title: Safety considerations in the management of allergic diseases: focus on antihistamines.
abstract: OBJECTIVE
  To conduct a systematic review of evidence supporting the safety profiles of frequently used oral H(1)-antihistamines (AHs) for the treatment of patients with histamine-release related allergic diseases, e.g. allergic rhinitis and urticaria, and to compare them to the safety profiles of other medications, mostly topical corticosteroids and leukotriene antagonists (LTRA).
  
  
  METHODS
  Systematic search of the published literature (PubMed) and of the regulatory authorities databases (EMA and FDA) for oral AHs.
  
  
  RESULTS
  Similarly to histamine, antihistamines (AHs) have organ-specific efficacy and adverse effects. The peripheral H(1)-receptor (PrH1R) stimulation leads to allergic symptoms while the brain H(1)-receptor (BrH1R) blockade leads to somnolence, fatigue, increased appetite, decreased cognitive functions (impaired memory and learning), seizures, aggressive behaviour, etc. First-generation oral AHs (FGAHs) inhibit the effects of histamine not only peripherally but also in the brain, and additionally have potent antimuscarinic, anti-α-adrenergic and antiserotonin effects leading to symptoms such as visual disturbances (mydriasis, photophobia, and diplopia), dry mouth, tachycardia, constipation, urinary retention, agitation, and confusion. The somnolence caused by FGAHs interferes with the natural circadian sleep-wake cycle and therefore FGAHs are not suitable to be used as sleeping pills. Second-generation oral AHs (SGAHs) have proven better safety and tolerability profiles, much lower proportional impairment ratios, with at least similar if not better efficacy, than their predecessors. Only SGAHs, and especially those with a proven long-term (e.g., ≥12 months) clinical safety, should be prescribed for young children. Evidence exist that intranasally applied medications, like intranasal antihistamines, have the potential to reach the brain and cause somnolence.
  
  
  CONCLUSIONS
  Second-generation oral antihistamines are the preferred first-line treatment option for allergic rhinitis and urticaria. Patients taking SGAHs report relatively little and mild adverse events even after long-term continuous treatments. An antihistamine should ideally possess high selectivity for the H(1)-receptor, high PrH1R occupancy and low to no BrH1R occupancy.
authors.affiliation: Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan. yanai@med.tohoku.ac.jp
authors.forename: K
authors.initials: K
authors.lastname: Yanai
authors.forename: B
authors.initials: B
authors.lastname: Rogala
authors.forename: K
authors.initials: K
authors.lastname: Chugh
authors.forename: E
authors.initials: E
authors.lastname: Paraskakis
authors.forename: A N
authors.initials: AN
authors.lastname: Pampura
authors.forename: R
authors.initials: R
authors.lastname: Boev
mesh_terms: D000284:Administration, Oral; D000305:Adrenal Cortex Hormones / Q000009:adverse effects / Q000627:therapeutic use; D064420:Drug-Related Side Effects and Adverse Reactions; D006634:Histamine H1 Antagonists / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy* / Q000378:metabolism; D020024:Leukotriene Antagonists / Q000009:adverse effects / Q000627:therapeutic use; D012449:Safety
chemical_list: D000305:Adrenal Cortex Hormones; D006634:Histamine H1 Antagonists; D020024:Leukotriene Antagonists