Metabolism and release
The term autacoids comes from the Greek words autos (self) and acos (remedy). In addition to histamine, this group includes prostaglandins, cytokines, and nitric oxide (NO). All of them are characterized by a short duration of action and a local effect.
Histamine synthesis occurs through the decarboxylation of the amino acid histidine. Once formed, the mediator is stored in specialized structures:
- granules of mast cells and basophils;
- enterochromaffin-like cells;
- neurons and epidermal cells.
The release (liberation) of the mediator can occur upon exogenous exposure to venoms of certain snakes and insects. However, in pharmacology, histamine liberators are of particular importance; these are chemical and medicinal substances that provoke histamine release without the involvement of the immune system. They include the muscle relaxant tubocurarine, morphine, polymyxin, and compound 48/80.
Classification of histamine receptors
The mediator's action on target cells is mediated through specific G protein-coupled receptors. There are four main types:
- H1 receptors. Coupled with the Gq protein. Located predominantly on the postsynaptic membrane, in the smooth muscle of the bronchi and intestines. Receptor excitation activates phospholipase C, which cleaves membrane phosphatidylinositol bisphosphate. This leads to the production of secondary messengers (inositol trisphosphate and diacylglycerol), an increase in intracellular calcium (Ca2+) levels, and, consequently, smooth muscle contraction.
- H2 receptors. Coupled with the Gs protein. Located on postsynaptic membranes in the central nervous system and on gastric parietal cells. Activation leads to increased cAMP levels, which stimulates the secretion of protons (hydrochloric acid).
- H3 receptors. Coupled with the Gi protein. Unlike the first two types, they are located on the presynaptic membrane and are found predominantly in the central nervous system.
- H4 receptors. Also coupled with the Gi protein. Present in the immune and hematopoietic systems (thymus, spleen, bone marrow, leukocytes), as well as in the liver, lungs, and gastrointestinal tract.
Pharmacological effects
The systemic effects of histamine affect multiple organs, causing various reactions:
- Cardiovascular system. In the heart, the mediator causes positive inotropic (increases contraction force) and chronotropic (increases rate) effects. In blood vessels, it stimulates the release of nitric oxide (NO) by the endothelium, leading to vasodilation and a drop in blood pressure. In the microvasculature, capillary permeability increases sharply. On the skin, this manifests as a "triple response": redness (hyperemia), edema, and a local temperature rise (subjectively felt as heat).
- Respiratory system. Pronounced bronchospasm and stimulation of the secretion of exocrine glands of the respiratory tract are observed.
- Gastrointestinal tract. Increased intestinal motility and increased gastric juice secretion occur.
- Smooth muscle. Spasm occurs in most organs.
- Nervous system. Irritation of sensory nerve endings leads to sensory effects: itching (as in urticaria) or pain (as in a bee sting).
Briefly: answers to topical questions
Which enzymes are involved in the inactivation and metabolism of histamine in the body?
Two main enzymes ensure the rapid breakdown of histamine by participating in its inactivation and metabolism.
- Histamine N-methyltransferase — methylates histamine to form N-methylhistamine (accounts for about 70% of metabolism). S-adenosylmethionine (SAM) serves as the methyl group donor.
- Diamine oxidase (histaminase) — catalyzes oxidative deamination to form imidazole acetaldehyde, which is then converted to imidazole acetic acid (accounts for about 30% of metabolism).
What generations of antihistamines exist and what are their differences?
H1 histamine receptor blockers are divided into two generations, the main difference between them being their ability to cause a sedative effect.
| Characteristic | 1st generation | 2nd generation |
|---|---|---|
| Sedative effect | Pronounced | Virtually absent |
| Blood-brain barrier (BBB) penetration | Cross the BBB | Practically do not cross the BBB |
| Selectivity | Low: in addition to H1 receptors, they block M-cholinergic receptors and alpha-adrenergic receptors | High selectivity for H1 receptors |
| Duration of action | Short-acting | Longer-acting |
| Additional effects | An antiemetic effect is typical for many drugs; diphenhydramine has a pronounced M-anticholinergic action | — |
| Representatives | Diphenhydramine, clemastine, mebhydrolin, phencarol | Cetirizine |
It is easy to remember the localization of receptors: H1 stands for allergy and spasms (bronchi, intestines), H2 stands for the stomach (parietal cells and acid), H3 stands for the brain (presynaptic membranes of the CNS), and H4 stands for immunity and hematopoiesis.
Class and exam questions
What are histamine liberators?
These are drugs or chemical substances (e.g., morphine, tubocurarine, polymyxin) that provoke the release of histamine from mast cells directly, without triggering an immune response.
How does histamine affect blood pressure?
It lowers blood pressure. This happens because the mediator stimulates the release of nitric oxide (NO) by the endothelium, leading to vascular expansion (vasodilation).
What is the main feature of H3 receptors?
Unlike H1 and H2, which are located on the postsynaptic membrane, H3 receptors are localized predominantly on the presynaptic membrane in the central nervous system.
What is the "triple response" in the skin?
This is a classic microcirculatory response to histamine: redness (hyperemia), local edema due to increased capillary permeability, and a local temperature rise perceived subjectively as heat.
What else to study on this topic
- Intracellular phospholipase C cascade upon H1 receptor activation
- Mechanism of hydrochloric acid secretion stimulation via H2 receptors
- Role of enterochromaffin-like cells in histamine metabolism
- Differences between immune and non-immune (liberator-induced) histamine release
- Effect of histamine on the endothelium and nitric oxide (NO) synthesis
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