Medical Pharmacology Chapter 21:  Histamine

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Receptor Subtype


Receptor coupling

Antagonists (partially selective)


Endothelium, brain, smooth muscle

Receptor activation causes and increased IP3, DAG (diacylglycerol)  production  



Mast cells, gastric mucosa, cardiac muscle, brain

Receptor activation causes an  increase in cAMP production 

Ranitidine (Zantac), cimetidine (Tagamet)


Presynaptic: brain, mesenteric plexus (other neurons)

G protein coupled


Organ System Effects: Histamine

Receptor Type: Sites of Action


Endothelium, brain, smooth muscle


Mast cells, gastric mucosa, cardiac muscle, brain


Clinical Uses: H1 Histamine Receptor Blockers


Allergic Rhinitis

  • H1 antihistamines

    • Effective for treating nasopharyngeal itching, sneezing,  watery rhinorrhea, and ocular itching, tearing, erythema.

    • Side effects associated with older H1 antihistamines include sedation, visual disturbance, urinary retention, and arrhythmias

  • Newer H1 antihistamines:( terfenadine (Seldane) astemizole (Hismanal))

    • These agents exhibit less sedation associated with their reduced ability to cross the blood brain barrier.

    • However, there are very important drug-drug interactions associated with this category.

      • For example, macrolide antibiotics such as erythromycin, clarithromycin (Biaxin), ketoconazole-class broad-spectrum antifungal drugs, inhibit  terfenadine (Seldane) or astemizole (Hismanal) metabolism.

      • Toxic levels of terfenadine (Seldane) or astemizole (Hismanal) may induce potentially fatal cardiac arrhythmias.

      • These new H1 antihistamines are contraindicated for concurrent use with macrolide antibiotics and ketoconazole-class and fungal drugs or in the presence of impaired hepatic function or inpatients predisposed to arrhythmias.

  • Topical α-adrenergic agonists:

    • Phenylephrine (Neo-Synephrine) or oxymetazoline (Afrin) reduce nasal congestion/obstruction.

      • Efficacy duration: limited due to rebound rhinitis and systemic effects which may include insomnia, irritability, and hypertension.

      • Hypertension is seen more commonly with oral αadrenergic agonists.

  •  Oral α-adrenergic agonists:

    • Useful in diminishing antihistamine-mediated sedation while improving antihistamine efficacy in relieving congestion. 

      • There is a concern that these agents due to their potentially hypertensive effects, may precipitate adverse cardiovascular effects, such as stroke. 

      • RThere has been an effort to remove such "pressor" agents from common over-the-counter cold medications.

  •  Cromolyn sodium:

    • This agent is a liquid provided as a nasal metered-does spray.

    • Cromolyn sodium (Intal) is not associated with side effects and typically is used prophylactically to reduce episodic allergen nasal mast cell activation. 

      • This agent may be used as part of a anti-asthma drug regimen.

  • Intranasal glucocorticoids

    • Intranasal glucocorticoids are the most potent drugs available for management of established rhinitis (seasonal or perennial) and including vasomotor rhinitis

      • Topical-to-systemic activity greater for: flunisolide (AeroBid) or budesonide (Rhinocort), compared to beclomethasone (Banceril) or triamcinolone (Aristocort).

    • Despite the different route of administration,  intranasal-administered glucocorticoids exhibit the same efficacy but with reduced systemic side effects compared to same agent administered orally.

    • Side effects include local irritation, which is the most frequent side effect to Candida over-growth which is an unusual side effect

    • Topical high potency glucocorticoids exhibit superior efficacy compared antihistamines during pollen season.

  • Immunotherapy (hyposensitization):

    • This approach is based on repeated, subcutaneous injections of gradually increasing allergen (specific for the symptom complex) over a period of 3-5 years.

    • Contraindications include significant cardiovascular disease and unstable angina

    • Cautious use applies to patients receiving beta adrenergic blockers (due to difficulty in managing possible anaphylactoid responses to treatment)

    • Clinical Management Sequence:

      1. Identification of allergens confirmed by allergens-specific IgE skin testing and/or serum assay.

      2. Avoidance of offending allergen

      3. Mild symptoms: prophylaxis with topical cromolyn sodium or single (bedtime) dose of  chlorpheniramine (Chlor-Trimeton) or astemizole (Hismanal) or terfenadine (Seldane) (decision based on side effects and presence of other concurrent medications or disease.

      4. Prominent symptoms: Topical beclomethasone (Banceril) or if needed budesonide (Rhinocort) or flunisolide (AeroBid)

      5. Management failure: immunotherapy


Clinical Uses: H1 Histamine Receptor Blockers continued


Drug-Drug Interactions


H2 Receptor Antagonists

H2 receptor blocker

Mechanism of Elimination

 Cimetidine (Tagamet)

Mainly renal

 Ranitidine (Zantac)

Mainly renal

 Famotidine (Pepcid)

Mainly renal

 Nizatidine (Axid)

Mainly renal


Pharmacodynamics: H2 Receptor Antagonists


Clinical Uses: H2 Receptor Antagonists

Cimetadine inhibits clearance of these agents (partial listing):


 Phenytoin (Dilantin)

Propranolol (Inderal)

Metoprolol (Lopressor)

Labetalol (Trandate, Normodyne)

 Quinidine gluconate (Quinaglute, Quinalan)


Lidocaine (Xylocaine)


 Alprazolam (Xanax)

Triazolam (Halcion)

Chlordiazepoxide (Librium)

Carbamazepine (Tegretol)


Tricyclic antidepressants

 Metronidazole (Flagyl)

Calcium channel blockers


 Diazepam (Valium)

 Flurazepam (Dalmane)


  1. Burkhalter, A, Julius, D.J. and Katzung, B. Histamine, Serotonin and the Ergot Alkaloids (Section IV. Drugs with Important Actions on Smooth Muscle), in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 261-286.

  2. Friedman, L. S. and Peterson, W.L. Peptic Ulcer and Related Disorders In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., and Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp. 1597-1616.


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