Study Notes on Histamine and Antihistamines

HISTAMINE AND ANTIHISTAMINES

• Histamine is an endogenous amine produced by mast cells in tissues and basophils in blood.

• It belongs to compounds called autocoids, which refers to their self-healing properties.

Physiological Functions of Histamine

• Plays an important role in several physiological functions, including:

  • Small vessels vasoconstriction

  • Increased capillary permeability

  • Inflammation

  • Bronchoconstriction

  • Skin reactions

• These effects are symptomatic of allergic reactions.

Histamine Receptors

• So far, four types of histamine receptors have been elucidated:

  • H-1

  • Mediate allergic responses such as watery eyes, nasal congestion, bronchoconstriction, redness, swelling on the skin, rashes, and itching.

  • H-2

  • Located in the gastrointestinal tract; mediate gastric acid production.

  • H-3

  • Found in the central nervous system; exert inhibitory control on the brain.

  • H-4

  • Expressed in cells of the immune system, e.g., monocytes.

Role of Histamine in Allergic Reactions

• Histamine acts as a key mediator of allergic reactions.

• It is stored in mast cells, complexed with heparin.

• Histamine can be released by various mechanisms such as:

  • Tissue injury

  • Drugs like morphine

• Synthesis: Histamine is synthesized in the body by the decarboxylation of the amino acid L-histidine, catalyzed by the enzyme histidine decarboxylase.

• Metabolism: Metabolized primarily through oxidation and N-methylation.

Counteracting Histamine Effects

• Various approaches have been developed to counter the effects of histamine:

  • (i) Use of enzymes that metabolize histamine:

  • This approach is unsuccessful since enzymes are proteins and can be destroyed before reaching the site of action. Additionally, they can cause allergic reactions.

  • (ii) Reduce synthesis of histamine:

  • Using inhibitors of L-histidine decarboxylase, e.g., brocresing, α-methylhistidine.

  • This approach is also unsuccessful due to toxicity and associated side effects in asthma.

  • (iii) Counter the physiological effects through functional antagonism:

  • Example: Use of sympathomimetic bronchodilators like salbutamol.

  • This approach is successful but allergic reactions recur once the drug is removed.

  • (iv) Use of mast cell stabilizers:

  • Examples: sodium chromoglycate, nedocromil sodium, lodoxamine.

  • These agents are successful in preventing mast cells from disintegrating and releasing histamine, but they do not affect histamine already in circulation.

  • They are utilized in respiratory, eye, and nasal allergies and are not orally active due to their polarity.

  • (v) Use of compounds that antagonize histamine at H-1 receptors:

  • Known as antihistamines or H-1 antagonists.

  • Agents vary in chemical composition but share a common structural formula R-X-C-C-N.

  • Antihistamines can be classified into three major groups based on the nature of X:

    • X=O: Ethanolamines (e.g., doxylamine)

    • X=N: Ethylenediamines (e.g., phenbenzamine)

    • X=C: Propylamines/alkylamines (e.g., chlorpheniramine)

Structure-Activity Relationship (SAR) of Antihistamines

• General structure: R-X-C-C-N-

  • (i) R should be a bulky group typically comprising two aryl groups or a larger functional group.

  • (ii) Substitution of the aromatic ring with a halogen at the para position increases activity; for example, chlorpheniramine.

  • (iii) The carbon chain between X and N must be an ethylene chain. Longer or shorter chains show no activity.

  • (iv) A tertiary amine group is necessary for activity, with dimethyl compounds showing better therapeutic indices compared to others.

  • (v) The terminal nitrogen can be incorporated into a ring structure while retaining activity (e.g., piperazine derivatives of ethylenediamines).

  • (vi) In the presence of optical isomerism, the d-isomer is more potent than the l-isomer.

Classification of H-1 Receptor Antagonists

• H-1 receptor antagonists are classified into generations:

  • 1st generation

  • 2nd generation

  • 3rd generation

First Generation Agents

• Ethanolamines:

  • Examples include: Doxylamine, Carbinoxamine, Diphenhydramine (Benadryl®), Clemastine, Dimenhydrinate.

  • Includes other agents like Orphenadrine (used in parkinsonism).

• Ethylene diamines:

  • Examples: Phenbenzamine, Tripelenamine, Antazoline, Mepyramine (Pyrilamine), Clemizole.

• Piperazines:

  • Derived from ethylene diamines; examples include Cyclizine, Meclizine, Buclizine, Hydroxyzine, and Cetirizine (a second-generation agent).

• Tricyclic antihistamines/phenothiazines:

  • Examples: Promethazine (a sedative-hypnotic), Pyrathiazine, Trimeprazine, Azatadine, Ketotifen, Cyproheptadine (Periactin®, an appetite stimulant).

• Alkylamines/Propylamines:

  • Examples: Chlorpheniramine (Piriton®), Dexchlorpheniramine (Polaramine®), Brompheniramine, Dexbrompheniramine, Pheniramine, Triprolidine (in Actifed®).

Properties of First Generation Antihistamines

• Highly potent and generally exhibit strong sedation compared to other antihistamines.

• Sedative effects vary among individual drugs.

• Also possess anticholinergic, serotonergic, and α-adrenergic effects.

Second Generation Antihistamines

• Characterized by:

  • High H1 selective activity

  • Little to no sedative effects

  • Minimal anticholinergic effects

  • Poor lipid solubility; do not cross the blood-brain barrier (BBB), thus non-sedating.

• Examples include:

  • Piperazines: Cetirizine, Hydroxyzine (also exhibits antiemetic activity).

  • Piperidines: Terfenadine (withdrawn due to cardiovascular adverse effects).

  • Its active metabolite, Fexofenadine, is currently in use (classified as a third generation).

  • Other examples: Levocarbastine, Loratadine (Claritine®), Astemizole (withdrawn due to cardiovascular adverse effects), Ebastine (Kestine®), Acrivastine, Mizolastine, Ketotifen.

• Topical formulations: Azelastine, Levocarbastine, and Ketotifen are formulated for eye drops, nasal drops, and skin allergy treatments.

• Loratadine and Mizolastine cause less sedation than other antihistamines due to lower penetration of the BBB.

• Most second-generation antihistamines are long-acting, allowing daily dosing intervals.

Third Generation Antihistamines

• Include:

  • Desloratadine (Aerius®): A major metabolite of Loratadine.

  • Fexofenadine: Active metabolite of Terfenadine.

  • Levocetirizine: Levo isomer of Cetirizine.

• Third-generation H1-antihistamines are designed to have increased efficacy with fewer adverse drug reactions.

• Notably, Fexofenadine is associated with a decreased risk of cardiac arrhythmias compared to Terfenadine (which has been withdrawn from use).

Clinical Uses of Antihistamines

• Indications include:

  • Nasal, eye, and skin allergies: E.g., allergic conjunctivitis, allergic rhinitis, rhinorrhea.

  • Drug allergies and anaphylaxis.

  • Management of motion sickness, nausea, and vomiting, including morning sickness.

  • Some are used as sedative-hypnotics.

  • Due to anticholinergic effects, some are utilized to manage cold symptoms.

  • Management of serum sickness and blood incompatibility reactions.

  • As anorexics or to improve appetite.

  • Prophylaxis of allergic asthma.

  • Management of skin allergic reactions:

  • Pruritus (atopic dermatitis, insect bites).

  • Dermatitis.

  • Urticaria.

  • Hay fever, contact dermatitis, angioedema.

H-2 Receptor Antagonists

• The H2 antagonists are competitive antagonists of histamine at the parietal cell H2 receptor.

• Their primary role is to suppress normal secretion of acid by parietal cells and prevent meal-stimulated secretion of acid.

• Accomplished through two mechanisms:

  • Histamine released by ECL cells in the stomach is blocked from binding to parietal cell H2 receptors, which results in reduced acid secretion.

  • Other substances that promote acid secretion (such as gastrin and acetylcholine) have less effect when H2 receptors are blocked.

Clinical Uses of H-2 Antagonists

• H2-antagonists are used for treating acid-related gastrointestinal conditions, including:

  • Peptic ulcer disease (PUD)

  • Gastroesophageal reflux disease (GERD/GORD)

  • Dyspepsia

  • Prevention of stress ulcers (specific indication for ranitidine)

  • Zollinger-Ellison syndrome

  • Stress-related mucosal injury

• Individuals with infrequent heartburn may take antacids or H2-receptor antagonists as treatment.

• Advantages of H2-antagonists over antacids include:

  • Longer duration of action (6–10 hours versus 1–2 hours for antacids)

  • Greater efficacy

  • Ability to be used prophylactically before meals to prevent heartburn occurrence.

• Proton pump inhibitors are preferred for treating erosive esophagitis due to better healing effectiveness compared to H2-antagonists.

Management of Peptic Ulcers

• Two primary approaches for managing ulcers:

  • (i) Reduction of intra-gastric acidity:

  • Through the use of antacids and agents that decrease H⁺ ion secretion.

  • (ii) Promoting mucosal defense mechanisms:

  • Stimulated by gastrin, histamine, pepsin, and acetylcholine (which binds to M3 receptors).

• Parietal cells in the stomach lining contain these receptors, and their action stimulates acid secretion through the H^+/K+ ATPase (proton pump), promoting H⁺ secretion and exchanging it with K⁺.

• Histamine is crucial for the action of gastrin and acetylcholine at their receptors.

Drugs Used in Peptic Ulceration and Related Hyperacidity Disorders

1. Antacids

   • Weak bases that react with HCl, releasing H₂O and salt, thereby reducing intragastric acidity.

   • Antacids can also stimulate the production of prostaglandins, enhancing the mucosal defense mechanism.

   • Examples include: NaHCO₃, CaCO₃, Mg(OH)₂, Al(OH)₃, Magnesium trisilicate.

2. NaHCO₃ Properties

   • Reacts with HCl to form NaCl, CO₂, and H₂O.

   • CO₂ may lead to gastric distention and belching.

   • Unreacted alkali may cause metabolic alkalosis if doses are high and in patients with renal insufficiency.

   • NaCl absorption can worsen fluid retention in patients with heart failure, hypertension, and renal insufficiency.

3. CaCO₃ Properties

   • Less reactive with HCl than NaHCO₃.

   • Can cause metabolic alkalosis and belching.

   • Excessive doses, especially with calcium-containing daily products may cause hypocalcemia, renal insufficiencies, and metabolic alkalosis.

4. Mg and Al Properties

   • Do not cause belching or metabolic alkalosis.

   • Unabsorbed Mg may lead to osmotic diarrhea, while unabsorbed aluminium may cause constipation.

   • Both are inappropriate for renal disease because they are excreted by the kidneys.

   • Antacids may affect absorption of some drugs through binding or altering pH; they must be administered 2 hours apart from such drugs (e.g., tetracyclines, fluoroquinolones such as ciprofloxacin).

5. Uses of Antacids

   • Primarily for dyspepsia and GERD.

   • Al(OH)₃ is specifically used in hypophosphatemia and for short-term relief of hyperacidity.

   • Long-term use is not preferred due to risks like fluid retention and metabolic alkalosis.

   • Some antacids are commercially available in combination with silicones and alginates, which offer protection and reduce gas/flatulence.

H-2 Receptor Antagonists

• They are structurally unrelated to H₁ antagonists but chemically related to histamine.

• Mechanism of Action:

  • They competitively inhibit/antagonize histamine at the H₂ receptors on parietal cells.

  • Bulkiness causes steric hindrance, providing high selectivity for H₂ receptors without affecting H₁ and H₃ receptors.

  • Their effect is reversible, resulting in inhibition of acid production.

• Common drugs include:

  • Cimetidine

  • Ranitidine

  • Famotidine

  • Nizatidine

• Cimetidine (Tagamet®) was the first clinically useful H-2 antagonist.

  • Contains an imidazoline ring similar to that of histamine.

  • The imidazoline ring can be replaced with isosteres to create compounds with reduced hepatic and nephrotoxicities, e.g., ranitidine, famotidine, nizatidine.

  • Cimetidine has more drug interactions than other compounds as it inhibits CYP450, affecting metabolism of drugs like phenytoin, theophylline, and warfarin, thereby increasing their plasma concentrations.

• They are effective in inhibiting nocturnal acid secretion, which is largely histamine-dependent.

• H-2 antagonists are less effective in Zollinger-Ellison syndrome than proton pump inhibitors.

• Except for Cimetidine, other agents are considered safe and more effective than Cimetidine due to its noted interactions.

Proton Pump Inhibitors (PPIs)

• Proton pump inhibitors block the final step of acid secretion by inhibiting the H^+/K+ ATPase (the proton pump).

• Advantages:

  • Their inhibition of acid secretion is not limited to any particular receptor.

• Examples of PPIs include:

  • Omeprazole (Losec®)

  • Esomeprazole (Nexium®)

  • Lansoprazole (Lansec®)

  • Pantoprazole (Pantecta®)

  • Rabeprazole (Pariet®)

• These drugs are pro-drugs that undergo activation in vivo.

Clinical Uses of Proton Pump Inhibitors

• Indications include:

  • Gastric and peptic ulcers

  • GERD

  • Eradication of H. pylori infection

Mucosal Protective Agents

• Mucosal prostaglandins stimulate mucus and bicarbonate secretion, enhancing blood flow to the mucosal membrane.

  • Example: Sucralfate

    • A sucrose salt complexed with sulfated aluminium hydroxide that forms a viscous paste in water or acid condition.

    • Binds selectively to ulcers or erosions.

    • Administered at doses of 1 g four times daily on an empty stomach.

    • Mainly used for preventing stress-related GI bleeding.

• Colloidal bismuth compounds:

  • Examples include Bismuth subsalicylate, Bismuth subcitrate, Bismuth dinitrate, Tripotassium dicitrato bismuth.

  • These compounds coat ulcers and create a protective layer against acid and pepsin.

• Prostaglandin analogs:

  • E.g., Misoprostol: believed to enhance mucosal blood flow and provide acid protection.

  • Used illegally for abortions, but clinically used in reproductive health.

Prokinetic Agents / Drugs That Stimulate Gastric Motility

• These agents selectively regulate motor function or stimulate gastrointestinal motility.

• Agents that increase lower esophageal sphincter pressure may be used for GERD.

• Those that stimulate gastric emptying are useful in conditions like gastroparesis and post-surgical gastric emptying.

• Those stimulating the small intestine are helpful in postoperative ileus and chronic pseudo-obstruction.

• Agents that enhance colonic transit may be used for constipation.

• Examples: Domperidone (Motillium®), Metoclopramide (Plasil®), Cisapride, Levosulpride.

H. pylori Eradication

• Treatment involves triple therapy consisting of:

  • One antibiotic

  • One anti-infective

  • One proton pump inhibitor (PPI)

• Examples of antibiotics:

  • Amoxicillin, Clarithromycin, Metronidazole, Omeprazole.

• Regimen:

  • Pantoprazole 40mg BD x 5/7

  • Amoxicillin 1g BD x 5/7

  • Clarithromycin 500mg BD x 5/7

  • Tinidazole 500mg BD x 5/7

Histamine is an endogenous autocoid amine synthesized from the decarboxylation of $L-histidine$. It plays critical roles in allergic responses, gastric acid secretion, and neurotransmission through four distinct receptors ($H<em>1, H</em>2, H<em>3, H</em>4$).

H-1 Receptor Antagonists

Antihistamines are classified into three generations based on their selectivity and side effect profiles:

• First Generation: Highly potent but non-selective, causing significant sedation and anticholinergic effects (e.g., Diphenhydramine, Chlorpheniramine).

• Second Generation: More selective for $H_1$ receptors with poor lipid solubility, leading to minimal sedation (e.g., Cetirizine, Loratadine).

• Third Generation: Active metabolites or isomers designed for higher efficacy and fewer cardiac risks (e.g., Fexofenadine, Desloratadine).

Gastric Acid Management

The management of peptic ulcers and GERD involves several classes of drugs:

• Antacids: Weak bases like $NaHCO<em>3$ and $Al(OH)</em>3$ that neutralize gastric acid.

• H-2 Receptor Antagonists: Structurally related to histamine, these competitively inhibit acid secretion at parietal cells (e.g., Ranitidine, Famotidine).

• Proton Pump Inhibitors (PPIs): Irreversibly block the $H^+/K^+$ ATPase pump, representing the most effective method for suppressing acid secretion (e.g., Omeprazole).

Other Gastrointestinal Agents

• Mucosal Protective Agents: Compounds like Sucralfate and Bismuth that coat ulcers to prevent further damage.

• Prokinetic Agents: Drugs such as Domperidone that stimulate gastric motility.

• H. pylori Eradication: A triple therapy regimen typically involving a PPI combined with antibiotics like Amoxicillin and Clarithromycin.