Promethazine toxicity

Block and Beysovec (1982) reported a 16-month-old male weighing 11.5 kg treated with 2% promethazine cream for generalized eczema. The child showed abnormal behavior, loss of balance, inability to focus, irritability, drowsiness and failure to recognize his mother after 15-20 g of the cream had been applied. One day later, all symptoms had spontaneously disappeared. A diagnosis of promethazine toxicity through percutaneous absorption was made. 

Block R, Beysovec L (1982) Promethazine toxicity through percutaneous absorption. Contin Pract 9 28 Bork K, Morsches B, Holzmann H (1973) Mercury absorption out of ammoniated mercury ointment. Arch Dermatol Forsch 248 137-143... 

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). 

Several first-generation Hi antagonists are potent local anesthetics. They block sodium channels in excitable membranes in the same fashion as procaine and lidocaine. Diphenhydramine and promethazine are actually more potent than procaine as local anesthetics. They are occasionally used to produce local anesthesia in patients allergic to conventional local anesthetic drugs. A small number of these agents also block potassium channels this action is discussed below (see Toxicity). 

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... 

It is important that the agent be washed from the skin with soap and water as soon after exposure as possible. The eyes should be thoroughly flushed. The onset of symptoms typically is delayed and an absence of immediate effect does not rule out toxicity. Although ingestion is unlikely, due to the sources of mustard gas, an emetic should not be administered because of the extreme caustic nature of the chemical. If the patient is not comatose, dilution of stomach contents with milk or water, prior to gastric lavage, may be attempted. Application of a solution of sodium thiosulfate to the skin and inhalation of a nebulizing mist of sodium thiosulfate may speed inactivation of mustard gas. Animal studies have shown that administration of corticosteroids (e.g., dexamethasone) and antihistamines (e.g., promethazine) may prove beneficial. 

D. Toxicity and Interactions Sedation is common, especially with diphenhydramine, doxylamine, and promethazine. It is much less common with second-generation agents, which do not enter the CNS readily. Antimuscarinic effects such as dry mouth and blurred vision occur with some first-generation drugs in some patients. Alpha-blocking actions may cause orthostatic hypotension. 

Some data indicate that nitrites exert their action by a mechanism other than methemoglobin formation. It has been suggested that the protective effect is due to the vasodilating effect of nitrite.52 Several a-adrenergic antagonists (eg, chlorpromazine, promethazine, promazine, and phenoxybenzamine) that cause vasodilation also antagonize cyanide toxicity.5657 Further information is needed to determine the mechanism or mechanisms by which chlorpromazine and phenoxybenzamine reverse cyanide intoxication.57... 

Chlorpromazine has been reported to increase the analgesic effect of pethidine, but increased respiratory depression, sedation, CNS toxicity and hypotension can also occur. Other phenothiazines such as levomepromazine, promethazine, prochlorperazine, pro-piomazine and thioridazine may also interact with pethidine to cause some of these effects. Additive CNS depressant effects would be expected when opioids are given with phenothiazines. 

A study in healthy subjects found that intramuscular promethazine hydrochloride 25 mg, given with intramuscular chloroquine phosphate 200 mg increased the AUC of chloroquine and its metabolites by 85%. This may be due to promethazine enhancing the absorption of chloroquine from the injection site or displacing it and its metabolites from binding sites in the blood. The initial rate of excretion of chloroquine and the total drug excreted within 3 hours was unaffected by promethazine. The increased bioavailability of chloroquine may improve its therapeutic effects but could also increase toxicity. In vitro and animal studies suggest the combination may be effective in the treatment of uncomplicated chloroquine-resistant malaria. More study is needed. For mention that chloroquine may increase chlorpromazine levels, see Phenothiazines + Antimalarials , p.759. 

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. 

B. N. Halpern and T. Neveu, Toxicity of the Histamine-Liberating Compound 48j80, in Normal and Adrenalectomized Rats, and the Protective Action of Promethazine, C. r. Seanc. Soc. Biol. 150, 105-108 (1956). 

Pregnancy Self-poisoning with large doses of promethazine during pregnancy does not appear to result in teratogenic, feto-toxic, or neurotoxic effects in the children born to these mothers [21 ]. 

Atropine or common antiemetics can be given to provide relief from nausea and vomiting, early signs of HD intoxication (Yu et al., 2003). Excellent choices for pediatric-specific antiemetics include medications such as promethazine, metoclopramide, and ondansetron (Sidell et al., 1997). Persistent vomiting and diarrhea are later signs of systemic toxicity requiring prompt fluid replacement. 

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