First Versus Second Generation Antihistamines at the BBB

Samantha Woolcock
Seton Hill University
SPA 220-01
October 28, 2020
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Samantha Woolcock
Allergic rhinitis is a chronic respiratory illness that develops from immunoglobulin E
(IgE), an antibody secreted with antigen contact.1 Antihistamines are a treatment option for
moderate to severe symptoms of pruritus, rhinorrhea, and nasal congestion. Antihistamines
subdivide into two categories; first generation antihistamines cross the blood-brain barrier
(BBB) and evoke sedative effects unlike second generation antihistamines, which rarely
penetrate the BBB.1 First and second generation antihistamines differ in concentration in the
central nervous system (CNS) due to structural characteristics and transmembrane binding
proteins.
Allergic rhinitis arises from an increase of type 2 T lymphocyte (T H2) and the production
of IgE antibodies in the presence of an allergen.1,2 Within 30 minutes of exposure, this triggers
an early phase response, where degranulation of mastocytes and release of histamine and
leukotrienes from basophils occurs.2 Histamine and leukotrienes affect vascular permeability by
smooth muscle constriction and an increase in mucous production. In the following two to six
hours, the late phase accounts for the release of chemokines, localization of inflammatory cells
around the antigen, and an increase in eosinophils and TH2.2 A reaction can continue any
duration of time with uninterrupted antigen exposure.
The tuberomammillary nucleus of the posterior hypothalamus produces histamines.
These endogenous neurotransmitters interact with H1-H2-H3-H4 specific receptors in the CNS.3
Specifically, H1 receptors directly influence allergic reactions and inflammation. H 1 receptors
reside in the frontal, temporal, and occipital lobes of the cerebral cortex, the thalamus,
putamen, caudate nucleus, and cingulate.3 Apart from allergies and inflammation, the
histaminergic system provides various functions such as the release of acetylcholine, the sleep-
wake cycle, and alertness.4 Histaminergic neurons increasingly activate with alertness because
of orexin, a peptide neurotransmitter, secretion.3 Sedative first generation antihistamines block
orexin from reaching H1 receptors, causing sedative effects. First and second generation
antihistamines are similarly antagonists of the H1 histaminergic receptor but contrast in effects
on the CNS.
Collectively, antihistamines reduce allergic inflammation by targeting H 1 receptors in
blood vessels, sensory nerves, and the brain.3 First generation antihistamines bind to H1
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receptors in the brain, causing sedative effects, while second generation antihistamines bind to
H1 receptors in blood vessels and sensory nerves.2 Antihistamines target the inactive
conformation of H1 receptors, providing stability.3 Competitive inhibition prohibits the
histamine from binding to the specific H1 receptor, minimizing symptoms. Additionally,
antihistamines reduce mastocytes’ intracellular concentration of calcium providing more
stability and control over histamine function. Mastocytes are granular connective tissue cells
containing histamines. High intracellular concentrations of calcium lead to degranulation,
triggering the release of histamines; antihistamines prevent this process. 3
First generation antihistamines have a sedative effect on the CNS and include
brompheniramine, chlorpheniramine, clemastine, hydroxyzine, pyrilamine, and
diphenhydramine.5 Diphenhydramine or 2-(diphenylmethoxy)-N,N,-dimethylethanamine, also
known as Benadryl, is a common treatment for allergic rhinitis. 1 Diphenhydramine is similar to
all first generation antihistamines regarding its properties, structure, and interactions with the
BBB. Therefore, diphenhydramine is a model for the interaction of all first generation
antihistamines with the BBB. Histamine H1 receptor occupancy, using positron emission
tomography (PET) and [11C]doxepin, determines the level of sedation of antihistamines.4
[11C]doxepin is an antagonistic molecule with a radionuclide tracer that provides a visual aid of
the occupancy of H1 receptors after use of an antihistamine. First generation antihistamines
occupying H1 receptors in the brain outnumber that of second generation antihistamines. 4
Sedative effects occur from first generation antihistamines creating a bond in the brain. These
sedative effects result from the stability of the bond between the antihistamine and H 1
receptors. Since histamines regulate the sleep-wake cycle, the stable bond increases
drowsiness; orexin no longer reaches histaminergic receptors, causing a decrease in alertness. 3
Fatigue and impaired mental status from sedation of diphenhydramine and other first
generation antihistamines results from blocking of neuronal transmission in the histaminergic
nervous system.1,4
First generation antihistamines cross the BBB due to lipid solubility. 1 The functional
groups composing diphenhydramine are nonpolar, contributing to its overall nonpolar, or
lipophilic, structure. The molecular structure of first generation antihistamines allows them to
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penetrate directly through the phospholipid bilayers by passive diffusion. In addition to the
diffusion of lipophilic first generation antihistamines, an unknown membrane transporter is the
primary penetration mechanism of first generation histamines. 6 Diffusion of first generation
antihistamines is challenging regardless of lipophilicity due to the four phospholipid bilayers.
The cerebral capillaries contain tight junctions of simple squamous epithelial cells, providing
two membranes of the BBB with few integral membrane proteins for facilitated passive
diffusion. Additionally, astrocytes contribute two more phospholipid bilayers to further control
what substances permeate the BBB. The potential to penetrate the BBB is independent of
molecular weight even though diphenhydramine has a lesser molecular weight than second
generation antihistamines.3,7
The unknown membrane transporter accounts for the majority of diphenhydramine
movement across the BBB.6 The actual chemical makeup of this transporter is unknown, but it
is a proton (H+)-antiporter in the capillary membrane of the BBB endothelial cells. The specific
transport mechanism is a secondary active transport membrane protein that moves protons
from basolateral to apical surfaces, or brain to blood, while transporting diphenhydramine from
apical to basolateral surfaces, or blood to brain.6 Substrates of other known H+-antiporters in
the CNS are cationic secondary or tertiary amines. Diphenhydramine is an overall neutral
tertiary amine.7 The amine group remains responsible for the binding of diphenhydramine to H 1
receptors in the brain. The H+-antiporter is of low affinity for diphenhydramine due to its
structure. The overall net neutral charge of diphenhydramine limits the attracting forces
between the substrate and integral membrane protein.6 To overcome the low affinity for
diphenhydramine, the specific antiporter rapidly transports diphenhydramine across the BBB.
The quick transport of diphenhydramine and protons allows for more movement across the
BBB to occur. Also compensating for the low affinity, the H+-antiporter functions in high
capacity or full saturation of diphenhydramine.6 The H+-antiporter transports more than one
molecule of diphenhydramine every time it pumps protons from the brain. The specific
transporter propels diphenhydramine across the BBB in a low-affinity and high-capacity
mechanism for diphenhydramine and accounts for the majority of its influx into the CNS.
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After first generation antihistamines move into the CNS, efflux back through the BBB
does not occur. First generation antihistamines are not substrates for the efflux transporter, P-
glycoprotein (Pgp).5 Pgp, a member of the ATP-binding cassette family, is an active transport
pump between the simple squamous epithelial cells of the BBB. Pgp removes foreign
substances from the brain by hydrolysis of adenosine triphosphate (ATP). 3,5 ATP divides into
adenosine diphosphate (ADP) and inorganic phosphate, generating energy that supplies Pgp for
active transport. All first generation antihistamines display a higher apical to basolateral
permeability than basolateral to apical permeability across the BBB. 5 The lack of basolateral to
apical transport, or efflux, means that first generation antihistamines are not substrates of Pgp.
The H+-antiporter responsible for the influx of first generation antihistamines works
independently from Pgp and remains unaffected by Pgp deficiency.6 As a result, the high
concentration of first generation antihistamines in the CNS remains constant due to H+-
antiporters, assisting in influx and lack of efflux by Pgp. First generation antihistamines
penetrate deep into the gray matter of the brain, including the caudate nucleus, putamen, and
thalamus, resulting in sedative effects on the CNS from the binding of H 1 receptors .3
Second generation antihistamines exhibit more complex structures, decreasing mobility
through the BBB. They include cetirizine, desloratadine, fexofenadine (Allegra), loratadine,
terfenadine, and levocetirizine (Xyzal).1,5 In comparison to diphenhydramine, levocetirizine is a
larger compound with more functional groups. Additionally, the functional groups of
levocetirizine are individually polar, contributing to an overall polar, or lipophobic, compound.
Second generation antihistamines do not cause sedative effects because of minimal presence in
the CNS, but they remain effective in treating nasal and ocular symptoms. The effectiveness
prevails because of the binding at the H1 receptor in blood vessels and sensory nerves.1 The
ability to treat allergic rhinitis without high CNS concentrations allows for treatment without
adverse effects.
Second generation antihistamines are lipophobic with minimal ability to passively
transport across the BBB. Small amounts of second generation antihistamines pass through the
BBB by unknown facilitated transport mechanisms.5 This unknown process accounts for
cetirizine and other second generation antihistamines, causing dose-dependent sedative effects
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on the CNS.1,5 Cetirizine is a more potent histamine antagonist than other second generation
antihistamines; it binds to more H1 receptors in the CNS, increasing adverse effects.1 Including
the unknown transport process, the apical to basolateral permeability of second generation
antihistamines is significantly less than first generation antihistamines. 5 Cetirizine and other
second generation antihistamines that pass through the BBB shallowly penetrate the brain,
binding to H1 receptors in the frontal, temporal, and occipital lobes, producing minor sedative
effects.3 Only sedative second generation antihistamines have the potential to cross the BBB,
but all second generation antihistamines are substrates for Pgp. 5
The main reason second generation antihistamines are non-sedative is due to efflux
from the CNS. After the rare occasion of crossing the BBB, second generation antihistamines
experience entire removal.5 All second generation antihistamines can bind to Pgp. However, the
concentration of influx is greater than the concentration of efflux. Also, with inhibited Pgp,
removal from the CNS still occurs. Therefore, not all elimination of second generation
antihistamines from the CNS occurs by Pgp transport. Unknown transport mechanisms also aid
in efflux.5 Cetirizine, unlike non-sedative second generation antihistamines, remains in the CNS
after Pgp transport. Since cetirizine experiences transport by Pgp, it cannot be a substrate for
the unknown transport. Without being a substrate for the unknown transport mechanism,
cetirizine resides in the CNS, producing sedative effects.
Allergic rhinitis is a chronic respiratory illness caused by an increase in inflammatory
cells, eosinophils, and TH2 lymphocytes after contact with an antigen.1,2 First and second
generation antihistamines are treatment options for allergic rhinitis as histamine antagonists
that bind to H1 histaminergic receptors.1 First generation antihistamines permeate the CNS by
crossing the BBB. This transport occurs by passive diffusion and H+-antiporter mechanisms to
enter the CNS, causing sedative effects.6 Lipophobic second generation antihistamines can
permeate the BBB on rare occasions due to large, polar molecular structures. 7 Efflux by Pgp
occurs with all second generation antihistamines, preventing sedative effects on the CNS. 5 An
additional efflux mechanism aids in the total removal from the CNS. Cetirizine, an exception to
non-sedative second generation antihistamines, is not a substrate for the unknown efflux
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Samantha Woolcock
mechanism, allowing for adverse effects on the CNS. First and second generation
antihistamines are both treatment options for allergic rhinitis as histamine antagonists.
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Samantha Woolcock
References
1. Sur DK, Scandale S. Treatment of allergic rhinitis. Am Fam Physician. 2010;81(12):1440-
1446. https://www.aafp.org/afp/2010/0615/p1440.html
2. Tonelli LH, Katz M, Kovacsics CE, et al. Allergic rhinitis induces anxiety-like behavior and
altered social interaction in rodents. Brain Behav Immun. 2009;23(6):784-793. doi:
10.1016/j.bbi.2009.02.017
3. Montoro J, Bartra J, Sastre J, et al. H1 antihistamines and benzodiazepines. J Investig
Allergol Clin Immunol. 2013;23:17-26.
4. Kikuchi A, Nasir FBM, Inami A, et al. Effects of levocetirizine and diphenhydramine on
regional glucose metabolic changes and hemodynamic response in the human
prefrontal cortex during cognitive tasks. Hum Psychopharmacol Clin Exp. 2018;33. doi:
10.1002/hub.2655
5. Obradovic T, Dobson GG, Shingaki T, et al. Assessment of the first and second
generation antihistamines brain penetration and role of p-glycoprotein. Pharm Res.
2007;24(2):318-27. doi:10.1007/s11095-006-9149-4
6. Auvity S, Chapy H, Goutal S, et al. Diphenhydramine as a selective probe to study h+-
antiporter function at the blood-brain barrier: application to [11C]diphenhydramine
positron emission tomography imaging. Sage Journals. 2017;37(6):2185-2195. doi:
10.1177/0271678X16662042
7. National Center for Biotechnology Information. Pubchem Compound Summary.
Accessed Oct. 8, 2020. https://pubchem.ncbi.nlm.nih.gov/compound/.