PR2154

IC2: Antihistamines

Usage of antihistamines
- Allergic rhinitis
- Allergic conjunctivitis
- Urticaria
- Mastocytosis
- Cough & cold
- Food allergy
- Insect bites

Chemical class First (Old) Generation Second (New) Generation

Alkylamines Chlorpheniramine Acrivastine

Dexchlorpheniramine
Triprolidine

Piperazines Cyclizine, Cinnarizine Cetirizine, Levocetirizine

Hydroxyzine

Piperidines Cyproheptadine Loratadine, Desloratadine

Ketotifen Fexofenadine, Bilastine,
Levocabastine

Ethanolamines Dimenhydrinate
Diphenhydramine

Phenothiazines Promethazine

Other Azelastine, Olopatadine

Sedating Non(Less)-Sedating
Sources of Histamine

Mast Cell Degranulation: IgE-mediated Allergy

Mast Cell Degranulation: Non-IgE-mediated Pseudoallergy

Histamine: (Patho)physiological Actions

- Smooth muscle contraction (e.g. bronchial)
- Vasodilation (endothelium-derived NO-mediated)
- Increased vascular permeability (contraction of epithelial barrier and increase
gap junctions) – extravasation and edema
- Immediate symptoms of wheal-and-flare reaction in skin
- Sensory neuron to mediate pain and itch
- Increase release of histamine and other mediators from mast cells and basophils
- Stimulation of gastric acid secretion
- Modulation of histaminergic neurotransmissions, sleep/wake cycle, arousal,
alertness, attention, cognition, learning, memory
- Immunomodulation

Targets of antihistamines
- H1R: Immediate allergic response, inflammatory response
- H2R: Gastric acid secretion, suppression of immune cells, inflammatory
response
- H3R: Regulation of arousal and cognition, Control of inflammatory response
- H4R: Allergic and inflammatory responses, immune cell chemotaxis
Histamine Receptors

Functions of Histamine Receptors

H1-Antihistamines are Inverse Agonists

- H1 -Histamine receptors are

constitutively active.
- Inactive and Active receptors in
equilibrium.
- Histamine stabilizes H1-receptors in
Active form.
- Antihistamines stabilize H1 -receptors in
Inactive form.
- In principle, H1 -Antihistamines are
Inverse Agonists, NOT competitive
antagonists

Clinical Uses of Antihistamines

Allergic disorders:
2nd Generation Antihistamines are the Preferred Choice for mild-moderate allergy
- Allergic rhinitis: relieve nasal itching, sneezing, rhinorrhea
- Allergic conjunctivitis: relieve itching, erythema, tearing, edema
- Allergic urticaria: decrease itching, and the number, size and duration of wheals
and flares
- Food allergy
- Mastocytosis: relieve itching and flushing
Non-Allergic conditions: 1st Generation Antihistamines are commonly used
- Motion sickness and vertigo (e.g. promethazine, cyclizine, diphenhydramine)
- Nausea and vomiting as antiemetic (e.g. cyclizine, diphenhydramine)
- Insomnia and perioperation (e.g. promethazine, diphenhydramine)
Anaphylaxis: use adrenaline (epinephrine) as drug of choice. Oral 2nd gen
antihistamines have SLOW ONSET at 1-2 h. DO NOT relieve laryngeal edema,
respiratory tract obstruction, or shock and is NOT life-saving.
Mechanisms of Action of H1-Antihistamines

1 st (Old) vs 2nd (New) Generations of H1-Antihistamines

1st (old) generation 2nd (new) generation

Sedating Non-sedating or Less-sedating

Low H1-receptor selectivity High H1-receptor specificity

Anti-muscarinic cholinergic NIL

Anti-adrenergic
Anti-hydroxytryptaminergic (5-HT)

Highly lipophilic Less lipophilic

Lower molecular weight Higher molecular weight

Readily pass Blood-Brain Barrier(BBB) Less readily pass BBB

Lack interaction with P-glycoprotein efflux High affinity with P-glycoprotein efflux
pump pump

High CNS H1 receptor occupancy Low CNS H1 receptor occupancy

Onset of action: 2-3 Onset of action: 1-2 h

Duration: ~12 h Duration: 24 h (once daily)

Clinical Properties of Antihistamines
- Azelastine nasal spray: rapid onset of action in 15 min
- Azelastine and ketotifen eye drops: rapid onset of action in 15 min. Both have
mast cell stabilizing action
- For nausea and vomiting as anti-emetic and for vertigo and motion sickness:
inhibit histaminergic neurons from the vestibular nucleus to the vomiting
center in the medulla.
- Atopic dermatitis: 1st generation used for their sedative effects
- For insomnia and perioperative sedation: 1st generation used for their sedative
effects
- Combined H1-antihistamine and H2-blocker showed synergistic effects on acute
and chronic urticaria: H2-blocker (e.g. famotidine) acts by blocking H2-mediated
vasodilation to reduce wheals and flare.

Side Effects of 1st (Old) Generation of Antihistamines

- CNS H1 receptors
- Decreased alertness, cognition and psychomotor performance
- Increased impairment
- Muscarinic receptors
- Dry mouth, dry eyes
- Increased urinary retention
- Sinus tachycardia
- Blurred vision
- Constipation
- Serotonin receptors
- Increased appetite, weight gain (Ketotifen, Cyproheptadine)
- 𝜶-adrenergic receptors (Promethazine)
- Dizziness
- Postural hypotension
- Cardiac ion channels
- Prolonged QT intervals
- Ventricular arrhythmias
- 1st generation antihistamine should be avoided for pilots, drivers and any
machinery operators requiring psychomotor skills. Fexofenadine is
recommended.
- Contraindications: glaucoma, prostatic hyperplasia
- Drug abuse: euphoria, hallucination (cyclizine, diphenhydramine)
Chemistry of Histamine (Physicochemical properties of histamine)

Degree of Ionization

- Basic imidazole ring (N𝝅, pKa 5.8) connected to an aliphatic amino group in the
side chain (N𝜶 , pKa 9.4)
- 3 forms co-exist at physiological pH of 7.4 = unionized (1%), monocation (96%)
and dication (3%)
- The mono cationic form is believed to be the active species at physiological pH
while the unionized form penetrates membranes.

Histamine-Receptor Complex

For histamine binding at the H1 receptor, there are strict requirements:

(i) A protonated cationic side chain amine
(ii) A N with lone pair of electrons in the position adjacent to the protonated
aminoethyl side chain, which is fulfilled by N𝛕-H tautomer
(iii) A freely rotating imidazole ring that can achieve coplanarity with the ethylamino side
chain
Ethylenediamines

- Low H1 antihistaminic activity, low anticholinergic effect; and moderate sedative

effect

Ethanolamine Ethers

- Diphenhydramine is the
prototype (still widely used today)
for this class of H1 antihistamine.
- Bromodiphenhydramine is
more lipophilic than
diphenhydramine due to Br group
- Carbinoxamine maleate with
increased antihistaminic activity.
Marketed as racemate(due to
chiral centre) maleate salt.

Structural requirements for ethanolamine ethers

- Para-substitution on one of the phenyl rings in ethanolamine ethers gives
selective antihistaminic activity over the anticholinergic activity.
- Ortho-substituted phenyl ring restricts rotation of the 2 aryl rings => decrease
in antihistaminic activity with increased anticholinergic activity.
Alkylamine (Propyl Amines)

- Collectively referred to as pheniramines.

- The halogen increases lipophilicity → increases antihistaminic activity and
exhibit also longer duration of action. The p-halogenated pheniramines are
less sedating than ethylenediamines and the ethanolamine ethers.
- They exhibit only moderate anticholinergic activity compared to the ethanolamine
ethers.
- Racemate chlorpheniramine and brompheniramine are in clinical use.
- Formulate as the maleate or tannate salt (formed by acid and basic amine group)
to make the compound more water-soluble.

Piperazines
- Hydroxyzine is used pre- and
post-op for nausea, anxiety,
pruritus and allergic rhinitis, as
well as sedative. The terminal
hydroxymethyl group undergoes
sequential oxidation by
cytosolic alcohol dehydrogenase
and aldehyde dehydrogenase to
provide the active carboxylic acid
metabolite – cetirizine

- Meclizine is an analogue of
hydroxyzine with the
hydroxyether side chain replaced
by a 3-methylbenzyl group. This
group significantly increases the
lipophilicity relative to
hydroxyzine.
Tricyclic H1 Antihistamines

- Promethazine possesses high antihistaminic and anticholinergic effects.

While it is used for its antihistaminic effect to treat allergic rhinitis, it is used
more often as a sedative, an antiemetic in the prevention of motion
sickness, and used pre- or post-op to treat nausea & vomiting.

- Cyproheptadine can be considered as an analogue of promethazine in

which the S in phenothiazine is replaced by a vinyl (ethylene) bridge. It
also exhibits moderate anticholinergic and low sedative properties.

- The tricyclic structure is formed by the 2 rings being connected by a

heteroatom (O or S) or 1C or 2C. The earliest tricyclic antihistamine has
phenothiazine ring system (eg. in promethazine), where there is no
substituent on the tricyclic ring and a 2-3C aliphatic basic side chain.

General SAR of first generation H1 antihistamines

Structural features of 1st gen AH:
- Tertiary amino group
- Some are chiral
- 2 aromatic rings or 1 tricyclic ring
- 2-3 atoms distance between amino group and
the atom that links to the 2 aromatic rings.
Non-Sedative Second Generation H1 Antihistamines

Permeation Across the Blood Brain Barrier

- Different mechanisms are involved in the permeation of drugs across the blood
brain barrier.
- Drugs able to penetrate the blood brain barrier may produce desired therapeutic
or side effects.
- Factors that influence permeation:
- Lipophilicity of the drug molecule (LogP vs LogDpH 7.4 )
- Substrate of transporters (influx vs efflux)
- Molecular mass
- Hydrogen bonding capacity

Log P vs Log D(pH x)

- Permeation by passive diffusion depends on lipophilicity of the drug molecule.
- Lipophilicity is defined by partition coefficient (P) or distribution coefficient
(D) if the molecule can be ionized.
- For acids, the neutral/anion ratio of molecules in solution decreases with
increasing pH; therefore, the log D decreases with increasing pH.
- Conversely, for bases, the neutral/cation ratio of molecules in solution increases
with increasing pH; therefore, the log D increases with increasing pH.

Log Dacid = Log P – Log(1 + 10pH-pKa )

Log Dbase = Log P – Log (1 + 10pKa-pH )
Chemistry of Nasal Decongestants and Bronchodilators

Nasal Congestion and its Treatment

- Sympathetic activation – causes vasoconstriction
- Parasympathetic activation – inhibits vasoconstriction
- Congestion can be treated by constricting the dilated vasculature, thus bringing
cells closer, decreasing leakage.
- Adrenergic receptor agonist
- Cholinergic receptor antagonist

Association of Therapeutic Value with Target and Nature of Interaction

Phenylephrine as nasal decongestant
- Vascular smooth muscles of the nasal pathway (and the eye) are rich in
𝛂1-adrenergic receptors.
- Activation of 𝛂1 receptors causes vasoconstriction and smooth muscle
contraction that is needed for treating congestion.
- Phenylephrine has a phenylethanolamine pharmacophore.
- 3-phenolic hydroxyl moiety improves 𝛂1-receptor selectivity while
decreasing 𝜷-receptor binding → minimal cardiac stimulatory properties
- Treat nasal and sinus congestion and itchy eyes.

2-Aryl Imidazoline as nasal decongestant

- 2-aryl imidazoline derivatives are selective 𝛂1-agonists with

vasoconstriction/ vasopressor activity.
- Lipophilic substitution (eg. CH3 ) on the phenyl ring ortho to the
methylene bridge appears to be required for agonist activity at 𝛂1
and 𝛂2 receptors. Bulky lipophilic groups attached to the phenyl
ring at para positions provide selectivity for the 𝛂1-receptor by
diminishing the affinity for 𝛂2-receptors.
- Imidazoline derivatives bind differently at the 𝛂1-adrenoceptor
compared to the phenylethanolamine.
Treatments for Asthma and Chronic Obstructive Pulmonary Disease (COPD)

- Terbutaline sulfate is the N-t-butyl analogue of

metaproterenol and is more potent.

- Formoterol fumarate has a 𝜷-directing

N-isopropyl-p-methoxyphenyl group and a unique
m-formamide and p-methoxyphenyl ring, which provides
selectivity for 𝜷2-receptor.
- Formoterol has quicker onset due to its greater water
solubility, allowing it to get to the receptor site faster.
- Moderate lipophilicity allows it to stay locally in the lungs.
It is indicated for long term maintenance treatment of
asthma for patients with nocturnal asthma.

Synthetic Glucocorticoid Esters for asthma & COPD

Esters of Glucocorticoids

- There are at least 3 hydroxyl groups (at C21, C11 and C17𝛂)
that can be esterified to different extent to form esters of the
glucocorticoids.
- C21 OH group is the most accessible OH group for
esterification; followed by C17𝛂, and C11 OH group is the
least accessible for esterification due to the steric hindrance
from C10 and C13 methyl groups.
- C21 OH group must be free to H-bond with Arg 564 in the
glucocorticoid receptor, therefore esters at this position are
prodrugs.
- C17𝛂 OH is metabolised by oxidation. Esterification of this
OH group inhibits oxidation and prolongs the duration of
action. This ester undergoes tubular reabsorption thus
prolonging its action in the body.
Common lipophilic esters of glucocorticoids