Overview
This lecture covers histamine as a mediator of allergic inflammation and the drugs that block it. It starts with inflammation and Type I hypersensitivity, follows the sensitization and activation of mast cells that release histamine, describes histamine’s storage, release and metabolism, then sets out the four histamine receptors and the effects of the two that matter clinically. H1 mediates allergy symptoms and H2 drives gastric acid secretion, so the drug half of the lecture splits the same way: H1 antagonists (first generation sedating and anticholinergic, second generation peripherally selective) used for allergy, motion sickness, sedation and cough, plus the mast cell stabiliser cromolyn as an exception, the terfenadine case study, and H2 antagonists for reflux and ulcers.
Inflammation and allergic disease
- Inflammation is a protective response involving increased blood flow, immune activation, swelling, heat, pain, and often loss of function. The redness and heat reflect increased circulation, like a flame.
- It occurs following infection, tissue injury, or immune hypersensitivity such as allergy, and serves to contain damage and initiate repair.
- In allergy the immune system responds to harmless substances (pollen, dust mites, food proteins) by releasing histamine, producing allergy symptoms.
- These are hypersensitivity reactions, classified into 4 types. Type I is the one involving histamine release.
Type I (immediate) hypersensitivity
- Rapid onset, typically within minutes, as seen in skin prick testing.
- Triggered by allergens: substances harmless to most people (pollen, dust, foods, insect bites, drugs, animal fur) that provoke production of IgE antibodies.
- Affects the nose (hay fever), bronchial airways (asthma), and skin (urticaria).
- Affects roughly 20 to 30% of the population.
- Routes of allergen exposure with example triggers: skin contact (poison plants, animal dander, pollen, latex); injection (bee sting, medication); ingestion (medication, nuts and shellfish); inhalation (pollen, dust, mold and mildew, animal dander).
Sensitization and activation
Sensitization phase (initial exposure):
- A B cell encounters the allergen (ragweed pollen in the example) and, recognizing it as foreign, differentiates into a plasma cell.
- The plasma cell produces IgE antibodies specific to that allergen.
- These IgE molecules bind to mast cells, arming them for future encounters.
Activation phase (re-exposure):
- On subsequent exposure the allergen cross-links the IgE on mast cells.
- This triggers degranulation: mast cells release histamine, cytokines and other mediators into surrounding tissue.
- Allergic symptoms follow (itching, swelling, sneezing), depending on tissue location.
Histamine: structure, storage and metabolism
- Histamine is a ubiquitous biogenic amine, structurally related to neurotransmitters such as dopamine and serotonin. Its structure is an imidazole ring connected to an ethylamine side chain, and the imidazole ring contributes to its biological activity.
- Widely distributed, with especially high concentrations in the lungs, skin, gastrointestinal tract and brain, regions often involved in allergic or inflammatory responses.
- Primary tissue source is the mast cell; in the bloodstream basophils are its progenitors. Both store histamine in granules ready for rapid release during immune activation.
Two storage pools:
- Slow turnover pool: stores histamine in intracellular granules, so this is pre-formed histamine ready for immediate release. Replenishment after degranulation takes several weeks (mast cell stores replenish over days to weeks).
- Fast turnover pool: does not store histamine; synthesizes it de novo via histidine decarboxylase upon stimulation, that is, on demand. Gastric histamine turnover is rapid.
Release and breakdown sequence: storage, then a calcium signal (release from granules is triggered by increased intracellular calcium), then degranulation, then metabolism. Histamine is metabolized by diamine oxidase (DAO, histaminase) and/or imidazole N-methyltransferase (NMT).
Histamine receptors
All four are G protein-coupled receptors.
| Receptor | Role |
|---|---|
| H1 | Allergy, inflammation, smooth muscle contraction |
| H2 | Regulates gastric acid secretion |
| H3 | CNS autoreceptor, modulates histamine release |
| H4 | Immune cell chemotaxis |
H1 and H2 are the primary targets of antihistamine drugs.
H1 receptor
- Gq coupled. Signalling consequences: 1. increased intracellular calcium, 2. smooth muscle contraction, 3. increased vascular permeability.
- Vascular endothelium: increases vasodilation and vascular permeability, contributing to swelling, redness and hypotension.
- Bronchial smooth muscle: causes constriction, contributing to asthma symptoms.
- Sensory nerve endings: triggers itching and pain.
Effects of histamine at H1:
- Dilates blood vessels via release of nitric oxide, giving flushing and redness, increased skin temperature, and decreased blood pressure.
- Contracts intestinal and bronchial smooth muscle.
- Increases vascular permeability causing oedema, by contraction and separation of endothelial cells.
- Sensitises afferent nerve terminals.
- Acts as a neurotransmitter (H1 and H3) promoting wakefulness.
Triple response
First described by Sir Thomas Lewis in 1927. It forms the basis of skin test reactions in allergy and inflammation.
- Wheal: localized oedema due to plasma leakage from post-capillary venules, mediated by endothelial contraction and gap formation.
- Flare: an axon reflex leads to antidromic release of vasodilators, producing erythema around the wheal. Antidromic conduction runs from axon backward to cell body, a local non-synaptic reflex that dilates blood vessels without involving the spinal cord.
- Itch: sensitization and stimulation of cutaneous sensory nerve endings.
H2 receptor
- Gs coupled.
- Stomach (parietal cells): stimulates HCl secretion via activation of H+/K+-ATPase.
- Cardiovascular (cardiac muscle): increased heart rate and cardiac output, a beta-adrenergic-like effect.
Effects of histamine at H2: stimulates gastric acid secretion; increases cardiac rate and output.
H1 antihistamines
Mechanism: competitive antagonists at H1 receptors.
Generations:
- First generation, sedating: diphenhydramine (Benadryl), promethazine (Phenergan), meclozine (Sea-Legs), hydroxyzine. Most cross the blood brain barrier.
- Second generation, non-sedating: fexofenadine (Telfast), cetirizine (Zyrtec), loratadine (Claratyne). Do not cross the BBB appreciably, being selective for peripheral H1 receptors, so minimal to no CNS effects.
Clinical uses of the anti-allergy agents: allergic rhinitis, acute urticaria (hives), hay fever, insect bites, conjunctivitis.
Side effects, especially first generation: anticholinergic effects giving dry nasal mucosa and dry mouth, and sedation from crossing the BBB.
Note on Benadryl in New Zealand: it is not used for allergy treatment and is marketed only as a cough suppressant. Diphenhydramine-based antihistamine tablets are regulated as pharmacist-only sedating antihistamines and are not sold OTC for allergy.
Anticholinergic burden of first generation agents
First generation H1 antagonists also block muscarinic acetylcholine receptors.
- Peripheral effects: dry mouth, blurred vision, constipation, urinary retention, tachycardia.
- Central effects: sedation, impaired concentration and memory, delirium or confusion, and possible interaction with other anticholinergics such as TCAs.
Other uses of H1 antihistamines
- Anti-emetic: diphenhydramine. Crosses the BBB; central anticholinergic action reduces vestibular stimulation. Effective in motion sickness, vertigo and nausea.
- Anti-tussive: Benadryl in various combinations. Acts on the medullary cough centre to suppress the reflex. Used for non-productive cough. Can cause drowsiness, especially in older adults.
- Sedative/hypnotic: diphenhydramine, hydroxyzine. Block CNS post-synaptic H1 receptors, contributing to sedation and drowsiness. Often used as OTC sleep aids.
- Motion sickness: H1 antagonists act on neurons in the brainstem vestibular nuclei involved in motion detection, and also have anticholinergic effects. Examples promethazine (Phenergan) and meclozine (Sea-Legs). Should be taken about 1 hour prior to travel. Effective for motion-induced nausea and vomiting. Common side effects: drowsiness and sedation, dry mouth, blurred vision, urinary retention, constipation.
Choosing a generation: first generation is preferred for insomnia, motion sickness and acute allergy; second generation is preferred for daytime use and chronic allergy.
Cromolyn: an exception to H1 antagonism
- Cromolyn (cromoglicate) is an antiallergy antihistamine that inhibits release of histamine from mast cells and does not affect the H1 receptor.
- Used in allergic rhinitis (nasal spray), allergic conjunctivitis (eye drops) and ulcerative colitis (oral).
- Must be used prophylactically, prior to allergen exposure.
- Minimal systemic absorption, so a low side effect profile.
Case study: terfenadine and fexofenadine
- Teldane (terfenadine) is a prodrug metabolised to the non-toxic, pharmacologically active fexofenadine. It was effective at relieving allergies, but carried an increased risk of cardiac arrhythmias due to prolonged QT interval, and interacted with CYP3A4 inhibitors such as erythromycin and grapefruit juice.
- Telfast (fexofenadine) superseded terfenadine. It is the non-toxic active metabolite, has fewer side effects, and has no CYP3A4 liability.
- Terfenadine was withdrawn due to QT prolongation arising from its CYP3A4 metabolism.
Important
Some antihistamines, especially first generation agents and cimetidine, affect CYP450 enzymes.
H2 receptor antagonists
- Examples: cimetidine, ranitidine.
- Main use is to inhibit gastric acid secretion: reflux oesophagitis and peptic ulcers.
- Largely now replaced by proton pump inhibitors such as omeprazole. They are less effective than PPIs, have CYP liabilities, and drug tolerance can develop within 3 days.
- Retained where rapid onset and/or short duration of action is indicated.
Uses:
- Peptic ulcers.
- Gastroesophageal reflux disorder (GORD or GERD), affecting 20 to 40% of the population. Caused by reflux of gastric acid into the oesophagus; if untreated it can result in erosive oesophagitis and even carcinoma.
- PPIs can be contraindicated for patients on drugs that are highly dependent on higher gastric pH to be absorbed (PPI duration of action 24 to 48 hours); in such cases H2 antagonists may be used, with a duration of action of 6 to 12 hours.
Self-test
- Define inflammation and list the features of the response.
- Describe the sensitization phase and the activation phase of a Type I hypersensitivity reaction, in order.
- What proportion of the population is affected by Type I hypersensitivity, and which three tissues does it classically affect?
- Distinguish the slow turnover pool from the fast turnover pool of histamine, including how each supplies histamine and how quickly each is replenished.
- Describe what happens between histamine storage and histamine breakdown, naming the trigger for release and the two metabolising enzymes.
- List the four histamine receptors and give the main role of each.
- Explain how H1 receptor signalling produces oedema, from G protein to tissue change.
- List the effects of histamine mediated by H1 receptors.
- Describe the three components of the triple response and the mechanism of each.
- Explain how H2 receptor activation increases gastric acid secretion, and name the other main H2 effect.
- Distinguish first from second generation H1 antagonists in terms of BBB penetration, sedation, anticholinergic effects, and preferred clinical situation.
- List the peripheral and central anticholinergic effects of first generation H1 antagonists.
- Explain the mechanism by which an H1 antihistamine relieves motion sickness, and when it should be taken.
- Explain why cromolyn is an exception among antiallergy antihistamines, and how this changes the way it must be used.
- A patient taking terfenadine for hay fever is prescribed erythromycin and develops a cardiac arrhythmia. Explain the pharmacological basis, and say why fexofenadine does not carry the same risk.
- What is the duration of action of PPIs compared with H2 antagonists, and in what situation does this difference make an H2 antagonist the better choice?
- Predict what would happen to allergic symptoms if mast cell degranulation occurred normally but H1 receptors were fully blocked, and explain which lecture drugs act at each of those two points.
Answers
Reveal answers
- A protective response involving increased blood flow, immune activation, swelling, heat, pain, and often loss of function; the redness and heat reflect increased circulation. It follows infection, tissue injury or immune hypersensitivity, and serves to contain damage and initiate repair.
- Sensitization: a B cell encounters the allergen, recognizes it as foreign and differentiates into a plasma cell; the plasma cell produces allergen-specific IgE; the IgE binds to mast cells, arming them. Activation: on re-exposure the allergen cross-links IgE on mast cells; this triggers degranulation with release of histamine, cytokines and other mediators; symptoms such as itching, swelling and sneezing follow depending on tissue location.
- About 20 to 30% of the population. Nose (hay fever), bronchial airways (asthma) and skin (urticaria).
- Slow turnover pool stores pre-formed histamine in intracellular granules for immediate release, and takes several weeks (days to weeks for mast cells) to replenish after degranulation. Fast turnover pool does not store histamine and instead synthesizes it de novo on demand via histidine decarboxylase upon stimulation; gastric histamine turnover is rapid.
- Storage, then a calcium signal (increased intracellular calcium triggers release), then degranulation, then metabolism by diamine oxidase (DAO, histaminase) and/or imidazole N-methyltransferase (NMT).
- H1: allergy, inflammation and smooth muscle contraction. H2: regulates gastric acid secretion. H3: CNS autoreceptor modulating histamine release. H4: immune cell chemotaxis. All four are G protein-coupled.
- H1 is Gq coupled, so activation raises intracellular calcium, causes smooth muscle contraction and increases vascular permeability. At the vascular endothelium the endothelial cells contract and separate, opening gaps that let plasma leak into tissue, producing oedema (and, with vasodilation, swelling and redness).
- Vasodilation via nitric oxide release causing flushing and redness, increased skin temperature and decreased blood pressure; contraction of intestinal and bronchial smooth muscle; increased vascular permeability and oedema by endothelial contraction and separation; sensitisation of afferent nerve terminals; neurotransmitter action (H1 and H3) promoting wakefulness.
- Wheal: localized oedema from plasma leakage out of post-capillary venules, mediated by endothelial contraction and gap formation. Flare: an axon reflex causes antidromic release of vasodilators, giving erythema around the wheal, a local non-synaptic reflex not involving the spinal cord. Itch: sensitization and stimulation of cutaneous sensory nerve endings.
- H2 is Gs coupled; on gastric parietal cells it stimulates HCl secretion by activating H+/K+-ATPase. The other main effect is on cardiac muscle, increasing heart rate and cardiac output, a beta-adrenergic-like effect.
- First generation (diphenhydramine, promethazine, hydroxyzine) cross the BBB, so they are sedating and also block muscarinic receptors giving anticholinergic effects such as dry mouth and dry nasal mucosa; preferred for insomnia, motion sickness and acute allergy. Second generation (fexofenadine, cetirizine, loratadine) do not cross the BBB appreciably and are selective for peripheral H1 receptors, so are non-sedating with minimal CNS effects; preferred for daytime use and chronic allergy.
- Peripheral: dry mouth, blurred vision, constipation, urinary retention, tachycardia. Central: sedation, impaired concentration and memory, delirium or confusion, and interaction with other anticholinergics such as TCAs.
- They act on neurons in the brainstem vestibular nuclei involved in motion detection and have anticholinergic effects, with the central anticholinergic action reducing vestibular stimulation. Take about 1 hour before travel. Examples are promethazine and meclozine.
- Cromolyn (cromoglicate) inhibits the release of histamine from mast cells rather than antagonising the H1 receptor, so it cannot reverse symptoms once histamine is already released and must be given prophylactically, before allergen exposure. It is used as a nasal spray in allergic rhinitis, eye drops in allergic conjunctivitis and orally in ulcerative colitis, with minimal systemic absorption and a low side effect profile.
- Terfenadine is a prodrug metabolised by CYP3A4 to the active fexofenadine. Erythromycin is a CYP3A4 inhibitor, so terfenadine accumulates, and terfenadine itself prolongs the QT interval and increases the risk of cardiac arrhythmias. Fexofenadine is the non-toxic active metabolite given directly, so it has no CYP3A4 liability and fewer side effects; terfenadine was withdrawn for this reason.
- PPIs have a duration of action of 24 to 48 hours, H2 antagonists 6 to 12 hours. When a patient takes drugs that are highly dependent on higher gastric pH for absorption, the prolonged acid suppression of a PPI can be contraindicated, so the shorter-acting H2 antagonist is used. H2 antagonists are also chosen where rapid onset and/or short duration is wanted.
- Histamine would still be released, but its H1-mediated effects (vasodilation and flushing, increased vascular permeability and oedema, bronchoconstriction, itch through sensitised sensory nerves) would be blocked, so allergic symptoms would be largely suppressed; H2-mediated effects such as gastric acid secretion would persist. Drugs acting at degranulation: cromolyn, which stabilises mast cells and must be used prophylactically. Drugs acting at the receptor: competitive H1 antagonists such as fexofenadine, cetirizine, loratadine and diphenhydramine.