Blockade of histamine at the H₁ receptor will have the following results:

Smooth Muscle --
no bronchoconstriction due to histamine.  However, in asthma and allergic reactions, many other mediators (acetylcholine, bradykinin, leukotrienes, prostaglandins) contribute to bronchoconstriction.  While antihistaminics may lessen the bronchoconstriction in these situations, they are unlikely to totally reverse it.

less pronounced decreases in blood pressure due to vascular dilatation.  RECALL, however that H₂ receptors also mediate the hypotensive effects of histamine.

no changes in capillary permeability, therefore, no formation of œdema.
 

CNS --  Sedation and drowsiness are the most common effects observed with H₁ antihistaminics.  These effects are most pronounced in those agents that readily cross the blood brain barrier (1st generation antihistaminics) and those that also possess anti-cholinergic activity.  However, CNS stimulation may also occur.  This is more common in children and overdose situations.  Additionally, CNS stimulation appears to occur more often with those antihistaminics that have relatively weak anti-cholinergic activity.  The second generation antihistaminics generally do not produce sedation as an adverse effect.

Antihistaminics may also exhibit mild alpha-adrenergic blockade.  This action generally manifests as orthostatic (postural) hypotension.  Those patients taking diuretics and/or other antihypertensives should be warned of the potentially greater risk of this effect when anti-histaminics are added to their regimen.

Promethazine (a phenothiazine antihistaminic) also possesses local anæsthetic and anti-dopaminergic activity.  At high doses, these actions may result in arrhythmias and movement disorders such as tardive dyskinesia or other Parkinsonian effects.

The specific kinetics of antihistaminics vary with the specific structure and metabolism of the respective compound.  Generally, the duration of action of older antihistamines is 4 to 6 hours, while many of the newer agents act for 12 - 24 hours or longer.  NOTE that while this is the duration of action for the majority of effects, the ability of antihistamines to reduce local itch and swelling in response to contact dermatitis may last much longer (up to 36 hours following a single dose).  Therefore, dosing may often be reduced and side effects minimised when anti-histaminics are used expressly for this purpose.

Some of the second generation antihistaminics (especially terfenadine and astimezole) may cause life-threatening arrhythmias.  These arrhythmias (a lengthening of the QT interval called torsade des pointes) are caused by the inactive prodrug, which produces these effects by blocking the delayed rectifier potassium channels in the conduction system of the heart.  In normal circumstances, these agents are activated by the hepatic microsomal system (cytochrome P₄₅₀) to metabolites that are responsible for the anti-histaminic activity.  In cases of hepatic dysfunction or failure, the prodrug is not metabolised and concentrations increase to a point that results in the arrhythmia.  The enzyme may also be inhibited by other drugs, especially the macrolide antibiotics (erythromycin, clarithromycin), antifungals (itraconazole, ketoconazole), and grapefruit juice.  This effect is not as pronounced with the antihistaminics loratidine, cetirizine, and acrivastine nor with the macrolide azithromycin or the antifungal fluconazole.  However, prudence dictates that any combination of second generation antihistamine and macrolide antibiotic or antifungal should be viewed as a potentially lethal drug interaction and therefore avoided.

Other drug interactions common with antihistaminics include any compounds that depress the CNS, leading to enhanced sedation/drowsiness.

H₁ antihistaminics have been found to be teratogenic in rodents.  While these effects have not been confirmed in humans, they should be considered dangerous and avoided during pregnancy.

SPECIFIC H₁ ANTI-HISTAMINICS

 Ethanolamines -- Diphenhydramine, Dimenhydrinate, Clemastine, Doxylamine, Carbinoxamine -- These agents have high anti-cholinergic activity with concommittant high incidences of sedation. They have relatively few gastrointestinal side effects.  Due to their anti-cholinergic activity, diphenhydramine and dimenhydrinate are some of the most effect anti-histaminics in preventing motion sickness.  Due to their sedative action, these are often employed as sleep aids.

Ethylenediamines -- Pyrilamine,  Tripelennamine -- Pyrilamine has fewer CNS effects relative to the ethanolamines.  It does, however, exhibit a greater incidence of GI effects.  It is most often used either as a sedative or to treat severe pruritus.   It is relatively more selective for the H₁  receptor.

Alkylamines -- Chlorpheniramine, Brompheniramine, Acrivastine -- These agents have little anti-cholinergic activity.  Consequently, they produce less sedation that other first generation anti-histaminics.  They also have a greater tendency to cause paradoxical CNS excitation.  They are among the most potent antihistaminics and are most commonly employed in the treatment of allergic and cold symptoms.  Acrivastine is a second generation, non-sedating anti-histaminic.

Piperazines -- Hydroxyzine, Cyclizine, Meclizine, Cetirizine --Hydroxyzine is used primarily for its effectiveness in controlling itch and rash associated with pruritic conditions.  It is also sometimes used as a mild anxiolytic.  Meclizine and cyclizine are used primarily to prevent motion sickness and treat vertigo.  While less effective than diphenhydramine in this respect, these agents are also less prone to adverse effects such as sedation or dry mouth.  Cetirizine is a second generation antihistamine and an active metabolite of hydroxyzine.

Phenothiazines -- Promethazine --This agent is used as an anti-emetic and to relieve severe pruritus and cold symptoms.  It has high anti-cholinergic activity, similar to that seen with the ethanolamine class of anti-histaminics.

Piperidines (1st Generation)  -- Azatadine, Cyproheptadine, Phenindamide -- These have relatively low anti-cholinergic activity.  Cyproheptadine and azatadine also exhibit anti-serotonergic activity.  Due to its ability to block both histamine and serotonin, cyproheptadine has been used to stimulate appetite.

Piperidines (2nd Generation) -- Fexofenadine, Levocabastine, Loratidine, and  (Astimezole and Terfenadine -- no longer marketed) -- These agents are all second generation antihistaminics.  As such, they possess little anti-cholinergic activity, do not readily cross the      blood brain barrier, and consequently are relatively non-sedating.  Fexofenadine is the active metabolite of terfenadine.

Phthalazinone (2nd Generation) -- Azelastine -- This second generation anti-histaminic is formulated for use as a nasal spray and ophthalmic drops for the local treatment of allergic reactions.