Histamine & Antihistamines

Histamine is an autacoid chemical messenger mostly generated in mast cells that mediates a wide range of cellular responses, including allergic and inflammatory reactions, gastric acid secretion, and neurotransmission in parts of the brain. Histamine has no clinical applications, but agents that interfere with the action of histamine (antihistamines) have important therapeutic applications.

Location, synthesis, and release: Location: Histamine occurs in practically all tissues, but it is unevenly distributed, with high amounts found in nose, lung, skin, and the gastrointestinal tract (sites where the “inside” of the body meets the “outside”). It is found at high concentration in mast cells or basophils. Histamine also occurs as a component of venoms and in secretions from insect stings. Synthesis: Histamine is an amine formed by the decarboxylation of the amino acid L -histidine by histidine decarboxylase an enzyme that is expressed in cells throughout the body, including central nervous system (CNS) neurons, gastric mucosa parietal cells, mast cells, and basophils .

Once formed, histamine is either stored or rapidly inactivated Once formed, histamine is either stored or rapidly inactivated. In mast cells, histamine is stored in granules as an inactive complex composed of histamine and the polysulfated anion, heparin, along with an anionic protein. If histamine is not stored, it is rapidly inactivated by methylation and oxidation reactions that are catalyzed by a methyltransferase enzyme and diamine oxidase, respectively. Release of histamine: The release of histamine may be the primary response to some stimuli, but, most often, histamine is just one of several chemical mediators released. The release of histamine from tissues is caused by: the destruction of cells as a result of cold, bacterial toxins, bee sting venoms, or trauma. Allergies and anaphylaxis also cause histamine release. Stimuli include complement components C3a and C5a, which interact with specific surface receptors, and the combination of antigen with cell-fixed immunoglobulin (Ig)E antibodies. In common with many secretory processes, histamine release is initiated by a rise in cytosolic [Ca2+]. Various basic drugs, such as morphine and tubocurarine, release histamine

Mechanism of action: Histamine is released in response to various stimuli exerts its effects by binding to one or more of four types of histamine receptors: H1, H2 ,H3 and H4 receptors. H1 and H2 receptors are widely expressed and are the targets of clinically useful drugs. While H3 receptors are located in various tissues in the periphery and on nerve terminals. Activation of these presynaptic receptors(H3) in the brain inhibits the release of histamine and other neurotransmitters. The H4 receptors are located on leukocytes especially eosinophils and mast cells and is involved in chemotactic responses by these cells. Histamine binds to G protein-coupled H1 receptors and stimulates the inositol phospholipid signaling pathways, resulting in the formation of inositol-1,4,5- trisphosphate (IP3) and diacylglycerol and an increase in intracellular calcium. Stimulation of H2 receptors enhances the production of cyclic adenosine monophosphate (cAMP) by adenylyl cyclase. All four histamine receptors have been shown to have constitutive activity in some systems; thus, some antihistamines previously considered to be traditional pharmacologic antagonists must now be considered to be inverse agonists

Actions: Smooth muscle effects: Histamine, acting on H1 receptors, contracts the smooth muscle of the ileum, bronchi, bronchioles and uterus. Histamine reduces air flow in the first phase of bronchial asthma . Cardiovascular effects: Histamine promotes vasodilatation of small blood vessels by causing vascular endothelium to release nitric oxide by an action on H1 receptors & also increasing capillary permeability . It also increases the heart rate and the output of the heart by action on cardiac H2 receptors. Gastric secretion: Histamine stimulates the secretion of gastric acid by action on H2 receptors. So, it is implicated in the pathogenesis of peptic ulcer. Exocrine excretion: Increased production of nasal and bronchial mucus, resulting in respiratory symptoms

Nervous system effects : Histamine is a powerful stimulant of sensory nerve endings, especially those mediating pain and itching. This H1-mediated effect is an important component of the urticarial response and reactions to insect and nettle stings. Histamine is a transmitter in the CNS. It has effects on neuroendocrine control, cardiovascular regulation, thermal and body weight regulation, arousal, appetite & vomiting. Skin effects: When injected intradermally, histamine causes a reddening of the skin, accompanied by a wheal with a surrounding flare. This is the triple response. This mimics the 'triple response of Lewis' to scratching of the skin.The reddening reflects vasodilatation of the small arterioles and precapillary sphincters, and the wheal: the increased permeability of the postcapillary venules. These effects are mainly mediated through activation of H1 receptors. The flare is an axon reflex: stimulation of sensory nerve fibers evokes antidromic impulses through neighbouring branches of the same nerve, releasing vasodilators such as calcitonin gene-related peptide causing arteriolar dilatation & redness in the surrounding area. Itching occurs if histamine is injected into the skin because it stimulates sensory nerve endings by an H1-dependent mechanism.

Role in allergy and anaphylaxis: The symptoms resulting from intravenous injection of histamine are similar to those associated with anaphylactic shock and allergic reactions. These include contraction of airway smooth muscle, stimulation of secretions, dilation and increased permeability of the capillaries, and stimulation of sensory nerve endings. Symptoms associated with allergy and anaphylactic shock result from the release of certain mediators from their storage sites. Such mediators include histamine, serotonin, leukotrienes, and the eosinophil chemotactic factor of anaphylaxis. In some cases, these mediators cause a localized allergic reaction, producing, for example, actions on the skin or respiratory tract. Under other conditions, these mediators may cause a full-blown anaphylactic response.

It is thought that the difference between these two situations results from differences in the sites from which mediators are released and in their rates of release. For example, if the release of histamine is slow enough to permit its inactivation before it enters the bloodstream, a local allergic reaction results. However, if histamine release is too fast for efficient inactivation, a full-blown anaphylactic reaction occurs. Despite the fact that histamine release is evidently capable of reproducing many of the inflammatory signs and symptoms, histamine H1 antagonists do not have much clinical importance in the acute inflammatory response, because other mediators are more important. However, histamine and through action on H1 receptor is implicated in type I hypersensitivity reactions such as allergic rhinitis , urticaria.

H1 Antihistamines The term "antihistamine" refers to the classic H1-receptor neutral antagonists or inverse agonists. These compounds do not influence the formation or release of histamine. Rather, they block the receptor-mediated response of a target tissue (The H1 antihistamines contain an alkylamine group that resembles the side chain of histamine and permits them to bind to the H1 receptor and act as competitive receptor antagonists.). [Note: This contrasts with the action of cromolyn & nedocromil (mast cell stabilizers), which inhibit the release of histamine from mast cells and are useful in the treatment of asthma.] The H1-receptor blockers can be divided into first- and second- generation drugs:

The older first-generation drugs are still widely used because they are effective and inexpensive. However, most of these drugs penetrate the CNS and cause sedation. Furthermore, they tend to interact with other receptors, producing a variety of unwanted adverse effects. The second-generation agents are specific for H1 receptors and because they carry polar groups ,mainly by adding carboxyl groups (for example, cetirizine is the carboxylated derivative of hydroxyzine), they do not penetrate the blood-brain barrier, causing less CNS depression than the first-generation drugs. Among these agents: desloratadine, fexofenadine and loratadine show the least sedation.

Actions: The action of all the H1-receptor blockers is qualitatively similar. They are much more effective in preventing symptoms than reversing them once they have occurred. However, first-generation H1-receptor blockers have a low specificity, interacting not only with histamine receptors but also with muscarinic cholinergic receptors, α-adrenergic receptors, and serotonin receptors. Some of these actions are of therapeutic value and some are undesirable (adverse effects).

Therapeutic uses: First-generation H1-receptor blockers are among the most extensively promoted and used over-the-counter (OTC) drugs. The prevalence of allergic conditions and the relative safety of the drugs contribute to this heavy use. The fact that they do cause sedation contributes to heavy prescribing of second- generation antihistamines. 1. Allergic and inflammatory conditions: H1-receptor blockers are useful in treating and preventing allergies caused by antigens acting on immunoglobulin E antibody–sensitized mast cells. For example, antihistamines are used in controlling the symptoms of allergic rhinitis(hay fever) and urticaria because histamine is the principal mediator.

However, the H1-receptor blockers are not used in treating bronchial asthma because histamine is only one of several mediators of that condition. [Note: Epinephrine has actions on smooth muscle that are opposite to those of histamine, and it acts at different receptors. This is called (Physiologic antagonism) Therefore, epinephrine is the drug of choice in treating systemic anaphylaxis and other conditions that involve massive release of histamine.]. 2. Motion sickness and nausea: Along with the antimuscarinic agent scopolamine, certain H1- receptor blockers, such as diphenhydramine, dimenhydrinate , cyclizine, meclizine, cinnarizine and promethazine are the most effective agents for prevention of the symptoms of motion sickness. They are usually not effective if symptoms are already present and, thus, should be taken prior to expected travel. The antihistamines prevent or diminish vomiting and nausea mediated by both the chemoreceptor and vestibular pathways.

3. Sleeping aids : Although they are not the medications of choice, many first- generation antihistamines, such as hydroxyzine diphenhydramine and doxylamine, have strong sedative properties and are used in the treatment of insomnia. They are available over the counter, or without a prescription. The use of first-generation H1 antihistamines is contraindicated in the treatment of individuals working in jobs in which wakefulness is critical.

Pharmacokinetics: First and second generation drugs are administered orally or parenterally. Azelastine is an intranasal antihistamine for rhinitis and ophthalmic preparations for conjunctivitis include levocabastine, ketotifen, epinastine and olopatadine. H1-receptor blockers are well absorbed after oral administration, with maximum serum levels occurring at 1 to 2 hours. The average plasma half-life is 4 to 6 hours, except for that of meclizine and the second- generation agents, which is 12 to 24 hours. The duration of action for many oral H1 antihistamines is at least 24 hours, allowing once-daily dosing. First-generation H1-receptor blockers have high bioavailability and are distributed in all tissues, including the CNS. They are mainly metabolized in the liver and excreted in the urine.

Adverse effects: 1. Sedation: First-generation H1 antihistamines, such as chlorpheniramine, hydroxyzine, diphenhydramine and promethazine bind to H1 receptors and block the neurotransmitter effect of histamine in the CNS. The most frequently observed adverse reaction is sedation. {At ordinary dosages, children occasionally (and adults rarely) manifest excitation rather than sedation.} Other central actions include tinnitus, fatigue, dizziness, uncoordination, blurred vision, and tremors. Regular use of first-generation antihistamines is not advisable in children, because the CNS depressant property may interfere with learning tasks.

2. Anticholinergic adverse effects: Oral antihistamines also exert anticholinergic effects (more with diphenhydramine, dimenhydrinate & promethazine) leading to dry mouth , blurred vision, constipation and retention of urine. 3. Other adverse effects : gastrointestinal disturbances which are fairly common, allergic dermatitis which can follow topical application. The most common adverse reaction associated with second-generation antihistamines is headache.   Drug interactions: Interaction of H1-receptor blockers with other drugs can cause serious consequences, such as potentiation of the effects of all other CNS depressants, including alcohol. Persons taking monoamine oxidase inhibitors (MAOIs) should not take antihistamines because the MAOIs can exacerbate the anticholinergic effects of the antihistamines.

Overdoses: Although the margin of safety of H1-receptor blockers is relatively high, and chronic toxicity is rare, acute poisoning is relatively common, especially in young children. The most common and dangerous effects of acute poisoning are those on the CNS, including hallucinations, excitement, ataxia, and convulsions. If untreated, the patient may experience a deepening coma and collapse of the cardiorespiratory system.