Histamine, Antihistamines & Kinins – Comprehensive Lecture Notes

Administrative & Exam Announcements

• Exam 2

  • Scores posted by teaching assistant; final authority remains with Dr. Metcalf.

  • One-point “bonus” question still pending review by Dr. Fair (returning next week).

  • Students who perceive grading issues should e-mail Dr. Metcalf directly.

• Remediation Policy
  • Low-scoring questions (≤ class avg) may be repeated on next exam as “bonus”.
  • Bonus points add only to the numerator (raise score without expanding denominator).

• Overall performance on TA-written items judged “good”; primary miss (≈ 68 % correct) = Fenton reaction.

Quick Review of Exam Items Discussed

• Acetaminophen overdose
  • Antidote = N-acetylcysteine (NAC).
  • Mechanism = replenishes glutathione, scavenges $\text{O}_2^{!*}$-derived radicals.

• Valproic-acid-induced hepatotoxicity
  • Rescue agent = L-carnitine.

• Two “mostly acidic” intracellular enzymes in plasma → marker of cell lysis (conceptual rationale for lab values).

• Fenton reaction (commonly tested):
  $\text{Fe}^{2+}+\text{H}<em>2\text{O}</em>2 \rightarrow \text{Fe}^{3+}+\text{OH}^{!*}+\text{OH}^-$
  • Generates highly reactive hydroxyl radical → oxidative cell damage.

Inflammation Refresher

• Essential, protective process; becomes pathologic when persistent.

• Classic signs $(\text{Calor},\,\text{Dolor},\,\text{Rubor},\,\text{Tumor},\,\text{Functio laesa})$.

• Sources: trauma, toxins, microbes; response layers: innate → adaptive.

• Early events
  • Vasodilation (local heat/redness) — partly histamine & NO mediated.
  • ↑ vascular permeability → exudate, edema.
  • Leukocyte extravasation & phagocytosis, ROS / lysosomal enzyme release.

• Chronic inflammation
  • Failure of resolution → fibrosis, collagen deposition, organ remodeling (e.g., vascular stiffening → essential HTN).

Autacoids vs. Classical Hormones

• Autacoids: locally synthesized/locally acting “local hormones”.

• Classes
  • Amines → histamine (focus of today).
  • Lipids → eicosanoids (prostaglandins, leukotrienes) – future lectures.
  • Peptides → kinins, cytokines.

• Contrast w/ endocrine hormones (e.g., HPA axis) that travel systemic distances.

Histamine Chemistry, Synthesis & Storage

• Biogenic amine derived from L-histidine via histidine decarboxylase (removal of $\text{CO}_2$).

• Major pools
  • Mast cells (tissues) & basophils (blood): stored in granules complexed with acidic proteoglycans (heparin, chondroitin sulfate).
  • Non-mast sources: gastric ECL cells (stimulate acid), certain neurons.

Histamine Metabolism

• Two inactivation routes → urinary excretion

  1. N-methyl-transferase → $N$-methyl-imidazole-acetic acid.

  2. Diamine oxidase → imidazole-acetic acid riboside.

Histamine Release Mechanisms

• Immunologic (IgE-mediated) — MOST important clinically
  • Allergen cross-links surface-bound IgE on mast cell → degranulation → immediate (Type I) hypersensitivity (hay fever, urticaria, anaphylaxis).

• Chemical / mechanical
  • Direct displacement (e.g., opioids → classic morphine “itch” & flush), insect venoms, basic drugs.

Histamine Receptors (All GPCRs)

Pharmacological / Physiological Actions of Histamine

• Microcirculation regulator: rapid arteriolar dilation, post-capillary venule permeability ↑.

• Bronchial smooth muscle → constriction (H1).

• Exocrine glands: ↑ nasal/bronchial secretions (H1); ↑ gastric acid/pepsin (H2).

• Nervous system: nociception (itch, pain), wakefulness, temperature regulation.

“Triple Response” (Lewis)

1. Red spot (seconds) — direct H1 vasodilation.

2. Flare — axon reflex; secondary mediators (kinins, prostaglandins).

3. Wheal — plasma exudation from ↑ permeability.

Systemic Anaphylaxis

• Massive mast-cell histamine release → systemic vasodilation, venous pooling → ↓ venous return → shock; bronchospasm & glottic edema.

• Emergency therapy = epinephrine IM (EpiPen): $\alpha$-vasoconstriction + $\beta<em>1/\beta</em>2$ cardiac & bronchial rescue.

H1-Receptor Antagonists (Antihistamines)

• True mechanism: inverse agonists that stabilize the inactive H1 receptor conformation (reduce constitutive activity).

• Do NOT block histamine release (except some 2nd-gen agents w/ mast-cell stabilization).

Therapeutic Effects

• Block histamine-induced:
  • Vasodilation & permeability (↓ edema, erythema).
  • Bronchial constriction (limited utility in asthma — leukotrienes dominate).
  • Sensory nerve stimulation (↓ itch, sneeze).

• Additional (off-target) benefits via antimuscarinic, anti-serotonergic, local anesthetic Na⁺-channel block.

FIRST-Generation H1 Antihistamines

• Examples: Diphenhydramine, Dimenhydrinate, Chlorpheniramine, Promethazine, Doxylamine, Hydroxyzine, Meclizine.

• Properties
  • Lipophilic, small → readily cross BBB.
  • Marked CNS depression → sedation, impaired alertness; paradoxical excitation in children possible.
  • Strong anticholinergic (dry mouth, blurred vision, urinary retention, constipation).
  • α-blockade → orthostatic hypotension.
  • Local anesthetic (Na⁺-channel) activity.

• Clinical uses
  • Allergic rhinitis, urticaria.
  • Adjunct to anaphylaxis after epinephrine.
  • OTC sleep aids (e.g., diphenhydramine, doxylamine).
  • Motion sickness & vertigo (dimenhydrinate, meclizine).
  • Anti-emetic (promethazine).
  • Mild anxiolysis (hydroxyzine).

• Drug–drug cautions: additive CNS depression w/ alcohol, benzodiazepines, opioids, barbiturates; anticholinergic synergy w/ TCAs, antipsychotics.

• Pediatric warning: FDA advises avoid < 2 yrs (labels often say < 4 yrs) due to fatal respiratory depression.

SECOND-Generation H1 Antihistamines

• Examples: Cetirizine, Levocetirizine, Loratadine, Desloratadine, Fexofenadine, Azelastine (intranasal).

• Molecular design
  • Higher MW, ↓ lipophilicity.
  • Substrates for P-glycoprotein efflux pump at BBB → minimal CNS penetration.
  • Some possess mast-cell-stabilizing effect (↓ histamine release).

• Clinical advantages
  • Little to no sedation; suitable for pilots, drivers, students.
  • Once-daily dosing (t½ ≈ 12–24 h).
  • Minimal anticholinergic burden.

• Metabolism/PK
  • Many undergo $CYP<em>{3A4}$ or $CYP</em>{2D6}$; active metabolites often become marketed drugs (e.g., loratadine → desloratadine; terfenadine → fexofenadine).
  • Caution with strong CYP3A4 inhibitors (ketoconazole, grapefruit) for QT risk in legacy agents.

First- vs Second-Generation At-a-Glance

Kinins: Bradykinin & Kallidin

• Generated by kallikrein–kininogen system
  • High-molecular-weight kininogen (HMWK) + plasma kallikrein → Bradykinin (9 aa).
  • Low-molecular-weight kininogen (LMWK) + tissue kallikrein → Kallidin (10 aa, bradykinin + Lys).

• Rapid local action (t½ ≈ 15 s).

Receptors

Metabolism

• Kininase II = ACE / neprilysin → inactive fragments (degrades bradykinin; explains ACE-inhibitor cough/angioedema).

• Kininase I (carboxypeptidase) or aminopeptidase removes terminal Arg/Lys → active des-Arg metabolites (B1 agonists).

Pharmacological / Pathophysiological Roles

• Pain: potent algogens activating C-fiber nociceptors.

• Vasodilation ⇢ hypotension (blocked by NSAIDs due to PG dependence).

• ↑ Vascular permeability → edema (key in hereditary angioedema, HAE).

• Airways: bronchoconstriction, mucus, cough.

• Kidneys: ↑ renal blood flow, natriuresis (ACE-inhibitors augment → BP benefit but cause cough).

Therapeutic Modulators

• Icatibant – synthetic B2 receptor antagonist (SC) for acute hereditary angioedema.

• Ecallantide – recombinant plasma kallikrein inhibitor for HAE.

• (Historical) Aprotinin – broad serine protease inhibitor formerly used in surgery, now withdrawn for nephrotoxicity.

Sample Poll-Style Questions & Instructor Commentary

• “Most important pathological mechanism of mast-cell histamine release?” → Immunologic (IgE) degranulation, not mechanical damage.

• “Which antihistamine is markedly sedating?” → First-generation (e.g., diphenhydramine) > loratadine (2nd-gen minimal sedation).

• “Bradykinin causes visceral vasoconstriction – True/False?” → False (it causes vasodilation via B2 & NO).

Practical & Exam-Focused Take-Home Points

• Know antidotes: NAC for APAP, L-carnitine for valproate.

• Recall Fenton reaction equation and concept.

• Distinguish H1 vs H2 receptors: inflammation vs gastric acid; “classical” antihistamines = H1.

• First- vs second-generation H1 antagonists: BBB penetration, sedation, anticholinergic profile, dosing.

• Kinins: source enzymes, receptors (B1/B2), why ACE-inhibitors → cough/angioedema.

• For case stems, note:
  • Morphine itch = non-IgE histamine release.
  • Diphenhydramine use in insomnia/motion sickness but improper for common cold virus itself.
  • Icatibant choice in acute HAE with facial swelling.

• Drug-interaction red flag: additive CNS depression (alcohol, benzodiazepines) with 1st-gen agents.

• FDA restriction: avoid OTC sedating antihistamines in children < 2–4 yrs.

Links to Future Content

• Next lecture: H2 receptor antagonists & gastric pharmacology.

• Upcoming series: Eicosanoids & NSAIDs, cytokine modulators.

First-generation H1 antihistamines exert strong anticholinergic effects, which can lead to side effects such as dry mouth, blurred vision, urinary retention, and constipation.

First-generation H1 antihistamines exert strong anticholinergic effects, which can lead to side effects such as dry mouth, blurred vision, urinary retention, and constipation.

The generic names for first-generation H1 receptor blockers (antihistamines) include: Diphenhydramine, Dimenhydrinate, Chlorpheniramine, Promethazine, Doxylamine, Hydroxyzine, and Meclizine. The generic names for second-generation H1 receptor blockers (antihistamines) include: Cetirizine, Levocetirizine, Loratadine, Desloratadine, Fexofenadine, and Azelastine (intranasal).

The generic names for first-generation H1 receptor blockers (antihistamines) include: Diphenhydramine, Dimenhydrinate, Chlorpheniramine, Promethazine, Doxylamine, Hydroxyzine, and Meclizine. The generic names for second-generation H1 receptor blockers (antihistamines) include: Cetirizine, Levocetirizine, Loratadine, Desloratadine, Fexofenadine, and Azelastine (intranasal).

H1 receptor blockers are inverse agonists that stabilize the inactive H

Kinins: Bradykinin & Kallidin

Receptors

• B2 Receptor:

  • Ligands: Bradykinin & Kallidin.

  • Signaling: $G_q$ protein activation, leading to PLC/IP₃/Ca²⁺ pathway activation, increasing NO and prostaglandin production.

  • Downstream Effects: Vasodilation, hypotension, increased vascular permeability leading to edema, pain (potent algogens activating C-fiber nociceptors), bronchoconstriction, increased mucus secretion, cough, increased renal blood flow, and natriuresis.

• B1 Receptor:

  • Ligands: Des-Arg⁹-bradykinin and Des-Arg¹⁰-kallidin (active metabolites produced by Kininase I).

  • Signaling: $G_i/o$ protein activation (though not explicitly detailed in the provided note, it is typical for B1 interactions), primarily associated with chronic inflammatory effects.

  • Downstream Effects: Involved in chronic inflammation and hyperalgesia.