Diphenhydramine, sedative

Antihistamines. After alcohol, antihistamines are the most commonly self-administered sleep medications. Foremost among these is diphenhydramine (Benadryl), which is also available as a component in a variety of over-the-counter nighttime medications including Tylenol PM and Excedrin PM. Prescription antihistamines like hydroxyzine (Vistaril, Atarax) are also occasionally used to treat insomnia. Finally, it is the antihistamine effect of some antidepressants and anti-psychotics that contribute to their utility as sedative-hypnotics. 

Antagonists. Most of the so-called Hi-antihistamines also block other receptors, including M-cholinoceptors and D-receptors. Hi-antihistamines are used for the symptomatic relief of allergies (e.g., bamipine, chlorpheniramine, clemastine, dimethindene, mebhydroline pheniramine) as antiemetics (meclizine, dimenhydrinate, p. 330), as over-the-counter hypnotics (e.g., diphenhydramine, p. 222). Promethazine represents the transition to the neuroleptic phenothiazines (p. 236). Unwanted effects of most Hi-antihistamines are lassitude (impaired driving skills) and atropine-like reactions (e.g., dry mouth, constipation). At the usual therapeutic doses, astemizole, cetrizine, fexofenadine, and loratidine are practically devoid of sedative and anticholinergic effects. Hj-antihistamines (cimetidine, ranitidine, famotidine, nizatidine) inhibit gastric acid secretion, and thus are useful in the treatment of peptic ulcers. 

Antihistamines are popular as nonprescription (over-the-counter) sleep remedies (e.g., diphenhydramine, doxylamine, p. 114), in which case their sedative side effect is used as the principal effect. 

Diphenhydramine is one of the main representatives of antihistamine drngs that block Hj receptors. Besides antihistamine activity, diphenhydramine exhibits a local anesthetic effect, relaxes smooth mnscle, and has sedative and soporific action. 

Histamine Hi receptor antagonists which enter the brain (diphenhydramine, promethazine and others) have sedative actions and polysomnographic recordings have shown that they suppress REM sleep and modestly increase SWS. A rebound in REM sleep sometimes occurs on discontinuation. Stimulation of central Hi and H2 receptors markedly potentiates signals produced by excitatory amino acids and it has been suggested that histamine acts as a waking amine (Schwartz et al., 1986). The effects of centrally acting antihistamines on sleep may be due to inhibition of these effects. 

Several Hi histamine antagonists (e.g., diphenhydramine, promethazine, and hydroxyzine) have been used as sedative-hypnotics, since they produce some degree of sedation. While this sedation is usually considered a side effect of their antihistaminic activity, in some cases the sedation is sufficient to allow the drugs to be used in the treatment of anxiety and sleep disturbances. For these drugs, the anxiolytic properties are thought to be a direct consequence of their ability to produce sedation. 

A wide variety of sedative-hypnotic products that do not require a prescription are available. Most of these over-the-counter products have antihistamines, such as pyrilamine, diphenhydramine, or promethazine, as the active ingredient. In most cases, the dose of the active ingredient is low and the preparations are safe. 

Many Hj-receptor blocking drugs have sedative properties, and some have been used in over-the-counter sleep aids. The most widely used Hj-blocking drugs for sleep induction are diphenhydramine, promethazine, and pyrilamine. 

Dizziness, drowsiness, and dry mouth are expected side effects of diphenhydramine, but the patient may develop a tolerance to the drug s sedative effects... 

The first generation Hi blockers (including diphenhydramine and hydroxyzine) cross the blood-brain barrier. Subsequent generations of antihistamines have been developed so that they do not cross the blood-brain barrier, and therefore are not effective as sedatives or anxiolytics. 

Antihistamines have been used for several decades in the treatment of anxiety in children (Tader, 1988). Prescription data show that antihistamines are widely used in pediatric psychiatric practices (Zito et ah, 2000). Diphenhydramine and hydroxyzine have been reported to modify anxiety symptoms in children with various psychiatric disorders. They are mainly used as a sedative in patients with insomnia. Occasionally they are used for mild acute agitation (AACAP, 1997). 

The unpleasant sedative CNS effect of most antihistamines, combined with their slight anticholinergic activity, is exploited for the prevention of motion sickness. Diphenhydramine (2.5), in the form of an 8-chlorotheophylline salt (dimenhydrinate, 4.148), is widely used for this purpose. The theophylline derivative was originally added to counteract the drowsiness produced by diphenhydramine, since it is a central excitant related to caffeine. 

Majority of antihistaminic drugs produce variable degree of CNS depression i.e. sedation, drowsiness and sleep. Drugs like diphenhydramine, promethazine are potent sedatives and is often accompanied by inability to concentrate. 

Adolescent boys may be more vulnerable to acute dystonia than adults. Although these adverse effects can be treated with anticholinergic agents, dose reduction should also be considered. For acute dystonia, diphenhydramine (25 to 50 mg) may be given orally or intramuscularly, as can equivalent doses of benztropine (1 to 2 mg/day). Diphenhydramine has both sedative and anticholinergic properties, with the former being helpful in calming the patient whereas the latter reverses the reaction itself. 

The prototype antihistamine of this group is diphenhydramine. It has antimuscarinic and pronounced central sedative properties and also an antitussive effect. The mechanism of the latter is unclear, but diphenhydramine is a common ingredient of propriety preparations for the treatment of coughs and colds. It is an effective anti-emetic, especially useful for prevention and treatment of motion sickness. Because of its anticholinergic properties it is occasionally used in the treatment of mild forms of Parkinson s disease. It is also of use in the treatment of drug-induced extrapyramidal effects. Piperazine derivatives... 

Angioedema may be precipitated by histamine release but appears to be maintained by peptide kinins that are not affected by antihistaminic agents. For atopic dermatitis, antihistaminic drugs such as diphenhydramine are used mostly for their sedative side effect, which reduces awareness of itching. 

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... 

Antihistamines Provide sedative-hypnotic effects Diphenhydramine Hydroxyzine Oral 50 mg 20 to 30 minutes before surgery Oral 50-100 mg... 

Iatrogenic Reactions broadly refer to any adverse reactions that are unintentionally produced by physicians in their patients. For example, one of the side effects of many antihistaminic preparations (Hj antagonists) such as ethanolamine derivatives (prototype diphenhydramine) is heavy sedation. Although sedation may be desirable for some patients, it may interfere with daytime activities, and this needs to be considered when prescribing such medications. Other antihistaminic preparations (also 11 antagonists) such as piperidine derivatives (prototypes terfenadine or astemizole) have no sedative properties (Figure 3.2). 

Diphenhydramine causes heavy sedation Terfenadine causes no sedation FIGURE 3.2 Terfenadine does not have sedative effects. 

Phenobarbital, meprobamate, and sedative-autonomic drugs are used occasionally as antianxiety agents. The antihistaminics (diphenhydramine, hydroxyzine, promethazine) continue to be used presurgically for their sedative and muscarinic receptor blocking actions. 

Although sedative antihistamines do not potentiate the effect of alcohol, they should be avoided in excess quantity. Overdose of astemizole can be treated with gastric lavage and supportive measures.86 Coadministration of astemizole and ter-fenadine with antiarrhythmics, antipsychotics, cisapride, and diuretics should be avoided. Chlorpheniramine maleate has been found to be incompatible with phe-nobarbitone sodium, kanamycin sulfate, and calcium chloride. Cyclizines have been used alone or with opioids in tablets or in injectable form for euphoric effects. Cyproheptadine has shown dependence in long-term use. Diphenhydramine is reported to be incompatible with amphotericin, cephalothin sodium, and hydrocortisone sodium succinate. Diphenhydramine and pheniramine maleate are sometimes used as drugs of abuse. Studies have shown that promethazine is adsorbed onto glass, plastic containers, and infusion systems.87... 

Nonprescription antihistamines with sedating properties, such as diphenhydramine and doxylamine (see p. 422), are effective in treating mild types of insomnia. However, these drugs are usually ineffective for all but the milder form of situational insomnia. Further, they have numerous undesirable side effects that make them less useful than the benzodiazepines. These sedative antihistamines are marketed in numerous over-the-counter products. 

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