Pharmacology of Histamine - Lesson 29

Histamine is a chemical messenger found in many tissues, particularly those exposed to the environment like the lungs, skin and gut. It plays a key role in allergic and inflammatory reactions, triggering several effects in the body.

Histamine is released from mast cells, a type of immune cell, when the body encounters allergens or inflammatory stimuli.

Histamine receptors are proteins on the surface of cells that bind to histamine, initiating a series of reactions. There are four types: H1, H2, H3 and H4, each with distinct functions.

The H1 receptor is primarily responsible for the contraction of smooth muscles (except blood vessels), resulting in bronchoconstriction (tightening of airways). It also contributes to vasodilation (widening of blood vessels) and increased vascular permeability (leakage of fluids).

The H2 receptor stimulates the secretion of gastric acid, which is essential for digestion. It also plays a role in cardiac stimulation, increasing heart rate and contractility.

The H3 receptor is involved in the regulation of sleep and wakefulness, acting on the brain. It is also implicated in neurotransmission and neuronal signaling.

The H4 receptor is primarily involved in inflammation and immune responses, acting on cells such as mast cells and eosinophils. It modulates the immune response by regulating the migration and activation of immune cells.

Histamine plays a crucial role in type I hypersensitivity reactions, also known as allergic reactions, such as allergic rhinitis (hay fever), urticaria (hives), and anaphylaxis.

Antihistamines are medications designed to counteract the effects of histamine. They are categorized as H1-receptor antagonists and, in newer generations, H1-receptor inverse agonists.

First-generation antihistamines are prone to crossing the blood-brain barrier, which can lead to drowsiness.

H1-receptor antagonists directly block histamine from binding to its receptor, essentially preventing its action.

H1-receptor inverse agonists not only block histamine but also reduce the receptor's natural activity, leading to a more potent anti-allergic effect.

Second-generation antihistamines are designed to be less likely to cross the blood-brain barrier, minimizing drowsiness.

First-generation antihistamines can have peripheral anticholinergic effects, meaning they can affect the nervous system outside of the brain.

Anticholinergic syndrome, a collection of symptoms like dry mouth, blurred vision, and confusion, is a major sign of overdose with first-generation antihistamines.

To reverse anticholinergic toxicity, consider administering an acetylcholine inhibitor to increase acetylcholine levels, countering the effects of the antihistamine.

Second-generation antihistamines like fexofenadine and cetirizine are used for allergic rhinitis and urticaria. They are also available in drops for allergic conjunctivitis and topical preparations for insect bites. Injectable formulations are used in emergencies for severe allergic reactions like anaphylaxis.

Azelastine is a nasal spray used to relieve symptoms of allergic rhinitis, such as sneezing, nasal itching, and runny nose.

Antihistamines like promethazine and doxylamine are used to prevent motion sickness. They also help with other causes of nausea, especially those related to inner ear problems.

Pitolisant is a H3 receptor antagonist/inverse agonist used to treat excessive daytime sleepiness in adults with narcolepsy. It works by increasing histamine production and release in the brain, promoting wakefulness.

Antihistamines are mainly broken down in the liver and eliminated in the urine. In allergy treatment, their sedative effects on the central nervous system are generally undesirable.

First and second-generation antihistamines should be avoided by individuals with: Alcohol consumption Anticholinergic medications Digestive obstruction Glaucoma

Second-generation antihistamines should be avoided in individuals with: Arrhythmias CYP3A4 inhibitors (drug interactions)

Common adverse effects of antihistamines include sedation, dry mouth, blurred vision, constipation, urinary retention, and digestive upset. Second-generation drugs may also cause cardiac toxicity (irregular heartbeat) when combined with grapefruit juice or CYP3A4 inhibitors. Antihistamines can also cause sensitivity to sunlight.