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Histamine (Systemic)

Primary: DX900

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.


Diagnostic aid (gastric function)—


Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.


Antacidity (diagnosis) or
Gastric histamine test or
Hypersecretory conditions, gastric (diagnosis) {10}—Histamine phosphate is indicated as a diagnostic aid for evaluation of gastric acid secretory function. Anacidity (achlorhydria) in response to histamine may indicate pernicious anemia, atrophic gastritis, adenomatous polyps of stomach, or gastric carcinoma. Gastric hypersecretion in response to histamine may indicate duodenal ulcer or the Zollinger-Ellison syndrome. {01} {03} {05} {10} {13} Use of this diagnostic aid for evaluation of gastric acid secretory function has generally been replaced by the pentagastrin test. {15}

[Asthma (diagnosis)]1—Histamine is indicated for use in an inhalation test to differentiate asthma from other pulmonary conditions. It should not be used in patients with clinically apparent asthma.{17}{18}{19}{20}{21}{22}{23}{24}{25}{26}{27}{28}{29}{30}

Histamine phosphate has been used for the presumptive diagnosis of pheochromocytoma; however, the use of histamine in patients suspected of having pheochromocytoma is hazardous and unwarranted due to the risk of precipitating a hypertensive crisis. {01} {06} Other tests, such as fluorometric measurements of unconjugated catecholamines, spectrophotometric measurement of total metanephrines, vanillylmandelic acid (VMA) in urine collections, or plasma catecholamine measurements, {05} provide a safer alternative in the diagnosis of pheochromocytoma. {11} {12}

Histamine phosphate has been used to produce short-term improvement in patients with vertigo, tinnitus, and deafness. However, it has not been proven effective in the symptomatic treatment of Menière's disease. {04}

Also, histamine phosphate has not been proven effective as a desensitizing agent in allergic diseases. {03}

1 Not included in Canadian product labeling.


Physicochemical characteristics:
Molecular weight—
    307.14 {13}

Mechanism of action/Effect:

Diagnostic aid (gastric function) {10}—Histamine stimulates gastric gland secretion, causing an increased secretion of gastric juice of high acidity. This action is probably due mainly to a direct action on parietal and chief gland cells. {03} {13}

Other actions/effects:

Histamine acts directly on the blood vessels to dilate arteries and capillaries; this action is apparently mediated by both H 1- and H 2-receptors. Capillary dilatation may produce flushing of the face, a decrease in systemic blood pressure, and an increase in skin temperature. Increased capillary permeability accompanies capillary dilatation, producing an outward passage of plasma protein and fluid into the extracellular spaces, an increase in lymph flow and protein content, and the formation of edema. Histamine increases rate and force of myocardial contraction as well as increasing cardiac output; it also tends to slow A-V conduction and (in large concentrations) may cause arrhythmias. Histamine also has a stimulant effect on chromaffin cells in the adrenal medulla or other extra-adrenal tissue, which causes the release of epinephrine and norepinephrine. In addition, histamine has a direct stimulant action on smooth muscle, producing contraction if H 1-receptors are activated, or mostly relaxation if H 2-receptors are activated. Smooth muscle response varies considerably among the different species. In humans, bronchoconstriction is more pronounced in patients with bronchial asthma, emphysema, or bronchitis. Also in humans, the stimulant effect of histamine may cause contraction of the intestinal muscle. However, little effect is noticed on the uterus, bladder, or gallbladder. Histamine has some stimulant effect on duodenal, salivary, pancreatic, bronchial, and lacrimal glands, but the effect of histamine on these glands is not clinically important. {03} {09} {13}


Readily absorbed after parenteral administration. {13}


Rapid diffusion into body tissues. {13} The mast cell is the primary storage site for histamine in most tissues. {03}


Primarily hepatic. Histamine is rapidly metabolized by methylation and oxidation. Methylation involves ring methylation and catalyzation by the enzyme histamine-N-methyltransferase, producing N-methylhistamine, which is mostly converted to N-methyl imidazole acetic acid. {03} Oxidative deamination produces imidazole acetic acid and its riboside. {13} Metabolites produced have no significant pharmacologic activity. {03}

Onset of action:

Rapid after subcutaneous or intramuscular administration. {03}

Duration of action:

Transient. {02} {13}

    Renal; 2 to 3% excreted as free histamine, 4 to 8% as N-methylhistamine, 42 to 47% as N-methyl imidazole acetic acid, 9 to 11% as imidazole acetic acid, and 16 to 23% as imidazole acetic acid riboside. {13}

Precautions to Consider


Studies have not been done in humans.

Studies have not been done in animals.


It is not known whether histamine is distributed into breast milk. {13} However, problems in humans have not been documented.


Appropriate studies on the relationship of age to the effects of histamine have not been performed in the pediatric population. Safety and efficacy have not been established. {13}


Appropriate studies on the relationship of age to the effects of histamine have not been performed in the geriatric population. No geriatrics-specific problems have been documented to date with the use of the gastric histamine test. However, elderly patients are more likely to have age-related renal function impairment, which may require careful monitoring in patients receiving histamine. {13}

Drug interactions and/or related problems
See Diagnostic interference.

Diagnostic interference
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With results of this test

Due to other medications
» Antacids    (administration on the morning of the test may decrease the total effect of histamine on gastric acidity and output {02})

» Anticholinergics or other medications with anticholinergic activity (See Appendix II ) or{13}
» Histamine H 2–receptor antagonists, such as cimetidine, famotidine, nizatidine, ranitidine{02}    (concurrent use may antagonize the effect of histamine on gastric secretion; administration of these medications is not recommended during the 24 hours preceding the test)

» Omeprazole    (concurrent use may antagonize the effect of histamine on gastric acid secretion; administration of omeprazole is not recommended during the 96 hours preceding the test {07})

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).

Except under special circumstances, this medication should not be used when the following medical problems exist:
» Cardiac disease, severe    (may be aggravated due to histamine-induced cardiovascular effects {10})

» Hypertension, severe or
» Hypotension or
» Vasomotor instability    (may be exacerbated {10} {13})

» Pheochromocytoma    (irreversible vascular and cerebral damage may be produced by prolonged paroxysms of hypertension {14})

» Respiratory disease, especially bronchial disease, or history of    (bronchial constriction induced by histamine may precipitate severe asthma attack {10})

Risk-benefit should be considered when the following medical problems exist
Cardiac disease or abnormality{10}    (condition may be exacerbated)

» Renal function impairment, severe    (may decrease excretion of histamine)

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Blood pressure determination and
Pulse rate determination    (recommended frequently during and/or immediately following administration of histamine {02} {13})

Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent {10}
Dilatation of cerebral vessels (continuing or severe headache)
hypertension (dizziness, continuing or severe headache)
hypotension (dizziness, lightheadedness, or fainting)
tachycardia (fast or pounding heartbeat)
Note: The above side effects may occur with average or large doses.

Incidence less frequent or rare {10}
Difficulty in breathing
flushing or redness of face
With large doses {10}
Bluish coloration of face
blurred vision
chest discomfort or pain
decrease in blood pressure, sudden
diarrhea, severe
difficulty in breathing, severe
flushing or redness of face
nausea and vomiting, severe

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent {10}
Abdominal or stomach spasms or cramps
gastrointestinal effects resembling symptoms of peptic ulcer due to increased acid secretion (nausea or vomiting, stomach pain)
metallic taste
swelling or redness at injection site —with subcutaneous administration
Note: With subcutaneous administration, swelling or redness at injection site is a characteristic intracutaneous effect of histamine known as the triple response. Involves erythema from capillary dilatation, wheal due to local edema from increased capillary permeability, and a flare from a neuronal reflex mechanism producing a surrounding area of arteriolar vasodilatation. {09}

For specific information on the agents used in the management of histamine overdose, see:
   • Antihistamines (Systemic) monograph;
   • Epinephrine in Sympathomimetic Agents—Cardiovascular Use (Parenteral Systemic) monograph; and/or
   • Histamine H 2-receptor Antagonists (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Treatment of overdose
Recommended treatment consists of the following {01} {03} {13}:

Specific treatment—:
Applying a temporary tourniquet near the injection site to slow down the absorption of histamine.

Administering 0.3 to 0.5 mL of epinephrine hydrochloride injection (1:1000) subcutaneously to treat hypotension, repeating every 20 minutes for two doses as needed. Legs of patient should be raised. {10} {16}

Administering antihistamines (H 1- and H 2-receptor blockers). {10}

Supportive care—:
Maintaining an adequate airway, with assisted respiration and administration of oxygen as needed. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.

Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Histamine (Diagnostic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Description of use
Test procedure for gastric histamine test: Possible administration of an antihistamine prior to test. Stomach contents emptied through stomach tube before administration of histamine; dose of histamine, based on body weight, is then injected subcutaneously; 5 minutes after injection, stomach contents emptied and tested for volume and acidity; stomach emptying and testing repeated every 15 minutes up to total of 4 times

Before having this test
»   Conditions affecting use, especially:
Other medications, especially antacids, anticholinergics, histamine H 2-receptor antagonists, or omeprazole
Other medical problems, especially severe cardiac disease, severe hypertension, hypotension, pheochromocytoma, severe renal function impairment, respiratory disease, urticaria, or vasomotor instability

Preparation for this test
» Importance of following physician's instructions about not taking certain medications before the histamine test

» Fasting for 12 hours before histamine test is administered

Precautions during administration of this test
» Not swallowing saliva during administration of test

Side/adverse effects
Signs of potential side effects, especially, dilatation of cerebral vessels, difficulty in breathing, flushing or redness of face, hypertension, hypotension, nervousness, seizures, and tachycardia

General Dosing Information
No food should be ingested for 12 hours before the administration of the gastric histamine test. {10}

Care should be taken to prevent the patient from swallowing salivary secretions. {02} The alkalinity of the saliva may interfere with the test results.

During and after the administration of histamine, epinephrine hydrochloride should be available in case of a severe hypotensive reaction. {10} {13}

The test is performed after the patient has rested in bed under standard basal conditions. Fasting gastric contents are then aspirated through a stomach tube. Histamine is administered subcutaneously, and 5 minutes afterwards gastric contents are collected and tested for volume, acidity, pH, and acid output. Stomach emptying and testing are repeated every 15 minutes until 4 collections have been made. {10} If no acidity is detected, a maximum histamine stimulation test can be performed. {10}

For the augmented histamine test, an appropriate dose of antihistamine (e.g., 10 mg of chlorpheniramine maleate, 50 mg of diphenhydramine hydrochloride, or 50 mg of pyrilamine maleate) is administered intramuscularly prior to the basal secretion study. After the basal study is completed, histamine is administered subcutaneously. {13}

Pulse rate and blood pressure should be determined immediately after histamine injection.

Parenteral Dosage Forms

Note: Bracketed information in the Dosage Forms section refer to categories of use and/or indications that are not included in U.S. product labeling.


Usual adult and adolescent dose
Diagnostic aid (gastric function)
Subcutaneous, 500 to 750 mcg, administered after collection of basal gastric secretion. {10}

Note: If no acidity is detected, a maximum histamine stimulation test can be performed using 40 mcg per kg of body weight subcutaneously, administered after basal secretion study. {10}
For augmented histamine test: Subcutaneous, 40 mcg of histamine phosphate per kg of body weight, administered after basal secretion study.

[Diagnostic aid (asthma)]1
Inhalation, 0.03 to 10 mg/mL phosphate-buffered histamine solution, administered by nebulizer, in 5 slow deep breaths, each separated by 3 to 5 minutes.

Usual pediatric dose
Safety and efficacy have not been established.
[Diagnostic aid (asthma)]1
Inhalation, 0.1 to 8 mg/mL phosphate-buffered histamine solution, using the tidal breathing method.

Usual geriatric dose
See Usual adult and adolescent dose.

Strength(s) usually available
Not commercially available.


1 mg (0.36 mg base) (Rx)[Generic]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from freezing.

Revised: 08/01/2001

  1. Facts & Comparisons. Jan 1988 rev: 748a-748b.
  1. McEvoy G, editor. AHFS Drug Information. Bethesda, MD: American Society of Hospital Pharmacists, 1992.
  1. Goodman & Gilman"s The pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press, 1990.
  1. AMA Drug Evaluations Annual. Chicago: American Medical Association, 1992.
  1. Wallach J. Interpretation of diagnostic tests. 4th ed. Boston: Little, Brown and Company, 1986: 174-5.
  1. Histamine phosphate injection product information (histamine test for pheochromocytoma) (Lilly—US). Rev 4/90, Rec 10/90.
  1. Omeprazole product information (Prilosec, MSD—US). Rev 9/89, Rec 8/91.
  1. Wilson J, et al., editors. Harrison's principles of internal medicine. 12th ed. New York: McGraw-Hill, 1988.
  1. Merck Manual. 14th ed. Rahway, NJ: MSD Labs, 1987.
  1. Histamine package insert, 1992 CPS.
  1. Wyngaarden J, Smith L, editors. Cecil"s textbook of medicine. 18th ed. Philadelphia: W.B. Saunders Co, 1988.
  1. Panel comments, 6/87.
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  1. Panelists comment, 1993 revision.
  1. Panelist comment, 1993 revision.
  1. Panelist comment, 1993 revision.
  1. Reviewers' consensus on the use of histamine (systemic) in an inhalation test to differentiate asthma from other pulmonary conditions, 11/1/00.
  1. Bennett JB, Davies RJ. A comparison of histamine and methacholine bronchial challenges using the DeVilbiss 646 nebulizer and the Rosenthal-French dosimeter. Br J Dis Chest 1987; 81: 252-9.
  1. ten Velde GP, Kreukniet J. The histamine inhalation provocation test and its reproducibility. Respiration 1984; 45: 131-8.
  1. Aquilina AT. Comparison of airway reactivity induced by histamine, methacholine, and isocapnic hyperventilation in normal and asthmatic subjects. Thorax 1983; 38: 766-70.
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  1. Cockcroft DW, Berscheid BA, Murdock KY. Unimodal distribution of bronchial responsiveness to inhaled histamine in a random human population. Chest 1983; 83: 751-4.
  1. Chatham M, Bleecker ER, Smith PL, et al. A comparison of histamine, methacholine, and exercise airway reactivity in normal and asthmatic subjects. Am Rev Respir Dis 1982; 126: 235-40.
  1. Chung KF, Morgan B, Keyes SJ, et al. Histamine dose-response relationships in normal and asthmatic subjects. Am Rev Respir Dis 1982; 126: 849-854.
  1. Hernandez MJ, Bradley BL, Miller WC. Rapid, shallow ventilatory pattern during exercise after histamine bronchoprovocation. Ann Allergy 1981; 46: 67-9.
  1. Monkare S, Haahtela T, Ikonen M, et al. Bronchial hyperreactivity to inhaled histamine in patients with Farmer's lung. Lung 1981; 159: 145-51.
  1. Ruffin RE, Alpers JH, Crockett AT, et al. Repeated histamine inhalation tests in asthmatic patients. J Allergy Clin Immunol 1981; 67: 285-9.
  1. Salome CM, Schoeffel RE, Woolcock AJ. Comparison of bronchial reactivity to histamine and methacholine in asthmatics. Clin Allergy 1980; 10: 541-6.
  1. Bleecker ER, Rosenthal RR, Menkes HA, et al. Physiologic effects of inhaled histamine in asthma: reversible changes in pulmonary mechanics and total lung capacity. J Allergy Clin Immunol 1979; 64: 597-602.
  1. Spector SL, Farr RS. A comparison of methacholine and histamine inhalations in asthmatics. J Allergy Clin Immunol 1975; 56: 308-16.

Further information

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