Medical Pharmacology Chapter 21:  Histamine

Histamine

• 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

• 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 an 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.

  • Receptor Types  include  H_1, H_2,and H₃ types.  We will focus our attention on the first two types (H_1,H₂)

• Receptor subtypes --H₁, H₂, and H₃

  • Intracellular G protein interactions

• H₁endothelial 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)

     

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:

    1. Increased contractility (positive inotropism)

    2. 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.

• • 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/Anti-nausea:

    • 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.

    • α-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

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 there are multiple mediators and H₁ histamine receptor blockers are ineffective.

  • Angioedema (hives) may be initiated by histamine but are maintained by bradykinins.  I

    • n 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. 

    • These medications tend to be more expensive than first-generation histamine receptor H₁ antagonists.  

Clinical Uses: H₁ Histamine Receptor Blockers continued

• 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:

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:

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

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

      3. 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.

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.