Pharm - lecture 21 - antihistamines

• What is histamine, and in which tissues is it found?

  Histamine is an autocoid, a locally acting chemical messenger that functions as a local hormone. It is present in virtually all tissues and is a key mediator in allergic reactions and inflammatory responses. It is stored in mast cells and basophils and is also a component of some insect and plant stings.
• Describe the process of histamine synthesis.

  Histamine is synthesized from the amino acid histidine by the enzyme histidine decarboxylase, which removes a carboxyl group. If not stored in mast cells or basophils, histamine is rapidly inactivated by amine oxidases.
• How is histamine released in the body?

  • Histamine can be released through:

  1. Acute inflammatory responses (e.g., in response to pathogens).
  2. Hypersensitivity reactions (e.g., allergies).
  3. Physical destruction (e.g., tissue damage).
  4. Complement system activation (via C3a and C5a receptors).
  5. IgE-mediated degranulation (in allergic responses).
  6. Neuronal release in the CNS (histaminergic neurons in the tuberomamillary nucleus control wakefulness and vomiting responses).
• What are the four histamine receptors, and what are their main functions?

  • H1 receptors → Found in smooth muscle, endothelium, CNS neurons. Functions: vasodilation, increased capillary permeability, smooth muscle contraction (bronchoconstriction), and sensory nerve stimulation (itching, pain).
  • H2 receptors → Found in the stomach, heart, and some immune cells. Functions: gastric acid secretion, increased heart rate (chronotropic effect), increased heart contraction (inotropic effect).
  • H3 receptors → Found in the CNS, mainly presynaptic neurons. Functions: modulate neurotransmitter release.
  • H4 receptors → Found in immune cells. Functions: regulate immune responses and inflammation.
• What conditions are caused by excessive histamine release?

  • Allergic reactions (mild to severe) → Histamine release from mast cells leads to symptoms like itching, swelling, and bronchoconstriction.
  • Anaphylaxis → A severe, systemic allergic reaction with rapid onset, causing breathing difficulties, hypotension, and shock.
  • Motion sickness → Histamine involvement in the vestibular system triggers nausea and vomiting.
  • Gastric ulcers and GERD → Excess H2 receptor activation leads to increased gastric acid secretion.
• What are first-generation H1 receptor antagonists, and how do they function?

  • First-generation H1 antihistamines (e.g., diphenhydramine, promethazine, hydroxyzine) are inverse agonists that bind to H1 receptors, preventing histamine from activating them. They are more effective when taken prophylactically before histamine release.They cross the blood-brain barrier (BBB), causing sedation. Additionally, some first-generation H1 antihistamines have anticholinergic properties, leading to dry mouth, urinary retention, and blurred vision.
• What are the major side effects of first-generation H1 receptor antagonists?

  • Sedation (crosses BBB).
  • Anticholinergic effects (dry mouth, blurred vision, urinary retention, constipation).
  • Hypotension (due to α1-adrenoceptor antagonism in some drugs like promethazine).
  • Paradoxical hyperactivity (especially in children taking diphenhydramine).
  • Potential drug interactions with monoamine oxidase inhibitors (MAOIs) and cholinergic drugs.
• What are second-generation H1 receptor antagonists, and how do they differ from first-generation?

  Second-generation H1 antagonists (e.g., cetirizine, loratadine, fexofenadine) have added polar groups, making them less likely to cross the BBB, reducing sedation.They also have fewer anticholinergic effects and are primarily used for allergic conditions like hay fever, urticaria, and allergic rhinitis.
• Why are H1 antihistamines not effective in treating asthma or anaphylaxis?

  • Asthma involves multiple mediators (leukotrienes, prostaglandins, etc.), not just histamine, so antihistamines have limited efficacy.
  • Anaphylaxis requires adrenaline (epinephrine), which acts on β2-adrenoceptors (bronchodilation), α1-adrenoceptors (vasoconstriction), and β1-adrenoceptors (increased heart rate and contraction).
• What are H2 receptor antagonists, and what is their role in treating gastric conditions?

  H2 receptor antagonists (e.g., ranitidine, famotidine, nizatidine) competitively block H2 receptors on gastric parietal cells, reducing gastric acid secretion by up to 70%. They are used to treat peptic ulcers and gastroesophageal reflux disease (GERD).
• What are the drawbacks of H2 receptor antagonists in clinical use?

  • Metabolism through cytochrome P450 enzymes → May interact with drugs like warfarin, diazepam, phenytoin.
  • Not as effective as proton pump inhibitors (PPIs), which irreversibly block gastric acid secretion for a longer duration.
• What are proton pump inhibitors, and why are they preferred over H2 antagonists?

  • PPIs (e.g., omeprazole, lansoprazole) irreversibly inhibit the H+/K+ ATPase (proton pump) in gastric parietal cells, completely blocking acid secretion for 18 hours.
  • They are more effective than H2 antagonists in treating ulcers, GERD, and Zollinger-Ellison syndrome.
• Summarize the key points about antihistamines.

  • H1 receptors → Mediate allergic reactions, inflammation, wakefulness, motion sickness.
  • H2 receptors → Stimulate gastric acid secretion, cardiac activity.
  • First-generation H1 antagonists → Sedating, anticholinergic effects (e.g., diphenhydramine).
  • Second-generation H1 antagonists → Non-sedating, used for allergies (e.g., loratadine).
  • H2 antagonists → Reduce gastric acid but are now largely replaced by PPIs.
  • PPIs → Most effective for reducing stomach acid.