The document discusses histamine and antihistamines. It defines histamine and explains its biosynthesis from histidine via histidine decarboxylase. It describes the different types of histamine receptors (H1, H2, H3, H4) and their locations. It also classifies and discusses various generations of H1 receptor antagonists (antihistamines), including their structures, mechanisms of action, and uses.

1.  The chemical name of Histamine
is “2-(4H-imidazol-5-yl) ethanamine (Histamine)”.
Histamine synthesized in cytoplasmic granules of a its storage cells, mast cells & basophils.
It is formed from naturally occurring amino acids, S-Histidine, via the catalysis of pyridoxal phosphate-
dependent enzymes histidine decarboxylase/ aromatic decarboxylase.
Histamine is a chiral molecule.
HISTAMINE
❑. Question:01 Write the chemical name & structure of Histamine?
❑. Question:02 Explain biosynthesis of Histamine?
NH2
N
HN
H
H
Histamine
HDC
COOH
HN N HN N
H
NH2
NH2
H
H
S-Histidine Histidine
Histidine
Decarboxylase
RAHUL PAL
5TH SEM
B. PHARAM

2. Drugs the block the action of histamine of H1, H2, H4 & H4 receptors.
The development of Antihistamines Began by the discovery of “Piperoxam”.
A. Drugs that inhibits the histamine release.
B. Drugs that inhibits the action of released histamine.
❑ H1 Antagonists (I, II, III generation Antagonists)
❑ H2 Antagonists.
❑ H3 Antagonists.
C. Drugs having dual action.
H1 Antagonists (1st
Generation)
The amine is substituted with the small alkyl group.
Classification: The commonly used antihistamines may be classified on the basis of their chemical
structures:
. Amino Alkyl Ethers: Diphenhydramine, Doxylamine, Clemastine, medrylamine,
Carbinoxmine, Bromodiphenhydramine.
. Ethylenediamine: Tripelenamine, pyrilamine, methapyrilene, thonzalamine, Zolamine.
. Propyl Amine Derivatives: Saturated drugs: pheniramine, chlorpheramine,
Unsaturated Drugs: Pyrrobutamine, triprolidine.
. Phenothiazine Derivatives. Promethazine, Trimeprazine.
. Piperazine Derivative. Cyclazine, chlorcyclines, meclizine.
H1 Antagonists (2nd
Generation)
Laratidine, Estemizole.
H1 Antagonists (3rd
Generation)
Acrivestine.
H2 Antagonists
Cemetidine, famotidine, ranitidine, nizatidine.
H3 Antagonist
Omeprazole, Lansoprazole, Rabeprazole, Pantoprazole.
❑. Question: 03 Classification of Antihistamines?

3. Histamines receptors are belonging to the family of G-Protein Coupled receptors.
These subtypes of histamine receptors:
A. H1.
B. H2.
C. H3.
D. H4.
Receptors H1 H2 H3 H4
Locations Brain, GIT, CVS,
Lymphocytes.
Myocardial cells,
parietal cells.
CNS, Myentric
plexus, gastric
Mucosa.
Spleen, thymus,
T-cells,
eosinophils.
❑. Question: 04 Name the different type of Histamine receptors & their
Distribution?

4. 01. Amino Alkyl Ether: Diphenhydramine, Bromodiphenhydramine, Dimenhydrinate, Doxylamine
succinate, Diphenylpyraline.
02. Ethylenediamine: Mepyramine, Tripelennamine, Thonzylamine, Zolamine.
03. Thiophene Derivatives: Methapyrilene, Methaphenilene, Thenyldiamine, Chlorothen Citrate.
04. Cyclic Basic Chain Analogues:
A. Imidazoline: Antazoline.
B. Piperazine: Cyclizine, Chlorcyclizine, Meclizine, Buclizine.
C. Piperidine: Thenalidine Tartarate.
05. Phenothiazine: Promethazine, Promethazine Teolclate, Trimeprazine, Methdilazine.
06. Second-Generation Non-Sedating Antihistamines: Terfenadine, Astemizole, Loratadine,
Acrivastine.
07. Miscellaneous Agents: Phenindamine, Triprolidine, Chlorpheniramine, Cyproheptadine.
Sedative antihistamines:
N-Dimethylthenamine.HCl & 1-Methyl Piperidine.
Non-Sedative Antihistamine:
Fexofenadine, Citrizine Levocetrazine, loratadine, Desloratadine, Acrivastine.
Ar is Aryl: Phenyl, substituted phenyl, heteroaryl groups such as 2-pyridyl.
Ar1: Second aryl or aryl methyl group.
(CH2) n: Represents a carbon chain, usually ethyl.
NRR1 = Basic, terminal amine functional group.
X = Connecting atom of 0, C & N.
❑. Question:01 Give the classification of H1 Antagonists?
❑. Question:02 Explain SAR of Amino Alkyl Ethers?
H1 ANTAGONISTS
R R1

5. Mepyramine, Tripelennamine, Thonzylamine, Zolamine.
❑. Question:03 Give Chemical Structure of Amino Alkyl Ethers?
❑. Question:04 Give Chemical Structure of Ethylenediamine Derivatives?
Mepyramine Tripelennamine Thonzylamine
Zolamine

6. ANS: Structure Activity Relationship:
➢ Ethylenediamine derivatives are characterized by “Nitrogen” connecting
atom.
➢ Phenbenzamine was first clinically useful member.
➢ Replacement of phenyl moiety of Phenbezamine with a 2-pyridyl system
yielded “tripelennamine”.
➢ Replacements of benzyl group of tripelennamine with a 2-thienulmethyl
group provided methapyrilene.
➢ Replacement of tripelennamine with 2pyridyl group with a pyrimidinyl
moiety yields thonzylamine.
➢ The anticholinergic & antiemetics action of these compounds are low.
#. Mode of Action:
H1 Antagonists act by competitively inhibiting the effects of Histamine at H1
receptor.

H1 receptor blockade results in decreased vascular permeability.

Reduction of pruritus, relaxation of smooth muscle in the respiratory.

GIT.
#. USES: 01. Allergic Reactions.
02. Block the release of histamine.
03. Not effective in humoral & cell mediated allergies.
❑. Question:05 Explain SAR of Ethylenediamine Derivatives?
❑. Question:06 Gives Uses & Mode of Action of H1 Antagonists?

7. The second-generation drugs have little affinity for muscarinic, adrenergic receptors.
The second-Generation have a relative low affinity for central H1 receptor & largely from sedation.
Examples: Terfenadine, Fexofenadine, cetirizine.
“Terfenadine” is a long acting H1 Antagonists.
“Fexofenadine” is a primary oxidation metabolite of “Terfenadine” & does not cross the BBB.
“Cetirizine” highly selective in its interaction with various neuronal binding sites & highly potent as well.
Ar
1 X C C N
Ar’ 3
In the above general structure, Ar is aryl group & Ar’ is aryl methyl group.
In the general structure the X part determines the class of drug to which that belongs i.e. if X = O (amino
alkyl analogue), X = N (Ethylene diamine derivatives).
Some times two aromatic rings are bridges that constitutes the tricycle ring derivatives.
❑. Question:08 Explain SAR of H1 Antagonists?
❑. Question:07 Write the note on Second generation H1 Antagonists?
Terfenadine Fexofenadine
Cetirizine
4
2

8. Most of the H1 Antagonists have ethylene chain, extension of this chain or branching of this chain leads
to reduce the activity of the compounds.
Homologation played to improve the drug like tricyclic anti-depressants, neuroleptics.
Due to the close resemblance of antihistamine structure to the cholinergic blocking agents, most of the
antihistamines show the activity of anti-cholinergic activity.
Diphenhydramine have maximum anti-cholinergic activity & maximum ability to cross the blood brain
barrier & are thus most effective in motion sickness.
#. Uses:
I. It is recommended in various allergic conditions & to a lesser as an antitussive & Parkinsonism
drugs.
II. It is also used OTC sleep air products.
III. Treatment of urticaria, seasonal rhinitis (hey fever) & some dermatoses.
❑. Question:09 Give Synthesis & Use of Diphenhydramine Chloride?

9. Promethazine hydrochloride is a white to faint yellow crystalline powder that Is very soluble in water, in
hot absolute alcohol, in chloroform.
#. USES:
I. Treating allergic illness such as hives, serum disease & hay fever.
II. Enhancing action of analgesics & local anesthetics.
III. Also, treatment of rheumatism with allergic components.
❑. Question:10 Give Synthesis & Use of Promethazine?

10. It is SP2 alkylamine.
It is available as an oral liquid or syrups & is administered every 6 hours.
#. USES:
I. It is used for allergy symptoms, rhinitis.
❑. Question:11 Give synthesis & uses of Triprolidine?

11. “Proton pump inhibitors (PPI) are a group of drugs whose main action is a pronounced & long-lasting
reduction of gastric acid production”.
GIT Problems, Gastritis, Dyspepsia, Peptic Ulcer disease (PUD) & Gastroesophageal reflux disease (GERD)
is the main uses of Proton Pump Inhibitors.
Gastritis Dyspepsia Peptic Ulcer GERD
Gastritis is an
inflammation, irritation
or erosion of the lining
of the stomach.
It can occur suddenly or
gradually.
Dyspepsia is an
uncomfortable feeling in
the upper middle part of
the stomach.
Peptic ulcer disease
refers to painful sores or
ulcers in the lining of
the stomach or first part
of the small intestine,
called the duodenum.
GERD is a digestive
disorder that affects the
lower esophageal
sphincter the ring of
muscle between the
esophagus & stomach.
Examples: Omeprazole, Lansoprazole, Esomeprazole, Pantoprazole & Rabeprazole etc.
Causes & Symptoms
PROTON PUMP INHIBITORS
❑. Question:01 Discuss about Proton Pump Inhibitors?
❑. Question:02 Draw the Chemical Structure of Proton Pump Inhibitors?
Omeprazole
Lansoprazole
Pantoprazole
Rabeprazole

12. Mechanism of blocking Na/K ATPase or Proton Pump
➢ Benzimidazole PPI’s are prodrug that are converted into sulfenamide within the acidic
environment of parietal cells in stomach.
➢ The consumption of food stimulates acid secretion and acid secretion activates PPIs.
➢ Then activated PPI is converted to a sulfenamide in the acidic secretory canaliculi of the parietal
cell.
➢ The sulfenamide interacts covalently with sulfhydryl groups (in cysteine amino acid of the
binding site) in the proton pump to create a disulphide bond between drug and pump and
thereby irreversibly inhibiting its activity.
• Irreversible covalent inhibitors are either substituted 2-
(pyridinemethylsulfinyl)benzimidazoles or a similar structure, pyridylmethyl sulfinyl
pyrido-imidazole, because they mainly inhibits the pump enzyme by covalently binding
to the α-subunit of the H+
,K+
-ATPase.
❑. Question:03 Explain the Mechanism of Action of Proton Pump Inhibitors?
❑. Question:04 Why Proton Pump Inhibitors are irreversible?

13. Mechanism of Acid Secretion: The H+
concentration in parietal cell secretions roughly 3 million-
fold higher than in blood, and Cl-
is secreted against both a concentration and electric gradient. The
parietal cell to secrete acid is dependent on active transport.
Acid secretion through "Proton Pump" located in the canalicular membrane. This ATPase is Mg+
dependent. The current model for explaining acid secretion in above.
• H+
are generated within parietal cell from dissociation of water. The H+
formed in this process
rapidly combine with CO2 to form HCO3
-
, a reaction catalyzed by carbonic anhydrase.
• HCO3
-
transport out from basolateral membrane in exchange for Cl-
. The outflow of bicarbonate
into blood results in a slight elevation of blood pH known as the "alkaline tide". This process
maintains intracellular pH in the parietal cell.
• Cl-
and K+
are transport into lumen of the canaliculus by conductance channels, necessary for
secretion of acid.
• H+
is pump out of cell, into the lumen, in exchange for K+
through the action of the proton pump;
K+
is thus effectively recycled.
• Accumulation of osmotically-active H+
generates an osmotic gradient across the membrane, the
resulting gastric juice is 155 mM HCl and 15 mM KCl with a small amount of NaCl.
❑. Question:05 Explain Secretion of Acid through the Proton Pump?

14. Neoplasm means: Tumour/Cancer.
Cancer is an uncontrolled proliferation express varying degree of fidelity to their precursors.
It can be “benign” or “Malignant”.
Benign: non-cancerous and not an immediate threat to life, even though treatment eventually may be
required for health.
Malignant: tending to worsen and cause death, invasive and metastasis.
01. Cancer involves the development and reproduction of abnormal cell.
02. Cancer cells are usually nonfunctional.
03. Cancer cell growth is not subject to normal body control mechanisms
04. Cancer cells eventually metastasize to other organs via the circulatory and lymphatic systems.
05. Metastasis.
Categorized based on the functions/locations as following:
1. Carcinoma - Skin or in tissues that line or cover internal organs. Ex: Epithelial cells, Glands. 80-
90% reported cancer cases are carcinomas.
2. Sarcoma - Bone, cartilage, fat, muscle, blood vessels, or other connective or supportive tissue.
3. Leukemia - White blood cells and their precursor cells such as the bone marrow cells, causes
large numbers of abnormal blood cells to be produced and enter the blood.
4. Lymphoma - Cells of the immune system that affects lymphatic system.
5. Myeloma - Beta-cells that produce antibodies- spreads through lymphatic system.
6. Central Nervous System Cancers - Cancers that begin in the tissues of the brain and spinal
cord.
Characterstics
Antineoplastic Drugs
(Cancer)
❑. Question:01 Define Cancer with its Characteristics?
❑. Question:02 Classify Tumors on the basis of their functions/locations?

15. Antineoplastic agents are drugs used for the treatment of cancer.
• The fraction of tumor cells that are in the replicative cycle (“Growth factor”), influence their
susceptibility to most cancer chemotherapeutic agent.
Rapidly dividing cells are generally more sensitive to anticancer drugs, whereas non proliferating
cells [those in G0 phase] usually survive the toxic effect of these drugs.
• Normal cells and tumor cells go through growth cycle. However, normal and neoplastic tissue
may differ only in the number of cells that are in the various stages in the cycle.
Chemotherapeutic agents that are effective only in replicating cells.
01. Phase Specific Agents: These drugs act at particular phase of cell cycle and more effective in
proliferating cells.
❑ G1 – Vincristine
❑ S– Methotrexate, Cytarabine, 6-TG, 6-MP, 5-FU, Daunorubicin, Doxorubicin
❑ G2 – Daunorubicin, Bleomycin
❑ M – Vincristine, Vinblastne, Paclitaxel etc.
02. Phase Non-Specific Agents: Nitrogen Mustards, Cyclphosphamide, Chlorambucil, Carmustine,
Dacarbazine, Busulfan, L-Asparginase, Cisplatin, Procarbazine and Actinomycin D etc.
a) These drugs are specifically effective against proliferating cells but they are not phase specific:
Ex: Fluorouracil, cyclophosphamide, Dactinomycin.
❑. Question:03 Explain the Cell cycle & relation with cancer drugs?
❑. Question:04 Classify Anticancer Agents based on its site of Action?

16. A. Alkylating Agents
1. Nitrogen Mustards – Mechlorethamine, Cyclophosphamide, Ifosfamide, Melphalan,
Chlorambucil.
2. Ethylenimine - Thio-Tepa, Hexamethyl melamine.
3. Alkyl Sulphonate – Busulphan.
4. Nitrosoureas – Carmustine, Lomustine, Streptozocin.
5. Triazines - Procarbazine, Dacarbazine, Temozolomide.
B. Platinum Coordination Complexes – Cisplatin, Carboplatin, Oxaliplatin.
C. Antimetabolites
I. Pyrimidine Analogs - 5-Fluorouracil, Cytarabine (cytosine arabinoside),
Capecitabine, Gemcitabine.
II.Purine Analogs – 6-Mercaptopurine, 6-Thioguanine, Azathioprine,
Fludarabine, Cladribine, Pentostatin.
II. Folic acid analogues – Methotrexate, Pemetrexed, Trimetrexate.
D. Anticancer Antibiotics – Actinomycin-D (Dactinomycin), Bleomycin, mitomycin- C, anthracyclines (e.g.
Doxorubicin, Daunorubicin, Idarubicin, epirubicin, Valrubicin), Streptozocin.
E. Plant Products- Vincristine, vinblastine, podophyllotoxin, etoposide, camptothecin, paclitaxel.
F. Protein Kinase Inhibitors- Imatinib, Dasatinib, Gefitinib, Erlotinib.
G. Miscellaneous – L-Asparaginase, Arsenic trioxide.
H. Hormonal Drugs –
1.Glucocorticoids – Prednisolon.
2. Estrogens – Fosfestrol, Ethinylestradiol.
3.Selective estrogen receptor modulator – Tamoxifen.
4.Selective estrogen receptor down regulator – Fulvestrant.
5. Aromatase Inhibitor – Anastrazole.
6. Antiandrogen – Flutamide, Bicalutamide.
7. 5 α Reductase Inhibitor – Finasteride.
8.GnRH Analog – Leuprorelin.
9. GnRH Antagonist – Cetorelix, Abarelix
10. Progestins – Hydroxyprogesterone acetate
❑. Question:05 Classify Anticancer Agents based on their chemical Structure?