Phenothiazines toxicity

Paulson, G. M. (1959). Phenothiazine toxicity, extrapyramidal seizures, oculo-gyric crises. Journal of Mental Science, 105, 798-802. 

The etiology is thought to be similar to that seen with phenothiazine toxicity such that an imbalance of dopamine and cholinergic blockade causes the dystonia. 

The principal manifestations of phenothiazine toxicity involve the CNS and cardiovascular system. Signs of CNS toxicity include sedation, coma, respiratory depression (uncommon), seizures, hypothermia or hyperthermia, and extrapyramidal movement disorders (acute dystonia, parkinsonism, akathisia, tardive dyskinesia, and neuroleptic malignant syndrome) the extrapyramidal symptoms result from an imbalance between inhibitory dopamine and... 

The cardiovascular, CNS, and anticholinergic symptoms of phenothiazine toxicity are similar to, but generally much less severe than, those for the tricyclic antidepressants. Phe-nothiazines are relatively safe, and few deaths have occurred when toxic doses have been ingested alone. Much more severe toxicity occurs when phenothiazines are co-ingested with tricyclic antidepressant drugs or other CNS depressant drugs, such as ethanol, opioids, barbiturates, or benzodiazepines. 

The effects of buspirone are decreased when the drug is administered with fluoxetine Increased serum levels of buspirone occur if the drug is taken with erythromycin or itraconazole Should any of these combinations be required, the dosage of buspirone is decreased to 2.5 mg BID, and the patient is monitored closely. Venlafaxine blood levels increase with a risk of toxicity when administered witii MAOIs or cimetidine There is an increased risk of toxicity when trazodone is administered with the phenothiazines and decreased effectiveness of trazodone when it is administered with carbamazepine Increased serum digoxin levels have occurred when digoxin is administered with trazodone There is a risk for increased phenytoin levels when phenytoin is administered witii trazodone... 

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). 

One of numerous examples of LOX-catalyzed cooxidation reactions is the oxidation and demethylation of amino derivatives of aromatic compounds. Oxidation of such compounds as 4-aminobiphenyl, a component of tobacco smoke, phenothiazine tranquillizers, and others is supposed to be the origin of their damaging effects including reproductive toxicity. Thus, LOX-catalyzed cooxidation of phenothiazine derivatives with hydrogen peroxide resulted in the formation of cation radicals [40]. Soybean LOX and human term placenta LOX catalyzed the free radical-mediated cooxidation of 4-aminobiphenyl to toxic intermediates [41]. It has been suggested that demethylation of aminopyrine by soybean LOX is mediated by the cation radicals and neutral radicals [42]. Similarly, soybean and human term placenta LOXs catalyzed N-demethylation of phenothiazines [43] and derivatives of A,A-dimethylaniline [44] and the formation of glutathione conjugate from ethacrynic acid and p-aminophenol [45,46],... 

The answer is b. (Katzung, p 4822) Haloperidol, a butyrophenone, is by far the most likely antipsychotic to produce extrapyramidal toxicides Other agents, such as piperazine (an aromatic phenothiazine), thiothixene (a thioxanthene), and pimozide (a diphenylbutyropiperidine) are comparitively less likely to produce extrapyramidal toxicity than haloperi-dol. The antagonism of dopamine in the nigrostriatal system might explain the Parkinson-like effects Both haloperidol and pimozide act mainly on D2 receptors, whereas thioridazine and piperazine act on ooadrenergie receptors, and have a less potent but definite effect on D2 receptors. 

Decreased cigarette consumption in smokers, easier to stop smoking Exaggerated response to warfarin and phenytoin Increased efficacy of omeprazole, increased toxicity of mephenytoin Absence of codeine efficacy, no effect of encainide, increased levels of tricyclic antidepressants, fluoxetine, phenothiazines Sustained paralysis to succinylcholine, possible increased toxicity of cocaine Unknown... 

Unfortunately, few of the studies that have attempted to relate the blood concentrations of neuroleptics to therapeutic response have fulfilled all these criteria. There is a suggestion that a "thera peutic window" exists for some phenothiazine neuroleptics. A therapeutic window is a range of concentrations of a drug measured in the blood that are associated with a good therapeutic response. Plasma concentrations outside this range are either too low to ensure a therapeutic response or so high that they induce toxic side effects. Despite the numerous studies of the relationship between the plasma concentration and the therapeutic response for a number of "standard" neuroleptics, it would appear that such correlations rarely account for more than 25% of the variance in clinical response to treatment. The existence of a therapeutic window for neuroleptics would therefore appear to be unproven. However, there could be ranges of plasma concentrations associated with optimal antipsychotic action, but these... 

Use cautiously in people with acute or chronic respiratory impairment, particularly children, because phenothiazines may suppress the cough reflex. If hypotension occurs, epinephrine is not recommended because phenothiazines may reverse its usual pressor effect and cause a paradoxical further lowering of blood pressure. Because these drugs have an antiemetic action, they may obscure signs of intestinal obstruction, brain tumor, or overdosage of toxic drugs. 

Hypotensive effect Narcotic analgesics may cause severe hypotension in individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or coadministration of drugs such as phenothiazines or general anesthetics. Renal toxicity Avinza doses over 1,600 mg/day contain a quantity of fumaric acid that has not been demonstrated to be safe, which may result in serious renal toxicity. 

CNS When used to treat extrapyramidal reactions resulting from phenothiazines in psychiatric patients, antiparkinson agents may exacerbate mental symptoms and precipitate a toxic psychosis. 

A number of drugs in addition to atropine and scopolamine have antimuscarinic properties. Tbese include tricyclic antidepressants, phenothiazines, and antihistamines. Physostigmine has been used in the treatment of acute toxicity produced by these compounds. However, physostigmine can produce cardiac arrhythmias and other serious toxic effects of its own, and therefore, it should be considered as an antidote only in life-threatening cases of anticholinergic drug overdose. 

C. Abuse of stimulants can produce toxic psychosis that closely resembles schizophrenia. An agent such as haloperidol or a phenothiazine will provide im-... 

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]. 

Acetylsalicylic acid, phenytoin, phenothiazines Competition for binding to glycoprotein TCA toxicity (cardiac effects, delirium, sedation) due to increased amount of free TCA Lower TCA dose Baldessarini, 1996... 

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) ... 

Haloperidol Blockade of D2 receptors >> 5HT2A receptors Some a blockade, but minimal M receptor blockade and much less sedation than the phenothiazines Schizophrenia (alleviates positive symptoms), bipolar disorder (manic phase), Huntington s chorea, Tourette s syndrome Oral and parenteral forms with metabolism-dependent elimination Toxicity Extrapyramidal dysfunction is major adverse effect... 

It is interesting to note that a number of researchers have attempted, more or less successfully, to construct reliable mathematical models which combine structural elements and experimental data to predict the toxicities of new substances not yet experimentally tested for humans and other species.110152 Furthermore pharmacology, toxicity, metabolism and enzyme-inhibiting effects of fluorine-containing aromatic systems (e.g., anilines, ben-zothiadiazines, butyrophenones, corticoids, phenothiazines, steroids, uracils) have been discussed in depth in the literature.153-156... 

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). 

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