pharmacology of antihistamines
In this lecture we’re gonna discuss pharmacology of antihistamines but before we do that let’s first talk about
What is Histamine and what does it do?
Histamine is a small molecule producing our bodies by decarboxylation of the amino acid histidine it is widely distributed throughout all tissues but is particularly concentrated in the skin lungs and gastrointestinal tract most of histamine is generated and stored within granules in muscles located within tissues basophils and eosinophils circulating in the blood and enter a chromatin like cells located in the stomach lining now there are three major conditions that trigger the release of histamine first allergic reaction so when an algae pran individual for the first time comes into contact with allergen such as ragweed pollen, their b-cells will become activated and will form plasma cells that produce large amounts of ragweed immunoglobulin E antibodies these antibodies abbreviated as IgE firmly attached themselves to mast cells now when that same person comes into contact with ragweed pawn again The Binding of allergen to IgE antibodies would trigger activation of the mast cell which will then release granules rich in histamine.
Now let’s move on to the second condition which triggers histamine release that is tissue injury so when tissue injury occurs the damaged mast cells release chemical mediators among them histamine which affect blood vessels and nerves in the damaged area finally the third major stimulus which triggers histamine release can come from drugs and foreign chemicals compounds found in Venom’s antibiotic bases dyes and alkaloids such as morphine are a few examples that can directly displace histamine from the granule stores so now what does histamine do following its release well histamine exerts its effects by binding to various types of histamine receptors found on many different cells throughout the body to date forth types of histamine receptors have been identified and these are h1 h2 h3 and h4 that being said in this lecture we’re going to focus only on the first two types as they’re the main targets of clinically useful drugs so the first type h1 receptors are expressed primarily on vascular endothelial cells smooth muscle cells as was in the brain and on peripheral nerve endings these receptors mediate mainly inflammatory and allergic reactions so when histamine binds to vascular endothelial receptors it causes blood vessels to dilate thus making them more permeable ultimately leading to redness and edema now when histamine binds to smooth muscle receptors particularly the ones located in bronchioles it causes bronchoconstriction histamine also acts as a neurotransmitter within the central nervous system histamine binding to the h1 receptors in the brain promotes among other things wakefulness and appetite suppression.
Lastly histamine mediated stimulation of peripheral nerve endings leads to pain and itching sensations now let’s move on to the histamine type 2 receptors so h2 receptors are expressed mainly on gastric parietal cells when histamine binds to these receptors it causes increased gastric acid secretion now let’s switch gears and let’s talk about drugs that block the action of histamine starting with h1 receptor blockers classically referred to as antihistamines so the h1 receptor blockers can be divided into the other or first generation agents and the newer or second generation agents these agents as does inverse agonists meaning they bind to h1 receptor on a target tissue and stabilize its inactive conformation this leads to inhibition of his dominica actions and gradual relief of allergy related symptoms such as inflammation itching runny nose and sneezing now the general structure of the first generation H on antihistamines consists of two aromatic rings connected to a substituted ethylamine group due to this lipophilic structure first-generation h1 antihistamines can cross the blood-brain barrier and thus cause sedation and potentially impaired cognitive function additionally first generation agents have relatively poor h1 receptor selectivity and as a result they are capable of occupying other receptors such as cholinergic alpha adrenergic and serotonin receptors this leads to a number of side effects for example blockade of cholinergic receptors may cause dry mouth blurred vision and urinary retention .
Blockade of alpha TRUenergy receptors may cause hypotension and reflex tachycardia and lastly blockade of serotonin receptors may cause increased appetite on the positive side blockade of central histamine and acetylcholine receptors seems to be responsible for antiemetic and anti nausea effects examples of first generation h1 antihistamine include braum pheniramine chlorpheniramine Clemmie Steen cyproheptadine diphenhydramine doxylamine hydroxyzine meclizine and promethazine although all of these drugs are useful in relieving allergy symptoms some of them are often used for other therapeutic indications for example diphenhydramine and doxylamine are often used in the treatment of insomnia while meclizine and promethazine are more often using the treatment of nausea and vomiting related to certain conditions such as motion sickness.
Now let’s move on to the second generation h1 antihistamines so unlike the first generation second generation agents have bulkier and less lipophilic structure therefore they do not cross the blood-brain barrier as readily furthermore they are much more selective for the peripheral h1 receptors involved in allergies as opposed to the h1 receptors in the central nervous system as a result second-generation drugs provide the same allergy symptom relief but with less side effects such as sedation examples of second-generation h1 and the histamine include cetirizine Desilu rattling fexofenadine levo cetirizine and loratadine additionally we can include in this group drugs that have both antihistamine and mast cells stabilizing effects namely a zealous teen and oppa 13 that are available in ophthalmic and nasal formulations as well as keith olefin which is currently available in optometry and as a side note here keep in mind that in some medical literature katara fan is classified as a first-generation antihistamine now before we end let’s quickly discuss histamine type two receptor blockers also called h2 antagonists so in order to understand how these drugs work first we need to take a closer look at their primary target that is acid producing parietal cells of the stomach so parietal cell has three types of receptors which control acid production that is a silicone receptor gastrin receptor and histamine h2-receptor now pass sympathetic vagus nerve that innervates the GI tract releases acetylcholine which acts on a silicon receptor to increase intracellular calcium.
Next gastrin which is a hormone produced by g cells located in the pyloric glands acts on gastrin receptor 2 just like a silicon increased intracellular calcium additionally Gascon stimulates nearby and terra chromatin like cells to synthesize and secrete histamine finally histamine secreted from enteric chromatin like cells acts on h2 receptor to activate at the nose cyclase leading to increase of intracellular cyclic MP levels now this increase in intracellular serine p.m. calcium results in activation of protein kinase which in turn stimulates hydrogen potassium ATPase this so called gastric proton pump secretes hydrogen ions into the lumen of stomach in exchange for potassium so h2 receptor antagonists selectively block h2 receptor sites does effectively reduce the secretion of gastric acid this makes them useful in treatment of strict ulcers and gastroesophageal reflux disease examples of h2 receptor antagonists include cimetidine famotidine knives a Dean and ranitidine in general these trucks are well tolerated so adverse effects are few and mild with the most common being headache out of the four sigh meta Dean is the most likely to cause drug drug interactions and side effects some of which may include gynecomastia and Galacta Rhea due to its anti-angiogenic and prolactin stimulating effects and with that
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