Scholarly article on 6-cyclohexyl-6-hydroxy-hexanoic acid 2903-13-1 from

Drugs 2001; 61 (2): 207-236

0012-6667/01/0002-0207/$27.50/0

REVIEW ARTICLE

New Insights into the Second

Generation Antihistamines

Garry M. Walsh,¹Lucio Annunziato,²Nelly Frossard,³Klaas Knol,⁴Sten Levander,⁵

Jean-Marie Nicolas,⁶Maurizo Taglialatela,²Michael D. Tharp,⁷Jean P. Tillement⁸and

Henk Timmerman⁹

1

Department of Medicine and Therapeutics, University of Aberdeen Medical School,

Aberdeen, Scotland

2

3

4

5

6

7

8

9

Department of Neuroscience, School of Medicine, University of Naples, Naples, Italy

Louis Pasteur University, Strasbourg, France

Department of Paediatrics, University Hospital, Groningen, The Netherlands

Department of Psychiatry, Lund University, Malmö, Sweden

Department of Product Safety and Metabolism, Pharma Sector, UCB S.A., Brussels, Belgium

Department of Dermatology, Rush-Presbyterian-Saint Luke’s Medical Center, Chicago, USA

Department of Pharmacology, University of Paris XII, Paris, France

Leiden/Amsterdam Center for Drug Research, Vrije University, Amsterdam, The Netherlands

Contents

Abstract

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 207

1. Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209

1.1 Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209

1.2 Physicochemistry and Tissue Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210

1.2.1 H₁Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210

1.2.2 Lipophilicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211

1.2.3 Volume of Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212

1.2.4 Zwitterionic Antihistamines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

2. Safety

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

2.1 Sedation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213

2.2 CNS Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215

2.3 Cardiotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216

2.4 Interaction with Cardiac Potassium Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . 217

3. Anti-Inflammatory Effects in Allergic Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . 219

3.1 In Vitro Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219

3.2 In Vivo Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

4. Clinical Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225

4.1 Comparison of the Potency of Antihistamines . . . . . . . . . . . . . . . . . . . . . . . . . . . 225

4.2 Antihistamine Use in Asthma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225

5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228

Second generation antihistamines are recognised as being highly effective

treatments for allergy-based disease and are among the most frequently pre-

scribed and safest drugs in the world. However, consideration of the therapeutic

Abstract

208

Walsh et al.

index or the benefit/risk ratio of the H₁receptor antagonists is of paramount

importance when prescribing this class of compounds as they are used to treat

non-life threatening conditions. There are many second generation antihistamines

available and at first examination these appear to be comparable in terms of safety

and efficacy. However, the newer antihistamines in fact represent a hererogeneous

group of compounds, having markedly differing chemical structures, adverse

effects, half-life, tissue distribution and metabolism, spectrum of antihistaminic

properties, and varying degrees of anti-inflammatory effects. With regard to the

latter, there is growing awareness that some of these compounds might represent

useful adjunct medications in asthma therapy. In terms of safety issues, the current

second generation grouping includes compounds with proven cardiotoxic effects

and others with the potential for adverse drug interactions. Moreover, some of

the second generation H₁antagonists have given cause for concern regarding their

potential to cause a degree of somnolence in some individuals. It can be argued,

therefore, that the present second generation grouping is too large and indistinct

since this was based primarily on the concept of separating the first generation

sedating compounds from nonsedating H₁antagonists. Although it is too early to

talk about a third generation grouping of antihistamines, future membership of

such a classification could be based on a low volume of distribution coupled with

a lack of sedating effects, drug interactions and cardiotoxicity.

Over the past 30 years the prevalence of asthma,

icant CNS and anticholinergic adverse effects.

Therefore, they are considered to be a major phar-

macological advance when compared with their

predecessors and have proved to be important ther-

apeutic tools in the treatment of atopic disease.^[3,4]

To date, the classification of antihistamines as first

or second generation drugs has been made on the

basis of H₁receptor versus muscarinic selectivity,

combined with a much reduced tendency to cause

sedation. The currently available second genera-

tion antihistamines include acrivastine, astemizole,

azelastine, cetirizine, ebastine, epinastine, fexofen-

adine, levocabastine, loratadine, mizolastine and

terfenadine (the last having recently been with-

drawn from use). Both ketotifen and oxatomide can

interfere with serotoninergic and cholinergic neuro-

transmission and are therefore considered to be

intermediate between the first and second genera-

tion;^[5]in addition to these compounds there are

several new drugs undergoing clinical trials.

rhinitis and dermatitis has increased remarkably in

many countries,^[1]and this in turn has led to a

greater awareness of the social and economic costs

of allergic diseases. Therapeutic intervention in

allergy has often focused on blocking the effects

of histamine release from mast cells and basophils,

a major contributor to the allergic response. The

emphasis of early research concentrated on antago-

nising the effects of histamine and led to the devel-

opment of several potent antihistamines for the

treatment of certain symptoms of allergic disease.

However, histamine also functions as a neurotrans-

mitter, being particularly important in maintaining

a state of arousal or awareness within the CNS.^[2]

First generation H₁receptor antagonists have or

show a marked tendency to cross the blood-brain

barrier and their consequent well documented sed-

ative and anticholinergic effects, together with a

short half-life, greatly limited their use in the treat-

ment of allergic symptoms. The second generation

H₁receptor antagonists have been developed over

the past 15 years and have major advantages over

the earlier drugs, most notably their lack of signif-

Thus, there are many second generation antihis-

tamines available, and at first glance, there appears

to be little to choose between them in terms of

safety and efficacy. However, with the passage of

Drugs 2001; 61 (2)

Second Generation Antihistamines

209

time it has become apparent that the newer antihis-

tamines in fact represent a heterogeneous group of

compounds, having markedly differing chemical

structures,^[6]with variations in therapeutic profiles,

adverse effects, half-life, tissue distribution, meta-

bolism, and varying degrees of anti-allergic effects.

There has also been a great deal of concern regard-

ing the possible cardiotoxic effects of some of the

newer medications.^[7]On this basis, it could be ar-

gued that the current grouping of second genera-

tion drugs is too large and that we need to recon-

sider and perhaps redefine what is meant by a true

second generation antihistamine. The aim ofthepres-

ent paper is to evaluate existing information con-

cerning the pharmacological properties of the sec-

ond generation antihistamines currently available

in an attempt to elucidate whether we are in a po-

sition to define a new third generation grouping.

though a substrate of CYP3A4, mizolastine is pri-

marily (65%) metabolised in vivo by glucuro-

nidation enzymes.^[9]Of interest, the zwitterionic

antihistamines cetirizine, acrivastine, carebastine,

fexofenadine and epinastine show negligible, if

any, metabolism.^[10-12]Although less well docu-

mented, some second generation antihistamines

have the potential to produce interactions through

induction^[13]or inhibition^[14]of CYP activities, al-

though the clinical significance of these findings

remains to be determined. Interestingly, a number

of in vitro studies suggest that terfenadine, azelast-

ine and ebastine can reverse multidrug resistance

by inhibiting an energy-dependent drug efflux

pump, the P-glycoprotein (Pgp), whereas the more

hydrophilic antihistamines cetirizine, fexofenad-

ine and acrivastine are devoid of such inhibitory

effects.^[15-17]Besides cancer cells, Pgp is also found

in the blood-brain barrier and in normal tissues

such as the intestinal wall and proximal renal tu-

bules. It is now recognised as an important factor

in drug distribution and excretion and, not surpris-

ingly, is the source of some important pharmaco-

kinetic interactions.^[18]To date, no studieshave eval-

uated whether antihistamines can produce drug-drug

interactions through inhibition of Pgp, although

the terfenadine lesson illustrates how interactions

with metabolising enzymes may have serious con-

sequences. All the documented interactions which

have been encountered with antihistamines relate

to their ability to interact with CYP3A4 inhibitors.

However, physicians must remain alert to other po-

tential interaction mechanisms.

1. Pharmacokinetics

With a few exceptions, antihistamines are rapidly

and completely absorbed following oral adminis-

tration; peak plasma concentrations are reached

after 1 to 4 hours and, following recommended

doses, are highly variable because of differences in

metabolism and tissue distribution. Most of the

second generation antihistamines (e.g. terfenadine,

ebastine, astemizole and loratadine) undergo an

extensive first-pass metabolism to pharmacologi-

cally-active metabolites; as a common feature, the

reaction is primarily supported by cytochrome

P450 (CYP) belonging to the CYP3A4 subfamily.

Under normal circumstances this extensive meta-

bolism leads to low or undetectable plasma concen-

trations of the parent drug. However, circumstances

exist where metabolism of the parent compound

can be compromised, e.g. in cases of liver insuffi-

ciency or of overdose. Although not genetically

polymorphic, CYP3A4 demonstrates wide interin-

dividual variability,^[8]and it remains to be deter-

mined whether and to what extent this variability

influences the safety and the therapeutic activity of

antihistamines that act as prodrugs.

1.1 Drug Interactions

Among the currently available second genera-

tion antihistamines only acrivastine, cetirizine and

fexofenadine are excreted with negligible liver me-

tabolism.^[10-12]The problem of interactions be-

tween second generation antihistamines and other

coadministered drugs is a cause for concern. Many

drugs can affect liver CYP enzyme function with

consequent elevations in the plasma concentrations

of unmetabolised parent compounds of those anti-

histamines which rely on extensive biotransforma-

There are some second generation antihista-

mines which are not metabolised via CYP3A4. Al-

Drugs 2001; 61 (2)

210

Walsh et al.

Table I. Common interactions of histamine H₁receptor antagonists

with concomitantly-administered medications

tion. Coadministration of substances such as anti-

fungals, macrolides and grapefruit juice can inhibit

the function of the CYP3A4 enzyme system lead-

ing to accumulation of the unchanged drug. Exam-

ples of drug interactions encountered with anti-

histamines are given in table I. These potential

interactions represent a major safety concern since

it has been reported that accumulation of un-

changed terfenadine and astemizole may affect car-

diac repolarisation mainly through prolongation of

the QT interval which, in some cases, can trigger

serious ventricular arrhythmias (see section 2.3 on

safety). Therefore, a number of studies have exam-

ined the effects of coadministration of antihista-

mines with other drugs.^[26]For example, when

cetirizine was administered concomitantly with

CYP3A4 inhibitors ketoconazole,^[27]erythromy-

cin^[28]or azithromycin,^[29]no electrocardiographic

change could be detected. The reported lack of sig-

nificant change in cetirizine plasma or serum con-

centrations confirms no significant drug interac-

tions or hepatic metabolism. Although ketoconazole

inhibits the metabolism of loratadine^[30]and there

has been one published case of ventricular tachy-

cardia with prolonged QT interval after loratidine

treatment and coadministration of quinidine in a

patient with ischaemic coronary disease,^[31]in a

clinical study, loratidine had no effect on the QTc

interval despite an increased plasma concentration

as a result of concomitant erythromycin treat-

ment.^[32]

Antihistamine

Astemizole

Interacting drug

Erythromycin

Ketoconazole

Erythromycin

Clarithromycin

Azithromycin

Erythromycin

Ketoconazole

Erythromycin

Ketoconazole

Cimetidine

Reference

19

Terfenadine

20

21

Ebastine

22

23

Loratadine

24

24, 25

24

cally limited.^[34]H₁receptors have a wide cellular

distribution being found on smooth muscle cells,

endothelial cells, mast cells, basophils and eosino-

phils; antihistamines exert their effects by compet-

ing with histamine for occupancy of these recep-

tors.^[35]In the 1980s it was established that the

sedation induced by antihistamines was a conse-

quence of their blockade of central H₁receptors.

Evidence for this was provided by a mouse model

in which the sedative properties of antagonists sig-

nificantly correlated with occupancy of the H₁re-

ceptor.^[36]In humans, administration of enantio-

mers of chlorphenamine and dimetindene caused

sedation limited to the enantiomer with higher H₁

receptor affinity.^[37]

It is possible that the reduced ability of the sec-

ond generation H₁receptor antagonists to cause se-

dation is related to the previously noted ‘existence

of differences’ between CNS and peripheral H₁re-

ceptors.^[5]This idea is supported by studies which

demonstrated that mequitazine^[38]and loratadine^[39]

have a somewhat lower affinity for CNS H₁recep-

tors compared with peripheral H₁receptors. How-

ever, a comprehensive study which examined both

first and second generation antihistamines found

no differences in their affinity for H₁receptors ob-

tained from either lung or cerebellum tissue.^[40]Fur-

thermore, work by Yamashita and colleagues^[41]

which utilised Northern blot analysis of mRNA for

H₁receptors cloned from bovine adrenal medulla

failed to demonstrate any difference between CNS

1.2 Physicochemistry and

Tissue Distribution

1.2.1 H₁Receptors

The first generation antihistamines have a rela-

tively high liposolubility and are thought to cross

the blood-brain barrier by a process of passive

transport to interact with the H₁receptors of the

brain. These are numerous and, in humans, consti-

tute about 40% of the total amount of H₁receptors.^[33]

In an ideal world H₁receptor antagonists would not

cross the blood-brain barrier; however, this situa-

tion is difficult to achieve in practice, although it

has been shown that brain transfer can be drasti-

Drugs 2001; 61 (2)

Second Generation Antihistamines

211

and lung receptors. Therefore, it is unlikely that the

reduced ability of the second generation antihista-

mines to cause sedation is a consequence of differ-

ences between CNS and peripheral H₁receptors.

Obviously, the apparent log P depends on the pH

of the solution and is indicated as log D. Assuming

that the only the neutral species is involved in par-

tition over the organic solvent and water, log D at

a certain pH can be calculated from: log D_pH= log

P – log(1 + 10^pKa-pH). When the log Ds of several

antihistamines are examined at neutral pH (log D_7.4

= log P – log (1+ 10^(pKa-7.4)) notable differences can

be observed (table II). For example, the sedating an-

tihistamine azatadine has a Log D_7.4of 1.68 whereas

its analogue loratadine has a Log D_7.4of 4.4. In

contrast cetirizine has a Log D_7.4of 1.04 whereas

the sedating first generation parent compound hy-

droxyzine has a higher Log D_7.4of 2.87.^[44]

Another useful parameter is Δlog P which is de-

fined as the difference of log Ps measured in l-

octanol/water and cyclohexane/water, i.e. Δlog P =

log P_oct-water– log P_cycl/water. Thus, a high Δlog P

denotes a compound which dissolves more readily

in octanol than cyclohexane which is dependent on

the hydrogen bonding capacity of octanol versus

the neutral behaviour of cyclohexane. A high Δlog

P is therefore associated with a high hydrogen

bonding capacity of a compound which in turn may

result in enhanced binding to serum proteins and

thus restrict penetration of the blood-brain bar-

rier.^[45]It can be appreciated from the data pre-

sented in table II that Δlog P alone is not a reliable

1.2.2 Lipophilicity

In general terms, and in the absence of active

transport mechanisms, it hasbeenobservedthat those

compounds with an appropriate degree of lipophil-

icity enter the CNS while highly hydrophilic com-

pounds do not;^[42]in addition, compounds with a

very high degree of lipophilicity do not pass the

blood-brain barrier. Lipophilicity can be expressed

as log P, indicating the partition of a given com-

pound over an organic solvent and water. Thus, log

P_oct/wateris defined as the logarithm of the ratio of

the concentrations of a compound in l-octanol and

water at equilibrium and at 25°C. A high log P de-

notes a high level of lipophilicity. The relationship

between the central effect of a compound and its

log P is often not linear but parabolic. The log P

value associated with optimal penetration of the

blood-brain barrier has in several cases been found

to have a value of around 2.^[43]The issue is further

complicated when, in addition to its lipophilicity,

the influence of the ionisation of a compound is

taken into account. In this situation the ratio be-

tween the concentration of the neutral and proton-

ated species of a compound depends on its pK_a.

Table II. Lipophilicity parameters of selected antihistamines.^[44]See figure 1 for application

Number for

Drug

log P_oct

log P_dod

Δ log_oct-alk

log D_{oct, 7.4}

reference to fig. 1

1.

Imipramine

Chlorpheniramine

Diphenhydramine

Mepyramine

Azatadine

4.44

3.17

2.96

3.59

3.05

2.70

4.40

4.48

3.19

3.56

3.51

5.69

3.98

2.09

2.56

2.00

1.82

1.09

1.65

2.4

0.46

1.08

0.61

0.96

1.77

1.96

1.05

2.00

3.87

1.91

2.61

1.75

3.06

2.33

1.40

1.58

1.43

1.68

2.87

1.61

4.40

1.04

3.19

3.48

-0.75

4.46

2.

3.

4.

5.

6.

Hydroxyzine

Dimetindene

Loratadine

7.

8.

9.

Cetirizine

0.61

1.28

0.95

1.76

2.63

10.

11.

12.

13.

Temelastine

Astemizole

Epinastine

Terfenadine

alk = alkaline pH; dod = dodecane; log D_{oct, 7.4}= log D in octanol at pH 7.4; oct = n-octanol.

Drugs 2001; 61 (2)

212

Walsh et al.

Potential brain penetration of antihistamines

log D_oct< 0

log D_oct> 3

log D_oct,7.4

Negligible brain penetration (12)

Hindered brain penetration (8,10,11,13)

0 < log D_oct< 3

Δlog P < 2

Δlog P ≥ 4

Δlog P_oct-alk

Good brain penetration (1,2,3,4,5,6,7)

Hindered brain penetration (9)

2 < Δlog P < 4

Intermediate cases

Fig. 1. Hypothetical model for the brain penetration capacity of antihistamines. See section 1.2.2 for explanation and definition of

lipophilicity parameters. Numbers in brackets refer to the antihistamines listed in table II with their associated lipophilicity parameters.

predictor of the ability of the first and second gen-

eration antihistamines to penetrate the CNS. How-

ever, when the data in table II is used in conjunction

with the hypothetical model for the brain penetra-

tion capacity of antihistamines shown in figure 1

and applied to those compounds with an interme-

diate log D_oct, the Δlog P concept becomes more

attractive. Whereas a Δlog P value of less than 2

denotes good brain penetration, values in the re-

gion of 4 indicate a poor capacity to reach the CNS.

Although the precise significance of Δlog P remains

to be elucidated, use of table II in combination with

figure 1 may be helpful in predicting the ability of

a given antihistamine to penetrate the CNS. Other

factors which might be important include the bind-

ing of antihistamines by serum proteins such as

albumin and also the volume of distribution (V_d)

of this class of compounds.

ceptors at effective concentrations while avoiding

organs where the drug is ineffective or potentially

toxic. A low V_dcan be defined as being less than

the volume of exchangeable water in the body

which is freely and quickly exchanged between

extracellular fluids and cytosol; this concept is il-

lustrated in figure 2. Evaluation with phenazone

(antipyrine) has shown the volume of exchange-

able water to be 0.6 L/kg.^[47]A low V_dmay repre-

sent a distinct advantage for an H₁receptor antag-

onist as it would optimise the body distribution to

the targeted receptors and minimise the potential to

cross the blood-brain barrier.

Table III shows the pharmacokinetic parameters

in humans of a number of the currently available

second generation antihistamines. Among these,

cetirizine has the lowest V_dfollowed by acrivastine

suggesting that their distribution is poor in tissues

and organs. In contrast, the majority of H₁receptor

antagonists have large apparent volumes of distri-

bution and total body clearance.^[46,48]It is unlikely

that an extensive tissue distribution would be re-

1.2.3 Volume of Distribution

In pharmacokinetic terms it is desirable for any

drug to have the lowest V_dcompatible with the

therapeutic goal of interaction with the target re-

Drugs 2001; 61 (2)

Second Generation Antihistamines

213

quired for the mode of action of H₁receptor antag-

onists and it may be of interest to look for a corre-

lation between the frequency of adverse effects and

corresponding V_das these might be linked to the

relative accumulation of this class of drugs. The

association constant of the binding of an antihista-

mine to human serum albumin (HSA) is insuffi-

cient in itself to explain its low V_d; this may be

related to other mechanisms including the ionisa-

tion of the molecule, its low lipophilicity and its

H₁receptor specificity.^[49]The advantages con-

ferred on a drug by having a low V_dinclude mini-

mal risk of dose-dependent toxicity, minimal inter-

individual variation in the therapeutic effect, a

reduction in unwanted drug-drug interactions and

no accumulation in the heart or liver.

terionic forms and these include acrivastine, cetiri-

zine, levocabastine and fexofenadine (table III).

The effect that this property confers on the phar-

macokinetic behaviour of an antihistamine has

been most extensively investigated for cetiriz-

ine.^[50]This recent study investigated the ionisa-

tion and lipophilicity behaviour of cetirizine and

demonstrated that it exists almost exclusively as a

zwitterion in the pH region 3.5 to 7.5 in which its

octanol/water lipophilicity was found to be con-

stant and low compared with other cationic antihis-

tamines (log D = log P^z= 1.5), whereas its hydro-

gen bonding capacity is relatively large (ΔlogP^z≥

3.1). Conformational, electronic and lipophilicity

potential calculations revealed that zwitterionic

cetirizine experiences partial intramolecular charge

neutralisation in folded conformers of lower polar-

ity factors. These observations may contribute fur-

ther to our understanding of the pharmacokinetic

behaviour of cetirizine.

1.2.4 Zwitterionic Antihistamines

Classical H₁receptor antagonists are lipophilic

drugs with a single strongly basic centre, which at

physiological pH exist mostly as lipophilic cations.

However, a number of antihistamines exist as zwit-

2. Safety

The currently available second generation anti-

histamines are recognised as being highly effective

treatments for allergy-based disease, and are among

the most frequently prescribed and safest drugs in

the world. However, consideration of the therapeu-

tic index or the benefit/risk ratio of the H₁receptor

antagonists is of paramount importance when pre-

scribing this class of compounds as they are used

to treat non-life-threatening conditions. Further-

more, antihistamines are frequently used by indi-

viduals who wish or have to remain alert and active,

and who might also be taking other medications.

Consequently, progress with this class of drugs

should involve not only increased efficacy but also

improvements in their safety and specificity.

Dilution in exchangeable water

(plasma, interstitial fluid, etc.)

0.6 L/kg

Concentration in a part of the exchangeable water

(0.1L/kg if albumin phase)

0.1-0.6 L/kg

Dilution in exchangeable water and binding

to cellular structures

2.1 Sedation

2-20 L/kg

For many people, sedation remains the primary

concern when considering the adverse effects of

the newer antihistamines, particularly since these

drugs are given to patients with chronic disorders

with treatment periods which often extend over

several months. This raises the question of how

Fig. 2. Schematic representation of the possible volumes of

distribution of a drug.^[46]

Drugs 2001; 61 (2)

214

Walsh et al.

Table III. Pharmacokinetic parameters of some second generation antihistamines in humans^[46,47]

Drug

Terminal half-life (hours)

Bound in plasma (%)

Volume of distribution (V_d)

Astemizole

Azelastine

Ebastine

26

96

48

25

NA

97

14.5

10 - 12

NA

Loratadine

Mequitazine

Mizolastine

Terfenadine

Acrivastine^a

Carebastine^a

Cetirizine^a

Fexofenadine^a

12

18

4

120

90

67

12.9 4.5

16 - 23

1.7 0.2

13 - 16

10

98

1.4 0.4

2.2 - 2.9

0.64 0.13

2.1 - 2.4

0.4

98

50

98

88-90

65

18.3 2.0

5.6 0.7

a

Zwitterionic drugs.

NA = not available.

sedation is defined and measured, and highlights

the need to delineate as precisely as possible what

is meant by terms such as sedation, drowsiness or

sleepiness.

by the fact that these drugs can induce both subjec-

tive feelings of drowsiness and objective levels of

cognitive and motor impairment. The fact that pa-

tients may be unaware of the latter two changes is

a cause for concern if they must function normally

during the day.

Sedation is an inner state; it may be defined as

impairment of cognitive and psychomotor func-

tioning and can be determined objectively through

measures such as reaction time (RT). Drowsiness

refers to an increased likelihood of falling asleep

and commonly is assessed subjectively using the

Stanford scale for sleepiness or visual analogue

scales (VAS). Sleepiness refers to the same mental

state as drowsiness; it can be subjectively measured

using VAS or objectively measured by electrophys-

iological methods such as electroencephalogram

(EEG). Psychomotor and perceptual function can

be assessed objectively using actual or simulator

driving, critical tracking, flicker fusion or auditory

vigilance tests, whereas cognitive function can be

tested by learning ability or information processing

tasks.

However, the primary limitation of subjective

assessments is that of bias, particularly given that

the meanings of descriptors can change consider-

ably over time, a phenomenon known as semantic

drift. Patients may mislabel a state on the basis of

suggestion or acquiescence and use words inter-

changeably which in fact describe different states.

The measurement of the tendency of an antihista-

mine to cause sedation may be complicated further

An additional problem concerning clinical trials

with antihistamines is that only a certain percent-

age of patients report sleepiness (or somnolence),

even when using classical first generation medica-

tions. To further complicate the picture, over a pe-

riod of time many patients will develop tolerance

to this adverse effect to a variable degree.^[51,52]

Subjective reports and objective assessments of

CNS effects are not always in agreement, which

emphasises the distinction between the tendency of

a drug to induce subjective drowsiness and its ac-

tual potential to influence CNS function and psy-

chological aspects of performance. Thus, symptoms

alone should not be relied upon to predict decre-

ments in performance or alertness. A number of

studies rely on the use of healthy volunteers to as-

sess the psychoactive properties of antihistamines

and individual variation in responses to these drugs

might hamper the predictive quality of volunteer

studies. In practice, however, any volunteer bias

can be overcome by the introduction of a positive

internal control whose effects should be demon-

strable in any volunteer sample.^[53,54]

Drugs 2001; 61 (2)

Second Generation Antihistamines

215

Given the complexity of the potential CNS ef-

fects of antihistamines it can be appreciated that

they cannot be reflected by a single measurement

of impairment. Thus, a variety of objective and

subjective methods of assessment are required to

reliably evaluate the sedative effects of this class

of drugs. When all these considerations are taken

into account, the literature on the sedating proper-

ties of second generation antihistamines is not con-

vincing. The currently available drugs need to be

re-assessed for sedative effects using more power-

ful experimental designs which combine robust

objective tests with subjective indices of sedation.

nificant and dose-dependent increase in mild-to-

moderate sleepiness (or somnolence) by cetirizine

compared with placebo.^[65]These findings have

resulted in the suggestion by some that cetirizine

should be regarded as a sedating antihistamine.^[71,72]

However, the logical conclusion of this approach

would be the paradox of cetirizine being grouped

with the sedating first generation drugs where it

does not belong. This view is supported by the

large number of clinical studies which have shown

cetirizine to be both efficacious and well tolerated

without significant subjective sedation for the

treatment of rhinitis in adults^[73-84]and in chronic

urticaria.^[85-90]Furthermore, cetirizine treatment has

been reported to improve not only the symptoms

of patients with allergic rhinitis but also their phys-

ical and social functioning, feelings of fatigue,

general perception of health, physical and social

limitations and their mental well-being.^[91,92]Im-

portantly, the safety of cetirizine has also been

shown in the treatment of allergic rhinitis in chil-

dren.^[93-95]More recently, in the longest prospec-

tive safety study of any H₁receptor antagonist con-

ducted in any age group,^[96]the safety of cetirizine

was also shown in a group of 817 very young chil-

dren (12 to 24 months old at study entry) with

atopic dermatitis. There was a low drop-out rate

and few adverse effects over the 18 months of the

study, despite treatment of very young children

with relatively high doses of cetirizine compared

with those given to older children or adults. Fur-

thermore, compared with placebo (396 children),

cetirizine treatment (399 children) did not result in

clinically relevant differences in growth or devel-

opment or in neurological and cardiovascular symp-

toms. Importantly, this study demonstrated that

neither fatigue nor somnolence were significantly

higher in the cetirizine-treated group compared

with the placebo-treated group.

2.2 CNS Effects

There is a widespread tendency to consider the

second generation antihistamines as being non-

sedating medications. Indeed, when used at their

recommended dosage in objective studies which

used healthy volunteers, CNS depressant effects

for both loratadine^[55]and fexofenadine^[56,57]ap-

pear to be no greater than those given by placebo.

However, this issue is further complicated by evi-

dence that sedation in allergic disease is a conse-

quence of the condition itself leading to perfor-

mance and learning impairment.^[58-60]This fact

raises concerns about claims of a risk-free sedation

profile for certain antihistamines when these are

often based on objective studies which used healthy

volunteers.^[61]Another issue is the tendency of pa-

tients with allergies to ‘self medicate’, titrating their

antihistamine dosage upwards to achieve symptom

relief.^[62]In fact, if the dose of terfenadine,^[63]

loratadine^[64]or cetirizine^[65]is increased enough,

sedation does occur. All of these considerations

have led to several commentators^[5,61,66-70]sug-

gesting that the second generation antihistamines

are more correctly termed as having minimal sed-

ative effects when given at their recommended

doses.

Objective measurements offer a more robust as-

sessment of the ability of a drug to cause sedation,

although they are less sensitive than subjective

measurements. Ramaekers and colleagues^[97]re-

ported that a single 10mg dose of cetirizine signif-

icantly affected actual driving performance by

Of the currently available second generation

drugs, there is much contention regarding the sed-

ative potential of cetirizine. This was illustrated

by a clinical study which investigated the efficacy

of cetirizine in allergic rhinitis and reported a sig-

Drugs 2001; 61 (2)

216

Walsh et al.

Table IV. Objective testing of impairment or non-impairment of psychomotor performance after cetirizine treatment

Test

Impairment

10mg^[97]

No impairment

10mg^{[3,53,102,103]}

Actual driving test: coarse steering frequency, obstacle

test, weaving index test

Computer-simulated driving test

10mg^{[97,53,104,105]}

Multiple Sleep Latency Test (MSLT) with

electroencephalographic potentials

10mg^[98]; 15mg^[98]

5mg^[97,100]; 10mg^{[3,97,102,105]}; 20mg ^[97,105]

P300-evoked electroencephalographic potential latency

Visual function: dynamic visual acuity, critical flicker fusion

Simple Reaction Time (SRT)

Choice Reaction Time (CRT)

Vigilance tests

10mg^[106]

10mg^{[53,103,107,108]}; 20mg^[53,103]

5mg^[97]; 10mg^{[97,103-105, 109]}; 20mg^[97]

10mg^[3,107]

5mg^[97]; 10mg^[97,105,110]; 20mg^[97]

10mg^[99]

5mg^[98]; 15mg^[98]

Simulated Assembly Line Tests (SALT)

Stroop (word-colour) test

10mg^[105,106]

Digit-symbol substitution

5mg^[97,104]; 10mg^[97,104]; 20mg^[97]

10mg^[107]

Finger tapping

Perceptual maze test

10mg^[107]

healthy volunteers, and Nicolson and Turner^[98]

found that cetirizine 10 and 15mg led to shortened

sleep latencies compared with placebo. However,

several other studies have demonstrated no effect

by cetirizine on daytime sleep latency at thera-

peutic doses.^[99-101]Table IV illustrates data from

a number of studies which examined the effect of

cetirizine on objective measurements of psycho-

motor performance. However, as the majority of

these studies used healthy volunteers, these data

must be viewed in the light of the caveat mentioned

above that the results may have been different if

patients with allergic diseases had been studied.

Thus, a question mark remains on this issue of

cetirizine and sedation. It is acknowledged that this

question might best be objectively answered by a

meta-analysis of the available data. However, as

discussed in this section, a major barrier to this

approach is the lack of the use of standardised ap-

proaches to assess the psychometric measurements

of antihistamines making a meta-analysis difficult

to perform, a view also shared by others^[66,72,111]

a high affinity for lean tissue^[112]and which might

account for some of the toxicity associated with

some members of this class of drugs. Recently, the

focus on the risk/benefit ratio of antihistamines has

shifted from sedation to other adverse effects such

as their potential to induce cardiac ventricular ar-

rhythmias of the torsades de pointes type, first re-

ported with astemizole^[113]and later with terfenad-

ine,^[114]of which the latter drug has been the most

widely prescribed. The European Commission has

recently adopted a decision to withdraw some ter-

fenadine preparations (120mg tablets and all ter-

fenadine/pseudoephedrine tablet formulations) and

the drug has also been withdrawn by the US Food

and Drug Administration. Both astemizole and ter-

fenadine rely on liver CYP for their metabolism to

the therapeutically-active metabolite. Accumula-

tion of unmetabolised terfenadine and astemizole

can result in blockade of cardiac K⁺channels which

regulate the duration of the action potential thereby

prolonging the QT interval and resulting in life-

threatening ventricular tachycardia.^[115-118]Predis-

posing factors to the induction of cardiac arrhythmias

by antihistamines include liver disease, concomi-

tant prescribing of interfering drugs such as mac-

rolides, overdose, congenital QT prolongation, is-

chaemic heart disease, congestive heart failure, or

2.3 Cardiotoxicity

As previously mentioned, with a few exceptions,

the second generation H₁receptor antagonists have

a highly lipophilic general structure which confers

Drugs 2001; 61 (2)

Second Generation Antihistamines

217

electrolyte imbalance. Thus, in conditions of over

dosage or when compromised liver function results

in reduced metabolism, the plasma concentration

of terfenadine or astemizole can rise which leads

to cardiac toxicity through direct blockade of a K⁺

channel expressed by the cardiac ventricular myo-

cyte.

or QTc were observed among children who re-

ceived astemizole, loratadine or cetirizine, with or

without erythromycin. Children who had received

terfenadine and erythromycin showed significantly

prolonged QT intervals, although analysis of the

QTc interval revealed no significant differences in

this group. Furthermore, in a recent pharmacosur-

veillance study which determined the heart rhythm

disorders and cardiac deaths for some of the most

common nonsedating antihistamines, cetirizine

displayed the lowest adverse drug reaction report

rate per million of defined daily doses sold for all

adverse events; however, the study should have in-

cluded a control group not taking antihistamines in

whom rates of spontaneous cardiac events could

have been quantified.^[131]

The possibility that cardiotoxicity is an adverse

effect common to all second generation antihista-

mines has been discounted.^[119,120]Although fexo-

fenadine, the active metabolite of terfenadine,

appears to be free of any adverse cardiovascular

effects,^[120]fexofenadine therapy was associated

with QT lengthening and life-threatening arrhyth-

mias in a single case report of a patient with mild

hypertension and mild left ventricular hypertro-

phy.^[121]This case indicates that fexofenadine may

increase the QTc time and induce ventricular ar-

rhythmias in susceptible patients. As discussed in

section 1.1, drug interactions occur with agents

other than astemizole and terfenadine. However,

conflicting results have been noted in guinea pigs

and rabbits with loratadine,^[122], terfenadine, aste-

mizole, ebastine, cetirizine, carebastine and noras-

temizole.^[123-125]In addition to the conflicting find-

ings with loratadine and concomitant medication

described in section 1.1,^[31,32]two studies have

demonstrated that neither loratadine^[126]nor acriv-

astine^[127]prolonged QTc interval in healthy vol-

unteers.

Cetirizine appears to be free of any cardiovas-

cular adverse effects.^[119]Healthy volunteers who

were treated for 7 days with up to 6 times the rec-

ommended daily dosage of cetirizine did not show

any lengthening of the QTc interval when com-

pared with healthy volunteers taking placebo.^[128]

Moreover, an accidental massive overdose of ce-

tirizine in an 18-month-old child did not cause any

adverse cardiac or neurological reactions.^[129]In a

clinical study, Delgado and coworkers^[130]investi-

gated the cardiac effects of recommended doses of

terfenadine, astemizole, loratadine and cetirizine in

children treated for perennial allergic rhinitis; treat-

ment was given alone or concomitantly with eryth-

romycin. No significant changes in the QT interval

2.4 Interaction with Cardiac

Potassium Channels

Recent evidence has demonstrated that the car-

diotoxic manifestations associated with astemizole

and terfenadine may be explained by their ability

to interfere with the cardiac repolarising current

IKr.^[117,132]These particular K⁺channels are en-

coded by the human ether-a-gogo-related gene

(HERG)^[133,134]and both astemizole and terfenad-

ine have been shown to block HERG K⁺channels

with nanomolar affinity.^[135,136]The possible inter-

action of antihistamines with HERG K⁺channels

can be studied either in cells in which these chan-

nels are constitutively expressed (such as cardiac

myocytes or human neuroblastoma cells)^[137]or

upon their heterologous expression in other cellu-

lar systems. An expression system commonly used

by pharmacologists studying ion channels is the

Xenopus oocyte, which can be microinjected with

in vitro-transcribed RNA derived from HERG

cDNA. These cells can be used for electrophysio-

logical study of the heterologously expressed HERG

K⁺channels by means of the 2 microelectrode volt-

age clamp technique.

This technique was recently applied to compare

the effect of terfenadine, astemizole, loratadine

and cetirizine on the inhibition of HERG K⁺chan-

nels expressed in Xenopus oocytes.^[138]Both

Drugs 2001; 61 (2)

218

Walsh et al.

Cetirizine

cardiac Kv1.5 channel which was cloned from hu-

man ventricle and stably expressed in a mouse cell

line.^[139]Thus, the results of these studies suggest

that cardiotoxic potential is not a property common

to all second generation antihistamines as they dis-

play marked heterogeneity in their ability to block

cardiac K⁺channels.

Loratadine

Astemizole

Terfenadine

100

80

60

40

20

0

In summary, it might be argued that the inci-

dence of cardiotoxic effects is negligible in view of

the widespread use of antihistamines on a world-

wide basis. However, it must be remembered that

these drugs are used to treat non-life–threatening

conditions and several of the drugs currently avail-

able are extremely efficacious while being free of

any serious cardiotoxic risk. Furthermore, many

antihistamines are available without prescription

and concomitant use of macrolides by patients tak-

ing antihistamines is common, particularly in

groups vulnerable to high levels of respiratory tract

infections such as infants and children. In such sit-

uations it might be preferable to offer an antihista-

mine whose pharmacokinetic profile is not modi-

fied by the use of antibacterials.

0.01

0.1

1

10

100

Drug (μM)

Fig. 3. Dose-response curve for human ether-a-gogo-related

gene (HERG) K⁺channel block expressed in Xenopus oocytes

by four second-generation antihistamines. The inward HERG

K⁺tail currents recorded in Xenopus oocytes upon repolarisation

to -100mV after depolarising pulses of 2 seconds to 0mV were

normalised to the control value and expressed as a function of

drug concentration. The solid lines represent the fit of the ex-

perimental data to the following binding isotherm: y =

max/(1+X/IC50)n, where X is the drug concentration and n the

Hill coefficient. Fitted values for n were between 0.72 and 0.96.

Each point is the mean (S.E.M.) of 3 to 6 determinations (repro-

duced from Taglialatela et al.,^[138]with permission).

100

80

astemizole and terfenadine had potent blocking ef-

fects whereas cetirizine had no measurable effect

in concentrations up to 30 μmol/L. On the other

hand, the same concentration of loratadine caused

a 20% blockade of I_HERG. Given the high drug con-

centrations required to exert these effects, the clin-

ical relevance of loratadine’s action may be ques-

tioned. These findings are summarised in figure 3.

Similar results were obtained from experiments

which utilised constitutively expressed HERG

channels in SH-SY5Y human neuroblastoma cells

60

40

20

0

AST

TERF

LOR

CET

Fig. 4. Effect of the 4 different H₁receptor antagonists astemiz-

ole (AST), terfenadine (TERF), loratadine (LOR) and cetirizine

(CET) on I_HERGconstitutively expressed in SH-SY5Y human

neuroblastoma cells. The same experimental protocol (holding

potential: -60mV; test potential: 0mV for 10 sec; return poten-

tials: from 0 to -140/-180mV in -20mV steps for 100ms) was

performed in several SH-SY5Y cells in control conditions and

after 5 min perfusion with each H₁receptor antagonist (3 μmol).

Drug effects are reported as percent of inhibition of the inward

I_HERGcurrent at -140 mV, without leak subtraction. Each value

is the mean (S.E.M.) of 4 determinations for each drug (repro-

duced from Taglialatela et al.,^[138]with permission).

(fig. 4). Again, cetirizine failed to affect I_HERG

,

whereas terfenadine and astemizole had potent

blocking effects with a lesser effect observed for

loratadine. A similar study also demonstrated that

high concentrations of loratadine above the thera-

peutic level had a blocking effect on the human

Drugs 2001; 61 (2)

Second Generation Antihistamines

219

mast cells, basophils, eosinophils and neutrophils.

However, on closer examination many of the studies

which reported a significant effect on inflamma-

tory cell function used drug concentrations which

were hundreds or in some cases thousands of times

higher than those that can be achieved in vivo.

Indeed, Church^[141]has recently pointed out that,

with some exceptions, the majority of the non-

H₁receptor-mediated effects of antihistamines

require higher concentrations than would be ex-

pected to occur in clinical practice. However, it

must also be remembered that most of the in vitro

studies of anti-inflammatory effects by antihista-

mines used pharmacological doses of agonists

which are likely to be far greater than those reached

in the tissues. These effects would have to be over-

come by correspondingly higher concentrations of

the antihistamine under test. An additional consid-

eration is that if high concentrations are required

in vitro, any inhibitory effect might merely be a

consequence of drug toxicity. This question is al-

most impossible to answer as few studies addressed

the issue of the effect of the test drug on the viabil-

ity of the cells under examination.

Therefore, with these considerations in mind

and for the sake of clarity, table V has been limited

to listing those studies in which significant inhibi-

tory effects on inflammatory cell function were ob-

served with drug concentrations which are equal to

or lower than the therapeutic plasma concentration

of the antihistamine under examination. This ap-

proach reduced the number of studies published on

in vitro anti-inflammatory effects of second gener-

ation drugs from over 100 to around 40. This in-

formation is presented with 2 caveats: first, local

levels of antihistamines may be higher at tissue

sites such as in the nose than in the plasma; and

secondly certain antihistamines might preferen-

tially accumulate in inflammatory cells in vivo. How-

ever, there is no current evidence to support either

notion.

3. Anti-Inflammatory Effects in

Allergic Inflammation

The mechanisms responsible for the accumula-

tion of pro-inflammatory cells at tissue sites of al-

lergic inflammation are complex but probably in-

volve a combination of selective adhesion of cells

to post-capillary venular endothelium, followed by

transmigration into the tissues under the influence

of chemotactic factors including lipid mediators,

cytokines and chemokines. Once in the tissues

there is an elaborate interaction between infiltrat-

ing cells, resident cells, and the mediators and

cytokines released as part of the inflammatory re-

sponse. The cells that are important in these pro-

cesses include those recruited to the inflammatory

site such as T cells, eosinophils, mast cells, mono-

cytes, basophils and platelets in addition to resi-

dent cells such as antigen presenting cells, epithe-

lial cells and endothelial cells. Thus anti-allergic

effects might include inhibition of cell migration,

mediator release, adhesion and adhesion molecule

expression. It has been recognised for some years

that, in addition to being potent antihistamines, a

number of the second generation drugs appear to

possess several anti-allergic effects which cannot

be explained by antagonism of the H₁receptor. Thus,

they may play an enhanced role in treating allergic

disease if, in addition to antagonising the effects of

histamine, they also inhibit the influx and/or acti-

vation of pro-inflammatory cells. In general terms,

these studies can be divided into in vitro effects on

the function of isolated pro-inflammatory cells or

in vivo effects where the impact of a given drug on

inflammatory parameters is assessed in addition to

its effects on symptom relief.

3.1 In Vitro Studies

Examination of the literature reveals an almost

bewildering number of studies on the anti-inflam-

matory effects of antihistamines in vitro (for a com-

prehensive review see Church et al.^[140]). Many of

these have concentrated on examining the ability

of the second generation drugs to prevent or inhibit

mediator release from diverse cell types including

It can be seen from table V that the majority of

the second generation antihistamines have at least

some inhibitory effects on mediator release from

diverse cell types, all of which appear to be inde-

Drugs 2001; 61 (2)

220

Walsh et al.

Table V. In vitro anti-inflammatory effects of antihistamines at relevant concentrations

Cetirizine

Inhibited fMLP-, PAF-,^[142,143]LTB₄-, IL-8– or C5a-^[144]dependent eosinophil chemotaxis

Significantly inhibited LTB₄- and fMLP-dependent monocyte chemotaxis^[145]

Inhibited PAF-induced human eosinophil hyperadherence to endothelial cells^[144]

PAF-induced neutrophil and eosinophil enhanced eosinophil cytotoxicity and complement- or IgG-dependent rosette formation^[146]

Decreased eosinophil membrane heterogeneity and blocked PAF-induced membrane fluidity changes^[147]

Inhibited PAF-dependent superoxide generation by eosinophils isolated from patients with allergies^[148]

An inhibitory effect on LTB₄production by isolated human neutrophils^[149]

Inhibition of LTB₄generation by fMLP- or NaF-stimulated neutrophils^[150]

Enhanced release of PGE₂from human monocytes and rat peritoneal macrophages^[151]

Inhibited IFNγ-mediated upregulation of ICAM-1 expression by primary cultures of human nasal epithelial cells^[152]

Inhibited PMA- or TNFα-stimulated IL-8 release from human epithelial cells by reducing IL-8 gene expression^[153]

Inhibited LTB₄, arachidonic acid and phospholipase A2 release from human PMN, ΔF508 cells, CHO cells and rabbit chondrocytes

stimulated with different agonists [fMLP, NaF, A-23187, bradykinin, epinephrine (adrenaline) or IL-1]^[154]

Calcium ionophore-dependent release of TNFα from a human mast cell line or mononuclear cells inhibited by μmol concentrations of

cetirizine^[155]

Loratadine

Calcium ionophore-dependent release of TNFα from human mast cell line or mononuclear cells inhibited by μmol concentrations of

loratadine^[155]

Inhibited PAF-induced eosinophil chemotaxis and O₂-generation^[156]

Inhibition of histamine-induced endothelial cell expression of P-selectin and secretion of IL-6 or IL-8^[157]

Inhibited ionophore- and antigen-dependent leukotriene release from human lung^[158]

Elevates cytosolic Ca²⁺in rat peritoneal macrophages or human platelets^[159]

Inhibited mitogen-induced mononuclear cells and allergen-induced T cell proliferation^[160]

Significantly ablated platelet aggregation and histamine release induced by anti-IgE^[161]

Desethoxycarbonyl-loratadine inhibited IgE- and A-23187–induced leucocyte histamine release^[162]

Increased mRNA expression for the anti-inflammatory cytokine IL-10 in cultured normal human keratinocytes^[163]

Desloratadine inhibited PAF-induced eosinophil chemotaxis, eosinophil adhesion to endothelial cells stimulated with TNFα and

PMA-induced eosinophil superoxide generation^[164]

Incubation of cultured human bronchial epithelial cells with loratadine significantly attenuated the NO₂-induced release of RANTES and

sICAM-1^[165]

Terfenadine

Inhibition of mediator (LTC₄/D₄) and cytokine (TNFα and GM-CSF) release from nasal polyp cells^[166]

Inhibited PAF- and fMLP-dependent eosinophil and neutrophil chemotaxis^[167]

Inhibited IgE-dependent mediator release histamine and PGD₂release from lung and skin mast cells^[168]

Fexofenadine

Inhibited GM-CSF and sICAM-1 release by epithelial cells cultured with eosinophils and latex beads^[169]

Inhibited histamine-induced release of TNFα and β-glucuronidase by human lung macrophages^[170]

Reduced ICAM-1 expression by a conjunctival epithelial cell line and fibroblast cell line and blocked IL-6 release by fibroblast cell line^[171]

Calcium ionophore (A-23187)–induced eosinophil cationic protein release inhibited by low (<1 μmol) concentrations of fexofenadine^[172]

Astemizole

Inhibited histamine release by rat peritoneal mast cells or by lung fragments in sensitised guinea pigs^[173]

Mequitazine

Prevented fMLP- and PMA-induced O_2-generation from rat neutrophils^[174]

Clemastine

Inhibited neutrophil superoxide radical generation^[175]

Azelastine

Inhibited PAF synthesis and release from neutrophils,^[176,177]alveolar macrophages^[178]and eosinophils^[179]and prevented eosinophil

superoxide radical production^[180,181]

Drugs 2001; 61 (2)

Second Generation Antihistamines

221

Table V. Contd

Suppressed TNFα secretion by rat mast cell line^[182]and cultured mouse mast cells^[183]

Inhibited PGE₂production by IL-1 stimulated cultured human skin fibroblasts^[184]

Inhibits calcium-ionophore–dependent generation of LTC₄and LTB₄in rat basophilic leukaemia cells^[185]

Blocks activation of NF-κB, IL-1α, IL-6, GM-CSF and TNFα mRNA in leucocytes and monocytes^[186]

Oxatomide

Inhibited eosinophil^[187]and neutrophil^[188]superoxide radical generation

C5a = 5th complement component (anaphylatoxin); CHO = chinese hamster ovary; fMLP = f-Met-Leu-Phe; GM-CSF = granulocyte

macrophage-colony stimulating factor; ICAM = intracellular adhesion molecule; IFN = interferon; Ig = immunoglobulin; IL = interleukin; LTB₄,

LTC₄, LTD₄= leukotrienes B₄, C₄, D₄; NaF = sodium fluoride; NF-κB = nuclear factor kappa B; NO₂= nitrogen dioxide; PAF = platelet-activating

factor; PGD₂, PGE₂= prostaglandins D₂, E₂; PMA = phorbol myristate acetate; PMN = polymorphonuclear leucocyte; RANTES = growth

factor (Regulated on Activation, Normal T cell Expressed and Secreted); sICAM-1 = soluble ICAM-1; TNF = tumour necrosis factor.

pendent of the potent H₁-blocking abilities of this

class of compounds. Additionally, azelastine,

loratadine, terfenadine and cetirizine have all been

reported to inhibit chemotaxis of eosinophils in

vitro. These are potentially important observations

as it is now well established that the eosinophil is

a key effector cell in the pathogenesis of allergic

inflammation.^[189]In addition, cetirizine inhibited

neutrophil and monocyte chemotaxis and also ap-

pears to have particular effects on other eosinophil

functions^[190]as well as on other cell types.^[191]

Interestingly, the antihistamine dexchlorphenir-

amine had no effect on f-Met-Leu-Phe (fMLP)– or

platelet-activating factor (PAF)–induced eosino-

phil chemotaxis, an observation supporting the no-

tion that inhibitory effects on eosinophil chemotaxis

by second generation drugs cannot be attributed to

H₁receptor blockade. However, there is a paucity

of data which would allow a definitive answer with

regard to the underlying cellular mechanisms re-

sponsible for these in vitro anti-inflammatory ef-

fects by several second generation drugs. The cat-

ionic amphophilic nature of many antihistamines

suggests that they might form an association with

cell membranes thereby inhibiting calcium binding

and the action of membrane associated enzymes.^[141]

For example, one study demonstrated an inhibitory

effect by azelastine on eosinophil chemotaxis. This

effect was observed only under conditions of low

calcium concentration (0.6 mmol/L) and was abol-

ished by higher calcium concentrations (3.0 mmol/

L), suggesting that azelastine may exert its anti-

inflammatory effects by inhibiting calcium entry

into cells.^[192]

Afinal consideration regarding the in vitro stud-

ies is that, of the currently available drugs, only

acrivastine, fexofenadine and cetirizine are not me-

tabolised in vivo; this fact raises additional doubts

as to the relevance of the in vitro testing of com-

pounds reliant on biotransformation to the active

metabolite, although some studies have examined

the anti-inflammatory effects of a number of active

metabolites (table V).^[140,141]

3.2 In Vivo Studies

Of potentially greater interest is the demonstra-

tion of an anti-inflammatory effect by an antihista-

mine in vivo as this is far more therapeutically

relevant than the in vitro studies. Although the abil-

ity of antihistamines to exert anti-allergic effects in

humans has been appreciated for some time,^[193]

the question of whether this enhances the therapeu-

tic effect of an antihistamine has been the subject

of much debate. It is difficult to give a definitive

answer owing to the problems inherent in isolating

the many anti-inflammatory effects from the H₁-

blocking effect of a given drug. Notwithstanding

this, however, demonstrable suppressive effects on

allergic inflammation which are additional to po-

tent H₁receptor blockade can only be seen as a

positive attribute for a drug. Examination of the

literature reveals a large number of in vivo studies

in which anti-inflammatory effects by the second

generation compounds have been reported and

these are presented in table VI.

Drugs 2001; 61 (2)

222

Walsh et al.

Table VI. In vivo anti-inflammatory effects of antihistamines (negative studies in italics)

Drug

Effects on cell accumulation

Effects on adhesion molecule

expression

Effects on other inflammatory events

Cetirizine

Inhibition of eosinophil accumulation in

Reduced epithelial ICAM-1 expression

Inhibited ex vivo monocyte

chemotaxis^[145]

Modulated ex vivo

atopic skin challenged with pollen^[194-198]associated with conjunctival

or PAF^[199]

No significant effect on Ag-induced

cutaneous LPR, some reduction in

eosinophil numbers^[201,202]

challenge-induced EPR and LPR[200]

Reduced nasal epithelium ICAM-1

expression, in patients with asthma^[203]leucocytes challenged with Dp

sulfido-leukotriene production by

Reduced nasal epithelium ICAM-1

antigen^[204]

Reduced symptoms and eosinophils and expression in nasal polyposis

neutrophils accumulation in conjunctival patients^[205]

Inhibited codeine-induced wheal and

flare^[206]and flare response to

bradykinin^[207]

Inhibited kallikrein-induced LPR in

patients with urticaria^[211]

Inhibited bradykinin-induced wheal

and flare in atopic and healthy

individuals^[216]

challenge-induced EPR and LPR^[200]

Inhibited EPR to antigen. No effect on

LPR, cellular responses nor lactoferrin

and ECP^[208,209]

Reduced levels of soluble ICAM-1 in

nasal lavage^[210]

Modulated keratinocyte ICAM-1 and

HLA-DR in psoriatic plaques^[215]

Decreased ICAM-1, sICAM-1 in nasal

lavage of patients with allergic

rhinitis^[218]

Inhibited Ag-induced eosinophil

recruitment in nose,^[212]lung,^[213]

protective effect on asthmatic LPR^[214]

No effect on allergen-induced eosinophil

accumulation in nose^[217]

No effect on ex vivo neutrophil

chemotaxis or O₂- production in

healthy individuals^[219]

Reduced eosinophilia in bronchial

challenged monkeys,^[220]the

ovalbumin-^[221]or PAF^[222]-induced rat

pleural cavity eosinophilia, Ag-induced

eosinophil influx into the trachea of

dogs^[223]

Decreased eosinophil and neutrophil

infiltration and ECP and EPO in nasal

lavage from patients with allergic

rhinitis^[95,225]

Reduced nasal TAME-esterase

activity and LTC₄[224]

Inhibited bradykinin-induced skin

reactions^[226]

Reduced histamine and tryptase in

nasal secretions after allergen

challenge^[227]

Loratadine

Reduced eosinophil and metachromatic Reduced epithelial ICAM-1 expression

No effect on codeine-induced

histamine release in normal skin^[231]

or kallikrein-induced LPR in urticaria

patients^[232]

Decreased numbers of IL-2R+,

HLA-DR+ PCNA in allergic rhinitis

mucosa^[234]

cells, ECP, EPO and histamine in nasal

secretions^[228]

following conjunctival challenge^[229,230]

Reduced ICAM-1 on nasal epithelium

following natural exposure to

allergen^[228]

In combination with flunisolide

significantly reduced eosinophilia in

patients with non-allergic rhinitis with

eosinophilia^[233]

No effect on PAF-induced eosinophil

influx into skin of urticaria patients^[232]

No significant inhibition of skin reactions

induced by histamine and grass pollen,

nor eosinophil accumulation^[198]

No effect on anti-IgE-mediated histamine

release or leucocyte accumulation in

skin ^[237]

Reduced levels of tryptase and

α2-macroglobulinin allergen-induced

nasal secretions^[235]

Inhibited pollen-induced histamine

and PGD₂release in nasal

secretions^[236]

Reduced TAME-esterase and

histamine levels in allergen-induced

nasal secretions^[238]

Terfenadine

Reduced inflammatory cell infiltration

during conjunctival provocation test^[239]

Reduced ICAM-1 expression

associated with conjunctival

Inhibited flare response to

bradykinin - little effect on wheal^[216]

Inhibited pollen-induced histamine

and PGD₂release in nasal

secretions^[236]

Significantly inhibited cutaneous

IgE-mediated inflammatory lesion

size^[242]

Reduced inflammatory cells and ECP in provocation test^[239]

allergic rhinitis mucosa^[240]

Reduced nasal epithelial ICAM-1 in

allergic rhinitis mucosa^[240]

Allergic bronchial eosinophilia in guinea

pigs was inhibited by orally administered

dexamethasone and methylprednisolone

but not by terfenadine^[241]

No effect on leucocyte infiltration in

response to cutaneous antigen

challenge^[242]

Reduced nasal histamine release,

kinin levels, and TAME-esterase

activity^[243]

Drugs 2001; 61 (2)

Second Generation Antihistamines

223

Table VI. Contd

Drug

Effects on cell accumulation

Effects on adhesion molecule

expression

Effects on other inflammatory events

Fexofenadine In a murine model of allergic

sensitisation inhibited

No effects reported to date

Inhibited antigen-induced

bronchospasm in sensitised

guinea-pigs and histamine release

from rat peritoneal mast cells^[245]

No effect on IL-4, IL-10, TNF,

MIP-1α or GM-CSF in nasal

secretions of patients after nasal

antigen challenge^[247]

methacholine-induced airway

hyperresponsiveness with no effect on

eosinophilic inflammation^[244]

Inhibited early and late reaction to

cutaneous allergen-challenge^[246]

Ebastine

Prophylactic against immediate

mosquito bite symptoms^[248]

No effects reported to date

Inhibited nasal GM-CSF in

Ag-challenged patients with

rhinitis^[249]

Astemizole

Mizolastine

Inhibition of eosinophil influx into the

trachea of antigen challenged dogs^[223]

No effects reported to date

Inhibited AA-induced rat paw

inflammation,^[250]and colitis^[251]and

ICAM-1 expression on airway stromal

cells^[252]

Inhibited soluble ICAM-1 secretion in

antigen-challenged human skin^[253]

Inhibited leukotriene release by

leukocytes stimulated with sera from

patients with chronic urticaria^[254]

Azelastine

Treatment of atopic asthmatics reduced Reduced conjunctival ICAM-1

Reduced histamine and tryptase in

nasal secretions after allergen

bronchial mucosal EG2+ eosinophils and expression^[256]

T cells^[255]

Decreased ICAM-1 expression by nasal challenge^[227]

epithelial cells in EPR and LPR^[257]

Inhibition of eosinophil influx in trachea

of antigen challenged dogs^[223]

Reduced conjunctival EPR/LPR and

inflammatory cell infiltration^[256]

Decreased nasal symptoms, eosinophils

and neutrophils in EPR and LPR^[257]

Inhibited PAF-induced microvascular

leakage in rats without affecting

neutrophil accumulation^[261]

Reduced substance P in nasal

secretions from patients with

rhinitis^[258]

Inhibited guinea-pig

leukotriene-mediated lung

anaphylaxis^[259]

Reduced conjunctival nonspecific

hypereactivity^[260]

Reduced levels of IL-4 and soluble

CD23+ in patients with nasal

allergy^[262]

Reduced late-phase reactions to

skin-prick with allergen^[263]

Oxatomide

Inhibited conjunctival EPR, LPR,

inflammatory cells & ICAM-1^[264]

Inhibited conjunctival ICAM-1

expression following antigen

challenge^[264]

Reduced substance P in nasal

secretions from patients with

rhinitis^[258]

AA = arachidonic acid; Ag = antigen; Dp = Der Pl (house dust mite); ECP = eosinophil cationic protein; EPO = eosinophil peroxidase; EPR

= early-phase reaction; GM-CSF = granulocyte macrophage-colony stimulating factor; HLA-DR = human leucocyte antigen (DR locus);

ICAM-1 = intracellular adhesion molecule; Ig = immunoglobulin; IL = interleukin; LPR = late-phase reaction; LTC₄,D₄= leukotrienes C₄, D₄;

MIP-1α = macrophage inflammatory protein-1 alpha; PAF = platelet-activating factor; PCNA = proliferating cell nuclear protein?; sICAM-1

= soluble ICAM-1; TAME = alpha-N-p-tosyl L-arginine methyl ester; TNF = tumour necrosis factor.

In terms of anti-inflammatory effects in vivo,

studies which have observed positive inhibitory ef-

fects by treatment with cetirizine on cell accumu-

lation, adhesion molecule expression or mediator

release are far more numerous than for any other

drug in the same class. Perhaps the most striking

effects by cetirizine were on the inhibition of eo-

sinophil accumulation at skin sites challenged with

pollen^[194-198]or PAF.^[199]This effect could not be

attributed to the activity of cetirizine at the H₁re-

ceptor since cetirizine does not block histamine-in-

duced eosinophil infiltration and astemizole did

not have any effect on eosinophil migration. Fur-

thermore, neither promethazine nor chlorphenam-

ine induced any alteration in allergen-induced

inflammatory cell infiltration.^[197]Moreover, lor-

atadine treatment had no effect on eosinophil in-

flux in response to an intradermal injection of PAF

Drugs 2001; 61 (2)

224

Walsh et al.

in patients with urticaria and did not influence the

pollen-induced skin reactions or eosinophil influx

seen in sensitive individuals.^[198]In addition, use

of the skin chamber technique failed to demonstr-

ate a significant effect for loratadine on inflamma-

tion, histamine release or recruitment of eosino-

phils or other leucocytes to skin sites in patients

with atopy challenged with anti-IgE.^[237]

Epithelial adhesion molecule expression is

thought to represent an important mechanism by

which these cells interact with other pro-inflamma-

tory cells and its modulation might result in clinical

benefit. For example, a conjunctival challenge of

allergic patients resulted in an increase in epithelial

cell intracellular adhesion molecule-1 (ICAM-1)

expression and a large increase in the total number

of inflammatory cells at the challenge site at 30

minutes; the effect persisted for up to 24 hours and

these changes paralleled the increase in symp-

toms.^[165]In several double-blind, randomised and

placebo-controlled trials oxatomide, cetirizine, lo-

ratadine and terfenadine reduced epithelial ICAM-

1 expression, eosinophil and neutrophil numbers

and the clinical symptoms associated with both the

early-phase reaction (EPR) and LPR to a conjunc-

tival challenge.^{[200,229,239,264]}In a further double-

blind, placebo-controlled, randomised, parallel

study of children with allergic asthma associated

with mite sensitivity, cetirizine treatment resulted

in a significant reduction and in some cases a total

absence of ICAM-1 expression by nasal epithelial

cells, which was associated with a trend towards a

reduction in eosinophil and neutrophil numbers.^[203]

An obvious question that arises from the obser-

vations presented in tables V and VI is whether

such properties are shared by all members of the

second generation antihistamines, that is, whether

this is a class effect or is confined to certain mem-

bers of the second generation drugs. Although the

widely differing chemical structures of antihista-

mines does suggest that these effects are rather

nonspecific, only carefully conducted, large scale,

comparative studies would allow this question to

be answered with confidence. An additional ques-

tion is whether such effects are therapeutically rel-

evant and, if so, whether they may enable us to

distinguish further between these compounds. One

final issue that remains to be clarified is the dissec-

tion of the mechanisms by which these drugs exert

their anti-inflammatory effects, information which

might facilitate the development of more effective

anti-inflammatory therapy.

Considerable debate has been generated by

more recent studies which re-evaluated the effect

of cetirizine on allergen-induced cutaneous late-

phase reaction (LPR) in patients with atopy. Two

of these used punch biopsies rather than skin win-

dows to study the nature and extent of the cellular

infiltrate.^[201,202]In neither study did pre-treatment

with cetirizine significantly inhibit the magnitude

of the cellular infiltrate during the LPR, although

both studies demonstrated a reduction in eosino-

phil numbers in some patients. In contrast, pre-

dnisolone pre-treatment of these patients signifi-

cantly decreased both the magnitude of the LPR

and eosinophil influx.^[201,202]The discrepancies be-

tween the skin window and biopsy studies might in

part be explained by methodology, for instance the

quantity and purity of the allergens necessary to

induce a LPR in all patients. Furthermore, the skin

window technique enumerates and identifies cells

that have undergone transendothelial migration

and, thus, have left the dermal post-capillary ven-

ules, whereas biopsies measure the gross cellular

content at the reaction site. This difference is a po-

tentially important one since cetirizine might exert

its effect by inhibiting eosinophil adhesion to and/

or migration across the microvascular endothelium.

However, further studies which utilised the skin

window technique and biopsies to evaluate allergen-

induced, late-phase, cutaneous, allergic inflamma-

tory cell accumulation found that this was unaffected

by cetirizine treatment.^[208,209]These negative find-

ings might be explained by the fact that in the later

studies the 6-hour time-point was chosen to evalu-

ate the effect of cetirizine on the LPR, whereas the

earlier studies only demonstrated a significant ef-

fect by cetirizine at 8 hours or later.^[194,195]

Drugs 2001; 61 (2)

Second Generation Antihistamines

225

the effect of cetirizine is not dependent on biotrans-

formation. In a direct comparative study, cetirizine

was equipotent to loratadine, administered at 4 times

the recommended dose, in suppressing histamine-

induced wheal and flare;^[271]it was also superior to

both loratadine^[272]and ebastine^[273]in reducing

cutaneous blood flow as assessed by laser Doppler

flowmetry. More recently, fexofenadine has been

shown to be both efficacious and well tolerated for

the treatment of allergic rhinitis^[274,275]and chronic

idiopathic urticaria.^[276]In terms of its ability to

block histamine-induced wheal and flare reactions,

fexofenadine was found to be very effective and to

have a more rapid onset of action than loratad-

ine.^[277]

A recent study further emphasises the potential

differences between members of the second gener-

ation class of drugs. This double-blind crossover

study compared cetirizine, ebastine, epinastine,

fexofenadine, terfenadine and loratadine with pla-

cebo for suppression of the histamine-induced

wheal and flare. Epinastine had the most rapid on-

set of action followed by cetirizine, while terfenad-

ine induced potent inhibition which was superior

to its metabolite fexofenadine. The rank order of

inhibitory effect was cetirizine, epinastine, terfena-

dine, ebastine, fexofenadine, loratadine and pla-

cebo. 13 of 14 patients showed greater than 95%

inhibition of wheal area by cetirizine; just 6 of 14

had a similar response after treatment with terfena-

dine, epinastine and ebastine; 5 of 14 after fexo-

fenadine; and 2 of 14 following loratadine treat-

ment.^[278]These findings suggest that if it is

assumed that these antihistamines exhibit compa-

rable receptor affinities, then cetirizine appears to

have superior dermal bioavailability.

4. Clinical Considerations

Oral antihistamines have for many years been

first-line, highly effective medications for the treat-

ment of allergic hypersensitivity reactions such as

hay fever and urticaria. Most patients do not use

their antihistamines on a regular basis and usually

expect fast symptomatic relief from their allergies

without undesirable adverse effects. In particular,

the second generation drugs are highly effective

treatments for allergic rhinoconjunctivitis in which

they give rapid relief from rhinorrhoea, sneezing

and itching.^[266,267]However, in general, they have

only a minor effect on nasal obstruction, which is

most probably because histamine is not the main

cause of nasal obstruction. Other mast cell-derived

mediators released during the anaphylactic response

probably play a part in these reactions and these

include prostaglandins, neuropeptides and leuko-

trienes. Nasal corticosteroids have an effect on na-

sal obstruction and a recent meta-analysis con-

firmed that they are superior to antihistamines in

the treatment of rhinitis.^[268]

4.1 Comparison of the Potency

of Antihistamines

One method which is useful when considering

the effectiveness and onset of action for an antihis-

tamine is to assess its ability to block the in vitro

intradermal histamine-induced wheal and flare re-

action in the skin. Histamine can be either injected

intradermally or administered by skin-prick test. In

one double-blind, crossover study cetirizine 10mg,

terfenadine 60 and 120mg, loratadine 10mg, aste-

mizole 10mg and chlorpheniramine 4mg were

compared with placebo for their ability to suppress

histamine-induced skin wheal and flare reactions.

Cetirizine was the only agent which gave greater

than 50% inhibition of the area of wheal and flare

24 hours after administration.^[269]In a more recent

study,^[270]cetirizine was found to be more consis-

tent than ebastine in suppressing cutaneous reac-

tivity to histamine in healthy volunteers. This find-

ing might be a reflection of the need for ebastine

to be metabolised into the active carebastine whereas

4.2 Antihistamine Use in Asthma

Histamine is also a mediator implicated in asthma

pathogenesis, causing smooth muscle contraction,

mucus hypersecretion and increased vascular per-

meability leading to mucosal oedema; moreover,

bronchial hyperresponsiveness to histamine is a

well known feature of asthma. Inhalation of hista-

mine will produce dose-dependent bronchial con-

Drugs 2001; 61 (2)

226

Walsh et al.

striction which is greater in people with asthma than

those without. Histamine concentrations in bron-

choalveolar lavage (BAL) from patients with aller-

gic asthma are higher than those from patients with

allergic rhinitis or healthy individuals, and hista-

mine can contribute to the hyperreactivity seen in

patients with asthma.^[279,280]Many patients with

asthma show an enhanced ability to release hista-

mine spontaneously in the peripheral circulation

and lungs compared with healthy individuals as a

result of increased peripheral basophil and mast

cell degranulation. Those patients receiving effec-

tive asthma medication release less histamine than

those not receiving treatment.^[281]Segmental antigen

challenge of healthy volunteers and people with

asthma demonstrated increased histamine levels and

increased bronchoconstriction in the challenged

area in the group with asthma^[282]and increased

levels of histamine in BAL fluid were associated

with increased hyperresponsiveness following

methacholine challenge.^[283]

The potential therapeutic efficacy of antihista-

mines in asthma would therefore appear to be con-

siderable. However, the use of the early antihista-

mines in asthma treatment was limited because

they were not effective at the doses recommended

for treatment of allergic rhinitis whereas higher

doses resulted in intolerable adverse effects.^[284]

What then is the evidence that some of the newer

antihistamines might be useful as adjunct therapy

in allergic asthma, particularly as it is now recog-

nised that inflammation of the airways is a key

pathogenic event in asthma and, as discussed in

section 3, many of the second generation drugs

have documented anti-inflammatory effects?

Although it is acknowledged that antihistamines

cannot be considered to be first-line medications

for asthma therapy, a number of studies have eval-

uated the potential of some second generation

antihistamines as adjunct therapies.

placebo in a single group of patients with asthma.

Compared with placebo, all the antihistamines

provided significant protection against histamine-

induced bronchoconstriction as determined by the

histamine PC₂₀(provocative concentration pro-

ducing a 20% decrease), with cetirizine giving the

greatest protection. None of the drugs tested was

protective against the effects of methacholine-

induced constriction.

In patients with atopic asthma, ebastine,^[286]ce-

tirizine and loratadine^[287]effectively reduced the

bronchial response to a histamine challenge. In

contrast, a double-blind, placebo-controlled, cross-

over study with 10 patients with mild asthma found

that cetirizine had no significant effect on PAF-

induced bronchoconstriction.^[288]In responding pa-

tients with atopic asthma, cetirizine inhibited cel-

lular recruitment 24 hours after allergen inhalation

challenge in terms of total numbers of inflamma-

tory cells in the bronchial wash and with a partic-

ular effect on eosinophil recruitment.^[213]

Wasserfallen et al.^[214]found that cetirizine had

no effect on the EPR to antigen but had a significant

protective effect on the LPR to allergen bronchial

challenge whereas, in contrast, Bentley and co-

workers^[289]failed to demonstrate an inhibitory ef-

fect by cetirizine on either the early- or late-phase

asthmatic reactions to inhaled allergen in sensitised

patients.

Treatment of patients with pollen-associated

asthma using cetirizine 15mg daily for 2 weeks pro-

duced a marked lowering of pulmonary symptoms

associated with a decrease in the use of other med-

ications including β₂agonists and corticosteroids

compared with the placebo group.^[290]Bousquet et

al.^[291]found cetirizine 10 or 15mg twice daily to

be more effective than terfenadine 60mg twice

daily in the control of seasonal asthma symptoms

in 97 patients allergic to grass pollen with recent

onset mild asthma. A similar study also concluded

that cetirizine could prevent exacerbation of sea-

sonal asthma caused by grass pollen.^[292]In con-

trast, Rafferty et al.^[293]were unable to demonstrate

a significant protective effect by either oral or in-

haled cetirizine on allergen-induced early broncho-

For example, Wood-Baker and Holgate^[285]com-

pared the inhibition of bronchospasm, induced by

inhalation of histamine or methacholine, by astem-

izole, brompheniramine, cetirizine, chlorphenira-

mine, clemastine, cyproheptadine, terfenadine and

Drugs 2001; 61 (2)

Second Generation Antihistamines

227

constriction in a double-blind, randomised, placebo-

controlled trial, and a similar study demonstrated

only a nonsignificant tendency for cetirizine to

protect against the allergen-induced immediate

asthmatic response.^[294]

blind crossover study of 35 patients with moderate-to-

severe asthma.^[306]A more recent study using 193

patients compared the combined medication lor-

atadine 5mg/pseudoephedrine 120mg versus pla-

cebo. Loratadine/pseudoephedrine was found to

significantly improve pulmonary function and

both rhinitis and asthma symptoms.^[307]

These studies suggest that the second genera-

tion antihistamines are well-tolerated and effica-

cious as adjunct therapies in patients with asthma

and concomitant rhinitis, dermatitis or urticaria. In

particular, the link between the upper and lower

respiratory airways is now well established^[308]and

this has provided an additional rational for the use

of H₁receptor antagonists in patients with both

rhinitis and asthma.

One other consideration is that the documented

anti-inflammatory effects of some of these drugs

might be effective in preventing the progression from

atopic dermatitis to allergic asthma in children, a

process known as the ‘allergic march’. A recent

double-blind, randomised, placebo-controlled, mul-

ticentre trial evaluated the ability of cetirizine 0.5

mg/kg bodyweight to prevent the development of

allergic asthma in over 800 at-risk children for a

period of 18 months. Children were selected on the

basis of a diagnosis of atopic dermatitis together

with a parent or sibling history of atopic disease.

Raised immunoglobulin (Ig)E levels and raised

specific IgE to house dust mite, grass pollen or cat

dander were found to be predictive of the develop-

ment of asthma. In the subgroups of children sensi-

tised to pollen or house dust mite, cetirizine treat-

ment was found to halve the number of patients

developing asthma. During this prolonged treat-

ment period in young children and infants aged 1

to 2 years there was no higher incidence of adverse

effects, including somnolence, in the cetirizine

group (2.3%) compared with the placebo group

(2.0%), with the exception of urticaria which was

significantly less frequent in the cetirizine-treated

group (5.8 vs 16.1% for the placebo group).^[309]

This study provides evidence that consideration

should be given to cetirizine as a primary pharma-

cological intervention strategy to prevent the de-

Azelastine 4 mg/day for 3 months in 13 patients

with asthma resulted in significant improvements

in asthma symptoms accompanied by a reduction

of activated eosinophils and T cells in the bronchial

mucosa compared with the placebo-treated group,

and significant correlations were found between

clinical data and immunohistochemical parame-

ters.^[255]Moreover, azelastine 6mg twice daily re-

duced the need for inhaled corticosteroids in pa-

tients with chronic bronchial asthma and did not

lead to a deterioration in pulmonary function.^[295]

In addition, in patients with chronic asthma, a sin-

gle dose of azelastine 4mg resulted in rapid onset

of bronchodilating activity with a 12-hour duration

of action as demonstrated by a clinically and sta-

tistically significant mean percent improvement in

forced expiratory volume in 1 second (FEV₁),^[296]

while the same dose of azelastine both improved

their symptoms and reduced their requirement for

adjunctive anti-asthma medication.^[297]

Grant and coworkers^[298]demonstrated that ce-

tirizine significantly improved asthma symptoms

in patients with seasonal allergic rhinitis and con-

comitant asthma, although cetirizine had no statis-

tically significant effect onlungfunction asmeasured

by peak flow or FEV₁. These findings are similar

to those from a number of other studies.^[299-301]

Two randomised crossover studies of terfenadine

and placebo reported improvements in symptoms

and lung function in treated patients with atopic

asthma.^[302,303]In an uncontrolled study which

looked at the effect of loratadine on 25 patients with

allergic asthma, Kroll et al.^[304]found that a dose

of 10mg daily for 6 weeks was associated with im-

proved pulmonary function, reduced asthma symp-

toms and reduced bronchodilator use. However,

loratadine administered to 17 patients with peren-

nial asthma failed to have an effect on symptoms or

peak flow,^[305]and when given as an adjunct to stand-

ard asthma therapy had little or no effect in a double-

Drugs 2001; 61 (2)

228

Walsh et al.

velopment of asthma in specifically-sensitised high

risk groups of infants.

Acknowledgements

The authors extend their thanks to Dr J. P. Rihoux and Dr

C. de Vos of UCB Pharma, S.A. and to Mrs C. Convery Walsh

of the University of Aberdeen for their valuable comments

on the manuscript and again to Mrs Convery Walsh for

comprehensive editorial assistance.

5. Conclusions

In the light of the foregoing, what conclusions

can we make with regard to the current classifica-

tion of antihistamines into first or second genera-

tion drugs? It can be argued that the latter repre-

sents too large and indistinct a grouping since it

was based primarily on the concept of separating

sedating from nonsedating drugs. The group com-

prises compounds with a spectrum of antihistamine

and anti-allergic properties, and includes drugs

with proven cardiotoxic effects and others with the

potential for adverse drug interactions. In terms of

safety, cetirizine, fexofenadine and loratadine ap-

pear to be the most reliable, although a question

mark does remain concerning the potential for ce-

tirizine to cause a degree of somnolence in some

individuals. However, all antihistamines possess

this potential as a function of histaminergic mech-

anisms involved in the control of CNS arousal.^[310]

When pharmacokinetic properties are taken into

account, cetirizine, fexofenadine and acrivastine

are the only drugs which are not metabolised by the

liver and which, to date, show no evidence of drug

interactions. Thus, they can be given with confi-

dence to patients who are in need of other treatment

or who demonstrate hepatic impairment. Cetirizine

has a remarkably low V_dand thus does not accu-

mulate in lean tissues, and has by far the most well

documented profile of anti-allergic effects. Impor-

tantly, it not only has potential as a useful adjunct

therapy in patients with asthma who experience

rhinitis, but documented evidence is also now

available demonstrating its usefulness in prevent-

ing the development of asthma in at-risk children

with atopy. In conclusion, it is too early to talk

about a third generation grouping of antihista-

mines; however, future membership of such a clas-

sification could be based on a low V_dcoupled with

a lack of sedation effects, drug interactions and car-

diotoxicity.

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Correspondence and offprints: Dr Garry M. Walsh, Depart-

ment of Medicine and Therapeutics, Institute of Medical

Sciences, University of Aberdeen, Foresterhill, Aberdeen,

AB25 2ZD, Scotland.

E-mail: g.m.walsh@abdn.ac.uk

Drugs 2001; 61 (2)

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