Antihistamines

Histamine is a biologically active substance that potentiates the inflammatory and immune responses of the body, regulates physiological function in the gut, and acts as a neurotransmitter. Antihistamines are drugs that antagonize these effects by blocking or inhibiting histamine receptors (H receptors). They are categorized as either H1 or H2 according to the type of H receptor targeted. H1 antihistamines are mostly used to treat allergic reactions and mast cell-mediated disorders. This subtype is further divided into two generations. While first-generation H1 antihistamines have a central effect and, thus, are also used as sedatives, second-generation H1 antihistamines have less central effects and are primarily used as antiallergic drugs. H2 antihistamines are indicated primarily for gastric reflux disease because they reduce the production of stomach acid by reversibly blocking the H2 histamine receptors in the parietal cells of the gastric mucosa. Most H1 and H2 antihistamines are contraindicated during pregnancy and childhood. First-generation H1 antihistamines are specifically contraindicated in angle-closure glaucoma and pyloric stenosis.

Antihistamine agents

Effects of antihistamine agents ^[2]

References:^[3]

Examples

• First-generation antihistamines
  • Diphenhydramine
  • Meclizine
  • Doxylamine
  • Promethazine
  • Clemastine
  • Dimenhydrinate
  • Brompheniramine
  • Hydroxyzine
  • Chlorpheniramine
  • Dimetindene
  • Cyproheptadine
• Second-generation antihistamines
  • Loratadine
  • Desloratadine
  • Cetirizine
  • Levocetirizine
  • Azelastine
  • Fexofenadine
  • Ketotifen

General physiology

• Target: histamine H1 receptors
• Location of H1 receptors
  • Smooth muscles (especially bronchial and nasopharyngeal lining)
  • Vascular endothelial cell surfaces
  • Central nervous system
  • Heart
• Histamine effects on H1 receptors
  • ↑ Capillary dilation and permeability → hypotension and edema
  • ↑ Bronchiolar smooth muscle contraction (via IP3 and DAG release) → bronchoconstriction
  • ↑ Nasal and bronchial mucus production
  • ↑ Activation of peripheral nociceptive receptors → ↑ pain and pruritus
  • ↓ Conduction in AV node

Effects

• Competitive, reversible antagonism or inverse agonism of histamine H1 receptors (G_q protein-coupled receptor)
  • Inhibition of increased vascular permeability
  • Inhibition of allergic bronchial constriction
  • Central action: sedation (especially first-generation antihistamines due to crossing of blood-brain barrier)

Side effects

• Sedation (significantly less pronounced in second-generation antihistamines due to their limited CNS activity)
• Anticholinergic effects, e.g., dry mouth and eyes, mydriasis, urinary retention, tachycardia, dizziness, tinnitus (mostly with first-generation antihistamines)
• Anti-α-adrenergic effects, e.g, postural hypotension (can lead to falls), weight gain
• Headaches

Indications

• First-generation antihistamines
  • Allergies
  • Anaphylactic shock (e.g., clemastine, dimetindene)
  • Insomnia: used as sedatives (sleep aid)
  • Nausea: used as antiemetic agents (e.g., diphenhydramine in hyperemesis during pregnancy) because of their central effects
  • Pruritus
  • Motion sickness
• Second-generation antihistamines
  • Allergies: used as antiallergic agent (e.g., in cases of rhinitis, conjunctivitis, hypersensitivity to drugs, urticaria)
  • Pruritus
  • Anaphylactic shock

Antihistamines are ineffective in acute hereditary angioedema attacks. ^[4]

Contraindications

• First-generation antihistamines
  • Benign prostatic hyperplasia
  • Angle-closure glaucoma
  • Pyloric stenosis
• Second-generation antihistamines: childhood and pregnancy

References:^[3]

Examples

• Ranitidine ^[1]
• Famotidine
• Nizatidine
• Cimetidine

General physiology

• Target: histamine H2 receptors
• Location of H2 receptors
  • Gastric parietal cells (oxyntic cells)
  • Vascular smooth muscle
  • Neutrophils
  • Central nervous system
  • Heart
  • Uterus
• Histamine effects on H2 receptors
  • Increased gastric acid secretion
  • Positive inotropism and enhanced automaticity
  • Smooth muscle relaxation leading to vasodilatation

Effects

Competitive, reversible antagonism of histamine H2 receptors (G_s protein-coupled receptor) on parietal cells → ↓ adenylyl cyclase activity → ↓ cAMP levels → ↓ protein kinase A activity → ↓ phosphorylation and activation of H⁺/K⁺ ATPase → ↓ gastric acid (H⁺) secretion

Side effects

• Almost all side effects are caused by cimetidine; side effects in other H2 blockers are rare.
• Cimetidine
  • Antiandrogenic effect (via release of prolactin) → erectile dysfunction, gynecomastia, low libido in men
  • Inhibition of cytochrome P450 (CYP2C19) → various drugs interactions, e.g., clopidogrel
  • Headaches, dizziness, confusion due to its ability to cross the blood-brain barrier
  • Can cross the placenta (but is considered safe)
  • Reduces renal creatinine excretion (along with ranitidine)

Indications

• Anaphylactic shock (together with H1 antihistamines)
• Symptomatic treatment of peptic ulcers: reduce the production of hydrochloric acid (less effective than PPIs )
• Gastroesophageal reflux disease (GERD): Consider as alternate maintenance therapy for NERD, or in addition to PPIs to control nighttime symptoms
• Gastritis
• Zollinger-Ellison syndrome

Relative contraindications

• Pregnancy, since cimetidine is known to cross the placental barrier
• Nursing mothers
• Children

Drink a glass of H₂O before dining: H2 blockers need to be taken before dinner.

References:^[3]