EXPLORING HISTAMINE AND ANTIHISTAMINE AGENTS

Overview of Histamine

Histamine is a biogenic amine that plays a crucial role in immune response, gastric acid secretion, and allergic reactions. It is formed through the decarboxylation of histidine, an essential amino acid, which is present in many protein-rich foods. The process of histamine formation involves several enzymes and takes place in specific locations within the body.

1) Synthesis of Histamine:

Histamine is synthesized through the action of the enzyme histidine decarboxylase (HDC) in various tissues, including the brain, gut, and immune cells. HDC catalyzes the conversion of histidine into histamine, releasing carbon dioxide as a byproduct. The reaction occurs in the cytoplasm of cells and is highly dependent on the availability of histidine.

2) Storage of Histamine:

Once synthesized, histamine is stored in specialized organelles called histamine-containing granules (HCGs) in certain immune cells, such as mast cells and basophils. These granules are found in the cytoplasm of these cells and can be released upon activation, allowing histamine to be rapidly secreted into the extracellular space.

3) Catabolism of Histamine:

Histamine is metabolized by the enzyme diamine oxidase (DAO) in the liver and other tissues. DAO catalyzes the oxidation of histamine into N-acetyl histamine, which is then further metabolized into other compounds. The breakdown of histamine is important for regulating its levels in the body and preventing excessive accumulation.

In summary, histamine is formed through the decarboxylation of histidine, stored in specialized granules in immune cells, and catabolized by DAO in the liver and other tissues. Understanding the synthesis, storage, and catabolism of histamine is crucial for understanding its role in various physiological processes and diseases.

 

H1 versus H2 receptors

H1 and H2 receptors are both histamine receptors, which are found on the surface of many different cell types in the body. However, they have different functions and properties.

H1 receptors are primarily found on immune cells, such as mast cells and basophils, and are involved in the regulation of allergic responses and the immune system. They are also found on smooth muscle cells and can cause vasodilation and increased blood flow. H1 receptors are responsible for the symptoms of allergies such as itching, sneezing, runny nose, and congestion.

H2 receptors, on the other hand, are found on a variety of cell types, including immune cells, smooth muscle cells, and glands. They are involved in the regulation of inflammation, immune response, and gastric acid secretion. H2 receptors are responsible for the secretion of gastric acid, which helps to break down food and kill pathogens in the stomach. They also play a role in the regulation of blood pressure and heart rate.

In terms of their physiologic/pathophysiologic function, H1 receptors are primarily involved in the regulation of allergic responses and the immune system, while H2 receptors are involved in the regulation of inflammation, immune response, and gastric acid secretion.

 

The “triple response of Lewis” explained

The “triple response of Lewis” refers to a set of three distinct physiological responses that occur in the skin following the application of certain irritants or stimuli. These responses were first described by the British physiologist Thomas Lewis in 1927 and have since been widely studied and recognized in the field of dermatology.

The triple response of Lewis consists of three sequential phases: the red spot, the flare, and the wheal. Each phase is characterized by specific mechanisms that contribute to the overall response.

1. Red Spot:

The initial phase of the triple response is the appearance of a small, localized red spot at the site of stimulation. This red spot is caused by the release of histamine from mast cells in response to the irritant. Histamine is a potent vasodilator, meaning it causes blood vessels to widen. The dilation of blood vessels in the area leads to increased blood flow, resulting in erythema (redness) at the site.

2. Flare:

Following the red spot, a larger area surrounding the initial site becomes red and shows an increased temperature. This phenomenon is known as the flare. The flare occurs due to a combination of neurogenic and axon reflex mechanisms. Neurogenic inflammation involves the release of neuropeptides, such as substance P and calcitonin gene-related peptide (CGRP), from sensory nerve endings in response to the irritant. These neuropeptides cause vasodilation and increased blood flow, resulting in the expansion of erythema beyond the initial red spot.

Additionally, axon reflexes play a role in the flare response. When sensory nerve endings are stimulated, they release neurotransmitters like acetylcholine, which activate nearby blood vessels and cause them to dilate. This further contributes to the expansion of erythema seen in the flare phase.

3. Wheal:

The final phase of the triple response is characterized by the formation of a raised, edematous area known as a wheal. The wheal is caused by the increased permeability of blood vessels in the area, allowing fluid to leak into the surrounding tissues. This increased vascular permeability is mediated by the release of various inflammatory mediators, including histamine, bradykinin, and prostaglandins.

Histamine, once again, plays a crucial role in this phase by increasing endothelial cell permeability. Bradykinin, a peptide involved in inflammation and pain signaling, also contributes to vascular leakage and edema formation. Prostaglandins, which are lipid mediators derived from arachidonic acid, further enhance vascular permeability and promote inflammation.

The wheal response is primarily mediated by mast cells and their degranulation, leading to the release of these inflammatory mediators. The accumulation of fluid in the tissues results in the characteristic swelling observed during this phase.

In summary, the triple response of Lewis involves a series of physiological changes in the skin following irritation or stimulation. The red spot is caused by histamine-induced vasodilation, while the flare results from neurogenic and axon reflex mechanisms leading to expanded erythema. Finally, the wheal phase is characterized by increased vascular permeability and edema formation due to the release of inflammatory mediators.

 

H1 and H2 antagonists and Antidegranulating Drugs

H1 and H2 antagonists, also known as antihistamines, are a class of drugs commonly used in the treatment of various allergic conditions. Antihistamines work by blocking the action of histamine, a chemical released by the body during an allergic reaction. This blockade helps to alleviate symptoms such as itching, sneezing, runny nose, and watery eyes.

A) Primary Therapeutic Uses:

H1 antagonists are primarily used to treat allergic rhinitis (hay fever), urticaria (hives), and pruritus (itching). They can also be used to manage symptoms associated with allergic conjunctivitis, atopic dermatitis, and insect bites. Additionally, some H1 antagonists have sedative properties and are used as sleep aids.

H2 antagonists are mainly employed in the treatment of gastric acid-related disorders such as gastroesophageal reflux disease (GERD), peptic ulcers, and Zollinger-Ellison syndrome. These drugs help reduce the production of stomach acid by blocking histamine receptors in the stomach lining.

B) Pharmacokinetic Properties:

The pharmacokinetics of H1 and H2 antagonists can vary depending on the specific drug. However, they generally share some common characteristics.

1. Absorption: Most antihistamines are well absorbed after oral administration, with peak plasma concentrations reached within 1-3 hours. Some H1 antagonists, such as loratadine and fexofenadine, have slower absorption rates but longer durations of action.
2. Distribution: Antihistamines are widely distributed throughout the body. They can cross the blood-brain barrier, leading to potential central nervous system (CNS) side effects.
3. Metabolism: Many antihistamines undergo extensive hepatic metabolism through various cytochrome P450 enzymes. This metabolism can result in active metabolites with prolonged effects or increased sedative properties.
4. Elimination: Antihistamines are primarily eliminated through renal excretion, with some drugs also undergoing biliary excretion. The elimination half-life can range from a few hours to several days, depending on the specific drug.

C) Side Effects:
H1 antagonists can cause various side effects, although they are generally well-tolerated. Common side effects include drowsiness, dizziness, dry mouth, blurred vision, and gastrointestinal disturbances. Sedating antihistamines, such as diphenhydramine, can cause significant drowsiness and impair cognitive function.

H2 antagonists are usually well-tolerated but may cause mild adverse effects such as headache, dizziness, diarrhea, and constipation. In rare cases, they can lead to more serious side effects like liver dysfunction or blood disorders.

 

Antidegranulating Drugs:

Antidegranulating drugs are a class of medications that inhibit the release of histamine and other inflammatory mediators from mast cells and basophils. These drugs are primarily used in the treatment of allergic conditions where histamine release plays a significant role.

One example of an antidegranulating drug is cromolyn sodium. It is available as a nasal spray for allergic rhinitis and as an inhaler for asthma. Cromolyn sodium works by stabilizing mast cells and preventing the release of histamine and other inflammatory substances.

Another antidegranulating drug is nedocromil sodium, which has similar mechanisms of action to cromolyn sodium. It is also used in the treatment of asthma and allergic rhinitis.