Diphenhydramine toxicity

Reilly JF Jr, Weisse ME. Topically induced diphenhydramine toxicity. J Emerg Med 1990 8(1) 59-61. 

Seizures and sodium channel blockade are recognized compUcations of diphenhydramine toxicity, but reports of status epilepti-cus are rare. The authors concluded that the symptoms of diphenhydramine overdose... 

Campath) hypotension prolonged immunosuppression (resulting in infectious complications) during treatment. Premedicate with acetaminophen, diphenhydramine, with or without a steroid to alleviate infusion-related reactions. Subcutaneous dosing may lessen acute toxicity. Initially 3 mg/day as a 2-hour infusion, increase to 1 0 mg/day, then 30 mg/day as tolerated. 

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). 

Diphenhydramine Competitive antagonism at Hi receptors Reduces or prevents histamine effects on smooth muscle, immune cells also blocks muscarinic and adrenoceptors highly sedative IgE immediate allergies, especially hay fever, urticaria some use as a sedative, antiemetic, and antimotion sickness drug Oral and parenteral t duration 4-6 h Toxicity Sedation when used in hay fever, muscarinic blockade symptoms, orthostatic hypotension Interactions Additive sedation with other sedatives, including alcohol some inhibition of CYP2D6, may prolong action of some 13 blockers... 

Elevations of TCA levels may occur when combined with CYP2D6 inhibitors or from constitutional factors. About 7% of the Caucasian population in the USA has a CYP2D6 polymorphism that is associated with slow metabolism of TCAs and other 2D6 substrates. Combination of a known CYP2D6 inhibitor and a TCA in a patient who is a slow metabolizer may result in additive effects. Such an interaction has been implicated, though rarely, in cases of TCA toxicity. There may also be additive TCA effects such as anticholinergic or antihistamine effects when combined with other agents that share these properties such as benztropine or diphenhydramine. Similarly, antihypertensive drugs may exacerbate the orthostatic hypotension induced by TCAs. 

A large number of prescription and nonprescription drugs, as well as a variety of plants and mushrooms, can inhibit the effects of acetylcholine at muscarinic receptors. Some drugs used for other purposes (eg, antihistamines) also have anticholinergic effects. Many of them have other potentially toxic actions. For example, antihistamines such as diphenhydramine can cause seizures tricyclic antidepressants, which have anticholinergic, quinidine-like, and a-blocking effects, can cause severe cardiovascular toxicity. 

While useful for evaluating substrate reduction and tissue distribution, the knockout mouse also presented specific challenges to the preclinical development program. After repeated administration of rhGAA, a predictable hypersensitivity response to the recombinant human protein was observed. Frequently this reaction resulted in morbidity and mortality associated with test article administration. This hypersensitivity reaction responded to diphenhydramine prior to, and as necessary, during dosing however, such intervention complicated interpretation of toxicity studies. 

Toxicity. The estimated minimum lethal dose is 5 g in non-tolerant subjects. Drug accumulation is likely in chronic dosing because of the long half-life. Toxic effects may be associated with plasma concentrations greater than 2 pg/ml, and plasma concentrations greater than about 8 pg/ml are likely to produce coma and may be lethal. The 2 -hydroxymethyl metabolite, which has been found unconjugated in both blood and urine in overdose cases, may contribute to the degree of intoxication. Abuse of methaqualone, particularly when taken in conjunction with diphenhydramine, has been reported. 

Topical apphcation of diphenhydramine can cause systemic toxicity. 

Acute anticholinergic toxicity with fever, hallucinations, and tachycardia occurred in a 2.5-year-old boy from apphcations of calamine + diphenhydramine lotion (10). 

Radovanovic D, Meier PJ, Guirguis M, Lorent JP, Kupferschmidt H. Dose-dependent toxicity of diphenhydramine overdose. Hum Exp Toxicol 2000 19(9) 489-95. 

Precautions Doses may be modified or therapy delayed for toxicity (myelosuppression). Adjust dose for hepatic impairment. Avoid use of docetaxel in patients with elevated bilirubin. Corticosteroids and antihistamines (i.e., cimetidine and diphenhydramine) are recommended to lessen risk for anaphylactoid reactions with paditaxel. Pretreatment with steroids is required for docetaxel to minimize risk for fluid retention and hypersensitivity. 

G Infusion-related toxicities secondary to amphotericin are common and may be prevented with premedication with diphenhydramine and acetaminophen. Meperidine is effective in halting rigors and muscle spasms. Thus, it is typically given in response to rigors, and not as premedication. Sodium loading with normal saline may prevent some of the renal toxicities, particularly prere-nal azotemia, associated with amphotericin and is administered prior to amphotericin. 

If a toxic or unknown amount of a cephalosporin has been ingested, gastric decontamination and the administration of activated charcoal is usually all that is needed. In the symptomatic patient, evaluation of renal function and electrolytes may be necessary. Chronic exposure usually requires discontinuation of the drug and supportive care. Anaphylaxis should be treated with epinephrine and/or diphenhydramine. 

The toxicity of antihistamines is related to their anticholinergic (antimuscarinic) activity. The action of acetylcholine at the muscarinic receptors is blocked, resulting in signs and symptoms of anticholinergic poisoning. Diphenhydramine may produce direct toxicity unrelated to its anticholinergic properties. 

Answer C. Muscarinic receptor antagonists such as benztropine, trihexyphenidyl, and diphenhydramine are used to manage the reversible extrapyramidal dysfunction (e.g., pseu-do-Parkinsonism) that results from treatment with drugs that block DA receptors in the striatum. Drugs that activate DA receptors, although theoretically possible, require doses that are toxic and exacerbate psychoses. Because the actions of DA in the striatum lead to... 

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. 

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