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A case of procyclidine abuse is described in which the clinical presentation was indistinguishable from mania. The patient was a long-standing poly-drug abuser and was obtaining the drugs from medical sources. Controlled exposure on the ward to drugs of abuse, including a double-blind comparison with placebo, confirmed that procyclidine caused a manic response in this patient.
1. The biotransformation of procyclidine in isolated hepatocytes, prepared from untreated and from phenobarbital-pretreated rats, is described. 2. Major metabolic pathways are ketone formation on carbon-4 and monohydroxylation in cis-4, trans-4 and (1R*, 3R*, 7S* (or R*))-trans-3 positions of the cyclohexyl ring. 3. Minor pathways consist of monohydroxylation in (1R*, 3S*, 7R*)- and (1R*, 3S*, 7S*)-cis-3 and vicinal diol formation in (1R*, 3R*, 4S*, 7R* (or S*))-cis-3, cis-4 and (1R*, 3S*, 4R*, 7S* (or R*))-trans-3, trans-4 positions of the cyclohexyl part of the molecule. 4. After phenobarbital treatment monohydroxylation in cis-4, trans-4 and trans-3 and vicinal diol formation in trans-3, trans-4 positions are significantly increased and the cis-4 to trans-3 ratio is reversed. 5. The hypothesis is made that the monohydroxylations in cis-3 and trans-3 represent an intermediate step in the formation of the dihydroxycyclohexyl metabolites, since this pathway is not observed in vivo. The hypothesis is supported by incubation experiments of synthetic monohydroxycyclohexyl derivates of procyclidine with isolated rat hepatocytes.
After intraperitoneal administration of procyclidine, eight metabolites were isolated from rat urine. They were identified as 1-(4-oxocyclohexyl)-1-phenyl-3-(1-pyrrolidinyl)-1-propanol, 1-(cis-4-hydroxycyclohexyl)-1-phenyl-3-(1-pyrrolidinyl)-1-propanol, 1-(trans-4-hydrocyclohexyl)-1-phenyl-3-(1-pyrrolidinyl)-1-propanol , (1R,3R,4S,7R)- and (1R,3R,4S,7S)-1-(cis-3,cis-4-dihydroxycyclohexyl)-1-phenyl-3-(1-py rrolidinyl)- 1-propanol, (1R,3R,4R,7R)- and (1R,3R,4R,7S)-1-(cis-3,trans-4-dihydroxycyclohexyl)-1-phenyl- 3-(1-pyrrolidinyl)-1-propanol, and one of both (1R,3S,4R,7R)- or (1R,3S,4R,7S)- 1-(trans-3,trans-4-dihydroxycyclohexyl)-1-phenyl-3-(1-pyrrolidinyl )-1-propanol by comparative TLC, GLC-MS and 13C-NMR spectroscopy.
Procyclidine, 1-cyclohexyl-1-phenyl-3-(1-pyrrolidinyl)-1-propanol, was incubated with the 9000g supernatant fraction of rat liver homogenates, fortified with a NADPH generating system. Three major metabolites were isolated from the incubation mixture. They were identified as 1-(cis-4-hydroxycyclohexyl)-1-phenyl-3-(1-pyrrolidinyl)-1-propanol, 1-(trans-4-hydroxycyclohexyl)-1-phenyl-3-(1-pyrrolidinyl)-1-propanol, and (1R*, 3R*, 7S(R?)*)-1-(trans-3-hydroxycyclohexyl)-1-phenyl-3-(1-pyrrolidinyl) -1-propanol. The latter has not been detected previously in rat urine and probably represents an intermediate metabolite.
We investigated the binding properties of the (R)- and (S)-enantiomers of the muscarinic antagonists trihexyphenidyl, procyclidine, hexahydro-difenidol, p-fluoro-hexahydro-difenidol, hexbutinol, p-fluoro-hexbutinol, and their corresponding methiodides at muscarinic M1, M2, M3 and M4 receptor subtypes. In addition, binding properties of the (R)- and (S)-enantiomers of oxyphencyclimine were studied. The (R)- enantiomers (eutomers) of all the compounds had a greater affinity than the (S)-isomers for the four muscarinic receptor subtypes. The binding patterns of the (R)- and (S)-enantiomers were generally different. We did not observe any general correlation between the potency of the high-affinity enantiomer and the affinity ratio (eudismic ratio) of the two enantiomers. The results are discussed in terms of a 'four subsites' binding model.
BACKGROUND: Neuroleptic Malignant Syndrome (NMS) is an adverse reaction to dopamine receptor antagonists, characterised by hyperpyrexia, extrapyramidal rigidity and impaired autonomic function. It might result from central dopamine receptor blockade that causes severe muscle contraction. METHOD: Case Study. RESULTS: High dose intravenous therapy with the anticholinergic drug, procyclidine hydrochloride, temporarily diminished the muscle rigidity and reversed most of the autonomic features in a patient with NMS occurring after a single intramuscular dose of the dopamine antagonist metoclopramide. Paradoxically, however, the heart rate decreased and bowel movements increased with this atropine-like drug. CONCLUSION: Since the degree of tachypnoea, tachycardia, and bowel hypotonia closely paralleled the severity of the muscle rigidity, it is suggested that these autonomic features of NMS result from sustained muscle contraction rather than a direct effect of neuroleptic drugs on the central nervous system.
A case is described in which a patient developed acute pancreatitis following an overdose of amoxapine and procyclidine. Pancreatitis is not at this time a recognized complication of the use or abuse of these two drugs. Other drugs were used in the medical management of the complications of the overdose, but none of these are drugs known to be associated with pancreatitis. Amoxapine is probably, but not certainly the cause of the pancreatitis. Possible mechanisms for this unusual and serious complication are described.
The absolute configuration of the more active (-)-enantiomer of the anticholinergic trihexyphenidyl hydrochloride has been established as (R) by syntheses of (S)-(+)-procyclidine hydrochloride, whose absolute configuration has been established previously, and (S)-(+)-trihexyphenidyl hydrochloride from the same chiral building block, viz. (S)-(-)-cyclohexyl-3-hydroxy-3-phenylpropanoic acid. Both enantiomers of this chiral synthon were prepared by optical resolution of the corresponding racemate, employing (R)- and (S)-1-phenylethylamine, respectively, as resolving agents.
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