Antihistamine Drugs Lecture (7) PDF

‫ميحرلا نمحرلا هللا مسب‬ Antihistamine Drugs Lecture (7) Mohammed Ali Khalifa Assistant Professor of Pharmacology July 2024 Chemistry & Pharmacokinetics Histamine occurs in plants as well as in animal tissues and is a component of some venoms and sting...

‫ميحرلا نمحرلا هللا مسب‬ Antihistamine Drugs Lecture (7) Mohammed Ali Khalifa Assistant Professor of Pharmacology July 2024 Chemistry & Pharmacokinetics Histamine occurs in plants as well as in animal tissues and is a component of some venoms and stinging secretions. Histamine is formed by decarboxylation of the amino acid L- histidine, a reaction catalyzed in mammalian tissues by the enzyme histidine decarboxylase. Chemistry & Pharmacokinetics Once formed, histamine is either stored in mast cell or rapidly inactivated. Most tissue histamine is sequestered and bound in granules (vesicles) in mast cells or basophils; the histamine content of many tissues is directly related to their mast cell content. Chemistry & Pharmacokinetics Non-mast cell histamine is found in several tissues, including the brain, where it functions as a neurotransmitter. Strong evidence implicates endogenous neurotransmitter histamine in many brain functions such as neuroendocrine control, cardiovascular regulation, thermal and body weight regulation, and sleep. Chemistry & Pharmacokinetics A second important nonneuronal site of histamine storage and release is the enterochromaffin-like (ECL) cells of the fundus of the stomach. ECL cells release histamine, one of the primary gastric acid secretagogues, to activate the acid-producing parietal cells of the mucosa. Storage & Release of Histamine The stores of histamine in mast cells can be released through several mechanisms. A. Immunologic Release Immunologic processes account for the most important pathophysiologic mechanism of mast cell and basophil histamine release. These cells, if sensitized by IgE antibodies attached to their surface membranes, degranulate explosively when exposed to the appropriate antigen. Storage & Release of Histamine B. Chemical and Mechanical Release Certain amines, including drugs such as morphine and tubocurarine, can displace histamine from its bound form within cells. This type of release does not require energy and is not associated with mast cell injury or degranulation. Pharmacodynamics A. Mechanism of Action Histamine exerts its biologic actions by combining with specific cellular receptors located on the surface membrane. The four different histamine receptors thus far characterized are designated H1–H4 receptor subtypes. Pharmacodynamics B. Tissue and Organ System Effects of Histamine Histamine exerts powerful effects on smooth and cardiac muscle, on certain endothelial and nerve cells, on the secretory cells of the stomach, and on inflammatory cells. Pharmacodynamics B. Tissue and Organ System Effects of Histamine 1. Nervous system Histamine is a powerful stimulant of sensory nerve ending. 2. Cardiovascular system In humans, injection or infusion of histamine causes a decrease in systolic and diastolic blood pressure and an increase in heart rate. Pharmacodynamics B. Tissue and Organ System Effects of Histamine 3. Bronchiolar smooth muscle In both humans and guinea pigs, histamine causes bronchoconstriction mediated by H1 receptors. 4. Gastrointestinal tract smooth muscle Histamine causes contraction of intestinal smooth muscle. Pharmacodynamics B. Tissue and Organ System Effects of Histamine 5. Other smooth muscle organs In humans, histamine generally has insignificant effects on the smooth muscle of the eye and genitourinary tract. 6. Secretory tissue Histamine has long been recognized as a powerful stimulant of gastric acid secretion and, to a lesser extent, of gastric pepsin and intrinsic factor production. Pharmacodynamics B. Tissue and Organ System Effects of Histamine 7. The “triple response” Intradermal injection of histamine causes a characteristic red spot, edema, and flare response that was first described many years ago. The effect involves three separate cell types: smooth muscle in the microcirculation, capillary or venular endothelium, and sensory nerve endings. Clinical Uses of Histamine In pulmonary function laboratories, histamine aerosol has been used as a provocative test of bronchial hyperreactivity. Histamine has no other current clinical applications. Toxicity & Contraindications Adverse effects of histamine release, like flushing, hypotension, tachycardia, headache, wheals, bronchoconstriction, and gastrointestinal upset are noted. These are dose related side effects. Histamine should not be given to patients with asthma (except as part of a carefully monitored test of pulmonary function). Or to patients with active ulcer disease or gastrointestinal bleeding. Histamine antagonists The effects of histamine released in the body can be reduced in several ways: A. Physiologic antagonists, especially epinephrine, have smooth muscle actions opposite to those of histamine, but they act at different receptors. This is important clinically because injection of epinephrine can be lifesaving in systemic anaphylaxis and in other conditions in which massive release of histamine. Histamine antagonists B. Release inhibitors Reduce the degranulation of mast cells that results from immunologic triggering by antigen-IgE interaction. Cromolyn and nedocromil appear to have this effect and are used in the treatment of asthma, although the molecular mechanism underlying their action is not fully understood. Beta2-adrenoceptor agonists also appear capable of reducing histamine release. Histamine antagonists C. Histamine receptor antagonists Represent a third approach to the reduction of histamine-mediated responses. H1-receptor antagonists Compounds that competitively block histamine at H1 receptors have been used in the treatment of allergic conditions for many years, and many H1 antagonists are currently marketed in the USA. H1-receptor antagonists Chemistry & Pharmacokinetics The H1 antagonists are conveniently divided into first-generation and second-generation agents. These groups are distinguished by the relatively strong sedative effects of most of the first-generation agents. H1-receptor antagonists Chemistry & Pharmacokinetics These agents are rapidly absorbed after oral administration, with peak blood concentrations occurring in 1–2 hours. They are widely distributed throughout the body, and the first- generation drugs enter the central nervous system readily. Some of them are extensively metabolized, primarily by microsomal systems in the liver. H1-receptor antagonists Chemistry & Pharmacokinetics H1-receptor antagonists Pharmacodynamics A. Histamine-Receptor Blockade Both neutral H1 antagonists and inverse H1 agonists reduce or block the actions of histamine by reversible competitive binding to the H1 receptor. They have negligible potency at the H2 receptor and little at the H3 receptor. H1-receptor antagonists Pharmacodynamics B. Actions Not Caused by Histamine Receptor Blockade Sedation. Anti-nausea and antiemetic actions. Anti-parkinsonism effects. Anti-cholinoceptor actions. Clinical uses of H1-receptor antagonists 1. Allergic Reactions. 2. Motion Sickness and Vestibular Disturbances. 3. Nausea and Vomiting of Pregnancy. Toxicity of H1-receptor antagonists 1. Sedation. 2. Antimuscarinic action side effects. 3. Excitation and convulsions in children. H2-receptor antagonists The development of H2-receptor antagonists was based on the observation that H1 antagonists had no effect on histamine-induced acid secretion in the stomach. Molecular manipulation of the histamine molecule resulted in drugs that blocked acid secretion and had no H1-agonist or antagonist effects. H2-receptor antagonists The high incidence of peptic ulcer disease created great interest in the therapeutic potential of these H2-receptor antagonists when first discovered. Even though they are not the most efficacious agents available, their ability to reduce gastric acid secretion with very low toxicity has made them extremely popular and they have become OTC items. H2-receptor antagonists Examples of H2 receptor antagonist Ranitidine. Famotidine. And Cimetidine ( withdrawn from market ).