1. Histamine

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

3. Synthesis: histamine is an amine formed by the decarboxylation of the amino acid histidine by histidine decarboxylase, an enzyme that is expressed in cells throughout the body, including central nervous system neurons, gastric-mucosa parietal cells, mast cells, and basophils. In mast cells, histamine is stored in granules as an inactive complex composed of histamine, heparin and anionic protein.

5. Release of histamine: The release of histamine may be the primary response to some stimuli including allergies, anaphylaxis, cell destruction as result of cold, bacterial toxins, bee stings or trauma. In most of cases, histamine is just one of several chemical mediators released.

6. Mechanism of histamine action:
Histamine 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.
H3 and H4 receptors are expressed in only few cell types, and their roles in drug action are unclear. Histamine has no therapeutic use but some drugs can cause histamine release( d-tubocurarine and morphine).

7. on H1 receptors include Action of histamine:
on exocrine secretion, it increases production of nasal and bronchial mucus resulting in respiratory distress.
on Bronchial smooth muscle, constriction of bronchioles results in symptoms of asthma and decreased lung capacity.

8. Intestinal smooth muscle, causes contraction results in intestinal cramps and diarrhea. Sensory nerve ending, causes itching and pain.

9. On H1 and H2 receptors
On cardiovascular system, it lowers systemic blood pressure by reducing peripheral resistance. Causes positive chronotropism and a positive inotropism.
On skin, dilatation and increase permeability of the capillaries results in leakage of proteins and fluid into the tissues.
In the skin, this result in the classic " triple response": reddening due to local vasodilatation, wheal formation, and flare.

11. On H2 receptors On stomach, causes
stimulation of gastric hydrochloric acid secretion.

12. Histamine H3 receptors
act as presynaptic autoreceptors that inhibit the synthesis and release of histamine in the histaminergic neurones in the central nervous system (CNS(
They also occur as hetero-receptors on nonhistaminergic neurones,
modulating the release of other neurotransmitters such as 5-hydroxytryptamine, dopamine, acetylcholine, noradrenaline and GABA in the CNS and periphery.

13. The H4 receptor
is expressed in various cells of the immune system and mast cells and induces the chemotaxis of, for example, eosinophils and mast cells.
It has also been identified on lymphocyte T cells and basophils.
It has been suggested that the H4 receptor is involved, along with the H2 receptor, in the control of IL-16 release from human lymphocytes, and it has been speculated that an H4-selective antagonist might be useful in helping to treat asthma.

14. Antihistamines: The effects of histamine can be opposed in three ways:
1-by using a drug with opposite effects e.g. epinephrine.
2-by blocking histamine binding to its site of action( receptors ) e.g. using competitive H1- and H2- receptor antagonists.
3-by preventing the release of histamine from storage cells; glucocorticoids, sodium cromoglicate and β2-agonists can suppress IgE - induced release from mast cells.

15. In this part, we will deal with H1 antihistamines which are H1 receptors blockers that do not influence the formation or release of histamine but they block the receptor-mediated response of a target tissue.
They have no effect on histamine-induced gastric secretion.

16. The H1 receptor blockers
can be divided into
1- First- generation
2- Second- generation drugs.
First-generation drugs are
1- Widely used
2- Effective
3- Inexpensive.
4-Most of these drugs penetrate the CNS
5- Cause sedation.
6-Interact with other receptors
7- Producing a variety of unwanted adverse effects.

17. the second-generation agents are
By contrast,
the second-generation agents are
1- Specific for H1 receptors
2- Do not penetrate the blood-brain barrier,
3- Less CNS toxicity than the first-generation drugs.
Generally, they have longer duration of action permit single daily dose.

20. Pharmacokinetics:
H1 receptors blockers are well absorbed after oral administration with average plasma t1/2 is 4-6 hr.
except for meclizine which has a t1/ hr.
H1 receptor blockers have high bioavailability and are distributed in all tissues, including the CNS.

21. All first-generation H1 antihistamines and some second-generation H1 antihistamines such as loratadine and desloratadine are metabolized by the hepatic cytochrome P450 system.
Cetirizine is excreted largely unchanged in the urine and fexofenadine is excreted largely unchanged in the feces.
Tolerance to the action of H1 antihistamines has not been observed.

22. Therapeutic uses: 1- allergic and inflammatory conditions,
especially those are caused by antigens acting on IgE antibody-sensitized mast cells.
However, the H1 receptors blockers are ineffective in treating bronchial asthma, because histamine is only one of several mediators of that condition and glucocorticoids show greater anti-inflammatory effects than H1 antihistamines in such case.
Antihistamines are most effective when used prophylactically before allergen exposure rather than as needed.

23. 2-motion sickness and nausea: along with the antimuscarinic agent scopolamine, certain H1 receptor blockers such as diphenhydramine, dimenhydrinate, cyclizine, meclizine and hydroxyzine are the most effective agents for prevention of the symptoms of motion sickness. The antihistamines prevent or diminish vomiting and nausea mediated by both the chemoreceptor and vestibular pathways. 3- Somnifacients( sleep producing): although they are not the medication of choice, many first-generation antihistamines, such as diphenhydramine and doxylamine, have strong sedative properties and are used in the treatment of insomnia.

24. Side effects:
First-generation H1 receptor blockers have a low specific i.e. they interact not only with histamine receptors but with muscarinic cholinergic receptors, α-adrenergic receptors and serotonin receptors.
The extent of interaction with these receptors and, as a result, the nature of the side effects vary with the structure of the drug.
Some side effects may be undesirable, and others may have therapeutic value and the incidence and severity of adverse reactions for a given drug varies between individual subjects.

25. 1- sedation, this the most common adverse effects seen with first-generation and less with the second-generation drugs, which do not readily enter the CNS. Other CNS effects include tinnitus, fatigue, dizziness, lassitude, incoordination, blurred vision and tremors. 2- dry mouth.

26. 3- drug interaction like potentiation of the effects of other CNS depressants. 4- overdose, 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

27. 5-Terfenadine can prolong the QT interval on the surface ECG
5-Terfenadine can prolong the QT interval on the surface ECG. This is especially likely to occur when 1- The recommended dose is exceeded 2- The drug is administered with substances that block hepatic metabolism (erythromycin, ketoconazole and grapefruit juice). Fexofenadine is the active metabolite of terfenadine and appears safe in this respect

29. Histamine H2 receptor blockers:
They block H2 receptors with no or little H1 receptors, their clinical use is as inhibitors of gastric acid secretion in the treatment of ulcers e.g.
cimetidine,
famotidine,
nizatidine,
ranitidine.

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