H1 Antagonists / Conventional Antihistaminics

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Chapter: Essential pharmacology : Histamine And Antihistaminics

These drugs competitively antagonize actions of histamine at the H1 receptors. The first compounds of this type were introduced in the late 1930s and have subsequently proliferated into an unnecessary motley of drugs.


(Conventional Antihistaminics)


These drugs competitively antagonize actions of histamine at the H1 receptors. The first compounds of this type were introduced in the late 1930s and have subsequently proliferated into an unnecessary motley of drugs. Nevertheless, they are frequently used for a variety of purposes. More commonly employed now are the less sedating second generation H1 antihistamines that have been added after 1980. Seemingly, H1 antihistaminics have diverse chemical structures, but majority have a substituted ethylamine side chain.


Pharmacological Actions


Qualitatively all H 1 antihistaminics have similar actions, but there are quantitative differences, especially in the sedative property.


1. Antagonism Of Histamine


They effectively block histamine induced bronchoconstriction, contraction of intestinal and other smooth muscle and triple response—especially wheal, flare and itArticle No. Fall in BP produced by low doses of histamine is blocked, but additional H2 antagonists are required for complete blockade of higher doses. Pretreatment with these drugs protects animals from death caused by i.v. injection of large doses of histamine. Release of Adr from adrenal medulla in response to histamine is abolished. Constriction of larger blood vessel by histamine is also antagonized. Action of histamine on gastric secretion is singularly not affected by these drugs.


2. Antiallergic action


Many manifestations of immediate hypersensitivity (type I reactions) are suppressed. Urticaria, itching and angioedema are well controlled. Anaphylactic fall in BP is only partially prevented. Asthma in man is practically unaffected though anaphylactic bronchoconstriction in guinea pig is largely prevented. This tissue and species dependence of response probably reflects extent of involvement of histamine in the reaction. It is now well established that leukotrienes (C4 and D4) and PAF are more important mediators for human asthma.


3. CNS


The older antihistamines produce variable degree of CNS depression. This appears to depend on the compound’s ability to penetrate bloodbrain barrier and its affinity for the central (compared to peripheral) H1 receptors. Individual susceptibility to different agents varies considerably, but an overall grading of the sedative property is presented in Table 11.2. Some individuals also experience stimulant effects like restlessness and insomnia. Excitement and convulsions are frequently seen at toxic doses. The second generation anti-histaminics are practically non-sedating.


Certain H1 antihistamines are effective in preventing motion sickness. It is not certain whether this is due to antagonism of histamine in the brain or reflects antimuscarinic property of these drugs. Promethazine also controls vomiting of pregnancy and other causes.


Promethazine and few other antihistaminics reduce tremor, rigidity and sialorrhoea of parkinsonism. Anticholinergic and sedative properties underlie the benefit.


Some H1 antihistamines are also effective antitussives.


1.     Anticholinergic Action


Many H1 blockers in addition antagonize muscarinic actions of AArticle No. The anticholinergic action can be graded as:


High Low  Minimal/Absent


Promethazine        Chlorpheniramine Fexofenadine

Diphenhydramine Hydroxyzine         Astemizole

Dimenhydrinate    Triprolidine Loratadine

Pheniramine Cyclizine     Cetirizine

Cyproheptadine              Mizolastine


If used concurrently with atropine or its substitutes, phenothiazines, tricyclic antidepressants or disopyramide, the anticholinergic action adds up.


2.     Local Anaesthetic


Some drugs like pheniramine, have strong while others have weak membrane stabilizing property. However, they are not used clinically as local anaesthetic because they cause irritation when injected s.c.


Membrane stabilizing activity also confers antiarrhythmic property to these compounds.


6. BP


Most antihistaminics cause a fall in BP on i.v. injection (direct smooth muscle relaxation). However, this is not evident on oral administration.




The classical H1 antihistaminics are well absorbed from oral and parenteral routes, metabolized in the liver and excreted in urine. They are widely distributed in the body and enter brain. The newer compounds penetrate brain poorly. Duration of action of most agents is 4–6 hours, except meclizine, loratadine, cetirizine and fexofenadine which act for 12–24 hours or more.


Side Effects And Toxicity


Side effects with first generation H1 antihistaminics are frequent, but are generally mild. Individuals show marked differences in susceptibility to side effects with different drugs. Some tolerance to side effects develops on repeated use.


Sedation, diminished alertness and concentration, light headedness, motor incoordination, fatigue and tendency to fall asleep are the most common. Objective testing shows impairment of psychomotor performance. Patients should be cautioned not to operate motor vehicles or machinery requiring constant attention. Alcohol synergises in producing these effects as do other CNS depressants. Few individuals become restless, nervous and are unable to sleep. Second generation compounds are largely free of CNS effects.


Dryness of mouth, alteration of bowel movement, urinary hesitancy and blurring of vision can be ascribed to anticholinergic property.


Epigastric distress and headache are also common.

Local application can cause contact dermatitis.

Some like cyclizine and fexofenadine are teratogenic in animals; but not in humans; caution is nevertheless to be exercised during pregnancy.


Acute overdose produces central excitation, tremors, hallucinations, muscular incordination, convulsions, flushing, hypotension, fever and some other features of belladonna poisoning. Death is due to respiratory and cardiovascular failure.


Second Generation Antihistaminics


The second generation antihistaminics (SGAs) may be defined as those H1 receptor blockers marketed after 1980 which have one or more of the following properties :


·        Higher H1 selectivitiy: no anticholinergic side effects.


·        Absence of CNS depressant property.


·        Additional antiallergic mechanisms apart from histamine blockade: some also inhibit late phase allergic reaction by acting on leukotrienes or by antiplatelet activating factor effect.


Some recent compounds like fexofenadine and cetirizine that are active metabolites of earlier drugs have also been referred as ‘third generation antihistamines’, but this has not been accepted by an international concensus group of experts.


These newer drugs have the advantage of not impairing psychomotor performance (driving etc. need not be contraindicated), produce no subjective effects, no sleepiness, do not potentiate alcohol or benzodiazepines. Some patients do complain of sedation, but incidence is similar to placebo. However, they have a narrow spectrum of therapeutic usefulness which is limited by the extent of involvement of histamine (acting through H1 receptors) in the disease state. Their principal indications are:


·        Allergic rhinitis and conjunctivitis, hay fever, pollinosis—control sneezing, runny but not blocked nose, and red, watering, itchy eyes.


·        Urticaria, dermographism, atopic eczema.


·        Acute allergic reactions to drugs and foods. They have poor antipruritic, antiemetic and antitussive actions.




It is the active metabolite of terfenadine, the first nonsedating SGA that was withdrawn because of several deaths due to polymorphic ventricular tachycarida (Torsades de pointes) occurring with its higher doses or when it was coadministered with CYP3A4 inhibitors (erythromycin, clarithromycin, ketoconazole, itraconazole, etc.). This toxicity is based on blockade of delayed rectifier K+ channels in the heart at higher concentrations. Astemizole is another SGA banned for the same reason. Fexofenadine has a low propensity to block delayed rectifier K+ channels, does not prolong QTc interval; no interaction with CYP3A4 inhibitors have been reported. It is largely free of arrhythmogenic potential, but some cases of ventricular arrhythmia in patients with preexisting long QT interval have been reported. Thus, it is not entirely safe in patients with long QT, bradycardia or hypokalemia.



Fexofenadine does not cross blood-brain barrier—does not produce sedation or impair psychomotor performance and is free of atropinic side effects. It is rapidly absorbed, excreted unchanged in urine and bile, has plasma t½ 11– 16 hours and duration of action 24 hours. Though erythromycin and ketoconazole increase its blood levels, but no arrhythmias have been observed.


Dose: For allergic rhinitis 120 mg OD; for urticaria and other skin allergies 180 mg OD.





Another longacting selective peripheral H1 antagonist which lacks CNS depressant effects and is fast acting. It is partly metabolized by CYP3A4 to an active metabolite with a longer t½ of 17 hr, but has not produced cardiac arrhythmia in overdose, though seizures are reported. No interaction with macrolides or antifungals has been noted. Good efficacy has been reported in urticaria and atopic dermatitis.





It is the major active metabolite of loratadine effective at half the dose. Noninterference with psychomotor performance and cardiac safety are documented.





It is a metabolite of hydroxyzine with marked affinity for peripheral H1 receptors; penetrates brain poorly, but subjective somnolence has been experienced at higher doses. It is not metabolized; does not prolong cardiac action potential or produce arrhythmias when given with erythromycin/ketoconazole.


Cetirizine in addition inhibits release of histamine and of cytotoxic mediators from platelets as well as eosinophil chemotaxis during the secondary phase of the allergic response. Thus, it may benefit allergic disorders by other actions as well. It attains high and longer lasting concentration in skin, which may be responsible for superior efficacy in urticaria/atopic dermatitis, as well as for once daily dosing despite elimination t½ of 710 hr. It is indicated in upper respiratory allergies, pollinosis, urticaria and atopic dermatitis; also used as adjuvant in seasonal asthma.





It is the active R(–) enantiomer of cetirizine. It is effective at half the dose and appears to produce few side effects.





This newer H1 blocker has good topical activity; in addition inhibits histamine release and inflammatory reaction triggered by LTs and PAF; and has bronchodilator property. After intranasal application it has been shown to down regulate intracellular adhesion molecule1 (ICAM1) expression on nasal mucosa. Its t½ is 24 hr, but action lasts longer due to active metabolite. Its metabolism is inhibited by CYP 3A4 inhibitors. Given by nasal spray for seasonal and perennial allergic rhinitis it provides quick symptomatic relief lasting 12 hr. Stinging in the nose and altered taste perception are the local side effects. Some somnolence has been reported on nasal application and a tendency to weight gain noted after oral use.




This nonsedating antihistaminic is effective in allergic rhinitis and urticaria by single daily dosing despite a t½ of 8–10 hr and no active metabolite.




Another newer SGA that rapidly gets converted to the active metabolite carbastine having a t½ of 10–16 hr. It is non-sedating and active in nasal and skin allergies. Animal studies have found it to prolong QTc interval which makes it liable to arrhythmogenic potential and CYP3A4 interaction, but actual reports are still few.




This recently introduced antihistaminic has additional PAF antagonistic property, and is indicated in allergic rhinitis.




The uses of H1 antihistaminics are based on their ability to block certain effects of histamine released endogeneously, as well as on sedative and anticholinergic properties.


1. Allergic Disorders


Antihistaminics do not suppress AG: AB reaction, but block the effects of released histamine—are only palliative. They effectively control certain immediate type of allergies, e.g. itching, urticaria, seasonal hay fever, allergic conjunctivitis and angioedema of lips, eyelids, etc. However, their action is slow—Adr alone is lifesaving in laryngeal angioedema. Similarly, they cannot be relied upon in anaphylactic shock and have a secondary place to Adr. Benefits are less marked in perennial vasomotor rhinitis, atopic dermatitis and chronic urticarias; combination with an H2 antagonist succeeds in some cases of chronic urticaria not responding to H1 antagonist alone.


The antihistaminics are ineffective in bronchial asthma: reasons may be—

a.   Leukotrienes (C4, D4) and PAF are more important mediators than histamine.

b.     Concentration of antihistamines attained at the site may not be sufficient to block high concentration of histamine released locally in the bronchi.


Certain newer compounds like cetirizine have adjuvant role in seasonal asthma.


Antihistaminics are also ineffective in other types of humoral and cell mediated allergies because histamine is not involved. They do suppress urticaria and swellings in serum sickness, but not other components of the syndrome.


Type I hypersensitivity reactions to drugs (except asthma and anaphylaxis) are suppressed. Some skin rashes also respond.


2. Other Conditions Involving Histamine


Antihistaminics block symptoms produced by histamine liberators; afford symptomatic relief in insect bite and ivy poisoning. Abnormal dermographism is suppressed. They have prophylactic value in blood/saline infusion induced rigor.


3. Pruritides


Many conventional antihistamines have antipruritic action independent of H1 antagonism. Though relief is often incomplete, older antihistaminics remain the first choice drugs for idiopathic pruritus.


4. Common Cold


Antihistaminics do not affect the course of the illness but may afford symptomatic relief by anticholinergic (reduce rhinorrhoea) and sedative actions. The newer nonsedating antihistamines are less effective in this respect.


5. Motion Sickness


Promethazine, diphenhydramine, dimenhydrinate and cyclizine have prophylactic value in milder types of motion sickness; should be taken one hour before starting journey. Promethazine can also be used in morning sickness, drug induced and postoperative vomiting, radiation sickness. Cyproheptadine has appetite stimulating effect; has been used in underweight children.


6. Vertigo


Cinnarizine is the H1 antihistamine having additional anticholinergic, anti5HT, sedative and vasodilator properties which has been widely used in vertigo. It modulates Ca2+ fluxes and attenuates vasoconstrictor action of many endogenous substances.


Cinnarizine inhibits vestibular sensory nuclei in the inner ear, suppresses postrotatory labyrinthine reflexes, possibly by reducing stimulated influx of Ca2+ from endolymph into the vestibular sensory cells. Beneficial effects have been reported in Méniére’s disease and other types of vertigo. Side effects are sedation and mild g.i. upset.


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