Antihistaminics sedative side effects

Whether due to their antihistaminic activity or their sedative side effects, pruritus caused by contact dermatitis can be relieved with the use of sedating oral antihistamines such as... 

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. 

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. 

In the 1950s, a more evidence-based approach to antipsychotic drug (AP) therapy was undertaken when structural variations of antihistamines were produced by a French scientist (Paul Charpentier), in order to make use of the unwanted sedative side effect produced by these drugs. Initially used to lower body temperature in patients undergoing cardiac surgery, chlorpromazine (Fig. II) was the first drug with antipsychotic properties successfully used in clinical trials [3],... 

In the case of a structurally inhomogeneous series of antihistamines, the sedative side-effects were found to be much better described by their octanol-water distribution coefficient at pH 7.4, log D, than by Alog P0ct.-aik. or their hydration capacity, Aalkane [b7[. 

In an attempt to compensate for the sedative side effect of this compound, a complex with 8-chlorotheophylline 40, dimen-hydrinate, was investigated. In addition to its antihistaminic quality it is also effective against travel sickness. 

Prototypical agent Diphenhydramine. Other first-generation antihistamines include chlorpheniramine, clemastine, promethazine, and cyproheptadine. Second-generation antihistamines— loratadine, cetirizine, and fexofenadine—were developed to circumvent anticholinergic and sedative side effects. 

The unwanted side-effects of drags can be a productive source of leads to new compounds. The evaluation of side-effects for their possible use in therapeutics has made a substantial contribution to our therapeutic arsenal. The various phenothiazine-type tranquillizers, for instance, are derived from the originally undesired sedative side-effect of promethazine, a phenothiazine-type antihistamine. Further incidental observations led to a large family of phenothiazines and related drags (Fig. 5). 

Although drug interactions may occur through a variety of mechanisms, most occur because of pharmacodynamic or pharmacokinetic interactions. Common examples of pharmacodynamic interactions resulting in enhanced effect include the excess sedation that can occur when antipsychotics are used concomitantly with other medications that have sedative side effects (e.g., mood stabUizers, hypnotics, alcohol, antidepressants, anxiolytics, or antihistamines). 

Chlorpromazine is used as a neuroleptic agent in psychiatry, but was developed from the antihistamine agent promethazine. This might appear an unexpected thing to do, but it is known that promethazine has sedative side effects and so medicinal chemists modified the structure to enhance the sedative effects at the expense of antihistamine activity (Figure 9.10). 

Two newer potent selective H -antagonists, terfenadine (23) (132) and astemizole (24) (133), have been developed which have neither the sedative nor the anticholinergic Habilities of the earlier agents. Both of these compounds have proven efficacious in the treatment of hay fever and produce very few side effects, prompting a re-evaluation of the role of antihistamines in asthma treatment. 

Since there was some evidence that these compounds owe their action to interference with the action of histamine, this class has earned the soubriquet "antihistamines." This class of drugs is further characterized by a spectrum of side effects which occur to a greater or lesser degree in various members. These include antispasmodic action, sedative action, analgesia, and antiemetic effects. The side effects of some of these agents are sufficiently pronounced so that the compounds are prescribed for that effect proper. Antihistamines, for example, are used as the sedative-hypnotic component in some over-the-counter sleeping pills. 

As sedation is one of the major side effects associated with antihistamines, the test compounds were also evaluated for their sedative potentials. This was determined by measuring the reduction in locomotor activity using an ac-tophotometer [6,7]. The test compounds and the reference standards (chlorpheniramine maleate and cetirizine) were administrated orally at a dose of 5 mg/kg in 1% CMC. 

Principal side effects are gastrointestinal and central nervous system symptoms, including drowsiness, dizziness, and diarrhea. Zolpidem may increase the depressant effects of other sedative drugs, such as the an-tipsychotics, tricyclic antidepressants, and antihistamines. 

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. 

Antihistamines, which penetrate into the central nervous system, have a non-specific sedative action, i.e. they can induce subjectively unpleasant side effects. 

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). 

Both prescription and over-the-counter antihistamines are the most commonly pre-scribed/recommended sedatives in pediatric practice. They bind to Hi receptors in the CNS, with only the first generation medications crossing the blood-brain barrier. They are generally rapidly absorbed. Effects on sleep architecture are minimal. Side effects include daytime drowsiness, cholinergic effects and paradoxical excitation. In general, these drugs are rather weak soporifics, but parental and provider familiarity tend to make them a more acceptable choice for many families. 

A range of medications is available to treat insomnia, ranging from herbal preparations such as valerian to the recently introduced z compounds, zopiclone, zolpidem and zaleplon. Many drugs used for other primary purposes have sedative and sleep-inducing properties as side effects these include many tricyclic antidepressants and antihistamines. 

The piperazine phenothiazines, as exemplified by fluphenazine, are the most potent members of the phenothiazine group, being at least 50 times more potent than chlorpromazine. Because of the structure of their side chain, members of this series lack anticholinergic, antihistaminic, adrenolytic and sedative effects. However, they are more likely to cause extrapyramidal side effects. 

The butyrophenones and diphenylbutylpiperidines differ from the phenothia-zines and thioxanthines in that they are not tricyclic structures. The first butyrophenone to be developed was haloperidol, and this is the most widely used, potent neuroleptic. Unlike many of the phenothiazines, these neuroleptics largely lack antihistaminic, anticholinergic and adrenolytic activity they are also non-sedative in therapeutic doses. Their potent antidopaminergic activity renders them likely to cause extrapyramidal side effects. Of the various butyrophenones shown in Figure 11.10, benperidol has been selectively used to suppress asocial sexual behaviour. 

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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