Antihistamine in Pharmacology
Reading File
Finding Sources
Finding Sources
Finding Sources
Finding Sources
Finding Sources
Reading File
Reading File
Reading File
Reading File
Reading File
I have enough comprehensive content from both Katzung and Goodman & Gilman. Let me now compile the full answer.
Antihistamines - Pharmacology
1. Histamine: Background
Histamine is synthesized from L-histidine via histidine decarboxylase and is stored mainly in mast cell and basophil granules in bound, inactive form. Non-mast cell histamine is found in the brain (neurotransmitter) and in ECL cells of the gastric fundus (stimulates parietal cell acid secretion). It is metabolized to N-methylhistamine, methylimidazoleacetic acid, and imidazoleacetic acid.
Histamine receptors:
| Receptor | Location | Main Effect |
|---|---|---|
| H1 | Smooth muscle, endothelium, CNS | Bronchoconstriction, vasodilation, itching, allergy |
| H2 | Gastric parietal cells, heart | Gastric acid secretion, cardiac stimulation |
| H3 | CNS (presynaptic) | Autoreceptor; modulates neurotransmitter release |
| H4 | Immune cells | Chemotaxis, immune modulation |
2. H1 Receptor Antagonists (Classical Antihistamines)
All H1 antagonists are technically inverse agonists - they reduce constitutive H1 receptor activity and competitively block histamine binding (Goodman & Gilman). Their chemistry features a tertiary amino group linked by a 2-3 atom chain to two aryl substituents.
Classification
First-Generation H1 Blockers (Sedating)
These agents are lipid-soluble, cross the blood-brain barrier readily, and have significant anticholinergic, anti-alpha-adrenergic, and antiserotonin side effects.
| Chemical Class | Drugs | Sedation | Notes |
|---|---|---|---|
| Ethanolamine | Diphenhydramine, Dimenhydrinate, Clemastine | +++ | Marked sedation; antiemetic; strong anticholinergic |
| Ethylenediamine | Pyrilamine, Tripelennamine | ++ | GI side effects |
| Alkylamine | Chlorpheniramine, Brompheniramine | + | Slight sedation; common in OTC cold medicines |
| Piperazine | Hydroxyzine, Cyclizine, Meclizine | + | Anti-motion sickness; hydroxyzine used as anxiolytic |
| Phenothiazine | Promethazine | +++ | Marked sedation; strong antiemetic; alpha-blocking |
| Miscellaneous | Cyproheptadine | + | Anti-serotonin activity; appetite stimulant |
Second-Generation H1 Blockers (Non-Sedating)
These are less lipid-soluble and are substrates of the P-glycoprotein transporter at the blood-brain barrier - they do not enter the CNS appreciably. They have minimal anticholinergic effects and are preferred for daytime allergy treatment.
| Drug | Dose | Notes |
|---|---|---|
| Fexofenadine (Allegra) | 60 mg | No sedation; active metabolite of terfenadine |
| Loratadine (Claritin) | 10 mg | No sedation; metabolite desloratadine (5 mg) |
| Cetirizine (Zyrtec) | 5-10 mg | Active metabolite of hydroxyzine; mildly sedating in some |
| Desloratadine | 5 mg | Active metabolite of loratadine; longer acting |
- Katzung, p. 441; Goodman & Gilman, Chapter 43
3. Pharmacokinetics of H1 Antagonists
- Absorption: Rapidly absorbed orally; peak levels in 1-2 hours
- Distribution: Widely distributed; first-generation agents enter CNS freely
- Metabolism: Primarily hepatic via microsomal enzymes; second-generation via CYP3A4 (important interaction: ketoconazole inhibits CYP3A4 → increased drug levels)
- Duration: Most 4-6 hours; meclizine and second-generation drugs 12-24 hours
- Active metabolites: Hydroxyzine → cetirizine; Terfenadine → fexofenadine; Loratadine → desloratadine
4. Pharmacological Effects of H1 Antagonists
Effects on Histamine Actions
| System | Histamine Effect | H1 Blocker Effect |
|---|---|---|
| Bronchial smooth muscle | Constriction (H1) | Blocks bronchoconstriction |
| Blood vessels | Vasodilation, increased permeability (H1) | Blocks vasodilation and edema |
| GI smooth muscle | Contraction (H1) | Blocks contraction |
| Skin | Itching, wheal-and-flare (H1) | Blocks pruritus, reduces wheal |
| CNS | Arousal, neuromodulation | Sedation (first-generation) |
Additional Properties of First-Generation Agents (Katzung)
- Anticholinergic: Dryness of mouth, urinary retention, constipation, blurred vision
- Local anesthetic: Diphenhydramine and promethazine are potent local anesthetics
- Anti-motion sickness: Dimenhydrinate, cyclizine, meclizine, promethazine
- Antiemetic: Promethazine (most potent)
- Anti-serotonin: Cyproheptadine
5. Therapeutic Uses
| Indication | Drug of Choice |
|---|---|
| Allergic rhinitis, urticaria | Second-generation (loratadine, cetirizine, fexofenadine) |
| Acute urticaria | H1 antagonists are first-line therapy |
| Anaphylaxis | Epinephrine is mainstay; H1 blockers are adjuvant only |
| Motion sickness | Scopolamine (most effective); dimenhydrinate, meclizine, promethazine |
| Nausea/vomiting (post-chemo) | Promethazine (only H1 agent with use here, but 5HT3 antagonists preferred) |
| Vertigo, Meniere's disease | Dimenhydrinate, meclizine |
| Insomnia (OTC) | Diphenhydramine |
| Anxiety | Hydroxyzine |
| Extrapyramidal side effects (antipsychotics) | Diphenhydramine (reverses EPS) |
| Pruritus (atopic/contact dermatitis) | H1 antagonists (topical corticosteroids more effective) |
Histamine antagonists are NOT effective in bronchial asthma (limited efficacy, not used as sole therapy) or the common cold (no antiviral effect; only weak anticholinergic drying of secretions).
6. Adverse Effects
First-Generation
- Sedation (most frequent; additive with alcohol and CNS depressants)
- Dizziness, tinnitus, lassitude, fatigue
- Anticholinergic effects: dry mouth, urinary retention, blurred vision, constipation
- Paradoxical CNS stimulation (especially in children)
Second-Generation
- Minimal sedation (cetirizine can be mildly sedating in some)
- No significant anticholinergic effects
- Terfenadine and astemizole (withdrawn): QT prolongation/torsades de pointes when CYP3A4 inhibited (e.g., by ketoconazole or erythromycin) - these have been withdrawn from the market
7. H2 Receptor Antagonists
H2 blockers act primarily on gastric parietal cells to reduce acid secretion and are used for peptic ulcer disease and GERD. Discovered by James Black (Nobel Prize 1988).
| Drug | Notes |
|---|---|
| Cimetidine | First H2 blocker; inhibits CYP450 (multiple drug interactions); anti-androgenic effects |
| Ranitidine | Fewer drug interactions; withdrawn in many countries (NDMA contamination) |
| Famotidine | No CYP450 inhibition; most potent of the class |
| Nizatidine | Similar to ranitidine; fewest drug interactions |
8. H3 and H4 Receptors (Brief)
- H3 receptors: Presynaptic autoreceptors in the CNS; modulate release of histamine and other neurotransmitters. H3 antagonists (e.g., pitolisant) are used in narcolepsy.
- H4 receptors: Found on immune/hematopoietic cells; role in chemotaxis and inflammation; under investigation as therapeutic targets.
Summary Table: Generations at a Glance
| Property | First-Generation | Second-Generation |
|---|---|---|
| CNS penetration | Yes (lipid soluble) | No (P-gp substrate) |
| Sedation | Marked | Minimal/none |
| Anticholinergic effects | Yes | No |
| Duration | 4-6 hours | 12-24 hours |
| CYP3A4 metabolism | Variable | Yes (fexofenadine, loratadine) |
| Examples | Diphenhydramine, Chlorpheniramine, Promethazine | Fexofenadine, Loratadine, Cetirizine |
Sources: Katzung's Basic and Clinical Pharmacology, 16th ed., pp. 435-441; Goodman & Gilman's The Pharmacological Basis of Therapeutics, Chapter 43
Classification of antihistamine in tabular form
Here is the complete classification of antihistamines in tabular form:
Classification of Antihistamines
A. Based on Receptor Type
| Receptor Blocked | Class | Examples | Main Use |
|---|---|---|---|
| H1 | H1 Antihistamines | Diphenhydramine, Cetirizine, Loratadine | Allergy, urticaria, pruritus |
| H2 | H2 Antihistamines | Cimetidine, Ranitidine, Famotidine | Peptic ulcer, GERD, acid reduction |
| H3 | H3 Antagonists | Pitolisant, Thioperamide | Narcolepsy, wakefulness |
| H4 | H4 Antagonists | JNJ 7777120 (experimental) | Under investigation (inflammation) |
B. H1 Antihistamines - By Generation
| Generation | Key Features | Chemical Class | Drugs | Sedation | Duration |
|---|---|---|---|---|---|
| First Generation | Lipid-soluble, cross BBB, anticholinergic | Ethanolamine | Diphenhydramine, Dimenhydrinate, Clemastine | +++ | 4-6 h |
| Ethylenediamine | Pyrilamine, Tripelennamine, Antazoline | ++ | 4-6 h | ||
| Alkylamine | Chlorpheniramine, Brompheniramine, Triprolidine | + | 4-6 h | ||
| Piperazine | Hydroxyzine, Cyclizine, Meclizine | + | 12-24 h | ||
| Phenothiazine | Promethazine, Trimeprazine | +++ | 4-6 h | ||
| Piperidine | Cyproheptadine, Ketotifen | + | 4-6 h | ||
| Second Generation | Low lipid solubility, P-gp substrate, no BBB entry, no anticholinergic | Piperidine | Fexofenadine, Terfenadine* | 0 | 12-24 h |
| Piperazine | Cetirizine, Levocetirizine | 0/+ | 24 h | ||
| Miscellaneous | Loratadine, Desloratadine, Azelastine, Olopatadine | 0 | 24 h | ||
| Third Generation | Active metabolites/enantiomers of 2nd gen; improved efficacy & safety | — | Levocetirizine, Desloratadine, Fexofenadine | 0 | 24 h |
*Terfenadine and astemizole - withdrawn due to QT prolongation/torsades de pointes risk
C. H1 Antihistamines - By Chemical Class (First Generation)
| Chemical Class | Prototype Drug | Other Drugs | Special Feature |
|---|---|---|---|
| Ethanolamine | Diphenhydramine | Dimenhydrinate, Clemastine | Strongest sedation; local anesthetic; anticholinergic; antiemetic |
| Ethylenediamine | Pyrilamine | Tripelennamine, Antazoline | Significant GI side effects; moderate sedation |
| Alkylamine | Chlorpheniramine | Brompheniramine, Triprolidine | Least sedating among 1st gen; common in OTC cold remedies |
| Piperazine | Hydroxyzine | Cyclizine, Meclizine | Anti-motion sickness; hydroxyzine used as anxiolytic |
| Phenothiazine | Promethazine | Trimeprazine | Marked sedation; strongest antiemetic; alpha-adrenergic block |
| Piperidine | Cyproheptadine | Ketotifen | Anti-serotonin activity; appetite stimulant |
D. H2 Antihistamines - Comparative
| Drug | Relative Potency | CYP450 Inhibition | Half-life | Special Notes |
|---|---|---|---|---|
| Cimetidine | 1x (reference) | +++ (strong) | 2 h | Anti-androgenic; multiple drug interactions |
| Ranitidine | 4-10x | + (mild) | 2-3 h | Withdrawn in many countries (NDMA contamination) |
| Famotidine | 20-50x | 0 | 3 h | Most potent; no CYP inhibition; drug of choice |
| Nizatidine | 4-10x | 0 | 1-2 h | Fewest drug interactions |
E. First vs Second Generation - Quick Comparison
| Property | First Generation | Second Generation |
|---|---|---|
| Lipid solubility | High | Low |
| BBB penetration | Yes | No (P-glycoprotein substrate) |
| Sedation | Marked (+++/++) | None to minimal |
| Anticholinergic effects | Yes | No |
| Anti-alpha-adrenergic | Yes (some) | No |
| Duration of action | 4-6 hours | 12-24 hours |
| CYP3A4 metabolism | Variable | Yes |
| Drug interactions (CYP3A4) | Less significant | Important (ketoconazole) |
| Use in elderly | Avoid (fall risk, confusion) | Preferred |
| Preferred for daytime use | No | Yes |
| Examples | Diphenhydramine, Chlorpheniramine, Promethazine | Fexofenadine, Loratadine, Cetirizine |
F. Active Metabolite Relationships
| Parent Drug (1st Gen) | Active Metabolite (2nd/3rd Gen) |
|---|---|
| Hydroxyzine | Cetirizine → further refined to Levocetirizine |
| Terfenadine | Fexofenadine |
| Loratadine | Desloratadine |
Sources: Katzung's Basic and Clinical Pharmacology, 16th ed., p. 441; Goodman & Gilman's Pharmacological Basis of Therapeutics, Chapter 43
This is a shared conversation. Sign in to Orris to start your own chat.