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An antihistamine is a drug which serves to reduce or eliminate effects mediated by histamine, an endogenous chemical mediator released during allergic reactions, through action at the histamine receptor. Only agents where the main therapeutic effect is mediated by negative modulation of histamine receptors are termed antihistamines - other agents may have antihistaminergic action but are not true antihistamines.
In common use, the term antihistamine refers only to H1-receptor antagonists, also known as H1-antihistamines. It has been discovered that these H1-antihistamines are actually inverse agonists at the histamine H1-receptor, rather than antagonists per se. (Leurs, Church & Taglialatela, 2002)
In allergic reactions an allergen (a type of antigen) interacts with and cross-links surface IgE antibodies on mast cells and basophils. Once the mast cell-antibody-antigen complex is formed, a complex series of events occurs that eventually leads to cell degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, histamine can react with local or widespread tissues through histamine receptors.
Histamine, acting on H1-receptors, produces pruritus, vasodilatation, hypotension, flushing, headache, tachycardia, bronchoconstriction, increases vascular permeability, potentiates pain, and more. (Simons, 2004)
While H1-antihistamines ameliorate these effects, they are only efficacious if administered prior to the allergen-challenge. In severe allergies, such as anaphylaxis or angioedema, these effects may be so severe as to be life-threatening. Epinephrine, often in the form of an autoinjector (Epi-pen), is required by people with such hypersensitivities.
Clinical use of antihistamines
H1-antihistamines are clinically used in the treatment of histamine-mediated allergic conditions. Specifically, these indications may include: (Rossi, 2004)
- allergic rhinitis
- allergic conjunctivitis
- allergic dermatological conditions (contact dermatitis)
- pruritus (atopic dermatitis, insect bites)
- anaphylactic or anaphylactoid reactions - adjunct only
- nausea and vomiting (first-generation H1-antihistamines)
- sedation (first-generation H1-antihistamines)
The authors of the American College of Chest Physicians Updates on Cough Guidelines (2006)recommend that for cough associated with the common cold, first-generation antihistamine-decongestants are more effective than newer, nonsedating antihistamines. First generation antihistamines include Diphenhydramine (Benadryl); Carbinoxamine (Clistin); Clemastine (Tavist);Chlorpheniramine (Chlor-Trimeton)and Brompheniramine (Dimetane).
Adverse drug reactions
Adverse drug reactions are most commonly associated with the first-generation H1-antihistamines. This is due to their relative lack of selectivity for the H1-receptor.
The most common adverse effect is sedation; this "side effect" is utilized in many OTC sleeping-aid preparations. Other common adverse effects in first-generation H1-antihistamines include: dizziness, tinnitus, blurred vision, euphoria, uncoordination, anxiety, insomnia, tremor, nausea and vomiting, constipation, diarrhoea, dry mouth, and dry cough. Infrequent adverse effects include: urinary retention, palpitations, hypotension, headache, hallucination, and psychosis. (Rossi, 2004)
The newer second-generation H1-antihistamines are far more selective for peripheral histamine H1-receptors and, correspondingly, have a far improved tolerability profile compared to the first-generation agents. The most common adverse effects noted for second-generation agents include: drowsiness, fatigue, headache, nausea and dry mouth. (Rossi, 2004)
First-generation H1-receptor antagonists
These are the oldest antihistaminergic drugs and are relatively inexpensive and widely available. They are effective in the relief of allergic symptoms, but are typically moderately to highly potent muscarinic acetylcholine receptor-antagonists (anticholinergic) agents as well. These agents also commonly have action at α-adrenergic receptors and/or 5-HT receptors. This lack of receptor-selectivity is the basis of the poor tolerability-profile of some of these agents, especially compared with the second-generation H1-antihistamines. Patient response and occurrence of adverse drug reactions vary greatly between classes and between agents within classes.
The first H1-antihistamine discovered was piperoxan, by Jeff Forneau and Daniel Bovet (1933) in their efforts to develop a guinea pig animal-model for anaphylaxis at Ryerson University. Bovet went on to win the 1957 Nobel Prize in Physiology or Medicine for his contribution. Following their discovery, the first-generation H1-antihistamines were developed in the following decades. They can be classified on the basis of chemical structure, and agents within these groups have similar properties.
Ethylenediamines were the first group of clinically-effective H1-antihistamines developed.
Diphenhydramine was the prototypical agent in this group. Significant anticholinergic adverse effects, as well as sedation too, are observed in this group but the incidence of gastrointestnal adverse effects is relatively low. (Nelson, 2002; Rossi, 2004)
The isomerism is a significant factor in the activity of the agents in this group. E-triprolidine, for example, is 1000-fold more potent than Z-triprolidine. This difference relates to the positioning and fit of the molecules in the histamine H1-receptor binding site. (Nelson, 2002) Alkylamines are considered to have relatively fewer sedative and gastrointestinal adverse effects, but relatively greater incidence of paradoxical CNS stimulation. (Rossi, 2004)
These compounds are structurally-related to the ethylenediamines and the ethanolamines; and produce significant anticholinergic adverse effects. Compounds from this group are often used for motion sickness, vertigo, nausea and vomiting. The second-generation H1-antihistamine cetirizine also belongs to this chemical group. (Nelson, 2002)
These compounds differ from the phenothiazine antipsychotics in the ring-substitution and chain characteristics. (Nelson, 2002) They are also structurally-related to the tricyclic antidepressants, explaining the antihistaminergic adverse effects of those two drug classes and also the poor tolerability profile of tricyclic H1-antihistamines. The second-generation H1-antihistamine loratadine was derived from compounds in this group.
Common structural features of classical antihistamine
- 2 Aromatic rings, connected to a central Carbon, Nitrogen or CO
- Spacer between the central X and the amine, usually 2-3 carbons in length, linear, ring, branched, saturated or unsaturated
- Amine is substituted with small alkyl groups eg CH3
- Chirality at X can increase both the potency and selectivity for H1-receptors
- For maximum potency, the two aromatic rings should be orientated in different planes.
- for example, tricyclic ring system is slightly puckered and the two aromatic rings lie in different geometrical planes, giving the drug a very high potency.
Second-generation H1-receptor antagonists
These are newer drugs that are much more selective for peripheral H1 receptors in preference to the central nervous system histaminergic and cholinergic receptors. This selectivity significantly reduces the occurrence of adverse drug reactions compared with first-generation agents, while still providing effective relief of allergic conditions.
- terfenadine (withdrawn from most markets due to risk of cardiac arrhythmias and replaced withfexofenadine)
Common structural features of non-sedating antihistamines
Structure of these drugs varies from case to case. There is no common structural feature for the second generation H1-receptor antagonists.
Third-generation H1-receptor antagonists
These are the active enantiomer (levocetirizine) or metabolite (desloratadine & fexofenadine) derivatives of second-generation drugs intended to have increased efficacy with fewer adverse drug reactions. Indeed, fexofenadine is associated with a decreased risk of cardiac arrhythmia compared to terfenadine. However, there is little evidence for any advantage of levocetirizine or desloratadine, compared to cetirizine or loratadine respectively.
Inhibitors of histamine release
These agents appear to stabilise the mast cells to prevent degranulation and mediator release.
Main article: H2-receptor antagonist
Clinically-relevant histamine H2-receptors are found principally in the parietal cells of the gastric mucosa. H2-receptor "antagonists" are also inverse agonists, rather than true antagonists; and are used to reduce the secretion of gastric acid. Examples include cimetidine, ranitidine, and famotidine.
H3- and H4-receptor antagonists
These are experimental agents and do not yet have a defined clinical use.
Other agents with antihistaminergic activity
- Forneau E, Bovet D (1933). Recherches sur l'action sympathicolytique d'un nouveau derive du dioxane. Arch Int Pharmacodyn 46, 178-91.
- Leurs R, Church MK, Taglialatela M (2002). H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects. Clin Exp Allergy 32 (4): 489-98. PMID 11972592.
- Nelson, WL (2002). In Williams DA, Lemke TL (Eds.). Foye's Principles of Medicinal Chemistry (5 ed.). Philadelphia: Lippincott Williams & Wilkins. ISBN 0-683-30737-1
- Rossi S (Ed.) (2004). Australian Medicines Handbook 2004. Adelaide: Australian Medicines Handbook. ISBN 0-9578521-4-2
- Simons FE (2004, Nov 18). Advances in H1-antihistamines. N Engl J Med 351 (21): 2203-17. PMID 15548781 Abstract.
Major Drug Groups
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