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DrX Whiz Niraj
Antihistamines, PPIs & Anti-Neoplastics
Rapid Revision Notes for Medicinal Chemistry II. Master Histamine Receptors, Cancer Drugs, and Proton Pump Inhibitors.
Histamine is a chemical messenger (autacoid) synthesized from the amino acid Histidine. It is primarily stored in Mast Cells and Basophils. During an allergic reaction, it is released and binds to specific receptors.
| Receptor | Distribution (Location) | Action when Stimulated |
|---|---|---|
| H1 Receptors | Smooth muscles (bronchi, intestines), Endothelium, Brain. | Bronchoconstriction, Vasodilation, Itching, Pain, Allergic response. |
| H2 Receptors | Gastric Parietal Cells (Stomach), Heart. | Stimulates Gastric Acid (HCl) secretion. |
| H3 Receptors | Central Nervous System (CNS). | Acts as an autoreceptor (inhibits further release of histamine). |
| H4 Receptors | Bone marrow, WBCs. | Regulates immune response and inflammation. |
H1-Antagonists (Anti-allergic)
They block H1 receptors to treat allergies, rhinitis, and urticaria.
- First Generation (Sedating): Cross blood-brain barrier. Cause sleepiness. Examples: Diphenhydramine*, Chlorpheniramine, Promethazine*.
- Second Generation (Non-sedating): Do not cross BBB easily. Examples: Cetirizine, Loratadine, Astemizole.
H2-Antagonists (Anti-ulcer)
They block H2 receptors in the stomach to reduce gastric acid secretion. Used in Peptic Ulcer Disease (PUD).
- Examples: Cimetidine*, Ranitidine, Famotidine.
- Side Effect Alert: Cimetidine inhibits CYP450 enzymes and can cause Gynecomastia (breast enlargement in males) due to anti-androgenic effects.
PPIs are the most potent inhibitors of gastric acid secretion. They irreversibly bind to and inhibit the H⁺/K⁺-ATPase pump located on the luminal surface of gastric parietal cells.
Drugs: Omeprazole, Pantoprazole, Lansoprazole, Rabeprazole.
Cancer (Neoplasm) is characterized by uncontrolled cellular proliferation. Anti-neoplastic drugs are designed to kill these rapidly dividing cancer cells. They are classified based on their mechanism of action:
1. Alkylating Agents
Mechanism: They attach an alkyl group to DNA bases (specifically Guanine at N-7 position). This causes cross-linking of DNA strands, preventing DNA replication and causing cell death.
- Nitrogen Mustards: Meclorethamine*, Cyclophosphamide, Chlorambucil, Melphalan.
- Alkyl Sulfonates: Busulfan.
- Aziridines: Thiotepa.
2. Antimetabolites
Mechanism: They are structurally similar to normal cellular metabolites (like folic acid or purines). They "trick" the cell into incorporating them during DNA/RNA synthesis, blocking the process.
- Folic Acid Antagonist: Methotrexate*.
- Purine Antagonists: Mercaptopurine*, Thioguanine, Azathioprine.
- Pyrimidine Antagonists: Fluorouracil, Cytarabine.
3. Antibiotics
Mechanism: These intercalate (insert themselves) between DNA base pairs, causing DNA strand breakage and preventing replication.
Examples: Dactinomycin, Doxorubicin, Daunorubicin, Bleomycin.
4. Plant Products & Misc.
- Vinca Alkaloids: Vinblastine, Vincristine (Bind to tubulin, blocking mitosis/spindle formation).
- Etoposide: Inhibits Topoisomerase II enzyme.
- Miscellaneous: Cisplatin (A platinum compound that causes DNA cross-linking like alkylating agents). Mitotane.
5-Marks Exam Q&A
Q1. Classify Antihistaminics with suitable examples.
Ans: Antihistaminics are classified into two main types:
1. H1-Antagonists (Anti-allergic):
- First Gen (Sedating): Diphenhydramine, Promethazine, Chlorpheniramine.
- Second Gen (Non-sedating): Cetirizine, Loratadine, Astemizole.
2. H2-Antagonists (Anti-ulcer): Reduce gastric acid. Examples: Cimetidine, Ranitidine, Famotidine.
Q2. Write the mechanism of action of Proton Pump Inhibitors (PPIs).
Ans: PPIs like Omeprazole are prodrugs. In the acidic environment of the stomach, they convert into active sulfonamide derivatives. They covalently (irreversibly) bind to the sulfhydryl groups of the H⁺/K⁺-ATPase pump located on gastric parietal cells. This blocks the final step of acid secretion, completely stopping HCl production.
Q3. Write the mechanism of action of Alkylating Agents.
Ans: Alkylating agents (e.g., Cyclophosphamide, Meclorethamine) form highly reactive carbonium ions in the body. They covalently bond (alkylate) the N-7 position of Guanine bases in DNA. This forms cross-links between the two DNA strands, preventing DNA unzipping. Consequently, DNA replication and transcription are blocked, leading to cell death.