Chlorpromazine toxicity

A number of other reports describe the emergence of severe extrapyram-idal adverse effects when chlorpromazine was given with lithium. " Ventricular fibrillation, thought to be caused by chlorpromazine toxicity, occurred in a patient taking lithium when both drugs were suddenly withdrawn. Severe neurotoxicity has also been seen in a handful of other patients taking lithium and chlorpromazine. ... 

Direct information about this interaction seems to be limited to this study. Its clinical importance is uncertain but it seems possible that these antimalarials could cause chlorpromazine toxicity. Monitor the effects of concurrent use closely and anticipate the need to reduce the chlorpromazine dosage. More study is need. See also Drugs that prolong the QT interval + Other drugs that prolong the QT interval , p.257. For mention that promethazine may increase chloroquine levels, see Chloroquine + Promethazine , p.223. 

The phenothiazines, chlorpromazine and promethazine, have been described as inhibitors of CCU-induced lipid peroxidation at relatively high concentrations in rat liver microsomes (Slater, 1968). Structural modifications of chlorpromazine were undertaken to try to increase antioxidant activity and maintain molecular lipophilicity. The 2-N-N-dimethyl ethanamine methanesulphonate-substituted phenothiazine (3) was found to be a potent inhibitor of iron-dependent lipid peroxidation. It was also found to block Cu -catalysed oxidation of LDL more effectively than probucol and to protect primary cultures of rat hippocampal neurons against hydrogen peroxide-induced toxicity in vitro (Yu et al., 1992). 

Chlorpromazine (CPZ) and pentoxifylline (PTX) were shown to inhibit TNF release and improve survival during murine endotoxemia (Gl). CPZ (M25) and epinephrine (PI6) pretreatment markedly up-regulated IL-10 production induced by LPS, a phenomenon also observed with cyclosporine (Dl). PTX pretreatment did not affect LPS-induced IL-10 release. Thus, TNF and IL-10 can be differentially regulated during murine endotoxemia. The sustained or even increased production of IL-10 could play a role in the protective effects of these drugs against LPS toxicity in vivo. 

Gl. Gadina, M., Bertini, R., Mengozzi, M., Zandalasini, M., and Ghezzi, P., Protective effect of chlorpromazine on endotoxin toxicity and TNF production in glucocorticoid-sensitive and glucocorticoid-resistant models of endotoxic shock. J. Exp. Med. 173, 1305-1310 (1991). 

In addition, other chemicals such as a-adrenergic blocking agents like chlorpromazine (O Flaherty and Thomas 1982 Way and Burrows 1976) or oxygen (Burrows et al. 1973 Sheehy and Way 1968) may be used to enhance the protective action of other antidotes. However, the mechanism of their action is not well understood. Further research for a potent and safe antidote, particularly among smoke inhalation victims who have carbon monoxide poisoning, to mitigate cyanide toxicity is desirable. 

Drew, R.T. and Fonts, J.R. The lack of effects of pretreatment with phenobarbital and chlorpromazine on the acute toxicity of benzene in rats, Toxicol. Appl. Pharmacol, 27 1) 183-19Z, 1974. 

Toxicity is remarkably low for a compound of such activity. In mice, the LDso value is about three times that of chlorpromazine [166] while none of the effects of the latter drug on the myocardium, liver, skin or eye have appeared in the studies of oxypertine. It is, however, still too early to appraise its chronic toxicity in man. As indicated earlier, dangerous interactions are likely to follow concurrent use of a MAO inhibitor, though simultaneous use of anti-Parkinsonism drugs, for example, to control the relatively minor extra-pyramidal symptoms seems to present no unusual problems. Hypotension may occasionally occur with high doses. 

Eye. Several drugs have an affinity for the retinal pigment melanin and thus may accumulate in the eye. Chlorpromazine and other phe-nothiazines bind to melanin and accumulate in the uveal tract, where they may cause retino-toxicity. Chloroquine concentration in the eye can be approximately 100 times that found in the liver. 

Morphine and other opioids exhibit intense sedative effects and increased respiratory depression when combined with other sedatives, such as alcohol or barbiturates. Increased sedation and toxicity are observed when morphine is administered in combination with the psychotropic drugs, such as chlorpromazine and monoamine oxidase inhibitors, or the anxiolytics, such as diazepam. 

Chronic stimulant abuse alters the personality of the abuser. These and related changes are the result of neurotoxicity and are not characterized as either acute drug effects or withdrawal signs. Individuals have delusions of being pursued or persecuted and therefore become suspicious and paranoid. They become self-occupied and hostile toward others. Long-term abuse can produce toxic psychosis that closely resembles schizophrenia and must be treated with neuroleptic drugs (haloperidol, chlorpromazine). This psychosis can develop even within 1 to 2 weeks if the person is on a run of very high doses of stimulants. 

Chlorpromazine is 92 to 97% bound to plasma proteins, principally albumin [5,20], It crosses the blood-brain barrier, and concentrations of the drug in the brain are higher than those in plasma [17], The relationship of plasma concentration to clinical response and toxicity has not been clearly established. Chlorpromazine and its metabolites cross the placenta and are distributed into milk [21]. About 10-12 metabolites of chlorpromazine in humans have been identified. In addition to hydroxylation at positions 3 and 7 of the phenothiazine nucleus, the N-dimethylaminopropyl side chain of chlorpromazine undergoes demethylation and is metabolized to an N-oxide or sulfoxide derivative. These metabolites may be excreted as their 0-glucouronides, with small amounts of ethereal sulfates of the mono- and dihydroxy derivatives. The major metabolites found in urine are the monoglucouronide of N-demethylchlorpromazine and 7-hydroxychlorpromazine [2]. Although the plasma half life of chlorpromazine itself has been reported to be few hours, the elimination of metabolites may be very prolonged [8, 22-24]. 

Though not used clinically, therapeutic serum level for chlorpromazine is 50-300 mcg/ml, and the toxic serum level is greater than 750 mcg/ml... 

Despite this favorable result, lithium was hardly considered as a psychopharmaceutical for many years. There were a variety of reasons for this. Firstly, mania is not a very common psychosis and there is spontaneous remission in many cases. There were thus not so many occasions where lithium treatment was indicated. Secondly, lithium salts were considered to be toxic because for some time they had been given in excessive doses to patients with heart failure and in this way, had led to a number of fatalities (Cade, 1970). Thirdly, a few years after Cade s first publication psychiatrists attention had been claimed by chlorpromazine and the subsequent neuroleptics and antidepressants, thus explaining why lithium almost fell into oblivion. It was onl> in the 1960s that it once more attracted some interest, after the Danish psychiatrist Mogens Schou had shown that lithium salts were not only useful in the manic phase of manic depressive illness but also could prevent depressive episodes in patients suffering from bipolar psychoses. 

The term behavioral toxicity has been used in the child psychiatry literature to describe the following adverse effects of antipsychotics, particularly low-potency phenothiazines (e.g., chlorpromazine, thioridazine) ... 

Chlorpromazine Blockade of D2 receptors >> 5 2 receptors .-Receptor blockade (fluphenazine least) muscarinic (M)-receptor blockade (especially chlorpromazine and thioridazine) Hx-receptor blockade (chlorpromazine, thiothixene) t central nervous system (CNS) depression (sedation) t decreased seizure threshold t QT prolongation (thioridazine) Psychiatric schizophrenia (alleviate positive symptoms), bipolar disorder (manic phase) nonpsychiatric antiemesis, preoperative sedation (promethazine) pruritus Oral and parenteral forms, long half-lives with metabolism-dependent elimination Toxicity Extensions of effects on a - and M- receptors blockade of dopamine receptors may result in akathisia, dystonia, parkinsonian symptoms, tardivedyskinesia, and hyperprolactinemia... 

The antimalarial drug quinacrine and some phenothiazine derivatives, acepro-mazine, chlorpromazine, and promazine, have been used for the treatment of prion diseases (Doh-ura et al., 2000 Korth et al., 2001 May et al., 2003). The molecular mechanism associated with the inhibition of PrPsc formation by quinacrine remains unknown. However, it is proposed that quinacrine binds with human prion protein at the Tyr-225, Tyr-226, and Gln-227 residues of helix 3 (Vogtherr et al., 2003) and provides neuroprotection. Quinacrine may also act as an antioxidant and reduce the toxicity of prP 6 (Turnbull et al., 2003). 

A number of toxic effects on the blood have been documented, including agranulocytosis caused by chlorpromazine, hemolytic anemia caused by methyldopa, and megaloblastic anemia caused by methotrexate. Toxic effects on the eye have been noted and range from retinotoxicity caused by thioridazine to glaucoma caused by systemic corticosteroids. 

Information on pemoline s tolerance and toxicity is not available. However, as with almost any drag, there is a chance of psychological and/or physical dependence with excessive doses and/or long-term misuse (57). In comparison to methylphenidate and amphetamine, pemoline has the least potential for abuse (39). Benowitz (41) suggests that approximately 3 mg/kg pemoline should be considered life-threatening. Treatment for overdose is similar to what has been recommended for methylphenidate and amphetamine. In cases of overdose, the administration of chlorpromazine has been found useful for decreasing the amount of CNS overstimulation (57). 

Trials of lithium in patients with acute psychosis (and not just mania) showed that lithium was inferior for the treatment of severely overactive patients, presumably because of its toxicity, but comparable to neuroleptics for the treatment of less overactive patients, regardless of diagnosis (Braden et al. 1982 Johnstone et al. 1988). A trial conducted in the 1960 comparing opium and chlorpromazine in acute schizophrenic patients showed equivalent improvement over three weeks with both drugs (Abse, Dahlstrom, Tolley 1960). 

Correction of fluid acidosis and electrolyte imbalance may be required (Ellenhorn and Barceloux 1988 Stutz and Janusz 1988). At the same time, drug therapy for pulmonary edema should be considered (Bronstein and Currance 1988). Diazepam may be necessary to control seizures (Bronstein and Currance 1988 Haddad and Winchester 1990). However, sedatives such as chlorpromazine may potentiate the action of DNOC (Clarke et al. 1981). However, a study in mice indicated that the effect of chlorpromazine may be dose-dependent. Mice that were pretreated with 8 and 12 mg/kg chlorpromazine were protected against DNOC toxicity, but a dose of 6 mg/kg potentiated the toxicity of DNOC (Tesic et al. 1972). However, the efficacy of chlorpromazine administered after intoxication with DNOC was not evaluated. In the same study, pretreatment with vitamin E, vitamin A and/or glucose 30 minutes before dosing with DNOC prolonged the mean time to death in mice. 

The antipsychotic chlorpromazine is a prototype heptotoxicant for production of cholestasis. Pleiotropic effects of chlorpromazine on membrane permeability and associated ion gradients and microfilament-mediated canalicular contraction have been attributed to detergent effects. Valproic acid, an anticonvulsant, is associated with microvesicular steatosis. Inhibition of mitochondial fatty acid (S-oxidation is an important component of this toxic effect and is apparently related to carnitine availability as evidenced by the protection afforded by L-carnitine supplements. The hypolipidemic drugs clofibrate, fenofibrate, and gemfibrozil are peroxisome prolif-erators in rodent liver, but not in humans. Isoniazid, an antibiotic used to treat tuberculosis, exhibits an approximately 1 % incidence of hepatotoxicity. Although toxicity is known to be metabolism-dependent and protein adduction has been well-... 

Hepatotoxicity may be as frequent with piperidine and piperazine phenothiazines as with chlorpromazine, despite previous suggestions that the toxicity of these compounds is less. 

Chlorpromazine, and in some cases other phenothiazines, has been reported to increase plasma phenytoin concentrations (656-659), to reduce plasma phenytoin concentrations (657-661), or to have no effect (658). In one case co-administration of thioridazine caused phenytoin toxicity (662). 

Toxic epidermal necrolysis has been reported in association with chlorpromazine (6). 

Purcell P, Valmana A. Toxic epidermal necrolysis following chlorpromazine ingestion complicated by SIADH. Postgrad Med J 1996 72(845) 186. 

PROPANOLOL, TIMOLOL CHLORPROMAZINE, HALOPERIDOL t plasma concentrations and efficacy of both chlorpromazine and propranolol during co-administration Propanolol and chlorpromazine mutually inhibit each other s hepatic metabolism. Haloperidol inhibits CYP2D6-mediated metabolism of propanolol and timolol Watch for toxic effects of chlorpromazine and propranolol 1 doses accordingly... 

CHLORPROMAZINE, PERPHENAZINE, RISPERIDONE BUPROPION T plasma concentrations of these substrates with risk of toxic effects Bupropion and its metabolite hydroxybupropion inhibit CYP2D6 Initiate therapy of these drugs at the lowest effective dose... 

CHLORPROMAZINE, CLOZAPINE, HALOPERIDOL, OLANZAPINE BUPROPION T plasma concentrations of these drugs with risk of toxic/adverse effects Smoking induces mainly CYP1A2 and CYP2E1. Thus de-induction takes place following cessation of smoking Be aware and watch for early features of toxicity. Consider reducing the dose... 

Caffeine 2. Chaste tree 3. Green tea 4. Plantain 1. Lithium 2. Phenothiazines (e.g. chlorpromazine, promazine, levomepromazine, pericyazine, pipotiazine, fluphenazine, perphenazine, trifluphenazine) 3. Clozapine L blood lithium levels with 1 clinical effects. 1 effects of phenothiazines Unknown mechanism (caffeine) Contains dopamine agonists (chaste tree) Induction of metabolizing enzymes (green tea may induce CYP1A2, which metabolizes clozapine) l absorption from the gut (plantain may l absorption of lithium) Be aware. Caffeine withdrawal may precipitate lithium toxicity, so avoid sudden caffeine withdrawal. Avoid concomitant use if possible... 

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