3. 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.
• .
4. • 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
• In the gut it is 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
6. 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.
7. rage and
ase
• 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,
8. 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, 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)
9. • 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
12. Fig: Effects of H1 antihistamines at histamine, adrenergic, cholinergic, and serotonin-binding receptors.
Many second generation antihistamines do not enter the brain and, therefore, show minimal CNS
effects.
13. 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.
17. SAR of H1 antihistamines (1st gen
only)
Nsubstituent
R2 C X (CH2)
n
R3
General framework of Anticholinergics
Note the similarity in H1 antihistamines and
Anticholinergics (this explains the origin of
Anticholinergic side effect of H1 antihistamines)
General framework of AntiHistamine (Ethanolamine
based)
R1
18. 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
19. 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
7) 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
20. C O CH2 CH2 N
R1
1
2
3
4
5
6
2C
2C
2C 2C CH
CH3
CH3
i-propyl
C
CH3
CH3
CH3
C2H5
CH3
Methyl Ethyl
t-butyl
Alkyl position Anticholinerg
ic
Antihistamini
c
At C2 Increases Decreases
At C4 Decreases Increases
Effect of increasing Alkyl group at C2
or C4
23. Chlorpheniramin
e
• It is a propylamine based 1st generation
H1 antihistaminic
• It is chlorinated pheniramine which improves
potency 10 times and changing toxicity
• It’s Dextro isomer has S configuration and
called DexChlorpheniramine is more potent
• It also acts as serotonin-norepinephrine
reuptake inhibitor or SNRI
• It is combined with opiods for cough medicine
because it can potentiate action of opiods
• It causes drowsiness by penetrating into brain
and acting on H1 receptor
• Uses
– Allergic rhinitis, in cough medicines
• MOA (from above)
24. 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?
Brompheniramine
H1
antihistaminic/Antiallergic
Zimelidine
Selective
Serotonin
reuptake
inhibitor/
Antidepressent
25. Clemastin
e
• It is a ethanolamine based 1st 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)
26. Pyrilamin
e
• It is a ethylenediaminebased 1st generation
H1 antihistaminic
• They are among the weakest antihistamines
• It is combined with opiods for cough
medicine because it can potentiate action
of opiods
• It causes drowsiness by penetrating into brain
and acting on H1 receptor
• Uses
– Allergic rhinitis, incest bites (topically)
• MOA (from above)
27.
28. Promethazin
e
• It is a phenothiazine based 1st generation
H1 antihistaminic
• It’s sedative action is strong to be used
clincally
• It causes drowsiness by penetrating into
brain and acting on H1 receptor
• Uses
– Allergic rhinitis, motion sickness, anti-
emetic, sedative
• MOA (from above)
29. Meclizin
e
• It is a Piperazine based 1st
generation H1 antihistaminic
• It has weak antihistaminic activity
• It causes drowsiness by penetrating into
brain and acting on H1 receptor
• Uses
– anti-emetic and motion sickness
• MOA (from above)
30. Cyproheptadin
e
• It is a Heptane based 1st generation
H1 antihistaminic
• It possesses both antihistamine and
anti- serotonin activity and is used as
an anti-itch agent
• It causes drowsiness by penetrating into
brain and acting on H1 receptor
• Uses
– Allergic rhinitis, allergic conjunctivitis,
allergic skin urticaria, hypersensitivity
reactions
• MOA (from above)
31. 2nd 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 1st gen molecules. (other hydrophilic
groups can be NH2,NO2,SO4,PO4)
• 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
32.
33. Fexofenadin
e
• It is a piperadine based 2nd gen H1
antihistaminic
• It produces no clinically significant
Anticholinergic or α1-adrenergic blocking
or sedative effect at therapeutic doses
and is safe even in higher doses
• It needs only single dosing daily
• Uses
– Allergic rhinitis, chronic urticaria
• MOA (from above)
34. Cetirizine/Levocetirizi
ne
• It is a Piperazine based 2nd gen H1
antihistaminic
• It produces no clinically significant
Anticholinergic or α1-adrenergic blocking or
sedative effect at therapeutic doses
• It needs only single dosing daily
• It’s R-enantiomer, called Levocetrizine, has
30- fold higher affinity than the S-
enantiomer
• Uses
– Allergic rhinitis, relief from urticaria,
water eyes caused by hay fever
