Introduction to Antihistaminic Agents & Antineoplastic Agents
This foundational unit covers two major therapeutic areas. Antihistaminics block the effects of histamine at H1 and H2 receptors — the H1 blockers treat allergies while H2 blockers and Proton Pump Inhibitors treat peptic ulcers. Antineoplastic agents are the chemical weapons used in cancer chemotherapy — understanding their mechanism of DNA damage is critical for designing safer, more selective anti-cancer drugs.
Syllabus & Topics
- 1Histamine: Biosynthesis from L-Histidine by histidine decarboxylase. Storage in mast cells and basophils. Release triggered by allergens, injury, or drugs. Acts on H1, H2, H3, and H4 receptors.
- 2H1 Receptors: Located in smooth muscles (bronchi, intestine, uterus), endothelium, and brain. Activation causes bronchoconstriction, vasodilation, increased capillary permeability, itching, and wakefulness.
- 3H1-Antagonists – Ethanolamine Derivatives: Diphenhydramine HCl (Benadryl – prototype, highly sedating), Dimenhydrinate (motion sickness), Doxylamine succinate (OTC sleep aid), Clemastine fumarate (long-acting).
- 4H1-Antagonists – Ethylenediamine Derivatives: Tripelenamine HCl – less sedating than ethanolamines but causes GI irritation.
- 5H1-Antagonists – Piperazine Derivatives: Chlorcyclizine HCl, Meclizine HCl (anti-emetic for motion sickness), Buclizine HCl. Long duration, strong anti-emetic activity.
- 6H1-Antagonists – Alkylamine Derivatives: Chlorpheniramine maleate (most widely used OTC antihistamine), Triprolidine HCl, Phenindamine tartrate. Less sedating, suitable for daytime use.
- 7H1-Antagonists – Phenothiazine Derivatives: Promethazine HCl (Phenergan – strong sedation, anti-emetic), Trimeprazine tartrate. Potent but highly sedating due to phenothiazine nucleus.
- 8H1-Antagonists – Piperidine Derivatives: Cyproheptadine HCl (antiserotonin + antihistamine, appetite stimulant), Azatidine maleate.
- 9H1-Antagonists – Second Generation (Non-sedating): Astemizole, Loratadine (Claritin), Cetirizine (Zyrtec), Levocetirizine. Cannot cross the BBB → no sedation. Selective peripheral H1 blockade.
- 10Mast Cell Stabilizer: Cromolyn Sodium – prevents degranulation of mast cells, blocking histamine release prophylactically. Used in asthma prophylaxis, not acute attacks.
- 11H2-Antagonists: Cimetidine (first H2 blocker, inhibits CYP450), Famotidine (most potent H2 blocker), Ranitidine (no anti-androgenic effects unlike cimetidine). Block gastric acid secretion by parietal cells.
- 12Gastric Proton Pump Inhibitors (PPIs): Omeprazole (Prilosec – prototype), Lansoprazole, Rabeprazole, Pantoprazole. Irreversibly inhibit H⁺/K⁺-ATPase (proton pump) on parietal cells. Prodrugs activated in acidic environment.
- 13Antineoplastic – Alkylating Agents: Meclorethamine* (nitrogen mustard prototype, synthesis required), Cyclophosphamide (prodrug activated by liver CYP450), Melphalan, Chlorambucil, Busulfan (for CML), Thiotepa. Mechanism: cross-link DNA strands → prevent replication.
Learning Objectives
Frequently Asked Questions (FAQs)
Q1. Why Are First-Generation Antihistamines Sedating While Second-Generation Are Not?
First-generation H1 antagonists such as Diphenhydramine and Chlorpheniramine are lipophilic and readily cross the blood–brain barrier, where they block central H1 receptors involved in wakefulness, causing sedation. Second-generation agents such as Cetirizine and Loratadine are more hydrophilic or are substrates for P-glycoprotein efflux transporters, limiting their penetration into the CNS and reducing sedation.
Q2. How Do Proton Pump Inhibitors Work?
Proton pump inhibitors (PPIs) such as Omeprazole and Pantoprazole are prodrugs that accumulate in the acidic canaliculi of gastric parietal cells. In this acidic environment, they convert to an active sulfenamide form that irreversibly binds to and inhibits the H⁺/K⁺-ATPase enzyme (proton pump), thereby suppressing gastric acid secretion for 24–48 hours until new pumps are synthesized.
Q3. What Is the Mechanism of Action of Cyclophosphamide?
Cyclophosphamide is a prodrug activated by hepatic cytochrome P450 enzymes to form 4-hydroxycyclophosphamide, which is converted to aldophosphamide and then to phosphoramide mustard (active metabolite) and acrolein. Phosphoramide mustard cross-links DNA at the N-7 position of guanine, inhibiting replication and leading to cell death. Acrolein can cause hemorrhagic cystitis, which is prevented by Mesna.
Q4. What Is the Difference Between Cimetidine and Ranitidine?
Both Cimetidine and Ranitidine are H2 receptor blockers that reduce gastric acid secretion. Cimetidine inhibits cytochrome P450 enzymes and may cause anti-androgenic effects such as gynecomastia and impotence. Ranitidine is more potent, has minimal CYP450 inhibition, and lacks significant anti-androgenic side effects.
Q5. How Do Vinca Alkaloids Kill Cancer Cells?
Vincristine and Vinblastine bind to tubulin and inhibit its polymerization into microtubules. Since microtubules are essential for formation of the mitotic spindle, their inhibition arrests cells in metaphase (M-phase specific), leading to cell death. Vincristine is primarily associated with neurotoxicity, whereas vinblastine is more commonly associated with myelosuppression.