Histamines are chemical messengers that communicate between cells. Antihistamines competitively inhibit histamines from binding to H1 and H2 receptors. First generation antihistamines are sedating but treat allergy symptoms, while second generation antihistamines are non-sedating. Cimetidine was the first H2 antagonist developed for treating gastric acid secretion by competitively blocking histamine at H2 receptors on parietal cells. It helped establish structural requirements for selective H2 receptor antagonism through its imidazole and substituted guanidine groups.

1. Anti Histamines Drugs
Ravish Yadav

2. What are histamines?
• Important chemical messenger, communicating information form one cell to another
• Involved in variety of biological actions
• Stored in inactive form and released as a result of an antigen antibody reaction initiated by
different stimuli.
• At physiological pH monocationic conjugate species 
Structure of histamine and nomenclature
4(5-)(2-aminoethyl)imidazole
80% NƮ
In aqueous solution
20% N∏
2
4:2 Ratio of
existence
Tautomers
HN
N
NH3
+

3. 3
HN
N
NH2
N
N
NH2
H
pKa 14( )
H3O+
pKa( )5.80
HN
N
NH3
+
N
N
NH3
+
H
Monocationic
HN
N+
NH3
+
H
N+
N
NH3
+
H
H
DICATIONIC SPECIESDICATIONIC SPECIES
At physiological pH monocationic conjugate species

4. Stereochemistry : Achiral, trans and gauche rotamers
4
Trans  H1 & H2 agonistic Gauche  H1 agonistic

5. Pharmacology of Histamine : Biosynthesis and Storage
Histidine decarboxylase
in presence of pyridoxyl phosphate
• In human : CSF, skin, bronchial and intestinal mucosa
• Storage and release : in mast cells and basophills.
Released by exocytosis as a response to immune (Ag-Ab) and non-immune
(Drug , phy. factors) stimuli.
• RECEPTORS : G - protein coupled receptors.
H1  Allergy
H2  Gastric acid secretion
H3 Neurotransmitter in CNS
5
N
HN
NH2
COOH
Histamine
N
HN
NH3
+
S-Histidine

6. Metabolism : by enzyme inactivation
6
NHN
NH2
NN
NH2
H3C NHN
COOH
Conjugation as
ribosyl residue
NƮ-Me-histamine
SAM
SAH
(BRAIN)
DAO/MAO
(Oxidative
Deamination)
NN
COOH
H3C
N-Me-imidazole acetic acid
HMT : Histamine N-Me-transferase
SAM : S-adenosyl –L-methionine
SAH : S-adenosyl –L-homocysteine

7. Histamine receptors and its function: 4 different types of receptors
(G-protein coupled)
H1 : found in mammalian brain , smooth muscle from airways, GI tract,
genitourinary system, CVS, adrenal medulla & endothelial cells & lymphocytes.
• Histamine which act on H1 receptors causes inflammation
• Anti- histamines, which act on this receptor are used as anti-allergy drugs
• Molecular mass of this receptor is 56 kd & represents 487 amino acids
• Receptor contains 7 hydrophobic trans-membrane domains (TM)
• TM-3 & TM-5 are main sites for binding of H1-receptor ligands.
7

8.  H2 : found in gastric parietal cells, vascular smooth muscles, CNS,
Neutrophils, Heart, Uterus
• function : stimulation gastric acid secretion, regulates gastrointestinal
motility &intestinal secreation.
• Molecular mass is 40 kd and has about 359 amino acids.
• Effects of H2 receptor ligand is mediated by a stimulatory Gαs protein
coupled receptor, which in turn activates adenylate cyclase promoting the
synthesis of cAMP.
8

9. H3 : found in CNS, PNS, Heart, lungs, GIT, endothelial cells
• function :It is coupled to a Gi/o protein, which inhibits the action of adenylate cyclase
and regulates MAP kinase and intracellular calcium levels.
 H4 : highly expressed in bone marrow & WBC’s & regulates neutrophil
release form bone marrow
• Also expressed in small intestine, spleen, colon, liver, lungs, tonsils
• These receptor subtypes may also be involved in allergic inflammatory
responses.
9

10. H1 Antagonist
• MOA of H1 antagonist : Competitively inhibit the action of histamine on
tissue containing H1 receptors
• 1st Generation or classical antihistamines
• 2nd Generation antihistamines : Non-sedating, antagonistic activity at other
neurotransmitter receptors like muscarinic receptors and cardiac ion
channels.
10

11. 1st generation : SAR:
• Diaryl substitution is essential for significant H1 receptor affinity
• Presence of two aryl rings and substituted amino moieties increases the
lipophilicity of the molecule than the endogenous agonist, Histamine.
• 2 aryl groups must be non-coplanar (not be in same plane) for effective receptor
interaction
• Basic amino group is necessary for attachment of an anionic site of the H1
receptor (N may be a simple dimethyl amino group or a part of heterocyclic ring)
• Carbon chain consists of usually 2 or 3 atoms. As a result distance between diaryl
& terminal N becomes 5 to 6 which is ideal for optimum activity
• X connecting moiety may be saturated C-O or simply C atom. This group along
with C chain, appears to serve as a spacer group for the key pharmacophoric
moieties
11

12. 1st generation antihistamines are further classified into 5 types depending upon
connecting moiety and the nature of the aryl moieties:
 Aminoalkyl ethers (Ethanolamines)
 Ethylenediamines
 Piperazines(cyclizines)
 Propylamines
 Tricyclic ring systems (Phenothiazine and heptanes)
12

13. 1 st generation
1. Aminoalkyl ethers (Ethanolamines)
Ar Ar1 R
1. Diphenhydramine Ph Ph H
(Benadryl)
2. Doxylamine Ph CH3
13
Ar1
Ar2
O
R
H2
C
H2
CN
CH3
CH3
S-form is ACTIVEAssymmetric
N
Increased
activity

14. 2. Ethylenediamines
Ar Ar1
1. Pyrilamine
2. Tripelennamine
14
22
3
3
r1
r
N
N
OCH3
H2
C
H2
C

15. 3. Piperazines(cyclizines)
R1 R2
1. Cyclizines H CH3
2. Chlorcyclizine Cl CH3
3. Buclizine Cl
15
N NR2CH
Ph
R1
H2C C
CH3
CH3
CH3

16. 4. Propylamines
Ar1 Ar
1. Pheniramine
2. Chorpheniramine
3. Bromopheniramine
16
CH
H2
C
H2
CN
CH3
CH3
Ar
Ar1
N
N
N
Cl
Br
sp2 / sp3

17. 5. Tricyclic ring systems - Phenothiazines
R
1.Promethazine
2.Trimeprazine
17
N
S
R
H2
C N
CH3
CH3
CH3
H2
C
N
CH3
CH3
CH3
Unsubstituted
heterocyclic ring

18. 6. Tricyclic ring systems – Dibenzocycloheptanes/Heptanes
1. Cyproheptadiene (X=C)
2. Azatidine maleate (X=N)
18
X
N
CH3
Bioisosterism
sp2 - C

19. 2nd Generation
1) Fexofenidine
4-[1-Hydroxy-4-[4-(hydroxyldiphenylmethyl)-1-piperinyl] butyl-α,α-
dimethyl benzeneacetic acid
19

20.  Fexofenidine is a primary oxidative metabolite of terfenadine
 Terfenadine is selective, long acting (>12hr) H1 antagonist with little affinity
for muscarinic, serotonergic or adrenergic receptors
 The histamine receptor affinity of this compound is believed to be related
primarily to the presence of diphenylmethyl piperidine moiety
 Terfenadine undergoes significant 1st pass metabolism, with the predominant
metabolite being fexofenidine, an active metabolite resulting from methyl
group oxidation
• When drug that inhibit this transformation such as imidazole antifungals or
macrolides, are used concurrently ,terfenadine level may rise to toxic level,
resulting in potential fatal heart rhythm problems
• Fexofenidine, like terfenadine is a selective peripheral H1 receptor ligand that
produces no clinically significant anticholinergic effect at therapeutic doses
• Fexofenadine is rapidly absorbed after oral administration
• Fexofenidine is 60-70% plasma protein bound & elimination half life is about
14 hrs
20

21. 2) Loratadine
4-(8-Chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-
carboxylic acid ethyl ester
21

22. • Related to tricyclic antidepressants, antihistamines azatadine and cyproheptadine
& is non sedating & neither it or nor its major metabolite, desloratidine, is
associated with potential cardiotoxic effects as that of terfenadine & astemizole
• Desloratidine is more potent H1 antagonist & more potent inhibitor of histamine
release
• The metabolic conversion of loratidine to descarboethoxyloratidine occurs via a
oxidative process & not via direct hydrolysis
• Both CYP2D6 & CYP3A4 appear to catalyzing this oxidative metabolic process
• Metabolite is excreted renally as a conjugate & elimination half life is about 8 to
15 hrs
22

23. Metabolism of loratidine
23

24. 3)Cetirizine
[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy] acetic acid
24

25. • Cetirizine is primary acid metabolite of hydroxyzine, resulting from complete
oxidation of primary alcohol moiety
• This compound is relatively polar & zwitterionic & thus does not penetrate the BBB
readily
• Has long duration of action & is highly selective for H1 receptor
• Advantages: rapid onset of activity, once-daily dosing, minimal CNS toxicity & lack
of clinical significant effect on cardiac rhythm when administered with imidazole
antifungals & macrolide antibiotics
• Side effects: fatigue, dry mouth, dizziness
• Since the drug is primarily eliminated by a renal route, its adverse reaction may be
more pronounced in individuals suffering from renal insufficiency
• Cetirizine is indicated for the temporary relief of runny nose , sneezing, itching of
nose or throat, etc.
• Terminal half life is 8.3 hrs
25

26. • Levocetirizine
• Levocetirizine (as levocetirizine dihydrochloride) is a third-generation non-
sedative antihistamine, developed from the second-generation
antihistamine cetirizine.
• Chemically, levocetirizine is the active enantiomer of cetirizine. It is the R-
enantiomer of the cetirizine racemate.
• Levocetirizine is called a non-sedating antihistamine as it does not enter the
brain in significant amounts, and is therefore unlikely to cause drowsiness.
• Latest research shows levocetirizine reduces asthma attacks by 70% in
children
26

27. 4)
(E,E)-3-[6-[1-(4-methylphenyl)-3- (1-pyrrolidinyl)
-1-propenyl-2-pyridinyl]-2-propenoic acid
• Acrivastine is an analogue of triprolidine containing a carboxyethenyl moiety at the 6 position of pyridyl ring
• Acrivastine shows antihistaminic potency and duration of action comparable to those of tripolidine
• Enhanced polarity of this compound resulting from carboxyethenyl substitution limits BBB penetration & thus producing
less sedation than tripolidine
• Half life is 1.7 hr of orally administered drug
27
Triprolidine

28. 5) Astemizole
1-[(4-flurophenyl)methyl]-N-
[1-[2-(4-methoxyphenyl)ethyl]
-4-piperidyl]benzoimidazol-2-amine
• One of the limitation of astemizole is that, it produce life threatening arrhythmias
when used concurrently with drugs that inhibit their metabolism (like imidazole
antifungals & macrolides)
• Slow onset of action & long duration
• It is metabolized slowly & extensively, mainly by aromatic hydroxylation
(CYP3A4)
• Desmethyl metabolite is pharmacology active & hence it could be the reason of
extended duration of antihistamine action
28

29. Metabolism of astemizole
Desmethyl
(active)
HO
OH
Aromatic
hydroxylation
29

30. 6) Mizolastine
2-[{1-[1-(4-flurobenzyl)
-1H-benzimidazol-2-yl]piperidin-4-yl}
(methyl)amino]pyrimidin-4(1H)-one
• Non sedating antihistamine, once daily
• Blocks H1 receptor & fast acting
• Does not prevent the actual release of histamine from mast cells, just prevents it
binding to receptors
• Side effects can include dry mouth & throat
• Used in treating allergic reactions
30

31. H2 Antagonist
31

32. • Histamine act on H2 receptor (present on parietal cell of stomach)
which in turn activates H+/K+ ATPase system
thus more secretion of acid (H3O+) in exchange for the uptake of K+
• Anti-histamine competitively inhibit action of Histamine on H2 receptors
& prevents exchange of acid (H3O+) for K+ ,thus preventing activation of
H+/K+ ATPase system
32

33. Structural requirements
• H2 anti-histamines specifically designed to decrease the secretion of gastric acid
• Cimetidine, in which imidazole ring is maintained (As that of histamine). The
imidazole ring is substituted with C-4 methyl group for H2 selectivity, a 4 C side
chain includes a S atom (sulfur atom increases potency compared to C & O
congeners) & a terminal polar non-basic unit , in this case an N-cyanoguanidine
substitution (guanidine substitution with electron withdrawing groups have
significantly decreased basicity compared to guanidine and they are neutral at
physiological pH)
Histamine Cimetidine
33

34. • Nitromethylene unit was replacement of N-cyanoimino group in the
substituted guanidine analogues affording compounds of increased potency
Ranitidine
• Replacement for the imidazole ring with other hetroaromatic rings resulted in
other useful analogue
Nizatidine
34

35. 1) Cimetidine
N’’-cyano-N-methyl-N’-[2-[[(5-methylimidazol-4-yl)methyl]-thio]ethyl]guanidine
35

36. Rational designing of Cimetidine
36
N
H N
N H 2
N
H N
N H 2
H 3 C
N
H N
N H N H 2
N H
Basic electron withdrawing side chain
H1 and H2 Agonist
Histamine
5-methyl histamine
Guanyl histamine
H2 Agonist > H1 (5-Me favours H2 receptor selectivity)
Basic
Weak H2 antagonist (partial agonist)

37. • Increase in length of side chain by 2-3 more carbons along with
replacement of strongly basic guanidino group by neutral .
• Methyl thiourea group gives H2 antagonistic activity.
37
Low potency & poor bioavailability becoz of
electron releasing –CH3 which favours N∏ -
tautomer (non pharmacophoric)
(Non basic, electron releasing side chain)
N
H N
H
N
H
N
S
C H 3
Burimamide

38. H2 antagonist of high potency because
• 5-Me high selectivity
• S- electronegative grp favours NƮ tautomer
But thiourea functional group leads to toxicity ,which is eliminated by
replacing ‘S’ with cyano-imino function
38
N
HN
S
H
N
H
N
S
CH3
H3C
Metiamide
Thioether

39. • Highly potent
• Selective H2 antagonist
• Good oral bioavailability
• Less toxicity
39
N
H N
S
H
N
H
N
N C N
C H 3
H 3 C
Cimetidine
But short acting  need more
dosing, also antiandrogenic
Hence, need of other backbone
is sought

40. • Other heterocycles can be tried.
• If imidazole ring is used then
a) NƮ – tautomer is active at H2  Antagonistic effect
b) Seperation of ‘N’ and ring with at least 4 ‘C’ is MUST
c) Thioether link N, bioisosteric N can also be used.
d) Terminal ‘N’ functionality must be  polar, nonbasic
Antagonistic effect α 1
Groups which are positively charged at body pH
EXCEPTION – 1,1-diamino nitroethene (hydrophilic) in Ranitidine and Azatidine
40

41. Famotidine
N-aminosulfonyl-3-(2-diamino methylene)-amino-4-thiazolyl-methyl
thio propanimidamide
41
N
S
S N
S
NH2
NH2N
H2N
NH2 O
O

42. O
S
N
H
C
NO2
N
H3C
H3C
NHCH3
42
NS
S
N
H
C
NO2
NHCH3
N
CH3
CH3
Nizatidine
Ranitidine

43. • Cimetidine reduces hepatic metabolism of drugs biotransformed by CYP450,
delaying elimination & increasing serum levels of these drugs
• Concominant therapy of patients with cimetidine & drugs metabolized by
hepatic microsomal enzymes, particularly those of low therapeutic ratio or in
patients with renal or hepatic impairment, may require dosage adjustment
• If concurrent azole therapy is required, it is best to administer it at least 2 hrs
before Cimetidine administration.
• Has weak antiandrogenic effect
• High oral bioavailability with plasma half life of about 2 hrs which is increased
in renal or hepatic impairment & in elderly
• Cimetidine is metabolized (S-oxidation, 5-CH3hydroxylation) & eliminated by
renal excretion
43

44. Metabolism of cimetidineS
O
O
Sulfone
N
H
N
HO
5-CH3 hydroxylation
44

45. 2) Ranitidine
N-[2-[[[5-(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]-N’-methyl-2-
nitro-1,1-ethenediamine
• Bioavailability of an oral dose is 50 -60% & is not affected by presence of food
• Some antacid may reduce it’s absorption & should not be taken within 1hr
administration of the H2 blocker
• Plasma half life is about 2-3hrs & metabolites are excreted in urine
• 3 metabolites, ranitidine N-oxide, ranitidine S-oxide & desmethyl ranitidine have
been identified
• Weak inhibitor of hepatic CYP450 mixed function oxidase system
• Ranitidine is used (as bismuth citrate) with macrolide antibiotics
(clarithromycin) in treating patients with an active duodenal ulcer associated
with H.pylori infection
45

46. Metabolism of ranitidine
N-oxide
desmethyl
S-oxide
(sulfoxide) 46

47. 3) Famotidine
N’-(aminosulfonyl)-3-[[[2-(diaminomethylene)-amino]-4-thiazolyl]methyl]thio]
propanimidamide
• Famotidine is a competitive inhibitor of H2 receptors & inhibits basal &
nocturnal gastric secretion as well as secretion stimulated by food & pentagastrin
• Used for short term treatment of duodenal & benign gastric ulcers, GERD,
pathological hypersecretory conditions ( eg. Zollinger-Ellison syndrome) &
heartburn
• Studies with Famotidine in humans, in animals models & in vitro have shown no
significant interference with the disposition of compounds metabolized by the
hepatic microsomal enzymes (eg. CYP450 system)
47

48. • It is incompletely absorbed and eliminated by renal & metabolic routes
• Famotidine sulfoxide is only metabolite identified in humans
48
Metabolism of famotidine

49. 4) Nizatidine
N-[2-[[[2-(dimethylamino)-methyl]-4-thiazolyl]methyl]thio] ethyl]-N’-methyl
-2-nitro-1,1-ethenediamine
• Nizatidine has excellent oral bioavailability (>90%) & effects of antacids &
food on its bioavailability are not clinically significant
• Elimination half life is 1-2 hrs
• Excreted primarily in urine & mostly as unchanged drug
• Metabolites include nizatidine sulfoxide, N-desmethylnizatidine & nizatidine N-
oxide
• No antiandrogenic action or inhibitory effects on CYP450-linked drug
metabolizing enzyme system
49

50. Metabolism of nizatidine
desmethyl
(less active)
N
CH3H3C
O
N-oxide
N
H
CH3
S
O
S-oxide
(sulfoxide)
50

51. Proton Pump Inhibitor (PPI)
• The final step in acid secretion in parietal cells of the gastric mucosa is a
process mediated by H+/K+ATPase, the gastric proton pump which catalyzes
the exchange of hydrogen ions for potassium ions
• PPI inhibits gastric acid secretion irrespective of receptor stimulation process
• These agents have irreversible effects on the secretion of gastric acid, because
molecule rearrange in strongly acidic environment of parietal cell
• Covalent bonding of rearranged inhibitor to H+/K+ATPase results in
inactivation of catalytic function of proton pump
• One of the site is cystein-813 & these cysteins are in different environment &
different PPI’s bind differentially to them & other sulfhydryl groups
• In covalent binding, disulfide bonds are formed with receptor
51

52. 52

53. 1)Omeprazole
5-methoxy-2-((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)sulfinyl)-1H-
benzimidazole
53

54. • Omeprazole is an amphoteric compound & is acid labile, hence, it is
formulated as delayed release capsule containing enteric coated granule
• Plasma half life is about 1 hr
• Most of an oral dose of omeprazole is excreted in the urine as metabolites with
insignificant antisecretory activity
• The primary metabolites of omeprazole are 5-hydroxyomeprazole (by
CYP2C19) and omeprazole sulfone (CYP3A4)
• The antisecretory actions of omeprazole persists 24-72 hrs, long after the drug
has disappeared from plasma, which is consistent with its suggested mechanism
of action involving irreversible inhibition of proton pump, H+/K+ ATPase.
• Used in treatment of heartburn, duodenal ulcer, gastric ulcer, etc.
54

55. 2) Lansoprazole
2-[[[3-methyl-4-(2,2,2-trifluroethoxy)
-2-pyridyl]methyl]sulfinyl]-1H-
benzimidazole
• Lansoprazole is a weak base (pyridine N, pKa 3.83) and a weak acid
(benzimidazole N-H, pK 0.62)
• Lansoprazole is essentially a prodrug that, in the acidic biophase of the parietal
cell, forms an active metabolite that irreversibly interacts with target ATPase of
the pump
• It is formulated as encapsulated enteric coated granules for oral administration
to protect the drug from the acidic environment of the stomach
• Drug is metabolized in liver (sulfone and hydroxy metabolites) and excreted in
bile and urine with plasma half life of 1.5 hrs
55

56. 3) Rabeprazole
2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]sulfinyl]-1H-
benzimidazole
• Rabeprazole is a weak base (pyridine N, pKa 4.53) and a weak acid
(benzimidazole N-H, pKa 0.62)
• It is formulated as enteric coated delayed release tablets to allow the drug to pass
through the stomach relatively intact
• Plasma half life is about 1-2 hrs
• Metabolized in liver & thioether and sulfone are primary metabolites resulting
from CYP3A oxidation, also desmethyl rabeprazole is formed via action of
CYP2C19
• Eliminated in urine as thioether carboxylic acid and its glucoronide and
mercapturic acid metabolites 56

57. 4) Pantoprazole
5-(Difluromethoxy)-2-[[[3,4-dimethoxy-2-pyridinyl]methyl]sulfinyl]-1H-
benzimidazole
• Pantoprazol is a weak base (pyridine N, pKa 3.96) and a weak acid
(benzimidazole N-H, pKa 0.89)
• The stability of this compound in Aq. Solution is pH dependent; rate of
degradation increases with decreasing pH
• With food, may delay its absorption but does not alter its bioavailability
• Metabolized in liver & metabolites are O-demethylation (CYP2C19), sulfur
oxidation (CYP3A4)
• Excreted in urine & feces through biliary excretion
57

58. Metabolism of PPI’s
58

59. 59
SYNTHESIS OF RANITIDINE

60. 60
1,1-bis(methylthionitroethene

61. References:
•Foye’s Principles of Medicinal Chemistry.
•Wilson & Grisvold’s Textbook of Organic Medicinal
and Pharmaceutical Chemistry.
•Textbook of Medicinal Chemistry (vol-1); K.Ilango &
P.Valentina(For synthesis only).
61