Amitriptyline Alcohol

Grignard gives the tertiary alcohol after hydrolysis. Reaction of the alcohol with hydrochloric acid proceeds with rearrangement and opening of the strained cyclopropane to give a chloride. Sn2 displacement of the chloride with dimethylamine forms amitriptyline. Alternatively, dibenzosuberone can be reacted with dimethylaminopropyl Grignard to form an alcohol, which upon dehydration forms amitriptyline. 

Amitriptyline Amitriptyline, 5-(3-dimethylaminopropyliden)-10,ll-dihydrodibenzocy-cloheptene (7.1.4), differs from imipramine in that the nitrogen atom in the central part of the tricyclic system is replaced by a carbon, which is bound to a side chain by a double bond. Amitriptyline (7.1.4) is synthesized by interaction of 10,ll-dihydro-A,iV-dimethyl-57f-dibenzo[a,d]cyclohepten-5-one with 3-dimethylaminopropyhnagnesium bromide and the subsequent dehydration of the resulting tertiary alcohol (7.1.3) using hydrochloric acid [ 11]. 

Topiramate may affect alcohol, amitriptyline, CNS depressants, lithium, oral contraceptives, digoxin, estrogens, hydantoins, metformin, risperidone, and valproic acid. 

London E, Fanelh RJ, Kimes A, et al Effects of chronic nicotine on cerebral glucose utilization in the rat. Brain Res 520 208-214, 1990 Lonnqvist J, Sihvo S, Syvalahti E, et al Moclobemide and fluoxetine in atypical depression a double-blind trial. J Affect Disord 32 169-177, 1994 Loo H, Malka R, Defance R, et al Tianeptine and amitriptyline controlled double-blind trial in depressed alcoholic patients. Neuropsychobiology 19 79-85, 1988... 

Thus, the patient with a toxic TCA concentration (see the case at the start of the Metabolism section) developed excessively high amitriptyline plasma levels due to the additive effects of diminished left ventricular function leading to decreased hepatic arterial blood flow alcohol and age-related decline in liver function and, finally. 

The synthesis of amitriptyline starts from the key intermediate dibenzo-suberone (manufactured from phthalic anhydride) and can proceed by two pathways (Fig. 1). Treatment of dibenzosuberone with cyclopropyl Grignard gives the tertiary alcohol after hydrolysis. Reaction of the alco-... 

A survey in Britain covering the decade of the 1980s demonstrated large numbers of successful suicides using BZs, either alone or in combination with alcohol (Serfaty et al., 1993 see also Buckley et al., 1995). Serfaty and Masterton (1993) found 891 fatalities with BZs alone and 591 in combination with alcohol. The total of all poisonings attributed to BZs was 1,576 during the 10-year period, putting them ahead of aspirin/ salicylates at 1,308 as well as amitriptyline (1,083) and dothiepin at 981. 

SCHEME 11.31 O-GlLicLironides (ethers) can form from phenols such as morphine (3-phenol), p-hydroxyphenobarbital (Scheme 11.1), p-hydroxyphenytoin (Figure 2.8), and alcohols such as morphine (6-hydroxyl). N-Glucuronides can be formed from aliphatic amines such as amitriptyline, or aromatic amines such as the nicotine metabolite cotinine. 

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). 

Trazodone is perhaps the most sedative antidepressant available, being more sedative than amitriptyline, trimi-pramine, doxepan, or imipramine. Therefore, death has occurred in patients taking trazodone with alcohol, chloral hydrate, diazepam, chlordiazepoxide, meprobamate, or amobarbital. 

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."... 

Koski A, Vuori E, Ojanperal. Rel on of postmortem blood alcohol and drug concentraticxis in fatal poisonings involving amitriptyline, propoj hene and promazine. Hum Exp Trxcicol (2005) 24, 389-96. 

Keir JS, Powell J, Hindmarch 1. The effects of reboxetine and amitriptyline, with and without alcohol on cognitive function and psychomotor performance. Br J Clin Phamiacol ( 996) 42, 239-41. 

Allen D, Lader M, Curran HV, A comparative study of the interactions of alcohol with amitriptyline, fluoxetine and placebo in normal subjects. ProgNeuropsychopharmacolBiolPsy-chiatry 12, 63-80,... 

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 study involving 332 fatal poisonings in Finland found that alcohol was present in 67% of cases involving amitriptyline, and when alcohol was present, relatively small overdoses of amitriptyline could result in fatal poisoning. It appears that amitriptyline 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. ... 

Imipramine 150 mg daily has also been reported to enhance some of the hypno-sedative effects of alcohol, and unexplained blackouts lasting a few hours have been described in 3 women after they drank only modest amounts of alcohol they had been taking amitriptyline or imipramine for only a month. The half-life of oral imipramine was about 45% lower in recently detoxified alcoholics (without liver disease) compared with healthy subjects, and the intrinsic clearance was 200% greater. ... 

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. ... 

Landauer AA, Milner G, Patman J. Alcohol and amitriptyline effects on skills related to driving behavior. Science (1969) 163, 1467-8. 

Seppala T. Psychomotor skills during acute and two-week treatment with mianserin (ORG GB 94) and amitriptyline, and their combined effects with alcohol. Am CtinRes (1977) 9,... 

Scott DB, Fagan D, Tiplady B. Effects of amitriptyline and zimelidine in conbination with alcohol Psychopharmacology (Beri) (1982) 76,209-11. 

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