Antihistaminic

NH,
A
H2C—CH2
5 4 a

(tele)1 N N3 ( pros )

H/r \/ t
2

Histamine
 Histamine -Pharmacology

* Histamine is an Autacoid , which are biological

chemicals which act like local hormones, have a
brief duration, and act near their site of
synthesis.
* Histamines has various function in body such as:
— Mediator of inflamation and local immune
responses
— regulating physiological function in the gut and
— acting as a neurotransmitter.
* During inflammation Histamine is produced by
basophils and by mast cells, found in nearby
connective tissues, which increases the permeability
of the capillaries to white blood cells and some
proteins, to allow them to engage pathogens in the
infected tissues
* Inthe gutitis produced by parietal cells and then
promotes gastric acid secretion and thus aids in
digestion. Here it acts like a local hormone
* As a neurotranmitter, it effects sleeping and waking,
food intake, thermal regulation, emotions and
aggressive behavior, locomotion, memory, and
learning
 Histamine - Chemistry
=T
Imidazole Ethyl Basic
ring side chain amin

* Histamine is a Nitrogenous base. It is composed of an

imidazole ring and ethylamine side chain. In Plasma pH
of 7.4 is exists in exclusively monocationic form
(96.6%). At lower pH higher levels of dication form
exist.
* |n solution form, 80% contain H in Nt tautamer and
20% in Nt tautamer
e But crystal form consist primarily of Nt form
 / i
80% has il /_<_ 20% has
Hin: Nt A/—< — NG Hin N1t
Nt tautamer N7t tautamer

Monocationic form
NH3* NH;"
/
et At plasma pH
/_: /—< 96.6% is

NS S W monocationic

“ Dicationic form “

Note that sp2 N is P il P

more basic than
HzC_CHQ H2C_CH2

sp3 N /_"< /—< Lower pH favors

"
N N = . =
W X H dicationic form
 Histamine Biosynthesis
NH2 /NH2

H,C— C H,C——CH,
[ %, COOH
L-Histidine Decarboxylase AR

\/N Pyridoxal Phosphate \ \/N

L-Histidine Histamine
Histamine biosynthesis.

Note- There some drugs that can block Histidine Decarboxylase such as
Floromethylhistine which in theory can act as direct acting antihistamine
but clinically were found to be not useful.
 Storage and release
Stored in mast cells in Complex with Heparin
(anticoagulant)
Stored in basophiles in Complex with Chondrotin
Histamine as stored in mast cells are found
almost everywhere : skin and the mucosal cells of
the bronchi, intestine, urinary tract, and tissues
adjacent to the circulation and within neurons of
CNS
It is released in response to a wide variety of
immune (antigen and antibody) and nonimmune
(bacterial products, xenobiotics, physical effects,
and cholinergic effects) stimuli
 Histamine receptors
Location and function
H1, H2, H3, H4; they all are GPCR’s
* H1 Location : CNS neurons, the smooth muscle of
respiratory, GIT, uterine tissues, epithelial and
endothelial cells, immune cells
Function: vasodilation, vascular permeability,
hypotension, flushing, pain, headache, tachycardia,
nasal congestion, bronco-constriction, stimulation of
cough receptors, allergic immune response
* Therapeutic usage: H1 antihistamine are anti-
allergic, and anti-emetic drugs,
* H1 receptor is 40% similar to muscarinic receptors
(thus some H1 antagonist shows unwanted
antimuscaric side effect)
H1 receptors belong to the superfamily of G protein
coupled receptors (GPCRs), and are encoded for by
chromosome 3
these receptors exhibit spontaneous activation of their
intracellular messengers, requiring no binding by an agonist
at surface level
It exists as a balance between activated (characterized by
the production of intracellular second messengers) and
inactive (no such intracellular signaling) state.
If the ligand stabilizes the active receptor conformation,
making it the predominant form, then the drug is referred
to as an agonist, while if the inactive conformation is
stabilized the drug is said to be a inverse agonist. In this
way, histamine is an agonist, while the antihistamines are
presently considered to be inverse agonists instead of
antagonists as previously believed
m' H, receptor

. Inactive state

. Active state
H2 function - gastric acid secretion, vascular
permeability, hypotension, flushing, headache,
tachycardia, broncho-dilation and respiratory mucus
production
Therapeutic use — H2 antihistamines are Anti-ulcer
drugs
H3 Location : CNS
Function: adrenaline release and autoreceptor of
Histamine in CNS
Therapeutic use — potential application against obesity
H4 function : differentiation of hematopoietic cells
Therapeutic use — none yet
 Differentiation

It is a process by which a less specialized cell

becomes a more specialized cell type
When cells divide into daughter cells, they are
the same exact cells. This is cell division/growth
But differentiation means when cells “divide”,
different cell types are formed.
At conception we all were just a single cell but
differentiation causes us to have diverse
specialized cells that make up different organs
 Undifferentiated cell, called stem cells
differentiates into diverse functioning cells
Stem Cell

‘| Structural
| Chondrocyte Bone
Erythroid Ostecblast
RBC o
Signaling .
i Beta cell InSU||n

Neural
Hematopolesls Astrocyte
Microglia
WBC i{:f,l:phages Myogenesis Oligodendrocyte
T-cells Cardiomycyte Photoreceptor
Smooth muscle
 Actions of Histamine by receptors

EXOCRINE EXCRETION CARDIOVASCULAR SYSTEM Stomach

Lowers systemic blood pressure by
Increased production of nasal and
reducing peripheral resistance,
Stimulation of gastric hydrochloric
bronchial mucus, resulting in acid secretion.
Causes positive chronotropism
respiratory symptoms.
(mediated by H, receptors) and a
BRONCHIAL SMOOTH MUSCLE positive inotropism (mediated by
both H; and H; receptors).
Constriction of bronchioles results
in symptoms of asthma and decreased
lung capacity. Dilation and increased permeability of
INTESTINAL SMOOTH MUSCLE the capillaries results in leakage of
proteins and fluid into the tissues.
Constriction results in Intestinal cramps
In the skin, this results in the classic
and diarrhea.
“triple response”; wheal formation,
SENSORY NERVE ENDINGS reddening due to local vasodilation,
Causes itching and pain. and flare (*halo”),
Adverse effects
 Hq Antihistamines

All Hy anti-
Particularly histamines
promethazine

‘
S - fi'r' ”‘1'1'
S ;‘.’.'.‘-
e ii.a,_ll.t:r .Iu._

"4 r*? "'! .:'|-"'|' l'l*:'l n' “{] Ili 4'|'r'---’I

Dry mouth Hypotension tAppetite Allergic inflammation, itching,

Urinary retention T Dizziness ‘mflmn‘flmm
# Sinus tachycardia T Reflex tachycardia in the CNS
4 Neurotransmission
4 Sedation
| Cognitive
and psychomotor performance
1 Appetite

Fig: Effects of H, antihistamines at histamine, adrenergic, cholinergic, and serotonin-binding receptors. Many second
generation antihistamines do not enter the brain and, therefore, show minimal CNS effects.
 H1 antihistamines
Their main application is as anti-allergic, anti-emetic and
The first generation of H1 antihistamines has sedative effect
due to effect on H1 receptor in brain. Structurally this effect is
linked to their high lipophilicity induced BBB penetration and
also they are poor substrate for brain’s endothelial P-
glycoprotein efflux pumps, thus can’t exist the brain once they
enter.
They also antagonize cholinergic receptors which causes dry
mouth, dizziness, fatigue and are alpha adrenergic blockers
which can cause cardiotoxicity by prolonging the QT interval
The second generation are more selective for H and don’t
penetrate brain and thus has no sedation or cardiotoxicity
MOA: They bind and stabilize the inactive form of H1 receptors
onto which Histamine is not capable of binding.
 Therapeutic Uses:H1 blockers

dermatosis
allergic rhinitis
.

motion sickness & emesis

Parkinson’s disease
S

EPS
A
20

Insomnia
 ECG of heart and prolonged QT interval
One beat (R to R) *The QT interval denotes
I
: time period taken by heart to
QRS T R
S empty it’s blood.

hd A *Prolonged QT interval
T Suggests problem in cardiac
QRS !| R muscle’s repolarization
mechanism after each
contraction.

*It is a dangerous side effect

that can cause ‘Ventricular
Fibrillation' which will lead
to sudden death unless a
Heart is full of blood at () . Heart contracts atend of T. defibrillator is used to reset
heart’s normal rhythm
 Classification
First Generation
1) Propylamines - Chlorpheniramine, Phenindamine
2) Ethanolamines - Diphenhydramine, Clemastine
3) Ethylenediamines - Pyrilamine, Tripelennamine
4) Phenothiazines - Promethazine, Trimeprazine
5) Piperazines - Cyclizine, Meclizine
6) Heptanes — Azatadine, Cyproheptadine
7) Phthalazinone — Azelastine
Second Generation (Peripherally Selective)
1) Piperazine- Cetirizine/Levocetirizine
2) Piperidines - Fexofenadine, Loratadine /Desloratadine
Note: Antihistamines have a lot of structural diversity
 Structures
R Ar R
/N\
R
N/N
R
F
Ar

CH—CH;—CH,—N
/ |
Ar——C——0—CH,—CH,—N CH,—CH;
; . | R Ar R'
Ar : R Ar . . :
Propylamines Ethanolamines Ethylenediamines

@]@ Q - —K
L O
cl-t2 -(CHp)— N

R" R
N

Phenothiazines Piperazines |
Heptanes
 SAR of H1 antihistamines (1%t gen only)
R" R

Ar’
|(|3—O—CH2—CH2—N\/
Ar R
General framework of AntiHistamine (Ethanolamine based)
Ry

Ro C X (CHQ) H_- N substituent

R
Generaia framework of Anticholinergics
Note the similarity in H1 antihistamines and Anticholinergics
(this explains the origin of Anticholinergic side effect of H1
antihistamines)
1. It needs a tertiary amine which is mostly di-
methyl substituted or part of cyclic ring
2. The methylene (-CH2-)groups can be about 2 or 3
3. The oxygen can be removed or replaced with C
4. The terminal carbon must have two aromatic
groups and R group is mostly H but can be CH3
too
Diphenhydramine Dighieriloyealine

CHOHCH,CH,N(CH3), CH_04<:\/N_CH3
5) Alkyl Substitution in these aromatic rings
influence selectivity
Increasing alkyl substituions at C4 increases
anticholinergic activity and decreases
antihistaminic activity
Increasing alkyl substituions at C2 decreases
anticholinergic activity and modestly increases
antihistaminic activity
6) Presence of halogen at C4 position enhances
potency
Replacement of one of the aromatic rings with
2-pyridyl group increases histaminic selectivity
8) For max potency, the terminal carbon must have
R configuration. R/S configuration at amine is
less important
 6 2

5 3
4 CHs CHa
2C —CH; 2C CoHs 2C——CH 2C——C——CHj
Methyl Ethyl \CH 3
_ |
CHa
1-propyl t-butyl
Effect of increasing Alkyl group at C2 or C4

Alkyl position |Anticholinergic m

At C2 Increases Decreases
At C4 Decreases Increases
Br
Diphenhydramine
Bromo
Diphen
hvdramine
CHOHCH,CH,N(CH3),

CHOCH,CH,N(CH3),
Halogen at C4
increases potency

QDoxylamine
CHOCH,CH,N(CH3),

2-pyridyl ring increases

<\ /g” histaminic selectivity
 Importance of stereomeric consideration
Cl

Configurati |ED50
Q on
(C N) mg/kg
CH, ”BC\ 0.04
N s,s 5.0
°_°”"C”2‘O R,S 0.28
O Clemastine S,R 11.0

Clemastine has two chiral centres, terminal carbon and amine

ED50 reflect potency. Entry 15t and 3™ are most potent. Both
contain R configuration at terminal carbon. Conversely Entry
2" and 4™ with S configuration at terminal carbon are the
least potent
Cl . o Cl
E Chlorpheniramine

Clemastine

CH; \

e
e N— CHz E= CH2 _N(CH:;)?

Pyrilamine
\
Chlorpheniramine
tis a propylamine based 15t generation H1
antihistaminic
t is chlorinated pheniramine which improves potency
10 times and changing toxicity
t’s Dextro isomer has S configuration and called
DexChlorpheniramine is more potent
t also acts as serotonin-norepinephrine reuptake
inhibitor or SNRI
t is combined with opiods for cough medicine because
it can potentiate action of opiods
t causes drowsiness by penetrating into brain and
acting on H1 receptor
Uses
— Allergic rhinitis, in cough medicines
MOA (from above)
Draw dextro isomer of Chlorpheniramine
in fisher projection
H,C” g2 H,C” R

o v
Br Br
. . Zimelidine
Brompheniramine
H1 antihistaminic/Antiallergic SEIGUIS ?erth-onm
reuptake inhibitor/
Antidepressent
Zimelidine is an anti-depressent. It is a derivative of brompheniramine
Note how a simple addition of double bond completely altered
pharmacology of drug. But was this structural alteration randomly
discovery or fully Intended?
Clemastine

It is a ethanolamine based 15t generation H1

antihistaminic
This class has a longer duration of action (10-12
hrs)
It causes drowsiness by penetrating into brain
and acting on H1 receptor
Uses
— Allergic rhinitis, urticaria (itchy skin rash), anti-emetic
MOA (from above)
Pyrilamine
It is a ethylenediamine based 1%t generation H1
antihistaminic
They are among the weakest antihistamines
t is combined with opiods for cough medicine
because it can potentiate action of opiods
t causes drowsiness by penetrating into brain and
acting on H1 receptor
Uses
— Allergic rhinitis, incest bites (topically)
MOA (from above)
J0 G2 CHz =t CH_N(CH3)2

CHs
N Promethazine
CH,
Cyproheptadine

Mecllzme
Promethazine

* Itis a phenothiazine based 1t generation H1

antihistaminic
* |t's sedative action is strong to be used clincally
* |t causes drowsiness by penetrating into brain
and acting on H1 receptor
* Uses
— Allergic rhinitis, motion sickness, anti-emetic,
sedative
* MOA (from above)
Meclizine

* |tis a Piperazine based 1%t generation H1

antihistaminic
* |t has weak antihistaminic activity
* |t causes drowsiness by penetrating into brain
and acting on H1 receptor
e Uses
— anti-emetic and motion sickness

MOA (from above)

Cyproheptadine
* |tis a Heptane based 1t generation H1
antihistaminic
* |t possesses both antihistamine and anti-
serotonin activity and is used as an anti-itch
agent
* |t causes drowsiness by penetrating into brain
and acting on H1 receptor
e Uses
— Allergic rhinitis, allergic conjunctivitis, allergic skin
urticaria, hypersensitivity reactions
* MOA (from above)
2"d generation H1 antihistamines
They don’t act on H1 receptor in brain because their
lower lipophilicity doesn’t allow them to penetrate
the BBB
They have low lipophilicity due to addition of
hydrophilic groups OH, and COOH in the 15t gen
molecules. (other hydrophilic groups can be
NH2,NO2,504,P04)
They have low affinity for off-targets such as
muscarinic, adrenergic, and serotonergic receptors
Advantage — negligible sedation, no cardiotoxicity
Limitation — high selectivity for H1 prevents their use
as anti-emetic, during motion sickness, potentiate
cough medicines
MOA — same as above
 Ci CH—N N——CH, H,C——C

Cetrizine

OH OH CHs
|
QlCN_CHQ—CHQ-CHg—lHOT—CH3

Fexofenadine -
Fexofenadine

* |tis a piperadine based 2" gen H1 antihistaminic

* |t produces no clinically significant
Anticholinergic or al-adrenergic blocking or
sedative effect at therapeutic doses and is safe
even in higher doses
* |t needs only single dosing daily
e Uses
— Allergic rhinitis, chronic urticaria
* MOA (from above)
Cetirizine/Levocetirizine
* |tis a Piperazine based 2" gen H1 antihistaminic
* |t produces no clinically significant Anticholinergic
or al-adrenergic blocking or sedative effect at
therapeutic doses
* |t needs only single dosing daily
* |t’'s R-enantiomer, called Levocetrizine, has 30-
fold higher affinity than the S-enantiomer
e Uses
— Allergic rhinitis, relief from urticaria, water
eyes caused by hay fever
* MOA (from above)
TABLE 23.2 General Pharmacologic Properties of Selected "Antihistamines”
Dosing Int. Sedative Anti-H1 Anti-M
Antihistamine Dase (mg) (hrs) Effects Activity Activity Antiemetic
First Generation: Propylamines
Brompheniramine 4 46 + - +4 -
Chlorpheniramine 4 4-6 + +4 5 —
Dexchlorpheniramine 2 4-6 + - - -
Triprolidine 25 4-6 B ++4+++ b =
Phenindamine 25 4-6 - ++ B -
First Generation: Ethanolamines (Aminoalkyl Ethers)
Clemastine 1 12 ++ =5 +++ ++/+++
Carbinoxamine 4-8 6-8 e +H++ + 44 414+ +
Diphenhydramine 25-50 68 +44 - 1t ++1+++
First Generation: Ethylenediamines
Pyrilamine 25-50 68 + 4+ - —
Tripelennamine 25-50 4-6 ERS +++ * —
First Generation: Phenothiazines
Promethazine 12.5-25 6-24 +4++ +++ +++ P
Trimeprazine 25 6 + o+ + 4+ + - +4+++
Methdilazine B 6-12 + + A+ +++ +4+4++
First Generation: Piperazines (Cyclizines)
Hydroxyzine 25-100 4-8 +++ +H4+++ 4+ s
First Generation: Dibenzocycloheptenes/Heptanes
Azatadine 1=2 12 ++ -4 B —
Cyproheptadine a 8 + ~+ +4 -
First Generation: Phthalazinone
Azelastine 0.5 12 + ++i+++ * -
Second Generation (Peripherally Selective): Piperazine
Cetirizine/Levocetirizine* 5* to10 24 + +4+H-44 - —
Second Generation (Peripherally Selective): Piperidines
Astemizole 10 24 + +++++ -
Fexofenadine 60 12 + — = —_
Loratadine /Desloratadine 10 24 + ++l4++ +

Wilson and gisvold’s textbook of organic medicinal and pharmaceutical chemistry

Prospect of B3 agonist as anti-obesity
drug
Around 1980’s, Agonists of B3 adrenergic
receptor was found to cause lipolysis, fat
oxidation, energy expenditure and insulin
action
This lead to hopeful research into anti-obesity
and type 2 diabetics
In vivo effect in rodents was also confirmed
However as of 2014 no good drug has ever
cleared human testing
Beta 3-adrenoceptor agonists as anti-diabetic and anti-obesity drugs in humans. Curr
Pharm Des. 2001 Sep;7(14):1433-49
* The failure has been attributed to
— Compounds that succeeded in rodent, such as CL-
316,243, did not perform in same way in human
due to pharmacological differences
— the lack of selectivity of previous compounds for
the beta(3)-AR over beta(1)-/beta(2)-ARs, and
— Newer compounds have unsatisfactory oral
bioavailability and pharmacokinetic properties
— Newer compounds did not lose weight when
used chronically
 History of anti-obesity drugs

The last anti-obesity drug was approved in

1999 was olristat
Recently 3 new drugs have been approved
Contrave
Qnexa/Qysmia
Belviq
Future possibility : GLP-1 agonist