Hepatitis piperazine

Neurotoxicity and allergic reactions are rare. Piperazine compounds should not be given to women during pregnancy, to patients with impaired renal or hepatic function, or to those with a history of epilepsy or chronic neurologic disease. 

The 3-aminomethyl-l-pyrrolidinyl radical, which was considered to be bioiso-steric to piperazine [91], also produced highly active quinolones, which were however also found not to be tolerated. In trovafloxacin 16 [92], the 3-aminomethyl-l-pyrrolidinyl radical is integrated into a bicydic amine structural unit with a free amino group [(la,5a,6a)-6-amino-3-azabicyclo[3.1.0]hexane]. A correlation probably exists between the increased central nervous system (CNS) side effects obtained with this quinolone [93] and the 2,4-difluorophenyl radical in the 1-posi-tion. Severe hepatic intolerance reactions finally resulted in major restrictions on its use, which was then limited in the USA to severe clinical infections [68]. 

A single incident resembling viral hepatitis after piperazine and recurring after further dosage has been reported (13). 

Hamlyn AN, Morris JS, Sarkany I, Sherlock S. Piperazine hepatitis. Gastroenterology 1976 70(6) 1144-7. 

Neurotoxic reactions resulting in convulsions have occasionally occurred in patients with neurological or renal abnormalities, and piperazine should not be used in people with severe renal or hepatic dysfunction or a history of epilepsy. 

A study, undertaken to confirm the involvement of the cytochrome P450 isoenzyme CYT2D6 in the metabolism of trazodone, found that when 11 depressed patients were given trazodone 150 to 300 mg at bedtime for 18 weeks, and then with thioridazine 20 mg twice daily for one week, the plasma levels of the trazodone and its active metabolite, /w-chlorophenyl-piperazine, rose by 36% and 54%, respectively. No adverse reactions were described. In contrast, a case of fatal hepatic necrosis with cholestasis has been attributed to the concurrent use of trazodone and phenothiazines. A 72-year-old woman taking trifluoperazine, trazodone and lithium carbonate developed an elevated alanine aminotransferase level. Trifluoperazine was replaced with thioridazine, but 9 weeks later she became jaundiced and developed hepatic encephalopathy, and died 6 weeks after the onset of jaundice. The authors consider that the combination of the phenothiazines and trazodone were the cause of her hepatic necrosis both phenothiazines and trazodone have been reported to individually cause hepatic adverse effects. ... 

Nefazodone is an anti-depressant drug that was withdrawn from United States in 2004 due to its possibility of hepatic injury that could lead to death. The synthesis of nefazodone involves cyclization for the formation of triazole and coupling reactions with piperazine moiety. ... 

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