant in all the experiments) and the applied voltage were studied to evaluate their effect on the resolution and efficiency. Maximum response was achieved at pH 2.0 and an applied voltage of 5 kV. After a repeatability study to check the precision of the electrophoretic method, as well as a suitable calibration, the usefulness of this optimized method was demonstrated through the determination of the listed histamines in pharmaceuticals, urine, and serum samples (recoveries were in agreement with the stated contents). Urine samples were diluted and directly injected in the CE system, while serum samples were previously extracted by means of a solid-phase extraction (SPE) procedure. 

The enantiomeric separation of some racemic antihistamines and antimalar-ials, namely (+/-)-pheniramine, (+/-)-bromopheniramine, (+/-)-chlorophen-iramine, (+/-)-doxylamine, and (+/-)-chloroquine, were investigated by capillary zone electrophoresis (CZE). The enantiomeric separation of these five compounds was obtained by addition of 7 mM or 1 % (w/v) of sulfated P-cyclo-dextrin to the buffer as a chiral selector. It was found that the type of substituent and degree of substitution on the rim of the cyclodextrin structure played a very important part in enhancing chiral recognition (174). The use of sulfated P-cyclo-dextrin mixtures as chiral additives was evaluated for the chiral resolution of neutral, cyclic, and bicyclic monoterpenes. While there was no resolution of the monoterpene enantiomers with the sulfated P-cyclodextrin, the addition of a-cyclodextrin resulted in mobility differences for the terpenoid enantiomers. Resolution factors of 4-25 were observed. The role of both a-cyclodextrin and sulfated P-cyclodextrin in these separations was discussed (187). The enantiomeric separation of 56 compounds of pharmaceutical interest, including anesthetics, antiarrhythmics, antidepressants, anticonvulsants, antihistamines, antimalarials, relaxants, and broncodilators, was studied. The separations were obtained at pH 3.8 with the anode at the detector end of the capillary. Most of the 40 successfully resolved enantiomers contained a basic functionality and a stereogenic carbon (173). 

Some of the antihistamine (Hi)-receptor antagonists that can cross the blood-brain barrier are used for their hypnotic activity. The primary antihistamines used for their sedative effect are diphenhydramine and doxylamine, which belong to the ethanolamine class of antihistamines (see Chapter 37). Both drugs are sold without prescription. Sleep laboratory-controlled studies indicate that the antihistamines (Hi-receptor... 

Diphenhydramine is consumed as well as doxylamine to a small extent. Both substances are also found as intensifiers in plant-derived hypnotic drugs used in self-medication. Sedative antihistamines are regularly consumed by alcoholics and medicament-dependent people over long periods. The dependence of most patients does not tend to attract clinical attention. 

Immunological methods for the determination of antihistamines are likewise not commercially available. However, both the substances and their metabolites can readily be determined chromatographically using HPLC/DAD or GC/MS using the sample preparation techniques described in Chapter 7. The mass spectra of doxylamine and diphenhydramine are less specific, so that the retention indices must be taken into consideration. However, as shown in Fig. 8-40, it is also possible to determine other metabolites of doxylamine with more specific mass spectra. 

The pharmacokinetics of a single 25-mg dose of doxylamine in 13 subjeets and the pharmacokinetics of a single 50-mg dose of diphenhydramine in 10 subjeets were not significantly altered by the use of low-dose eombined oral eontraceptives. Cases of oral contraceptive failure have been attributed to the use of doxylamine, chlorpheniramine, and an unnamed antihistamine, but these antihistamines were all used in con-junetion with penieillins, which would seem to be a more likely cause of contraceptive failure (see Hormonal contraceptives + Antibacterials Penicillins , p.981). The effect of the antihistamines on the pharmacokinetics and pharmacodynamics of contraceptive steroids appear not to have been studi. No particular precautions would seem necessary during concurrent use. 

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