Histamine, its receptors and drugs acting on these receptors

Histamine

Introduction

                Autacoids is a general term that refers to a number of compounds such as: histamine, serotonin, endogenous peptides, prostaglandins, and leukotrienes.

                The formal definition of autacoids is "self-remedy”, referring to the action of local hormones

                Histamine is a biogenic amine found in many body tissues and cells. It is synthesized from the amino acid L-histidine through mediation of the enzyme L-histidine decarboxylase, while its metabolism is mediated by the enzyme histamine N-methyltransferase, or alternatively by diamino-oxidase.  

Chemistry and Pharmacokinetics

                The formation of histamine occurs by the removal of a carboxyl group (decarboxylation) from amino acid  L-histidine.

                One of the important issues associated with formation of a biologically active compound is the mechanism that accounts for the compounds inactivation. 

                Histamine is active biologically, but the first step for its inactivation involves the addition of a methyl group (CH₃) followed by a chemical oxidation.

                Most of the time very little histamine is excreted unchanged because of these metabolic steps.  One exception would be the case of neoplastic disease (cancer).  For instance, significant histamine is excreted unchanged in the presence of these diseases: (a) systemic mastocytosis, (b) gastric carcinoid syndrome or (c) urticaria pigmentosa.

                Tissue Distribution:

                The primary site for histamine localization is the mast cell granules (or basophils)

                Mast cells are important in that they release histamine in response to potential tissue injury.

                Other sites include the central nervous system where histamine may function as a neurotransmitter and the fundus of the stomach (enterochromaffin-like cells) which are major acid secretagogues (They promotes accretion by activation of acid-producing mucosal parietal cells).

                Histamine: Storage and Release

Immunologic Release:  The most important mechanism for histamine release is in response to an immunological stimulus.  In Mast cells, if sensitized by surface IgE antibodies, degranulate when exposed specific antigen.  Degranulation means liberation of the contents of the mast cell granules, including histamine.  Degranulation is involved in the immediate (type I) allergic reaction.

                Release regulation is present in most mast cells.

                Histamine Modulation is associated with the inflammatory responses.  Following local injury, histamine first produces a local vasodilation (reddening of the area) followed by the release of acute inflammation mediators.  Inflammatory cells are involved in this process and include neutrophils, eosinophils, basophils, monocytes & lymphocytes.  In

Mechanical/Chemical Release: A second type of release occurs following chemical or mechanical injury to mast cells.  In these injuries caused degranulation as noted above including again histamine release.  Common drugs such as morphine or tubocurarine can displace histamine from granule storage sites.

                Pharmacodynamics-- Mechanism of Action -- Histamine mediates its effects by interacting with receptors.  In Receptor Types include H_1, H_2, H₃ and H₄ types.  We will focus our attention on the first two types (H_1, H₂)

Different histamine receptors (Latest)

Histamine receptor	Cell and tissue expression	Activated intracellular signals	G Proteins
HR1	Nerve cells, airway and vascular smooth muscles, endothelial cells, hepatocytes, epithelial cells, neutrophils, eosinophils, monocytes, DC, T and B cells.	Main signaling: enhanced Ca2+ Others: PhLC, PhLD, cGMP, PhLA, NFκ B	Gq/11
HR2	Nerve cells, airway and vascular smooth muscles, hepatocytes, chondrocytes, endothelial cells, epithelial cells, neutrophils, eosinophils, monocytes DC, T and B cells.	Main signaling: enhanced AMPc Others: Adenylate cyclase, c-Fos, c-Jun, PKC, p70S6K	G±S
HR3	Histaminergic neurons, eosinophils, DC, monocytes low expression in peripheral tissues. It inhibits histamine release and synthesis.	Main signaling: inhibition of cAMP Others: enhanced Ca2+, MAP kinase.	Gi/o
HR4	high expression on bone marrow and peripheral hematopoietic cells, eosinophils, neutrophils, DC, T cells, basophils, mast cells, low expression in nerve cells, hepatocytes peripheral tissues, spleen, thymus, lung, small intestine, colon and heart. It stimulates chemotaxis of eosinophils and mast cells.	Enhanced Ca2+, inhibition of cAMP	Gi/o

Eos, eosinophils; B cells, B lymphocytes; T cells, T lymphocytes; PKC, protein kinase C; cAMP, cyclic adenosine monophosphate; PhLC, phospholipase C; PhLD, phospholipase D; PhLA, phospholipase A; NF_B, nuclear transcription factor Kappa.

Adapted source: Jutel M, et al.

Receptor Subtype	Localization	Receptor coupling	Antagonists (partially selective)
H1	Endothelium, brain, smooth muscle	Receptor activation causes and increased IP3, DAG (diacylglycerol)  production	N/A
H2	Mast cells, gastric mucosa, cardiac muscle, brain	Receptor activation causes an  increase in cAMP production	Ranitidine (Zantac), cimetidine (Tagamet)
H3	Presynaptic: brain, mesenteric plexus (other neurons)	G protein coupled	N/A

Receptor subtypes --H₁, H₂, and H₃:

Intracellular G protein interactions

H₁:endothelial and smooth muscle cell localization; H₁ receptor activation causes can increase in phosphoinositol hydrolysis and an increase in intracellular calcium.

H₂: gastric mucosa, cardiac muscle cells, immune cell localization; H₂  receptor activation causes an increase in cyclic AMP.

H₃: primarily presynaptic; Activation causes a decrease in  transmitter release {transmitters: histamine, acetylcholine, norepinephrine, serotonin)

                Histamine is an important chemical messenger with stimulatory action (agonism) upon atleast four types of receptors, and with multiple regulatory functions in the nervous system, gastrointestinal tract and immune system. All histamine receptors transmit the corresponding extracellular signals via protein G systems coupled to intracellular second messengers. The activation of one of these messengers, specifically guanosine triphosphate (GTP) – binding protein, triggers a cascade of events at intracytoplasmic level that ultimately induce activation of the kappa nuclear factor (NF-κ). The latter is an important proinfl ammatory transcription factor that exerts its function by binding to the promoter regions of genes – thereby stimulating the synthesis of a large number of mediators.

Organ System Effects: Histamine

Cardiovascular:

                Systolic and diastolic blood pressure:  Vasodilation of arterioles and precapillary sphincters account for histamine's vasodilating effects. Vasodilation may be due in part to nitric oxide liberation.

                Following from the reduced blood pressure, the heart rate increases by autonomic reflex mechanisms and by direct action.

                Both H₁ and H₂ receptors involved in cardiovascular responses.

                Histamine-associated edema:H₁ receptor effects (postcapillary vessels)

                Increase in vessel permeability due to separation of endothelial cells, allowing transudation of fluid and molecules as large as small proteins.

                Responsible for urticaria (hives)

Endothelial cell separation: secondary to histamine-induced calcium influx causing intracellular actin/myosin-mediated contraction

Direct cardiac effects:

                Increased contractility (positive inotropism)

                Increased pacemaker rate (positive chronotropism)

Gastrointestinal tract:

                Histamine promotes intestinal smooth muscle contraction which is an H₁ receptor mediated effect

                Bronchiolar smooth muscle activation by histamine causes bronchoconstriction (H₁ receptor mediated )

                It is not surprising that inhaled histamine is a diagnostic, provocative test for bronchial hyperreactivity (asthma or cystic fibrosis)

Nerve Endings: Sensory nerve endings are stimulated by histamine, especially those endings which mediate pain and itching.

                These effects are H₁ receptor mediated effect and represent part of the local reaction to insect stings (urticarial responses)

Secretory tissue:

                Histamine cause the stimulation of release by secretory tissues.  For example, a significant increase in gastric acid secretion is caused by histamine.  Other examples of increased release include gastric pepsin.

Mechanism of Action: Considering the gastric parietal cells, histamine interacts with H₂ receptors and initiates a second messenger response which proceeds by

                (1)  Increasing adenylyl cyclase activity which

                (2)  Results in an increase in the second messenger, cyclic AMP which

                (3)  Causes an increase in intracellular calcium levels. 

                The increase in calcium triggers release. 

                This releasing characteristic of calcium applies broadly in physiology.

Histamine: Clinical Pharmacology-- Uses

Pulmonary Function: histamine aerosol may be used to test for bronchial hyperreactivity.

Toxicities include:

Flushing, hypotension, tachycardia, headache, bronchoconstriction, gastrointestinal disturbances.

Should not be given to asthmatics (except with extreme caution in pulmonary function testing).

Should not be given to patients with active ulcer disease or gastrointestinal hemorrhage.

Histamine Antagonists Introduction:

Physiologic antagonists: example -- epinephrine, agents that produce opposing effects, acting and different receptors

Release inhibitors: reduced mast cell degranulation: example: cromolyn and nedocromil

Receptor antagonists: selective blockade of histamine receptors (H₁, H₂, H₃ types)

H₁ receptor antagonists:

General properties:

H₁ antagonists include both first-generation and second-generation compounds

Both categories of agents are orally active and are metabolized by the liver using the cytochrome P450 drug-metabolizing system

The average duration of pharmacological action is about 4-6 hours

Meclizine (Antivert) and several second-generation drugs far longer acting, with effects lasting 12-24 hours. 

First-generation agents tend to be relatively more sedating and more likely than second-generation drugs to block autonomic receptors -- for example antimuscarinic effects (blockade of cholinergic, muscarinic-type receptors)

Second-generation agents   are relatively less sedating compared to the earlier first-generation agents and exhibit less CNS penetration, which accounts for reduced sedation. 

Some of the second-generation agents are metabolized by a cytochrome P450 type that  is inhibited by other drugs, such as the antifungal agent ketoconazole (Nizoral).

Therefore, plasma concentrations of certain second generation H₁ antagonists may increase, even the toxic levels, if the patients also taking drugs such as ketoconazole (Nizoral) or  erythromycin estolate (Ilosone).

Histamine Pharmacodynamics:

Histamine H₁ Receptor Blockade:

H₁ receptor blockers exhibit competitive antagonism for H₁ receptor sites whereas little effects at H₂ receptor sites and negligible effects of H₃ sites are observed.  

H₁ receptor blockers prevent bronchiolar or gastrointestinal smooth muscle constriction

H₁ receptor blockers do not completely prevent cardiovascular effects (some of these effects are mediated by H₂ receptors)

H₁ receptor blockers cannot affect increases in gastric acid secretion or mast cell histamine release because these effects are H₂ receptor site-mediated.

                [Until recently, it was believed that the H1 antihistamines were blockers (antagonists) of the H1 receptors. However, recently it has been shown that the H1 receptors may present two different conformational states: active and inactive. Histamine acts as an agonist by binding to and stabilizing the active conformation of the receptor, thereby deviating the balance in favor of an activation state. In the same way, the H1 antihistamines combine with and stabilize the inactive form of the receptor (inverse agonism), thereby deviating the balance in favor of the inactive receptor conformation. According to this model, the receptor is chronically “turned on” even in the absence of an agonist, and the degree of activation under conditions of equilibrium constitute its baseline activity level. Possibly some antihistamines that may be developed in future will behave as neutral antagonists, i.e., they may combine with both H1 receptor conformations without affecting baseline activity, but preventing the binding of an agonist (neutral agonism). The relative number of receptors occupied by histamine or by a given antihistamine depends on the relative concentrations of these substances in the proximity of the receptor.]

Receptor Type: Sites of Action

H₁           Endothelium, brain, smooth muscle

H₂                Mast cells, gastric mucosa, cardiac muscle, brain

Histamine Pharmacodynamics continued: Some important histamine promoted effects occur not true histamine's interaction with histamine receptors but by histamine interaction with other receptors.  Many of these interactions are responsible for "side effects" associated with antihistamines medications.  One prominent example is the side effect of sedation.  The side effect is the basis for antihistamine use as a sleep aid.

Non-Histamine Receptor-Mediated Effects

                First-generation H₁ receptor blockers cause effects mediated by many other receptor systems. These other effects in the mediated by  muscarinic cholinergic receptors, alpha adrenergic receptors, serotonergic receptors and local anesthetic receptor sites.

Sedation: Sedation is a common side effect of first-generation H₁ antagonists and provided the rationale for these agents to be used has sleep-aids, i.e. hypnotics.  These agents may produce a paradoxical excitement and children and toxic reactions can include stimulation, agitation, or even coma. The newer H₁ antagonists, by contrast, cause minimal or no sedation.

Anti-emetic/Antinausea: Some first-generation H₁ antagonists prevent motion sickness.  In this application these agent should be used as prophylaxis.  Therefore they should be taken well in advance of the activity which might be expected to induce motion-sickness.  

Anti-Parkinsonism:  Certain first-generation H₁ antagonists, because of their antimuscarinic properties, turn out to be effective in suppressing Parkinsonian symptoms which are side-effects of some antipsychotic medications.  The antipsychotic drugs involved here tend to be "first-generation" agents which have numerous neurological side effects.  The side effects are much less prevalent with newer antipsychotic drugs, such as olanzapine (Zyprexa) or risperidone (Risperdal).

Anticholinergic effects: Some first-generation H₁ antagonists have strong antimuscarinic actions (atropine-like effects).  Prominent anticholinergic effects include blurred vision (loss of accommodation) and urinary retention.  Therefore patients who may have benign prostatic hypertrophy may exhibit significant worsening of their clinical state due to antimuscarinic effects.  Probably benign prostatic hypertrophy would be one example of the syndrome for which there would be a relative contraindications for these drugs.

Alpha adrenergic blocking effects: Some first-generation H₁ antagonists block alpha adrenergic receptors. Alpha-adrenergic receptor blockade can cause orthostatic (postural) hypotension.  

Serotonergic blockade: Some first-generation H₁ antagonists block serotonin receptors

Local Anesthetic effects: Many first-generation H₁ antagonists are local anesthetics, exhibiting sodium channel blockade [similar in general to that caused by procaine (Novocain) and lidocaine (Xylocaine)].  For example, diphenhydramine (Benadryl) and promethazine (Pherergan) are more potent than procaine (Novocain) as a local anesthetic.

CHEMICAL CLASSIFICATION OF H1 ANTIHISTAMINES
Alkylamines	Ethanolamines	Ethylenediamines	Phenothiazines	Piperazines	Piperidines
Bromopheniramine Chlorpheniramine Dexchlorpheniramine Pheniramine Dimethindene  Triprolidine Acrivastine	Carbinoxamine Clemastine Dimenhydrinate Diphenhydramine Doxylamine Phenyltoxamine	Antazoline Pyrilamine Tripelenamine	Promethazine Mequitazine Trimepazine	Buclizine Cyclizine Meclizine Oxatomide Hydroxyzine Cetirizine Levocetirizine	Azatadine Cyproheptadine Ketotifen Loratadine Desloratadine Bilastine Ebastine Terfenadine Fexofenadine Levocabastine Mizolastine Rupatadine

Differences between first and second-generation H1 antihistamines
First-generation H1 antihistamines	Second-generation H1 antihistamines
Usually administered in three to four daily doses	Usually administered once or twice a day
Cross the blood-brain barrier (lipophilicity, low molecular weight, lack of recognition by the P-glycoprotein efflux pump	Do not cross the blood-brain barrier(lipophobicity, high molecular weight, recognition by the P-glycoprotein efflux pump)
Potentially cause side-effects (sedation /  hyperactivity / insomnia / convulsions)	Do not cause relevant side-effects (sedation / fatigue / hyperactivity / convulsions), in the absence of drug interactions
Case reports of toxicity are regularly published	No reports of serious toxicity
No randomized, double-blind, placebo-controlled in children	Some randomized, double-blind, placebo trials controlled studies in children
Lethal dose identified for infants/young children	Do not cause fatality in overdose

Adapted source: de Benedictis FM, et al.

[Because first-generation H1-antihistamines derive from the same chemical stem from which cholinergic muscarinic antagonists, tranquilizers, antipsychotics, and antihypertensive agents were also developed, they have poor receptor selectivity and often interact with receptors of other biologically active amines causing antimuscarinic, anti-adrenergic, and antiserotonin effects. But perhaps their greatest drawback is their ability to cross the blood-brain barrier and interfere with histaminergic transmission.]

[A major advance in antihistamine development occurred in the 1980s with the introduction of second-generation H1-antihistamines, which are minimally sedating or nonsedating because of their limited penetration of the blood brain barrier. In addition, these drugs are highly selective for the histamine H1-receptor and have no anticholinergic effects.]

Clinical Uses: H₁ Histamine Receptor Blockers

Allergic Reactions:

                The pharmacological objective in the use of these medications is to treat or prevent symptoms of allergic reaction.

                H₁ histamine receptor blockers are drugs of choice to treat  allergic rhinitis and urticaria.  In both cases, histamine is the primary mediator of the symptoms.

                By contrast, in asthma their multiple mediators and   H₁ histamine receptor blockers are ineffective.

                Angioedema (hives) may be initiated by histamine but are maintained by bradykinins.  In this clinical setting H₁ histamine receptor blockers are also ineffective.

                For atopic dermatitis, diphenhydramine which is a H₁ histamine receptor blocker proves effective in control of itching and for sedation.

                For allergic conditions, an example being hay fever, the H₁ histamine receptor blockers are effective for symptomatic relief.  The goal is to minimize sedating effects while retaining beneficial symptomatic relief.

                The Second-generation H₁ histamine receptor blockers, for example terfenadine (Seldane) or astemizole (Hismanal) are beneficial because they exhibit minimal sedation while being effective in management of allergic rhinitis and chronic urticaria.  At present, these medications tend to be more expensive than first-generation histamine receptor H₁ antagonists.  

Allergic Rhinitis

                H₁ antihistamines are 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 -- the latter which is seen more commonly with oral alpha adrenergic agonists.

                Oral α-adrenergic agonists may be useful in diminishing antihistamine-mediated sedation while improving antihistamine efficacy in relieving congestion.  However, there is a concern that these agents due to their potentially hypertensive effects, may precipitate adverse cardiovascular effects, such as stroke.  Recently, there 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:

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

                Avoidance of offending allergen

                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).

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

                Management failure: immunotherapy

Motion Sickness:

                Scopolamine and certain first-generation H₁ blockers are among the most effective drugs for motion sickness prevention.

                Diphenhydramine and promethazine  are the H₁ blockers with the greatest effectiveness.

                Cyclizine (Marezine) and  meclizine are also effective agents and are less sedating than those above. 

Nausea and Vomiting (Pregnancy)

                H₁ blockers are not recommended for use in management of nausea and vomiting associate with pregnancy because:

                Difficulty in assessment of possible birth defects associated with certain H₁ (benedictin) antagonists and known teratogenic effects of others (e.g., doxylamine) in animal models.

H₁ blockers: Toxicity 

Uncommon toxic effects following systemic demonstration:

                excessive excitation and convulsions in children

                orthostatic (postural) hypotension

Allergic responses

                Drug allergy -- relatively common, following topical use of H₁ antagonists

                First-generation overdosage: similar to atropine overdosage

                Second-generation overdosage: may induce cardiac arrhythmias

Drug-Drug Interactions

Second-generation H₁ blockers:

Myocardial toxicity:

                Toxicity follows combination of terfenadine or astemizole combined with ketoconazole (Nizoral), itraconazole (Sporanox), or macrolide antibiotics (e.g.,erythromycin) because-

Q-T (ECG) prolongation

Ventricular arrhythmias which may be potentially fatal.

Terfenadine (Seldane)/astemizole (Hismanal) are contraindicated in patients taking ketoconazole (Nizoral), itraconazole (Sporanox), macrolide antibiotics, and patients with diminished liver function.

patients taking ketoconazole (Nizoral), itraconazole (Sporanox), macrolide antibiotics, and patients with diminished 

Fexofenadine (Allegra), a metabolite of terfenadine (Seldane), is safer. 

H₂ Receptor Antagonists

Introduction-- overview

                H₂ receptor antagonists inhibit histamine-induced stomach acid secretion.

                Interest in these drugs: based on the high incidence of peptic ulcer disease (and related gastrointestinal disease).

                H₂ receptor antagonists: frequently prescribed, available as over-the-counter preparations in some dosage forms.

Pharmacology of H₂ receptor blockers:

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

Mechanism of action: H₂ Receptor Antagonists involves selective competitive antagonism at H₂ receptor sites.

Effects on organ systems

Acid secretion and gastric motility

                The most important action is a reduction in gastric acid secretion due to H₂ receptor blockade.

                Blockade of gastric acid secretion in the presence of H₂ receptor blockade following histamine, gastrin, cholinomimetics (acetylcholine-like drugs such as bethanechol (Urecholine)) and  vagal stimulation.

                Reduced gastric acid volume.

                Decreased pepsin concentration.

Other effects: unrelated to H₂ receptor blockade

Cimetadine (to lesser degree ranitidine; not famotidine or nizatidine): inhibits cytochrome P450 microsomal drug metabolizing system

Cimetadine and ranitidine inhibit renal clearance of basic drugs that use renal secretory transport systems

Cimetadine, by binding to androgen receptors, produce antiandrogen effects

Clinical Uses: H₂ Receptor Antagonists

Peptic Ulcer Duodenal Disease:

                H₂ receptor antagonists (low toxicity) by reducing gastric acidity has significantly advanced treatment of peptic ulcer disease

                Other agents that reduce gastric acid include:

Antimuscarinic drugs (at high dosages required, side effects are significant).

Antacids which require frequent dosing and may be associated therefore with  poor patient compliance.

Omeprazole (Prilosec) and lansoprazole (Prevacid) (proton pump blockers and) are very effective in reducing gastric acid by directly inhibiting an enzyme-pump which produce hydrogen ions (protons) in the stomach thus decreasing pH.

Sucralfate (Carafate) (a coating agent)  promotes healing

Antibiotics are prominent in current therapy because of the importance of H. pylori in gastric ulcer disease.  

Gastric Ulcer:

H₂ receptor antagonists reduce symptoms and promote healing for benign gastric ulcers

Gastroesophageal Reflux Disorder (erosive esophagitis)

H₂ receptor antagonists, at higher dosages than for management of peptic or gastric ulcer disease,are used as one component of treatment. Proton pump blockers (e.g. omeprazole) are usually also administered.

Hypersecretory Disease:

Zollinger-Ellison syndrome is associated with acid hypersecretion which is caused by gastrin-secreting tumor.  This disorder is often fatal; however, H₂ receptor antagonists often control symptoms.

Systemic mastocytosis and multiple endocrine adenomas are hypersecretory conditions in which H₂ receptor antagonists often control symptoms.

Toxicity: H₂ receptor antagonists:

Overview: these agents are generally well tolerated.  The most common side effects include diarrhea, dizziness, somnolence, headache and rash.

Cimetidine (Tagamet) has the most adverse effects whereas, nizatidine (Axid) has the fewest adverse effects.

CNS effects are uncommon.  However, in the elderly confusional of states, delirium, and slurred speech may occur.  These effects are often associate with cimetidine (Tagamet) and are unusual with ranitidine (Zantac).

Endocrine effects are also relatively uncommon.  However cimetidine (Tagamet) does exhibit antiantherogenic effects because the drug blinds to androgen receptors and therefore can cause gynecomastia (men) and galactorrhea (women).

Endocrine effects not associated with famotidine, ranitidine, nizatidine

Other uncommon side effects include blood dyscrasias [cimetidine (Tagamet): granulocytopenia, thrombocytopenia, neutropenia, aplastic anemia which is extremely rare], hepatotoxicity  with reversible cholestatic effects, reversible hepatitis, liver enzyme test abnormalities.

Use in pregnancy:

Harmful effects on the fetus have not been observed when H₂ blockers are prescribed to pregnant women even though  H₂ blockers are secreted into breast milk and may affect nursing infants.

The general rule, however is that since these drugs across the placenta, they should only be prescribed when absolutely required.

Since these drugs to cross the placenta, the drugs should only be prescribed when absolutely required. 

Drug-drug Interactions: 

Cimetidine (Tagamet) is the prominent agent in this category for drug-drug interactions. 

This observation occurs because cimetidine (Tagamet) is particularly effective in inhibiting the cytochrome P450 drug metabolizing system therefore influencing the metabolism of other drugs. 

Additionally, cimetidine (Tagamet) reduces liver blood flow and the combination of effects on blood flow and metabolism tend to decrease the clearance (removal from the body) of certain drugs.

Cimetidine inhibits clearance of these agents (partial listing):
Warfarin	Phenytoin (Dilantin)	Propranolol (Inderal)	Metoprolol (Lopressor)	Labetalol (Trandate, Normodyne)
Quinidine gluconate (Quinaglute, Quinalan)	Caffeine	Lidocaine (Xylocaine)	Theophylline	Alprazolam (Xanax)
Triazolam (Halcion)	Chlordiazepoxide (Librium)	Carbamazepine (Tegretol)	Ethanol	Tricyclic antidepressants
Metronidazole (Flagyl)	Calcium channel blockers	Sulfonylureas	Diazepam (Valium)	Flurazepam (Dalmane)