Doxepin Alcohol

Cyclization of 2-benzyloxybenzoic acid (66) by means of poly-phosphoric acid affords the dibenzoxepinone, 67. Condensation with the Grignard reagent from 3-dimethylaminopropyl chloride, followed by dehydration of the alcohol thus produced affords doxepin (68), presumably as a mixture of geometrical isomers. 

Doxepin Doxepin, (ll[16H]-(3-dimethylaminopropyMen)-6,ll-dihydrobenz[b,e] oxepine) (7.1.11), is synthesized in an analogous manner by reacting 6,1 l-dihydrodibenz-[b,e]oxepin-11 -one (7.1.9) with 3-dimethylaminopropylmagnesium bromide and the subsequent dehydration of the resulting tertiary alcohol (7.1.10) by hydrochloric acid [14-17]. 

The mechanism of action of doxepin is presumable linked to the effect on the adrenergic transmission in the CNS, in particular to the blockage of neuronal norepinephrine uptake. Doxepin is used in anxious-depressive and anxious conditions, neuroses, alcoholism, organic illnesses of the CNS, and psychoses. The most frequently used synonyms are adapin and sinequan. 

The dibenzapine derivatives are called tricyclic antidepressants and include imipramine (Tofranil), desipramine (Norpramin), amitriptyline (Elavil), nortriptyline (Aventyl), protriptyline (Vivactil), and doxepin (Adapin). Amitriptyline is indicated in depression major depression with melancholia or psychotic symptoms depressive phase of bipolar disorder depression associated with organic disease, alcoholism, schizophrenia, or mental retardation anorexia or bulimia associated with depression (see Figure 20). 

Sample preparation 1 mL Plasma + doxepin + NaOH + hexane isoamyl alcohol 98 2, extract. Remove the organic phase and add it to 0.03% phosphoric acid, extract, iiyect an aliquot of the aqueous phase. 

Messiha, F.S. Determination of carbamazepine by HPLC electrochemical detection and application for estimation of imipramine, desipramine, doxepin and nordoxepin. Alcohol, 1986, 3, 135-138 Soto-Otero, R. Mendez-Alvarez, E. Sierra-Marcuno, G. Simultaneous determination of ethosuximide, phenobarbital, phenytoin, and carbamazepine in brain tissue by HPLC. J.Liq.Chromatogr., 1985,8, 753-763... 

Sample preparation 1 mL Serum -I- 200 ng doxepin or desipramine -I- 500 (aL 2% pH 9.5 sodium tetraborate -I- 9 mL freshly prepared hexane isoamyl alcohol 99 1, shake vigorously for 5 min, centrifuge. Remove 8.5 mL of the organic phase and add it to 200 p-L 50 mM HCl, shake well for 1 min, centrifuge, inject a 50 pL aliquot of the aqueous phase. 

Chronic abuse of alcohol can lead to enhanced activity of cytochrome P450 enzymes and a consequent decrease in tricyclic antidepressant (TCA) serum levels. Central receptor interactions between alcohol and TCAs can cause impaired motor abilities (evident with amitriptyline, clomipramine, doxepin, and nortriptyline). 

The potentiometric determination of die dissociation constants of amitriptyline HCl, doxepin HCl, imipramine HCl, and noxiptiline HCl in ethyl alcohol and water systems is described."... 

Stromberg C, Seppala T, Mattila MJ. Acute effects of m aprotiline, doxepin and zimeldine with alcohol in healthy volunteers. ArchIntPharmaco[Pg.79]

The ability to drive, to handle dangerous machineiy or to do other tasks requiring complex psychomotor skills may be impaired by amitriptyline, and to a lesser extent by doxepin or imipramine, particularly during the first few days of treatment This impairment can be increased by alcohol Amoxapine, clomipramine, desipramine, and nortriptyline appear to interact with alcohol only minimally. Information about other tricyclics appears to be lacking, although most manufacturers of tricyclics warn that the effects of alcohol may be enhanced. There is also evidence that alcoholics (without liver disease) may need larger doses of desipramine and imipramine to control depression. However, the toxicity of some tricyclics may be increased by alcohol, and in alcoholics with liver disease. 

A double-blind, crossover study in 20 healthy subjects given various combinations of alcohol and either doxepin or a placebo found that with blood-alcohol levels of 40 to 50 mg% their choice reaction test times were prolonged and the number of mistakes increased. Coordination was obviously impaired after 7 days of treatment with doxepin, but not after 14 days. In an earlier study doxepin appeared to cancel out the deleterious eftects of alcohol on the performance of a simulated driving test. It appears that doxepin may be more toxic when given with alcohol and it has been suggested that a less dangerous alternative could be chosen when indications of alcohol abuse or suicide risk are present. ... 

Part of the explanation for the increased C3S1S depression is that both alcohol and some of the tricyclics, particularly amitriptyline, cause drowsiness and other CNS depressant effeets, which can be additive with the effects of alcohol. The sedative effects have been reported to be greatest with amitriptyline, then doxepin and imipramine, followed by nortriptyline, and least with amoxapine, clomipramine, desipramine, and protriptyline. In addition acute alcohol intake causes marked increases (100 to 200%) in the plasma levels of amitriptyline, probably by inhibiting its first pass metabolism. Alcohol-induced liver damage could also result in impaired amitriptyline metabolism. The lower serum levels of imipramine and desipramine seen in abstinent alcoholics are attributable to induction of the cytochrome P450 isoenzymes by alcohol. ... 

Milner G, Landauer AA. The effects of doxepin, alone and together with alcohol, in relation to driving safety. MedJAust( 913) 1,837- 1. 

F.S. Messiha, Determination of carbamazepine by HPLC electrochemical detection and application for estimation of imipramine desipramine, doxepin and nordoxepin, Alcohol, 1986, 3, 135-138. 

Po and Irwin (1979) used TLC to separate numerous tricyclic neuroleptic tranquilizers. Samples were dissolved in ethyl acetate, and the mobile phase consisted of mixtures of different n-alcohols with water. Circular development in a Camag U chamber was used, and spots were detected by fluorescence quenching. The /Jp values of some of the better known drugs developed in methanol-water (90 10) were amitriptyline, 0.17 clopenthixol, 0.40 doxepin, 0.42 nortriptyline, 0.37 and promazine, 0.14. Shirke et al. (1994) determined amitriptyline and chlordiazepoxide in combined dosage forms using ethyl acetate-methanol-dieth-ylamine (9.5 0.5 0.05) mobile phase and scanning at 245 nm. 

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