Antihistamines: a review

300 

REVIEW ARTICLE 

The chemical compound §-imidazole-ethylamine 

was first synthesised in 1907. It was later given 

the name "histamine" (meaning "an amine present 

in all tissues") 1 , and its role in allergy and inflammation 

was discovered shortly thereafter. The first 

antihistamines to be used in medical therapy (fenbenzamine 

and pirylamine) were developed 

during the '30s at the Pasteur Institute. In 1946, 

two further drugs were independently discovered 

in the U.S.A.: diphenhydramine and tripelennamine 

2 . Since that time, literally hundreds of molecules 

with antihistamine properties have been 

developed, and their use in clinical therapy has 

incessantly grown throughout the past 50 years. 

The classical antihistamines have always been 

associated with sedation and anticholinergic 

effects. Since the '80s research has attempted to 

avoid or prevent these unwanted side effects 

through the investigation and development of new 

active principles. Over the last decade, some of 

these new compounds have been shown to be 

associated to important drug interactions and 

potential toxicity. 

The aim of the present review is to provide a 

bibliographic summary on the clinical pharmacology 

of the main antihistamines, their safety profiles 

and their place in the therapeutic armamentarium 

for the management of allergic diseases. 

HISTAMINE AND ITS RECEPTORS 

Histamine is a chemical mediator participating 

in many cell physiology processes, among them 

H1 Antihistamines: a review 

I. J‡uregui Presa 

Allergy Unit, Basurto Hospital, Bilbao, Spain 

allergic reactions, inflammation gastric acid secretion 

and -probably- central and peripheral neurotransmission 

3 . It exerts its effects through three 

distinct types of postsynaptic receptors. 

H1 receptors. These receptors may be identified 

in the bronchial and gastrointestinal smooth muscle 

and in the brain. They are responsible for the 

constriction of the bronchial and vascular smooth 

muscle, for the activation of the afferent vagal 

nerves of the airways and of the cough receptors, 

for the increase in vascular permeability, for the 

local irritative manifestations such as pruritus and 

pain, and for the release of inflammatory mediators 

and the recruitment of inflammatory cells 4 . 

H2 receptors. These are present in the gastric 

mucosa, in the uterus and in the brain. They also 

increase vascular permeability, and they stimulate 

the gastric acid secretion 4 . 

H3 receptors. These may be found in the brain 

and in the bronchial smooth muscle. They are responsible 

for cerebral vasodilation and might be 

involved in the negative feedback system through 

which histamine inhibits its own synthesis and 

release from the nerve endings 3 . The main efforts 

in the investigation of antihistamine have been 

directed at the specific inhibitors of the H1 and H2 

receptors. The H3 antagonists, currently in the 

phase of animal experimentation, might find their 

use in the therapy of various processes affecting 

the central nervous system (CNS) 5 . The present 

review will be centred exclusively on the antagonists 

of the H1 receptors, which in pharmacological 

usage receive the generic denomination of 

antihistamines. 

Alergol Inmunol Clin, October 1999 Vol. 14, No. 5, pp. 300-312

No. 5 H1 Antihistamines: a review 301 

CHEMISTRY OF THE ANTIHISTAMINES 

The typical antihistamines have an ethylamine 

side chain (similar to that of histamine itself) 

which is united to one or more cyclic groups. The 

structural characteristics of the H1 receptor antagonists 

have been historically used for classifying 

them into six broad chemical families: ethanolamines, 

ethylenediamines, alkylamines, phenothiazines, 

piperazines and piperidines (Table I) 6 . 

Several of the new H1 receptor antagonists are 

chemically speaking piperidines, or at least they 

possess piperidine rings (Fig. 1). Many of them 

are direct derivatives of the parent compound or 

active metabolites of the primary molecules (such 

as cetirizine from hydroxyzine, or fexofenadine 

from terfenadine) 6 . 

Generally, the molecular nucleus of the H1 receptor 

antagonists is necessary for their H1 affinity and 

selectivity, while the side chains or radicals influence 

other properties of the molecules. As an example, 

the first-generation antihistamines contain aromatic 

rings and alkyl substituents which render them 

lipophyllic, thus explaining their ability to cross the 

haemato-encephalic barrier (HEB) 7 . Efforts have 

been directed at suppressing or preventing this property 

by adding or eliminating radicals in the molecular 

structure; thus, terfenadine requires its phenylbutanol 

structure in order not to cross the HEB 4,8 , 

and loratadine has a carboxyethyl ester radical which 

limits its distribution in the CNS 9 . 

The ethylamine group, which is common to all 

typical antihistamines, is also shared by many anticholinergic 

and adrenergic blocking compounds. 

For this reason, these compounds have antidopaminergic, 

antiserotoninergic and antimuscarinic 

effects, which in many patients become undesirable 

side effects. They have, however, also been taken 

advantage of for therapeutic purposes: the antiemetic 

and antikinetotic actions of many antihistamines 

(diphenhydramine, dimenhydrinate, phenothiazines) 

are predominantly due to their central sedative 

and anticholinergic properties 9 . Some antihistamines, 

such as cyproheptadine, ketotifen, astemizole 

and cetirizine also induce increased appetite, which 

has been ascribed to an antiserotoninergic action 9 . 

This undesired side effect, which is well documented 

particularly in the case of cyproheptadine, has 

been often taken advantage of in "reconstituents" 

and preparations for the treatment of hypo-orexia 10 . 

Table I. Chemical classification of the H1 antihistamines 

Chemical group Typical compounds Second-generation 

(first generation) compounds 

Alkylamines Bromphenyramine Acrivastine 

Chlorphenyramine 

Triprolidine 

Ethanolamines Diphenhydramine 

Dimenhydrinate 

Doxylamine 

Carbinoxamine 

Clemastine 

Ethylenediamines Pirylamine 

Tripelennamine 

Antazoline 

Phenothiazines Promethazine Mequitazine 

Piperazines Buclyzine, Ciclyzine 

Cinarizine, Flunarizine Oxatomide 

Hydroxyzine Cetirizine 

Piperidines Azatadine Loratadine 

Cyproheptadine Astemizole 

Ketotifen Levocabastine 

Mizolastine 

Ebastine 

Terfenadine 

Fexofenadine 

Miscellany Azelastine 

(ftalazinone 

derivative) 

MECHANISMS OF ACTION 

The antihistamines behave as competitive antagonists 

of histamine: they bind to the H1 receptor 

without activating it, and thus prevent histamine 

from binding to and activating this receptor. The 

binding of many antihistamines is readily reversible 

but some of them, such as terfenadine and 

astemizole, are not easily dissociated from their 

binding to the receptors 11 . Even though there are 

some specific molecules for which such effects 

have been documented, antihistamines as a group 

do not chemically inactivate histamine, nor do 

they antagonise it in a physiological sense, nor do 

they in any manner prevent its release 9 . 

Many recent studies suggest that some H1 

receptor antagonists might also have antiinflammatory 

or antiallergic properties in the broadest 

sense of those concepts. Although the first publication 

in this context referred to azatadine 12 , this 

type of additional actions has been later attributed 

to many second-generation antihistamines.

302 I. J‡uregui Presa Volume 14 

Cetirizine 13,14 reduces the attraction of inflammatory 

cells to the inflammatory focus after antigen 

challenge and inhibits the expression of the intercellular 

adhesion molecule 1 (ICAM-1) on the surface 

of epithelial cells. It also might be able to block the 

antigen-induced production of leukotrienes (LTC 4) 15 . 

Loratadine and its metabolite decarboethoxyloratadine 

inhibit the release of tryptase and amacroglobulin 

16 , of interleukins (IL) 6 and 8 17 and 

of leukotrienes and prostaglandin D2 (PGD2) 18 , and 

also the expression of ICAM-1 and of HLA-II 

antigens on the surface of epithelial cells 19 . 

Terfenadine inhibits the inflammatory cellular 

infiltrate and the eosinophil activation products in 

nasal lavage fluid and also the expression of surface 

ICAM-1 20 . It may also inhibit the release of leukotrienes 

from basophils and eosinophils and of 

histamine from basophils, as well as inhibiting skin 

reactivity to the platelet activation factor (PAF) 15 . 

Topical azelastine, which was initially studied as 

a "dual action" antihistamine with a clinical profile 

similar to that of ketotifen or oxatomide 2 , also seems 

to inhibit the eosinophyllic infiltrate and the expression 

of surface ICAM-1 in nasal epithelial cells 21 . 

Ebastine might have an antagonist action on the 

IgE-induced release of PGD2 and LTC 4/D 4 22 . 

A recent study in a rat model ascribes to mizolastine 

an antiinflammatory effect on the skin 

reaction induced by arachidonic acid 23 . 

Finally, fexofenadine inhibits the spontaneous 

release of IL-6 in fibroblast cultures 24 and the 

eosinophil-induced release of IL-8 and GM-CSF, 

as well as the expression of surface ICAM-1 in 

cultures of nasal epithelial cells. 

These antiinflammatory effects of antihistamines 

are not considered to be linked to H 1 receptor blockage. 

As they have mostly been demonstrated in 

vitro and with experimental concentrations of the 

drugs that are much higher than those achieved in 

vivo with the usual pharmacological dosages, their 

relative importance within the overall spectrum of 

the clinical efficacy of these drugs is still unknown 15 . 

PHARMACOKINETICS AND 

PHARMACODYNAMICS 

Almost all the H1 receptor antagonists have 

adequate oral absorption and can achieve maximal 

plasma concentrations within the 24 hours follo- 

Cl 

HN 

N 

HISTAMINA 

HISTAMINE 

CH 2 CH 2 NH 2 

CHLORPHENYRAMINE 

CLORFENIRAMINA 

N 

PRIMERA FIRST-GENERATION GENERACIîN DE ANTAGONISTAS H1 RECEPTOR ANTAGONISTS 

DE RECEPTORES H1 

Cl 

CH CH 2 CH 2 

CH O CH 2 

CH 2 

DIPHENHYDRAMINE 

DIFENHIDRAMINA 

Fig. 1a. Primary structure of histamine and of various H1 


wing administration. Most of the second-generation 

antihistamines, with the exception of acrivastine, 

cetirizine, levocabastine, fexofenadine and 

perhaps some other active metabolites experience 

hepatic first-pass metabolism, so that the plasma 

concentrations of the parent drugs are usually 

indetectable a few hours after administration 26 . 

Nevertheless, the effects of the antihistamines, as 

documented in studies of inhibition of histamineinduced 

skin reactions, persist over a time that is 

variable for each compound (Table II). This might 

be due to a greater tissue concentration, or to active 

metabolites maintaining the effect 27 . 

Because all the H1 receptor antagonists inhibit 

the skin reactions induced by histamine, this test 

has become a standardised biologic test for the 

action of antihistamines 15 . However, as several 

authors have pointed out 28 , there is not always a 

N 

OH N N CH2CH2 O CH2CH2 O 

H 

N 

CH 3 

CH 3 

CH 3 

CH 3 

HIDROXICINA 

HYDROXYZINE


HO N 

CH 3 

N 

CH CH 

N 

C CH CH 2 

ACRIVASTINE 

ACRIVASTINA 

CH 2 CH 2 CH 2 CH C 

TERFENADINA 

TERFENADINE 

O 

LORATADINA 

LORATADINE 

SEGUNDA SECOND-GENERATION GENERACIîN DE ANTAGONISTAS H1 RECEPTOR ANTAGONISTS 

DE RECEPTORES H1 Fig. 1b. Primary structure of histamine and of various H1 antihistamines. 

correlation between the degree of inhibition of the 

skin response and the clinical efficacy of the 

various drugs. 

All the "classical" antihistamines and also many 

of the second-generation ones (terfenadine 29 , ebastine 

30 , astemizole 31 , loratadine 26 , mizolastine 32 ) are 

metabolised to a greater or lesser extent by the 

hepatic cytochrome p-450 system (CYP), a fact of 

utmost importance in the development of drug interactions 

and drug toxicity. The CYP is an enzymatic 

system responsible for drug metabolism and 

detoxification present in the liver and in other tissues, 

and its constituent isoenzymes are classified 

into "families" according to the similarity of their 

aminoacid sequences 33 . As a result of genetic variability, 

the number of p-450 isoenzymes varies, and 

each drug is metabolised in a different manner 15 . 

Astemizole or terfenadine are metabolised by the 

3A4 family (CYP3A4). Within this same family, 

some substances can behave as enzymatic inhibitors 

while others act as enzyme substrates, and this 

OH 

N C O CH2CH2 O 

C OH 

HO N CH 2 CH 2 CH 2 C 

Q 

Q HCl 

N 

OH 

FEXOFENADINE 

FEXOFENADINA 

CH 3 

C 

CH 3 

CH 3 

CH 3 

CH 3 

COOH 

CH 2 

O 

AZELASTINE 

AZELASTINA 

N 

N 

N 

Cl 

CH N N CH2 CH2 O CH2 C OH 

CH 3 

ASTEMIZOLE 

ASTEMIZOL 

LEVOCABASTINE 

LEVOCABASTINA 

HC O 

N CH2 CH2 CH2 C C 

HC O 

EBASTINE 

EBASTINA 

N CH 2 CH 2 CH 2 C C 

CAREBASTINE 

CAREBASTINA 

F 

NC 

gives rise to multiple interactions 33 . Table III summarises 

some inhibitors and substrates of the 

CYP3A4. It should be noted that natural flavonoids 

present in grape juice may also inhibit the 3A4 

family 33,34 and that erythromycin is at the same time 

inhibitor and substrate for the CYP3A4 33 . 

On the other hand, erythromycin is by itself 

able to block some potassium channels in the 

myocardium 35 . This might be fundamental, as will 

be explained later, in its interactions with some 


SIDE EFFECTS ON THE 

CARDIOVASCULAR SYSTEM 

The potential cardiotoxicity of antihistamines 

was first reported in relation with astemizole 36 and 

later with terfenadine 37 . Considerable attention was 

focused on the latter drug, however, possibly because 

it was the most widely used one in the USA 38 . 

O 

N 

H 

O 

H 

CH 3 

CH 3 

CH 3 

CH 3 

CH 3 

O 

O 

C OH 

CH 3 

COOH


Table II. Chemical classification of the H1 antihistamines 15,24,26 

Drug Dose Plasma elimination Skin test Protein binding Clearance 

(mg/day) half-life suppression (%) (ml á min -1 á kg -1 ) 

Acrivastine 16 - 24 ~2 hours 8 hours 50 4.41 

Astemizole 10 - 20 12 - 20 days 6 - 8 weeks 97 11.0 

Azelastine (oral) 4 - 8 22 - 42 hours 1 week 77 - 88 8.45 

Bromphenyramine 9 - 18 24.9 hours 3 - 9 hours 

Chlorphenyramine 6 - 12 24.2 hours 24 hours 

Clemastine 2 - 3 7 - 12 hours 10 - 24 hours 

Cetirizine 10 7 - 10 hours 24 - 72 hours 93 - 98 0.8 

Hydroxyzine 75 20 hours 2 - 36 hours 

Ebastine 10 15 hours 28 hours 97.7 1.3 - 2.0 

Levocabastine 

Nasal spray 0.6 35 - 40 hours 10 - 12 hours 55 0.43 

Eye drops 0.2 35 - 40 hours 4 hours 

Loratadine 10 8 - 24 hours 12 - 14 hours 97 - 99 ? 

Mizolastine 10 14.5 hours 24 hours 1.15 

Noberastine 10 15 hours 32 - 72 hours 

Terfenadine 120 17 hours 24 - 72 hours 97 8.8 

Fexofenadine 120 - 180 14.4 hours 24 - 72 hours 

The reported arrhythmia associated to astemizole 

and terfenadine is a polymorphic ventricular tachycardia 

known by the name of torsades de pointes 

because of its changing electrical axis in the ECG, 

with waves of alternating amplitudes and directions 

(Figure 2). Torsades de pointes may appear as acute 

episodes with haemodynamic compromise and 

even sudden cardiac death 39 and are associated to a 

lengthening of the QT interval in the sinus rhythm 

ECG. The QT interval itself depends on the duration 

of the cardiac action potential, which is in its 

turn dependent on the ionic currents and fluxes in 

the myocardium and most particularly on the socalled 

potassium rectifier channel 40 . 

As already pointed out, terfenadine is a prodrug 

acting through its acid metabolite (terfenadine 

carboxylate, or fexofenadine), and this conversion 

occurs through a CYP3A4-dependent hepatic 

first-pass metabolism. Terfenadine is a potent 

blocker of the potassium rectifier channel 41 . Its 

accumulation in the organism because of overdosage 

or of the concomitant administration of other 

substrate drugs or CYP3A4 inhibitors may lengthen 

the heart rate-corrected QT interval (QTc). If 

the concomitant drug is erythromycin, which is at 

the same time a CYP3A4 substrate and a 

CYP3A4 inhibitor 33 and also a potassium rectifier 

channel blocker 35 , the heart repolarisation derangements 

will be even more marked. 

This effect might perhaps be shared by all the 

piperidine antihistamines 42 , but it has been 

demonstrated mainly with astemizole, terfenadine 

and ebastine 43 at a dosage one- to fourfold the respective 

peripheral antihistamine one although not 

with the active metabolites fexofenadine and carebastine, 

in experimental models 44,45 . Nevertheless, 

an isolated clinical observation has been published 

of torsades de pointes and lengthened QT 

interval in a patient with indetectable levels of 

astemizole and "therapeutic" concentrations of its 

major metabolite demethyl-astemizole 46 . 

Cetirizine, an active metabolite of hydroxyzine, 

does not prolong the QTc interval at dosages up to 

sixfold the indicated therapeutic ones 47 . Loratadine 

has the same interactions with macrolides and 

imidazoles as the other piperidines, yet this does 

not induce clinically significant changes in the 

QTc interval 48,49 . It has been reported that loratadine, 

contrary to astemizole, terfenadine and ebastine, 

does not block the potassium channels even at 

concentrations 100-fold its normal plasma level 50 . 

Even so, and according to WHO drug surveillance 

data, loratadine and cetirizine have also been 

associated, though much less frequently than terfenadine 

or astemizole, to reports of sudden or 

cardiac death 51 . There are also recent experimental 

studies suggesting that loratadine might be able to 

block certain potassium channels 52 .


Table III. Inhibitors of the 3A4 family of cytochrome P-450 

(CYP3A4) 

Enzymatic inhibitors 

Cimetidine, Ranitidine 

Clarythromycine, Erythromycine, Troleandomycine (TAO) 

Ketoconazole, Itraconazole 

Fluvoxamine, Norfluoxetine (a metabolite of fluoxetine) 

Natural flavonoids in grape juice 

Enzymatic substrates 

Astemizole, Terfenadine, Ebastine, Loratadine, Mizolastine 

Cisapride 

Erythromycin 

A number of added risk factors for the development 

of torsades de pointes in patients under treatment 

with antihistamines have been considered, 

such as previous hepatic dysfunction, hypokaliaemia, 

hypomagnesaemia, bradycardia situations and 

the congenital long QT syndrome (Table IV) 33,40 . 

Even though these side effects have not been as 

intensively investigated for other H1 antagonists, a 

quinidine-like effect on myocardial conduction has 

been described for antihistamines as a group 9. A 

cohort study actually demonstrated a greater incidence 

of ventricular arrhythmias and cardiac arrest 

in the group of patients receiving O.T.C. antihistamines 

as compared to the groups receiving terfenadine 

or clemastine 53 . However, other studies have 

not evidenced actions on cardiac electrophysiology 

for chlorphenyramine or pirylamine, suggesting 

that this may be a piperidine effect or a specific one 

of astemizole, terfenadine and ebastine 54 . 

The initial worry that cardiotoxicity might 

represent a class effect of the antihistamines, 

however, appears to be unfounded 38 considering 

that fexofenadine (with negligible hepatic metabolism 

24 ) and probably further active metabolites 

with potent H 1-antagonist action 45 are devoid of 

this adverse effect. Whatever the case may be, it 

appears to be important to keep in mind all the 

factors already pointed out (Table IV) when prescribing 

antihistamines in clinical practise. 

ANTIHISTAMINES IN BRONCHIAL ASTHMA 

There is a long-standing belief that antihistamines 

may be harmful in asthmatic patients because 

Table IV. Risk factors for ventricular arrhythmias in patients 

receiving antihistamines 33,40 

1. Coadministration of other drugs 

a. Agents which prolong the QT interval, such as quinidine 

or erythromycin 

b. Enzymatic substrates/inhibitors of CYP3A4 (Table III) 

2. Preexistent liver disease 

3. Electrolyte balance derangements 

a. Hypokaliemia 

b. Hypomagnesemia 

4. Congenital long QT syndrome 

5. Bradycardia situations 

of the mucosal dryness effect of the anticholinergic 

action of the initial preparations to which the 

induction of bronchial asthma in children was 

ascribed 55 . However, and considering that histamine 

causes bronchial constriction and oedema, it 

appears to be logical to think that antihistamines 

might revert some of its effects on the bronchial 

tree, and that they are not contraindicated in asthmatic 

patients 56 . In this context, there is ample 

experience in Spain with ketotifen, and a number 

of studies suggest that azelastine, cetirizine, loratadine, 

terfenadine and astemizole might at least 

block the bronchospasm induced by histamine 57 . 

In any case, the effects of histamine in the latephase 

reaction have not been fully clarified and 

further studies are warranted for defining the 

effects of H1 antagonism in this late phase, particularly 

in the case of the antihistamines with additional 

antiinflammatory properties 15 . 

As the aim of the present review is to try to 

define the place of the principal antihistamines in 

the therapeutic armamentarium, a brief chemical 

and therapeutic discussion of the main H1 antihistamines 

currently used in Spain follows as a conclusion. 

"CLASSICAL" H1 ANTIHISTAMINES 

Chlorphenyramine and dextrochlorphenyramine. 

The prototypes of the alkylamines (propylamines), 

chlorphenyramine and its isomer dextrochlorphenyramine 

are used in a host of O.T.C. 

"anticatarrhal" preparations, usually in associations 

with vasoconstrictors, expectorants and analgesics. 

Dexchlorphenyramine is furthermore the 

only antihistamine available for parenteral use in


Fig. 2. Ventricular tachycardia of the "torsades de pointes" variety. Simultaneous recording of leads I, II, III and V1. 

our country 10 . Their plasma half-life is about 24 

hours, the same as the duration of the suppression 

of the skin test with histamine 57 (Table II). The 

rationale for their retarded-release formulations 

("Repetabs") is mainly to delay the plasma concentration 

peak in order to reduce the adverse 

CNS 4 effects representing the main problem of 

these drugs: at therapeutic dosages they cause 

somnolence, abatement of the reflexes and electroencephalographic 

(EEG) changes 58 . 

Diphenhydramine. In Spain, this drug is at present 

only available in some anticatarrhal associations 

and as an hypnotic 10 because of the intensity 

of its CNS effects 58 . Its derivative dimenhydrinate 

is widely used in our country as an antikinetotic. 

Clemastine. This is the prototype of the ethanolamines, 

the same chemical family as diphenhydramine, 

in Spain. It is currently available only 

for oral administration 10 . Its plasma half-life is 7- 

12 hours, with a skin test suppression period of 

12-24 hours. Its anticholinergic, antidopaminergic 

and antiserotoninergic affects are similar to those 

of the other "classical" antihistamines 9 . 

Cyproheptadine and azatadine. With a very 

close structural correlation between them, the two 

classical piperidines are characterised by their 

potent antiserotoninergic, anticholinergic and 

sedative effects. The first one of these effects has 

been taken advantage of for indications such as 

Cushing's syndrome, the carcinoid syndrome or 

vascular migraine 9 , and also in the management of 

hypo-orexia 10 . Azatadine is the parent compound 

of loratadine. 

Hydroxyzine. This drug has an elimination halflife 

of 14-20 hours in the adult and concentrates 

rapidly in the skin, so that sustained high skin 

concentrations can be observed after both single 

and multiple dosing; it can inhibit the response to 

histamine during at least 36 hours after a single 

dose in healthy adult subjects 4 . It is classically 

considered to be the most effective antihistamine 

for the management of pruritus 59 , an effect that is 

in part attributable to its potent sedative action 

(which has been taken advantage of for therapeutic 

purposes). 

Cinarizine and flunarizine. These classical 

piperazines, which are structurally different from 

hydroxyzine and cetirizine, have been mostly 

used for their antikinetotic activity. Flunarizine is 

the bi-fluorinated derivative of cinarizine and also 

has a calcium channel-blocking action 6 ; it is used 

for prophylaxis of migraine and vertigo and in the 

management of cerebral and peripheral vascular 

conditions. 

Promethazine. An ethylamine derivative of 

phenothiazine, this compound has the same sedative 

characteristics of other phenothiazine drugs, 

together with potent antihistamine and antikineto-


tic actions 9 . During the '70s and '80s it was one of 

the most widely used antihistamines in our 

country despite its potential toxicity: it can cause 

blood dyscrasias, neuro- and hepatotoxicity and 

diverse skin reactions such as contact urticaria, 

systemic contact dermatitides and phototoxic and 

photoallergic reactions 60 . 

SECOND-GENERATION H 1 

ANTIHISTAMINES 

Mequitazine. A phenothiazine derivative similar 

to prometazine but without sedative effects at 

the recommended dosages; this characteristic has 

been attributed in principle to a greater affinity of 

the drug for the peripheral than for the central H1 

receptors 2 . Similar to other antihistamines, mequitazine 

has evidenced bronchodilator activity 

which was in this case ascribed to the calmodulininhibiting 

ability of phenothiazines, which would 

thus interfere the action of phospholipase A 2 61 . 

With the exception of the absence of sedation at 

low dosages, its adverse effects are those of phenothiazines 

as a group 9 . 

Ketotifen. A derivative of the tricyclic compound 

benzo-cyclo-heptathiofene, this drug has 

been marketed as a membrane stabiliser for the 

effector cells of the allergic reactions. Its pharmacologic 

profile is similar to that of the cromones, 

and it is orally active 62 . Its main action, however, 

is a double competitive and non-competitive inhibition 

of the H1 receptor 2 . It shares with other 

older antihistamines the sedative and antiserotoninergic 

effects 2,6,9 . 

Oxatomide. This is a piperazine and structurally 

and chemically very similar to the antikinetotic 

cinarizine. Also oxatomide was marketed as a 

mastocyte degranulation inhibitor 63 ; however, 

and similar to ketotifen, its main effects are H1 

antihistaminic, anticholinergic and antiserotoninergic 

2,64 . Recent publications from Japan stress its 

various antiinflammatory and antiallergic 

actions 65,66 . 

Astemizole. This molecule is metabolised by 

the hepatic cytochrome p-450 to demethyl-astemizole 

(DMA), which has significant antihistamine 

activity. Once oral administration is begun, stable 

plasma concentrations of astemizole are achieved 

after one week, and the plasma concentrations of 

astemizole plus its metabolites persist for over 

four weeks 31 . Astemizole has a half-life of 1.1 

days, and its metabolite DMA 9.5 days 4 . The suppressive 

effects on the skin response to histamine 

and the histamine-induced bronchoconstriction 

may persist for four to six weeks (Table II). As 

pointed out earlier, it is subject to the drug interactions 

of other antihistamines metabolised by 

the hepatic cytochrome p-450 and together with 

DMA is potentially cardiotoxic 36,46 . Astemizole 

has not been associated to drowsiness, but it has 

been associated to weight gain4. 

Terfenadine. This is chemically a butyrofenone 

derivative 29 and it is the most representative one 

among the non-sedative antihistamines, as it does 

not cross the haemato-encephalic barrier due to its 

phenylbutanol structure 8 . Its half-life is 16 to 24 

hours and, as already stated, it is a prodrug acting 

through its acid metabolite, terfenadine carboxylate 

or fexofenadine, after first-pass hepatic metabolism. 

Terfenadine rapidly inhibits the skin response 

to histamine, and this effect persists for 

seven days more after the withdrawal of the 

drug 4,29 . Its drug interactions and its cardiotoxic 

potential have already been discussed. In a number 

of studies, the side effects of terfenadine on 

the CNS and on the gastrointestinal tract, as well 

as its anticholinergic effects, have been similar to 

those of placebo 9 . 

Azelastine. This is a ftalazinone derivative and 

structurally unrelated to other antihistamines. It 

was initially investigated for oral use as an inhibitor 

of the mastocitary release of inflammatory 

mediators 67 . It is metabolised through hepatic oxidation; 

although it has a 22-hour half-life, its 

pharmacologically active major metabolite, 

demethyl-azelastine, has a half-life of 54 hours 68 . 

It is available in Spain for topical use as nasal 

spray and eye drops, and has demonstrated significant 

inhibition of the intranasal response to histamine 

69 and effectiveness in the control of the 

symptoms of rhinitis similar to that of a number 

of systemic antihistamines 70 . Dysgeusia, or changes 

in taste perception, is the most frequently 

reported adverse effect 4,70 . 

Levocabastine. This cyclohexyl-piperidine was 

developed for topical ocular and nasal administration. 

It has a 35 - 40 hour half-life and little or no 

systemic absorption 71 . In controlled studies it has 

been less effective that topical steroids 4 but at


least as effective as disodium cromoglycate 4 , topical 

azelastine 72 , terfenadine 73 or loratadine 74 in the 

control of the symptoms of allergic rhinoconjunctivitis. 

It is available as nasal sprays and eye 

drops. 

Cetirizine. This is the acid metabolite of 

hydroxyzine. Forty to sixty per cent of the amount 

administered is excreted unchanged in the urine 

and its elimination is reduced in renal failure 14 . 

Like hydroxyzine, it is rapidly concentrated in the 

skin. It is considered to be the most effective 

antihistamine, with the exception of astemizole, 

for the suppression of the skin response to histamine 

4,28 . The beginning of its action occurs one 

hour after administration and its peak effect is 

seen 4 to 8 hours after administration 14 . As previously 

stated, it has been attributed antiinflammatory 

13 and antiasthmatic 15 effects. As it is not 

metabolised by the CYP, it lacks the drug interactions 

of other compounds 26 . Cetirizine does not 

prolong the QTc interval at doses up to sixfold the 

therapeutic ones 47 . Even though in more objective 

studies cetirizine has no effect on the psychomotor 

performance at dosages up to 10 mg/day 4 , the 

clinical experience shows that it causes subjective 

drowsiness, which may be its major drawback. 

Loratadine. This is a piperidine with a structure 

similar to that of azatadine, from which it differs 

in the presence of a carboxyethyl radical that 

limits its distribution in the CNS 9 . Loratadine is a 

prodrug that is metabolised to a large extent by 

the CYP3A4 system to its active metabolite 

decarboethoxy-loratadine (DCL) 75 . Its half-life is 

8 to 11 hours, and that of DCL 17 to 23 hours. At 

the recommended dosages it does not cause sedation 

and does not have cardiovascular effects 76 . 

Loratadine is less effective than other piperidines 

in the suppression of the skin response to histamine, 

but this does not appear to hamper its clinical 

efficacy 28 . Because of its hepatic first pass metabolism, 

loratadine has the same drug interactions 

with macrolides and imidazoles as other piperidines 

but, as already stated, this does not cause significant 

changes in the QTc interval 48,49 , as it is not 

a potent potassium channel blocker 50 . 

Ebastine. Chemically this is a piperidino-butyrofenone 

6 , and it is structurally very similar to the 

terfenadine molecule (Fig. 1 b). It is also a prodrug 

and is metabolised by the hepatic CYP3A4 

system in first-pass metabolism, after which it 

acts through its carboxylated metabolite carebastine 

(or LAS-X-113), with a half-life of 10.6 

hours 77 . As already stated, and because they share 

chemical structure and metabolic pathways, ebastine 

has the same drug interactions as terfenadine 

30 . At least in theory, might also share a similar 

cardiotoxicity risk as it blocks the myocardial 

potassium rectifier channel 43 , though to a lesser 

degree than terfenadine 44 and its therapeutic dosage 

is also six times lower. Its acid metabolite carebastine 

is devoid of these effects and interactions 

44,45 . On the other hand, ebastine has been 

demonstrated not to have anticholinergic actions, 

nor does it impair the psychomotor performance 

at therapeutic dosages 78 . 

Mizolastine. Its structure is that of a piperidinebenzoimidazole 

derivative; it acts as a specific 

ligand for the H1 receptors with peak antihistamine 

activity four hours after administration, which 

is maintained for approximately 24 hours 32 . Its 

effectiveness in the suppression of the skin reaction 

to histamine is similar to that of cetirizine and 

terfenadine, and greater than that of loratadine 79 . It 

is metabolised in the liver, predominantly through 

glucuronisation of the original molecule and to a 

much lesser degree through oxidation through the 

CYP3A4 and CYP2A6 systems 32 , although it evidences 

the same interactions with imidazoles and 

macrolides as other piperidines 32 . As no active 

metabolites have been detected 80 , its pharmacologic 

activity appears to depend on the original 

compound. Mizolastine does not cause sedation at 

a dosage of 10 mg/day but it does so at 20 

mg/day 81 ; it does not appear to interact significantly 

with alcohol 82 , or to have anticholinergic 

effects 83 . 

Fexofenadine. This is the acid metabolite of terfenadine. 

As already stated, 99% of the administered 

dose of terfenadine undergoes first-pass 

hepatic metabolism to its carboxylic acid metabolite, 

and acts through it. Fexofenadine has a distribution 

phase of 2 to 4 hours and an elimination 

phase of 17 hours 24 , and shares the antihistamine 

properties and the lack of sedative and anticholinergic 

effects of the parent compound. However, 

as it undergoes practically no metabolisation in 

the liver 24 , it does not interact with the imidazoles 

or the macrolides nor, foreseeably, with other 

inhibitors or substrates of the cytochrome p-450. 

As it does not inhibit the myocardial K + chan-


nels 45 , it has no effects on the QTc interval of the 

ECG 24,33,38 . Fexofenadine has been investigated in 

multiple clinical studies in allergic rhinitis and 

chronic urticaria at dosages of 60 mg/12 hours 

and at single daily doses of 120 mg, 180 mg and 

240 mg 24,84,85 . It has evidenced optimal efficacy 

and tolerability although in a number of studies 

there does not appear to exist a linear dose-response 

relationship between a given dosage and 

the reduction of symptoms 15 . On the basis of these 

clinical studies, the dosage recommended as 

the optimal one for adults and children over 12 

years is 120 mg once a day for allergic rhinitis, 

and 180 mg once a day for chronic urticaria 86 . On 

the other hand, fexofenadine does not interact 

with alcohol nor does it affect psychomotor performance, 

and preliminary studies suggest that no 

dose adjustment is required in the elderly nor in 

patients with hepatic or renal failure 24,86 . 

Others. There are many new H1 receptor antagonists 

which have not yet been marketed in Spain, 

such as acrivastine (a triprolidine metabolite with a 

very short duration of action requiring four times 

daily dosage 4 ), noberastine (an astemizole derivative 

with a faster beginning of action than the parent 

compound 87 ) or epinastine (an antihistamine with 

antiinflammatory actions studied fundamentally in 

Japan for use in bronchial asthma 88 ). A number of 

new molecules are currently under study for oral or 

topical administration, but it is still too early to 

define their eventual role. 

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Antihistamines: a review

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