Chapter: Pharmacology of Histamine

1. Introduction/Overview

Histamine, chemically known as 2-(4-imidazolyl)ethylamine, is a biogenic amine with profound physiological and pathological roles. It functions as a critical mediator in immediate hypersensitivity reactions, gastric acid secretion, and neurotransmission within the central nervous system. The clinical relevance of understanding histamine pharmacology is paramount, as drugs modulating its actions—antihistamines—are among the most widely prescribed therapeutic agents globally. These compounds are essential for managing allergic conditions, gastrointestinal disorders, and certain forms of vertigo. Mastery of this topic provides a foundation for understanding autonomic pharmacology, immunopharmacology, and the management of a broad spectrum of clinical conditions.

Learning Objectives

• Describe the synthesis, storage, and release of endogenous histamine from mast cells and basophils.
• Classify the four known histamine receptor subtypes (H₁ to H₄) based on their tissue distribution, signaling mechanisms, and physiological roles.
• Explain the mechanism of action, pharmacokinetic profiles, therapeutic uses, and adverse effect spectra of H₁ and H₂ receptor antagonists.
• Compare and contrast first-generation (sedating) and second-generation (non-sedating) H₁ receptor antagonists.
• Apply knowledge of histamine pharmacology to clinical scenarios involving allergy, anaphylaxis, gastric ulcer disease, and motion sickness.

2. Classification

Drugs affecting the histaminergic system are classified primarily based on their interaction with specific receptor subtypes. The major therapeutic classes are receptor antagonists, with agonists having limited clinical use.

2.1. Histamine Receptor Agonists

These drugs mimic the action of endogenous histamine. Their use is largely restricted to diagnostic procedures.

• Histamine phosphate: Used in pulmonary function testing and diagnostic challenge for pheochromocytoma.
• Betahistine: A weak H₁ agonist and H₃ antagonist used in some countries for Ménière’s disease.

2.2. Histamine Receptor Antagonists (Antihistamines)

This is the principal therapeutic class, subdivided by receptor selectivity.

• H₁ Receptor Antagonists (H₁ Antihistamines)
  • First-generation (Classical/Sedating): Ethanolamines (e.g., diphenhydramine), Alkylamines (e.g., chlorpheniramine), Piperazines (e.g., hydroxyzine), Phenothiazines (e.g., promethazine). Characterized by high lipophilicity and significant central nervous system penetration.
  • Second-generation (Non-Sedating/Low-Sedating): Piperidines (e.g., fexofenadine, loratadine), Phthalazinones (e.g., azelastine), and others (e.g., cetirizine, levocetirizine). Designed to be hydrophilic and substrate for P-glycoprotein efflux pumps, minimizing CNS entry.
• H₂ Receptor Antagonists (H₂ Blockers)
  • Chemically classified as substituted heterocycles: Cimetidine (imidazole), Ranitidine (furan), Famotidine (thiazole), Nizatidine (thiazole).
• H₃ Receptor Antagonists/Inverse Agonists
  • Pitolisant is approved for narcolepsy. Others are under investigation for cognitive disorders.
• H₄ Receptor Antagonists
  • Primarily in preclinical and early clinical development for inflammatory and allergic diseases.

2.3. Mast Cell Stabilizers

Although not receptor antagonists, these drugs (e.g., cromolyn sodium, nedocromil) prevent degranulation of mast cells, thereby inhibiting the release of histamine and other mediators. They are prophylactic agents.

3. Mechanism of Action

The actions of histamine and drugs that modulate its effects are mediated through four G-protein-coupled receptor (GPCR) subtypes: H₁, H₂, H₃, and H₄. Each couples to distinct intracellular signaling pathways.

3.1. Histamine Receptors and Signal Transduction

H₁ Receptors: These receptors are predominantly expressed on smooth muscle cells (bronchial, vascular, intestinal), vascular endothelial cells, sensory nerve endings, and in the central nervous system. Activation of H₁ receptors couples to G_q/11 proteins, leading to phospholipase C (PLC) activation. PLC hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP₂) to generate inositol trisphosphate (IP₃) and diacylglycerol (DAG). IP₃ mobilizes intracellular calcium (Ca²⁺) from the endoplasmic reticulum, while DAG activates protein kinase C (PKC). The rise in intracellular Ca²⁺ is responsible for smooth muscle contraction (bronchoconstriction, intestinal cramps), increased vascular permeability, and sensory nerve activation (pruritus, pain). In the CNS, H₁ receptor activation is generally excitatory and involved in wakefulness.

H₂ Receptors: Located primarily on gastric parietal cells, cardiac myocytes, vascular smooth muscle, and some immune cells. These receptors signal via G_s proteins, which stimulate adenylyl cyclase to increase intracellular cyclic adenosine monophosphate (cAMP). Elevated cAMP activates protein kinase A (PKA), which phosphorylates target proteins. In parietal cells, this leads to activation of the H⁺/K⁺ ATPase (proton pump), stimulating gastric acid secretion. In the heart, H₂ receptor activation produces positive chronotropic and inotropic effects. It may also cause vasodilation in some vascular beds.

H₃ Receptors: These are predominantly presynaptic autoreceptors and heteroreceptors found in the central and peripheral nervous systems. They couple to G_i/o proteins, inhibiting adenylyl cyclase and reducing cAMP formation. Their activation inhibits the release of histamine (autoreceptor function) as well as other neurotransmitters like acetylcholine, norepinephrine, and serotonin. This modulates arousal, cognition, appetite, and vestibular function.

H₄ Receptors: Expressed mainly on hematopoietic cells such as eosinophils, mast cells, basophils, and T-cells. H₄ receptors also signal through G_i/o proteins, leading to inhibition of adenylyl cyclase and mobilization of intracellular calcium. They play a key role in chemotaxis of immune cells and the amplification of inflammatory and allergic responses.

3.2. Mechanism of Antihistamines

Most clinically used H₁ and H₂ antagonists are inverse agonists rather than simple competitive antagonists. In the two-state model of receptor activation, receptors exist in an equilibrium between inactive (R) and active (R*) conformations. Histamine, an agonist, stabilizes the R* state. Inverse agonists possess higher affinity for the R state, shifting the equilibrium away from R* and producing a constitutive reduction in basal receptor signaling. They competitively inhibit the binding of histamine, but their effect may be evident even in the absence of agonist.

The sedative effect of first-generation H₁ antagonists is attributed to their blockade of central H₁ receptors in the tuberomammillary nucleus of the hypothalamus, a key wake-promoting region. Their additional antimuscarinic, anti-α-adrenergic, and local anesthetic properties are due to interactions with other receptor systems at high concentrations.

H₂ antagonists bind reversibly to the H₂ receptor on the basolateral membrane of the parietal cell, preventing histamine-stimulated acid secretion. They are most effective against acid secretion stimulated by histamine, gastrin, and vagal input, as all these pathways converge on the cAMP-dependent activation of the proton pump.

4. Pharmacokinetics

The pharmacokinetic properties of antihistamines vary significantly between classes and individual agents, influencing their dosing regimens, onset of action, and potential for drug interactions.

4.1. H₁ Receptor Antagonists

Absorption: Most H₁ antagonists are well absorbed after oral administration, with peak plasma concentrations (C_max) typically achieved within 1-3 hours. Some, like diphenhydramine and promethazine, are also available for parenteral (intramuscular or intravenous) administration.

Distribution: Distribution characteristics define the key difference between generations. First-generation agents (e.g., diphenhydramine, chlorpheniramine) are highly lipophilic and readily cross the blood-brain barrier, leading to significant CNS effects. They also distribute widely into tissues. Second-generation agents (e.g., fexofenadine, loratadine, cetirizine) are designed to be more hydrophilic. Furthermore, many (like fexofenadine) are substrates for the P-glycoprotein efflux transporter at the blood-brain barrier, which actively pumps them out of the CNS, minimizing sedation. Volume of distribution (V_d) is generally large (>1 L/kg).

Metabolism: Hepatic metabolism via the cytochrome P450 (CYP) system is extensive for most H₁ antagonists. First-generation drugs and several second-generation drugs (e.g., loratadine, desloratadine, rupatadine) are metabolized primarily by CYP3A4 and, to a lesser extent, CYP2D6. This creates a potential for numerous drug interactions. Fexofenadine is an exception, undergoing minimal hepatic metabolism. Cetirizine is metabolized to a limited extent by non-CYP pathways. Active metabolites are common; for instance, loratadine is metabolized to desloratadine, and hydroxyzine is metabolized to cetirizine, both of which are active.

Excretion: Elimination occurs via both renal and biliary routes. The elimination half-life (t_1/2) varies:

• First-generation: Generally short (4-8 hours), necessitating multiple daily doses (e.g., diphenhydramine t_1/2 ≈ 4-8 hours).
• Second-generation: Generally longer (12-24 hours), allowing once-daily dosing (e.g., fexofenadine t_1/2 ≈ 14 hours, cetirizine t_1/2 ≈ 8-10 hours, loratadine t_1/2 ≈ 12-15 hours).

4.2. H₂ Receptor Antagonists

Absorption: Orally administered H₂ blockers are rapidly absorbed, with bioavailability reduced by 30-50% for some agents due to first-pass metabolism. Food may delay absorption but does not significantly reduce overall bioavailability.

Distribution: These drugs distribute widely throughout the body, including into the CNS to a limited degree. Protein binding is moderate (15-35%).

Metabolism: Hepatic metabolism is significant for cimetidine, ranitidine, and nizatidine. Famotidine undergoes minimal metabolism. Cimetidine is notable for its potent inhibition of several CYP isoenzymes (particularly CYP1A2, CYP2C9, CYP2D6, CYP3A4), mediated by binding to the heme iron of the cytochrome. Ranitidine is a weak CYP inhibitor. Nizatidine and famotidine have negligible effects on CYP enzymes.

Excretion: Renal excretion is the primary route for unchanged drug and metabolites. The t_1/2 is relatively short (1-3 hours), but the duration of antisecretory action (6-12 hours) often exceeds the plasma t_1/2 due to prolonged binding to the parietal cell receptor. Dosage adjustment is required in renal impairment.

5. Therapeutic Uses/Clinical Applications

Drugs modulating histamine pathways have diverse clinical applications, primarily targeting the consequences of H₁ and H₂ receptor activation.

5.1. Therapeutic Uses of H₁ Antagonists

• Allergic Diseases: This is the primary indication. H₁ antagonists effectively relieve symptoms of seasonal and perennial allergic rhinitis (sneezing, rhinorrhea, nasal and ocular pruritus) and allergic conjunctivitis. They are also first-line for acute and chronic urticaria (hives) and angioedema (excluding laryngeal edema, which requires epinephrine). Second-generation agents are preferred for chronic management due to their superior safety profile.
• Anaphylaxis and Acute Allergic Reactions: First-generation parenteral H₁ antagonists (e.g., diphenhydramine IV/IM) are used as adjunctive therapy to epinephrine and corticosteroids. They help control cutaneous symptoms (urticaria, pruritus) but do not reverse hypotension or bronchospasm.
• Motion Sickness and Vestibular Disorders: Certain first-generation H₁ antagonists with antimuscarinic properties (e.g., dimenhydrinate, meclizine, promethazine) are effective prophylactic agents for motion sickness. They are believed to act on vestibular nuclei and the chemoreceptor trigger zone.
• Insomnia and Sedation: The sedative side effect of first-generation agents like diphenhydramine and doxylamine is exploited for the short-term management of insomnia. However, tolerance to the sedative effect develops rapidly, and anticholinergic side effects limit long-term use, especially in the elderly.
• Antiemetic: Some H₁ antagonists (e.g., promethazine, cyclizine) are used to prevent and treat nausea and vomiting, particularly in postoperative settings, pregnancy (hyperemesis gravidarum), and vestibular-related nausea.
• Parkinsonism and Dystonic Reactions: Diphenhydramine, due to its central antimuscarinic action, can be used to treat acute dystonic reactions induced by antipsychotic drugs and as an adjunct in Parkinson’s disease.
• Upper Respiratory Infections: Often included in over-the-counter “cold and flu” preparations for their anticholinergic (drying) effect on respiratory secretions and mild sedative properties.

5.2. Therapeutic Uses of H₂ Antagonists

• Peptic Ulcer Disease (PUD): Used to promote healing of gastric and duodenal ulcers. Their role has diminished with the advent of proton pump inhibitors (PPIs) but they remain an option.
• Gastroesophageal Reflux Disease (GERD): Provide symptomatic relief (“heartburn”) and healing of erosive esophagitis, though PPIs are more effective for moderate to severe disease.
• Hypersecretory Conditions: Such as Zollinger-Ellison syndrome (often in combination with PPIs) and systemic mastocytosis.
• Stress Ulcer Prophylaxis: In critically ill patients, though PPIs are often preferred.
• Dyspepsia: For the relief of episodic, non-ulcer dyspepsia.

5.3. Therapeutic Uses of Other Agents

H₃ Receptor Antagonists: Pitolisant is approved for the treatment of narcolepsy with or without cataplexy. It enhances histaminergic tone in the CNS, promoting wakefulness.

Mast Cell Stabilizers: Cromolyn sodium is used prophylactically for allergic rhinitis, allergic conjunctivitis, and asthma, and for mastocytosis. It must be administered regularly to prevent mediator release.

6. Adverse Effects

The adverse effect profiles of antihistamines are closely linked to their receptor selectivity and pharmacokinetic properties.

6.1. Adverse Effects of H₁ Antagonists

First-Generation (Sedating) Agents:

• Central Nervous System Effects: Sedation, drowsiness, fatigue, impaired cognitive and psychomotor performance are common. Paradoxical excitation (nervousness, insomnia) can occur, particularly in children and the elderly. These effects pose significant risks for driving and operating machinery.
• Antimuscarinic (Atropine-like) Effects: Dry mouth, dry eyes, blurred vision, urinary retention, constipation, and tachycardia. These can be particularly problematic for elderly patients and those with glaucoma or prostatic hyperplasia.
• Gastrointestinal Effects: Nausea, vomiting, epigastric distress, and changes in appetite.
• Cardiovascular Effects: Postural hypotension, palpitations, and reflex tachycardia may occur, especially with high doses or parenteral administration. Some agents (e.g., astemizole, terfenadine – now withdrawn) were associated with life-threatening ventricular arrhythmias (torsades de pointes) due to blockade of cardiac potassium channels (hERG), particularly when metabolism was inhibited (e.g., by CYP3A4 inhibitors) leading to high plasma concentrations.
• Weight Gain: Associated with some agents like cyproheptadine.

Second-Generation (Non-Sedating) Agents: These drugs have a markedly improved safety profile regarding CNS and anticholinergic effects.

• Headache and mild gastrointestinal upset (e.g., nausea, dry mouth) are the most frequently reported side effects.
• Sedation is uncommon but may occur at high doses or in susceptible individuals (e.g., cetirizine has a slightly higher incidence of sedation than fexofenadine or loratadine).
• The cardiotoxic risk seen with withdrawn agents is not a class effect of second-generation drugs. Fexofenadine, loratadine, and desloratadine at therapeutic doses have no significant hERG channel blockade.

6.2. Adverse Effects of H₂ Antagonists

These are generally well-tolerated.

• Gastrointestinal: Diarrhea, constipation, nausea, vomiting.
• CNS Effects: Headache, dizziness, confusion, hallucinations (more common with high-dose intravenous cimetidine in elderly or critically ill patients).
• Endocrine Effects: Cimetidine has antiandrogenic effects due to binding to androgen receptors, which can cause gynecomastia, impotence, and loss of libido with prolonged high-dose use. This is rare with other H₂ blockers.
• Hematologic Effects: Rare blood dyscrasias (neutropenia, thrombocytopenia, aplastic anemia) have been reported, particularly with cimetidine.
• Cardiovascular: Bradycardia and hypotension have been noted with rapid intravenous infusion.
• Hepatic: Mild, reversible elevations in serum transaminases.

Black Box Warnings: Ranitidine was withdrawn from many markets due to the discovery of N-nitrosodimethylamine (NDMA), a probable human carcinogen, as a contaminant that could increase over time. This is not a pharmacologic class effect but a product-specific issue related to the molecule’s instability.

7. Drug Interactions

Significant drug interactions occur primarily through pharmacokinetic mechanisms, notably inhibition of hepatic cytochrome P450 enzymes.

7.1. H₁ Antagonist Interactions

• CNS Depressants: First-generation H₁ antagonists potentiate the sedative effects of alcohol, benzodiazepines, opioids, barbiturates, and other sedative-hypnotics, leading to dangerous impairment.
• CYP3A4 Inhibitors: Drugs like ketoconazole, itraconazole, erythromycin, clarithromycin, and HIV protease inhibitors can inhibit the metabolism of certain H₁ antagonists (e.g., loratadine), potentially increasing their plasma levels. While the risk of arrhythmia with modern second-generation agents is low, increased side effects may occur.
• Anticholinergic Drugs: Concurrent use with tricyclic antidepressants, antipsychotics, and other drugs with antimuscarinic activity can lead to additive anticholinergic toxicity (severe dry mouth, urinary retention, ileus, confusion).
• Monoamine Oxidase Inhibitors (MAOIs): May prolong and intensify the anticholinergic effects of H₁ antagonists.

7.2. H₂ Antagonist Interactions (Primarily Cimetidine)

Cimetidine is a major perpetrator of drug interactions due to its non-selective inhibition of CYP450 enzymes and reduction of hepatic blood flow. It can increase the plasma concentrations and effects of numerous drugs, including:

• Warfarin: Increased risk of bleeding.
• Phenytoin, carbamazepine, valproic acid: Increased risk of neurotoxicity.
• Theophylline: Risk of theophylline toxicity (nausea, seizures, arrhythmias).
• Benzodiazepines metabolized by oxidation (e.g., diazepam, alprazolam): Increased sedation.
• Lidocaine, quinidine, procainamide: Increased risk of cardiotoxicity.
• Metronidazole, tricyclic antidepressants, SSRIs (e.g., sertraline), calcium channel blockers: Potential for increased effects.
• Drugs requiring gastric acidity for absorption (e.g., ketoconazole, itraconazole, iron salts, atazanavir): H₂ antagonists may decrease their bioavailability by raising gastric pH.

Ranitidine is a weak inhibitor, while famotidine and nizatidine have negligible effects on drug metabolism.

7.3. Contraindications

• H₁ Antagonists: Contraindicated in patients with known hypersensitivity. First-generation agents are relatively contraindicated in narrow-angle glaucoma, symptomatic prostatic hypertrophy, bladder neck obstruction, severe hypertension, and peptic ulcer with pyloric obstruction. They should be used with extreme caution in the elderly.
• H₂ Antagonists: Hypersensitivity is a contraindication. Use with caution in patients with porphyria, as some agents may precipitate attacks.

8. Special Considerations

8.1. Pregnancy and Lactation

Pregnancy: Drug selection requires careful risk-benefit analysis. First-generation agents like chlorpheniramine and tripelennamine have a long history of use and are often considered first-line for allergies in pregnancy (FDA Category B). Some second-generation agents like loratadine and cetirizine are also considered low risk based on available data, though experience is more limited. Sedating agents may affect neonatal behavior if used near delivery. For nausea, doxylamine (in combination with pyridoxine) is specifically approved for morning sickness.

Lactation: Most antihistamines are excreted in breast milk. First-generation agents may cause sedation, irritability, or feeding problems in the infant. Second-generation agents like loratadine and cetirizine, which have low milk-to-plasma ratios and are poorly absorbed orally by the infant, are generally preferred if treatment is necessary.

8.2. Pediatric and Geriatric Considerations

Pediatrics: Children may exhibit paradoxical excitation (hyperactivity, insomnia) with first-generation H₁ antagonists. Second-generation agents are preferred for chronic allergic conditions due to better safety and lack of cognitive impairment. Dosage must be adjusted by weight or age. The use of over-the-counter cough and cold preparations containing antihistamines in children under 4-6 years is generally discouraged due to lack of efficacy and risk of serious side effects.

Geriatrics: Older adults are exquisitely sensitive to the adverse effects of first-generation H₁ antagonists. The anticholinergic effects can precipitate or worsen cognitive impairment, delirium, constipation, urinary retention, dry mouth leading to dental problems, and postural hypotension with risk of falls. These drugs are strongly implicated in the “Beers Criteria” for potentially inappropriate medication use in older adults. Second-generation H₁ antagonists should be used at the lowest effective dose. H₂ antagonists, especially cimetidine, may cause confusion; dosage reduction is often required due to age-related decline in renal function.

8.3. Renal and Hepatic Impairment

Renal Impairment: Many antihistamines and their active metabolites are renally excreted. For drugs like cetirizine, levocetirizine, and most H₂ antagonists (famotidine being particularly notable), dosage reduction is necessary in moderate to severe renal impairment (creatinine clearance < 30-50 mL/min) to prevent accumulation and toxicity. Fexofenadine dose may also need adjustment.

Hepatic Impairment: For H₁ and H₂ antagonists that undergo extensive hepatic metabolism (e.g., loratadine, many first-generation agents, cimetidine, ranitidine), clearance may be significantly reduced in cirrhosis or severe hepatic disease, necessitating dose reduction or avoidance. Drugs with minimal hepatic metabolism (e.g., fexofenadine, cetirizine, famotidine) may be preferred in such patients.

9. Summary/Key Points

• Histamine exerts its effects through four GPCR subtypes (H₁-H₄). H₁ activation mediates allergic and inflammatory responses; H₂ activation stimulates gastric acid secretion; H₃ acts as an autoreceptor; H₄ modulates immune cell function.
• H₁ receptor antagonists are inverse agonists classified into sedating first-generation and non-sedating second-generation agents. The key difference is CNS penetration, determined by lipophilicity and P-glycoprotein substrate status.
• H₂ receptor antagonists competitively inhibit gastric acid secretion and are used for PUD, GERD, and hypersecretory states. Cimetidine has significant CYP450 inhibition drug interaction potential.
• Therapeutic uses of H₁ antagonists extend beyond allergy to include motion sickness, insomnia, antiemesis, and Parkinsonism. H₂ antagonists are primarily used for acid-related disorders.
• Adverse effects of first-generation H₁ antagonists include sedation, antimuscarinic effects, and impaired performance. Second-generation agents are largely free of these effects. H₂ antagonists are generally well-tolerated, with cimetidine having unique endocrine effects.
• Special caution is required in the elderly and those with renal/hepatic impairment. First-generation agents are generally avoided in the elderly due to high anticholinergic burden.

Clinical Pearls

• For chronic allergic rhinitis or urticaria, a second-generation H₁ antagonist (e.g., loratadine, fexofenadine, cetirizine) is the first-line choice due to superior safety and once-daily dosing.
• In anaphylaxis, parenteral H₁ antagonists are an adjunct to, not a replacement for, intramuscular epinephrine.
• Avoid first-generation H₁ antagonists in the elderly; consider them a last resort due to risks of falls, confusion, and anticholinergic toxicity.
• When prescribing a drug with a narrow therapeutic index (e.g., warfarin, phenytoin, theophylline), avoid concomitant use of cimetidine. Famotidine or nizatidine are safer H₂ blocker alternatives from a drug interaction perspective.
• Recognize that “non-drowsy” labels on over-the-counter antihistamines refer to second-generation agents, but individual susceptibility to sedation still varies.

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