A REVIEW ON HISTAMINE ANTAGONIST

About Authors:
Mahaveer Kabra*¹, Sanjay Bhandari¹, Ami Sharma¹, Reema Jain²
Department of Pharmacology,
¹Kota College of Pharmacy, Kota
²Bhupal Noble’s Institute of Pharmaceutical science, Udaipur
*sanskarkabra@gmail.com

Abstract:
A histamine antagonist is an agent which serves to inhibit the release or action of histamine. Allergies are caused by an excessive response of the body to allergens, such as the pollen released by grasses and trees. An allergic reaction indicates an excessive release, of histamine by the body.Histamine is a natural chemical produced by the immune (disease-fighting) system of the body. The main action of histamine is related to allergies. An allergen is a substance that is not normally harmful, such as pollen, but which causes an overreaction by the immune system in some people.drugs show their action by binding with their specific receptor like H₁-receptor antagonists are Diphenhydramine, Meclizine etc. H₂-receptor antagonists Cimetidine, Famotidine. All antihistamines are reversible, competitive antagonists at histaminic (H₁) receptors. They act by inhibiting binding of circulating histamine to its receptor site, but do not prevent histamine release. Administration of an antihistamine results in inhibition of respiratory, vascular, and gastrointestinal smooth muscle constriction, a decrease in histamine-activated secretions from salivary and lacrimal glands, and anti-inflammatory effects. Antihistamines also decrease capillary permeability, which reduces the wheal and flare response to an allergen, as well as diminishes itching. Competitive inhibition of histamine at H₂ receptors of the gastric parietal cells resulting in reduced gastric acid secretion, gastric volume and hydrogen ion concentration reduced. Antihistamines are used as treatment for allergies.

REFERENCE ID: PHARMATUTOR-ART-1805

INTRODUCTION:
A histamine antagonist is an agent which serves to inhibit the release or action of histamine. Antihistamines are used as treatment for allergies. Allergies are caused by an excessive response of the body to allergens, such as the pollen released by grasses and trees. An allergic reaction indicates an excessive release, of histamine by the body. Histamine is a natural chemical produced by the immune (disease-fighting) system of the body. The main action of histamine is related to allergies. It is released when the body comes in contact with an allergen. An allergen is a substance that is not normally harmful, such as pollen, but which causes an overreaction by the immune system in some people. Histamine also has other functions around the body, such as widening and tightening blood vessels, and squeezing muscles in your breathing and digestive systems. Antihistamines prevent histamine carrying out these actions. Antihistamines prevent histamine carrying out these actions. They are most often used to treat allergic reactions, although certain types can be used in the treatment of other conditions such as migraines, travel sickness and stomach ulcers. Antihistamines are available as tablets (oral), creams, and injections. The older antihistamines tend to cause drowsiness (sedation is the medical term for drowsiness) and rare dangerous heart arrhythmias (terfenadine and astemizole). The more recently developed antihistamines cause less drowsiness. (1, 2)

Mechanism of Action:
All antihistamines are reversible, competitive antagonists at histaminic (H₁) receptors. They act by inhibiting binding of circulating histamine to its receptor site, but do not prevent histamine release. Administration of an antihistamine results in inhibition of respiratory, vascular, and gastrointestinal smooth muscle constriction, a decrease in histamine-activated secretions from salivary and lacrimal glands, and anti-inflammatory effects. Antihistamines also decrease capillary permeability, which reduces the wheal and flare response to an allergen, as well as diminishes itching. (2, 3)

Types of Antihistamine

1.Clinical: H₁- and H₂-receptor antagonists
1.1H₁-receptor antagonists
1.2H₂-receptor antagonists

2.Experimental: H₃- and H₄-receptor antagonists
2.1H₃-receptor antagonists
2.2H₄-receptor antagonists

3.Others
3.1 Inhibitors of histamine release
3.2 Other agents with anti histaminergic activity. (3, 4, 5)

1. Clinical: H₁- and H₂-receptor antagonists

1.1 H₁-receptor antagonists
Antihistamine refers only to H₁ antagonists, also known as H₁ antihistamines. H₁-antihistamines are actually inverse agonists at the histamine H₁-receptor, rather than antagonists.

Diphenhydramine
Meclizine
Quetiapine
Pheniramine
Cetirizine
Promethazine

1.2 H₂-receptor antagonists
H₂ antagonists are used to reduce the secretion of gastric acid, treating gastrointestinal conditions including peptic ulcers and gastroesophageal reflux disease

Cimetidine
Famotidine
Ranitidine
Nizatidine
Roxatidine

2. Experimental: H₃- and H₄-receptor antagonists
These are experimental agents and do not yet have a defined clinical use, although a number of drugs are currently in human trials. H₃-antagonists have a stimulant and ionootropic effect, and are being investigated for the treatment of conditions such as ADHD, Alzheimer's Disease and schizophrenia, while H₄-antagonists appear to have an immunomodulatory role are being.

2.1H₃-receptor antagonists

· Thioperamide

· A-349,821

· ABT-239

· Ciproxifan

· Clobenpropit

2.2 H₄-receptor antagonists

Thioperamide
JNJ 7777120
VUF-6002 (7, 8)

3. Others

3.1 Inhibitors of histamine release

Cromoglicate (cromolyn)

Nedocromil

3.2 Other agents with antihistaminergic activity
These include tricyclic antidepressants and antipsychotics. One drug initially developed as an antipsychotic, but now commonly used for its antihistaminic effect.

H₂Receptor Antagonist:
The H₂-receptor antagonists (H₂RA, often shortened to H₂ antagonist) are a class of drugs used to block the action of histamine on parietal cells in the stomach, decreasing the production of acid by these cells. H₂ antagonist are used in the treatment of dyspepsia, although they have largely been surpassed in popularity by the more effective proton pump inhibitors.

1. History and development
Cimetidine was the prototypical histamine H₂-receptor antagonist from which the later members of the class were developed. In 1964 it was known that histamine stimulated the secretion of stomach acid, but also that traditional antihistamines had no effect on acid production. Ranitidine was introduced in 1981 and was the world's biggest-selling prescription drug by 1988.

2. Pharmacology
The H₂ antagonists are competitive antagonists of histamine at the parietal cell H₂ receptor. They suppress the normal secretion of acid by parietal cells and the meal-stimulated secretion of acid.

3. Clinical use

Peptic ulcer disease (PUD)
Gastroesophageal reflux disease (GERD/GORD)
Dyspepsia
Prevention of stress ulcer (a specific indication of ranitidine)
Some studies suggest that H₂-antagonists might be effective in treating herpes viruses, such as shingles and herpes simplex.

4. Adverse effects
Infrequent ADRs include hypotension. Rare ADRs include: headache, tiredness, dizziness, confusion, diarrhea, constipation, and rash. Additionally, cimetidine may also cause gynecomastia in males, loss of libido, and impotence, which are reversible upon discontinuation.

5. Drug interactions
Specifically, cimetidine is an inhibitor of the P450 enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. By reducing the metabolism of drugs through these enzymes, cimetidine may increase their serum concentrations to toxic levels. Famotidine has negligible effect on the CYP system, and appears to have no significant interactions.^{(9, 10, 11)}

CIMETIDINE:
Cimetidine (prototypical histamine H₂-receptor antagonist) is in a group of drugs called histamine receptor antagonists.

1. Mechanism of Action
Competitive inhibition of histamine at H₂ receptors of the gastric parietal cells resulting in reduced gastric acid secretion, gastric volume and hydrogen ion concentration reduced.

2. Pharmacological action
Anti-Ulcer Agents - Various agents with different action mechanisms used to treat or ameliorate Peptic Ulcer or irritation of the gastrointestinal tract.

Enzyme Inhibitors - Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.

Histamine H₂ Antagonists - Drugs that selectively bind to but do not activate histamine H₂receptors, thereby blocking the actions of histamine.

3. Pharmacokinetics
Tagamet is rapidly absorbed after oral administration and peak levels occur in 45 to 90 minutes. The principal route of excretion of Tagamet is the urine.

4. Dosage and Administration
Oral- Duodenal and gastric ulcers: 800 mg daily at bed time for 4-8 weeks followed by 400 mg daily at bedtime. Zollinger Ellison Syndrome (ZES): 400 mg four times a day.

5. Drug Interaction
Tagamet, apparently through an effect on certain microsomal enzyme systems, has been reported to reduce the hepatic metabolism of warfarin-type anticoagulants, phenytoin, propranolol, nifedipine, chlordiazepoxide, diazepam, certain tricyclic antidepressants, lidocaine, theophylline and metronidazole, thereby delaying elimination and increasing blood levels of these drugs.

6. Antisecretory Activity
1) Acid Secretion : Nocturnal: Tagamet 800 mg orally at bedtime reduces mean hourly H⁺activity by greater than 85% over an 8-hour period in duodenal ulcer patients, with no effect on daytime acid secretion.

2) Pepsin: Oral Tagamet 300 mg reduced total pepsin output as a result of the decrease in volume of gastric juice.

3) Intrinsic Factor: Intrinsic factor secretion was studied with betazole as a stimulant. Oral Tagamet 300 mg inhibited the rise in intrinsic factor concentration produced by betazole, but some intrinsic factor was secreted at all times.

7. Cimetidine is used for
Treating and preventing ulcers of the stomach and small intestine, and treating gastroesophageal reflux disease (GERD).

Clinical Uses

Duodenal Ulcer
Active Duodenal Ulcer
Maintenance Therapy in Duodenal Ulcer:
Active BenignGastric Ulcer
Gastroesophageal Reflux Disease
Prevention of Upper Gastrointestinal Bleeding in Critically Ill Patients

8. Side Effects
Adverse effects reported in patients taking Tagamet are described below by body system. Incidence figures of 1 in 100 and greater are generally derived from controlled clinical studies. (12, 13)

I. Gastrointestinal
Diarrhea (usually mild) has been reported in approximately 1 in 100 patients.

II. CNS
Headaches, Dizziness ranging from mild to severe, have been reported in 3.5% of 924 patients taking 1600 mg/day, 2.1% of 2,225 patients taking 800 mg/day and 2.3% of 1,897 patients taking placebo.

III. Endocrine
Gynecomastia has been reported in patients treated for 1 month or longer.

IV. Hematologic Decreased white blood cell counts in Tagamet-treated patients (approximately 1 per 100,000 patients), including agranulocytosis (approximately 3 per million patients), have been reported.

V. Hepatobiliary
Dose-related increases in serum transaminase have been reported.

VI. Hypersensitivity
Rare cases of fever and allergic reactions including anaphylaxis

VII. Renal
Small, possibly dose-related increases in plasma creatinine,

VIII. Cardiovascular
Rare cases of bradycardia, tachycardia and A-V heart block have been reported with H₂-receptor antagonists.

9. Precautions
Pregnancy:-Teratogenic Effects.

Immunocompromised Patients:- In immunocompromised patients, decreased gastric acidity, including that produced by acid-suppressing agents such as cimetidine, may increase the possibility of a hyperinfection of strongyloidiasis. (13, 14, 15)

RANITIDINE:
Ranitidine is in a group of drugs called histamine-2 blockers. Ranitidine works by reducing the amount of acid your stomach produces.

1. Mechanism of Action
Competitive inhibition of histamine at H₂-receptors of the gastric parietal cells, which inhibits gastric acid secretion, gastric volume, and hydrogen ion concentration are reduced. Does not affect pepsin secretion, pentagastrin-stimulated intrinsic factor secretion, or serum gastrin.(13, 16)

2. Pharmacological Action
Anti-Ulcer Agents- Various agents with different action mechanisms used to treat or ameliorate Peptic ulcer or irritation of the gastrointestinal tract.

Histamine H-2 Antagonists- Drugs that selectively bind to but do not activate histamine H₂receptors, thereby blocking the actions of histamine.

3. Pharmacodynamics Kinetics
Absorption: Oral: 50%
Distribution: Normal renal function: V_d: 1.7 L/kg; Cl_cr 25-35 mL/minute: 1.76 L/kg minimally penetrates the blood-brain barrier; enters breast milk
Protein binding: 15%
Metabolism: Hepatic to N-oxide, S-oxide, and N-desmethyl metabolites
Bioavailability: Oral: 48%
Half-life elimination:
Oral: Normal renal function: 2.5-3 hours; Cl_cr 25-35 mL/minute: 4.8 hours
I.V.: Normal renal function: 2-2.5 hours
Excretion: Urine: Oral: 30%, I.V.: 70% (as unchanged drug); feces (as metabolites)

4. Clinical Pharmacology
Zantac is a competitive, reversible inhibitor of the action of histamine at the histamine H_2-receptors, including receptors on the gastric cells. Zantac does not lower serum Ca++ in hypercalcemic states. Zantac is not an anticholinergic agent.(17, 18, 19)

5. Pharmacokinetics
Absorption: Zantac is 50% absorbed after oral administration, compared to an intravenous (IV) injection
Distribution: The volume of distribution is about 1.4 L/kg. Serum protei binding averages 15%.
Metabolism: In humans, the N-oxide is the principal metabolite in the urine;
Excretion: The principal route of excretion is the urine, with approximately 30% of the orally administered dose collected in the urine as unchanged drug in 24 hours.
Geriatrics: The plasma half-life is prolonged and total clearance is reduced in the elderly population due to a decrease in renal function. The elimination half-life is 3 to 4 hours.

6. Uses:
This medication reduces the amount of acid in your stomach. It is used to treat and prevent ulcers, to treat gastroesophageal reflux disorder (GERD), and to treat conditions associated with excessive acid secretion.(20, 21, 22)

7. Clinical Uses

Active Duodenal Ulcer
Maintenance Therapy in Duodenal Ulcer
Gastric Ulcer
Maintenance of Healing of Gastric Ulcers
Pathological Hypersecretory Conditions (such as Zollinger-Ellison syndrome)
Gastroesophageal Reflux Disease (GERD)

8. Adverse Effect
Central Nervous System: Rarely, malaise, dizziness, somnolence, insomnia, and vertigo.
Cardiovascular: As with other H₂-blockers, rare reports of arrhythmias such as tachycardia, bradycardia, asystole, atrioventricular block, and premature ventricular beats.
Gastrointestinal: Constipation, diarrhea, nausea/vomiting, abdominal discomfort/pain, and rare reports of pancreatitis.}
Musculoskeletal: Rare reports of arthralgias and myalgias.
Hematologic: Blood count changes (leukopenia, granulocytopenia, and thrombocytopenia) have occurred in a few patients.
Endocrine: Controlled studies in animals and humans have shown no stimulation of any pituitary hormone by Ranitidine and no antiandrogenic activity,
Integumentary: Rash, including rare cases of erythema multiforme. Rare cases of alopecia and vasculitis.
Respiratory: increased risk of developing pneumonia

9. Precautions:
Before using this medication, tell your doctor or pharmacist your medical history, especially of heartburn. Alcohol can irritate the stomach and cause bleeding. pregnant lady consult doctor or pharmacist before taking this drug. It is excreted into breast milk.(22, 23) Histamine H₂ Antagonists- Drugs that selectively bind to but do not activate histamine H₂ receptors, thereby blocking the actions of histamine. Their clinically most important action is the inhibition of acid secretion in the treatment of gastrointestinal ulcers. Smooth muscle may also be affected. Some drugs in this class have strong effects in the central nervous system, but these actions are not well understood.

CONCLUSION:
A histamine antagonist is an agent which serves to inhibit the release or action of histamine. Antihistamine can be used to describe any histamine antagonist, but it is usually reserved for the classical antihistamines that act upon the H₁ histamine receptor.

Antihistamines are used as treatment for allergies. Allergies are caused by an excessive response of the body to allergens, such as the pollen released by grasses and trees. An allergic reaction indicates an excessive release, of histamine by the body.

The H₂-receptor antagonists (H₂RA, often shortened to H₂ antagonist) are a class of drugs used to block the action of histamine on parietal cells in the stomach, decreasing the production of acid by these cells. H₂ antagonists are used in the treatment of dyspepsia, although they have largely been surpassed in popularity by the more effective proton pump inhibitors. In the United States, all four FDA-approved members of the group—cimetidine, ranitidine, famotidine, and nizatidine—are available over the counter in relatively low doses. Antihistamines are used as treatment for allergies.

Peptic ulcer disease (PUD)
Gastroesophageal reflux disease (GERD/GORD)
Dyspepsia
Prevention of stress ulcer (a specific indication of ranitidine)
Some studies suggest that H2-antagonists might be effective in treating herpes viruses, such as shingles and herpes simplex. (7, 13, 24, 25)

REFERENCES:
1.Marie A, Stevent AR, Bradly AL. Remington the Science and Practice of Pharmacy. 21sted., 2005, vol. (II), 1544-1545.
2.Burkhart KK, Janco N, Kulig KW. Cimetidine as Adjunctive Treatment for Acetaminophen Overdose. Hum Exp Toxicol, 1995:14;299-304.
3.Block.JH, Beale JM, Wilson and Gisvolds. Text book of organic medicinal and pharmaceutical chemistry. 717-718.
4.Balestrazzi P, Gregori G, Bernasconi S. Bradycardia and Neurologic Disorders Associated With Ranitidine in a Child. Am J Dis Child. 1985:139(5);442.
5. Dellinger RP, Levy MM, Carlet JM. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock. Intensive Care Med 34th ed, 2008, vol. (I), 17-60.
6. Eddleston JM, Booker PD, Green JR. Use of Ranitidine in Children Undergoing Cardiopulmonary Bypass .Crit Care Med, 1989: 17(1);26-9.
7.Fennerty MD, Higbee M. Drug Therapy of Gastrointestinal Disease. 1993:585-608.
8.Fick DM, Cooper JW, Wade WE. Updating the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. Intern Med, 2003:163(22);2716-24.
9.Fontana M, Massironi E, Rossi A. Ranitidine Pharmacokinetics in Newborn Infants. 1993: (68);602-3.
10.Garcia LA, Jick H. Risk of Gynaecomastia Associated With Cimetidine, Omeprazole, and Other Antiulcer Drugs. 1994:308 (6927);503-6.
11.Inoue A, Teramae H, Hisa T. Fixed Drug Eruption Due to Cimetidine, Acta Derm Venereol, 1995:75 (3);250.
12.Kat Z, Bertram G. Basic and Clinical Pharmacology. 6thed, 1995;255-259.
13. Kadam SS, Mahadik RK, Bothara GK, Principal of Medicinal Chemistry. 6th ed, 2006: 233-253.
14.Koren G, Zemlickis DM. Outcome of Pregnancy After First Trimester Exposure to H2-Receptor Antagonists. Am J Perinatol, 1991:8(1);37-38.
15.Krenzelok EP, Litovitz T, Lippold KP. Cimetidine Toxicity: An Assessment of 881 Cases. Ann Emerg Med, 1987:16 (11);1217-21.
16.Lambert J, Mobassaleh M, Grand RJ. Efficacy of Cimetidine for Gastric Acid Suppression in Pediatric Patients. J Pediatr, 1992:120(3);474-8.
17.Lloyd CW, Martin WJ, Taylor BD. The Pharmacokinetics of Cimetidine and Metabolites in a Neonate. Drug Intell Clin Pharm, 1985:19(3):203-5.
18.Lloyd CW, Martin WJ, Taylor BD. Pharmacokinetics and Pharmacodynamics of Cimetidine and Metabolites in Critically Ill Children. J Pediatric, 1985:107(2):295-300.
19. Lopez-Herce J, Albajara L, Codoceo R. Ranitidine Prophylaxis in Acute Gastric Mucosal Damage in Critically Pediatric Patients. Crit Care Med, 6th ed 1988:(16);591-93.
20.Maack DK and Spiller HA. Rare Dystonic Reaction From Accidental Overdose of Ranitidine in a 3 Month Old. Vet Hum Toxicol, 1993;3-343.
21.Morris DL, Markham SJ, Beechey A. Ranitidine-Bolus or Infusion Prophylaxis for Stress Ulcer. Crit Care Med, 1988:16 (3);229-32.
22.Ohsawa T, Masuhara K, and Hirata W. Reversal of Ranitidine-Induced Hypergastrinemia by Cimetidine. Ann Pharmacother, 1994:28 (11);1303.
23.Penston J, Wormsley G. Adverse Reactions and Interactions with H2-Receptor Antagonists. Med Toxicol Adverse Drug Exp, 1986:1(3);192-216.
24.Roberts CJ. Clinical Pharmacokinetics of Ranitidine. Clin Pharmacokinet, 1984:9 (3);211-21
25.Sawyer D, Conner CS, Scalley. Cimetidine: Adverse Reactions and Acute Toxicity. Am J Hosp Pharm, 1981:38 (2);188-97.