Autocoids and Histamines PDF

AUTACOIDS ‫االستاذ الدكتور قاسم صالح النعیمی‬ Learning Objectives: After going through this lecture, the student will be able to: 1. Understanding what are the autacoids 2. Describe the major pharmacological actions of histamines. 3. List some of the therapeutic uses and ad...

AUTACOIDS ‫االستاذ الدكتور قاسم صالح النعیمی‬ Learning Objectives: After going through this lecture, the student will be able to: 1. Understanding what are the autacoids 2. Describe the major pharmacological actions of histamines. 3. List some of the therapeutic uses and adverse effects of H1 antagonists. Inflammation: During inflammation capillary dilate and this will cause vascular edema with increased vascular permeability that lead cu leakage of fluid form intravascular component to side of injury (tissues), this fluid contains immune cells that called inflammatory mediators which produce local effects , theste are the autocoids. Autacoids (Greek “self-remedy”) So autocoids are a collective term for various endogenous peptides, histamines, prostaglandins, leukotrienes, and cytokines. These are sometimes also called local hormones. Therefore the effects of the autacoids are usually restricted to the tissue in which they are formed (local action). They play important roles in physiologic processes such as pain, fever, inflammation, allergic reactions, asthma and thromboembolic disorders, and also have several pharmacological significances. TYPES OF AUTACOIDS: 1- Amine : histamines, serotonine (5-Hydroxytryptamine) 2- lipid : Eicosanoids (Prostglandines , leukotrienes ) 3- Endogenous peptides (small proteins) :Kinins, endothelin ,purine , Substance P &others 4- Cytokines :a big family such (TNF alpha), interleukines (IL1-IL35). 1  All these mediators could be present in patients with inflammation, that could be acute inflammation ( Histamines, Prostglandines , leukotrienes ) Or chronic inflammation such as interleukines. Allergic inflammation (histamines). Amine : 1. Histamine Synthesis and storage It is synthesized locally from the amino acid histidine by histidine decarboxylase. histamine is stored in mast cells and basophils, inactivated rapidly by oxidation and methylation once formed, Non-mast cell histamine it is a potent tissue amine widely distributed in plant and is found in several tissues, such as lung, skin, GIT, blood vessels, and in the brain, where it functions as a neurotransmitter.Also histamine storaged and released in the enterochromaffin-like cell of the fundus of the stomach., one of the primary acid secretagogues,. Release of histamine. Histamine can be realesed from cells in response to : 1- Antigen/antibody reaction. Histamine released by this mechanism is a mediator in immediate (type I) allergic reactions. - Snake and bee venom - Some drugs (pencillines , morphine, trimethaphan, d-tubocurarine and succinylcholine, vancomycin). - food. 2- Injury (as physical trauma) 3- Proteolytic enzymes Pharmacokinetics: histamine is not effective orally , because it is inactivated by (histaminase) enzyme. It is rapidly absorbed after S.C. or I.M. administration. It can not pass B.B.B. but it is present in brain. 2 Mechanisms of 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 a few cell types, and their roles in drug action are unclear. Pharmacological Actions: 1. CNS: Histamine does not penetrate blood brain barrier, but it is formed locally in the brain and is believed to be a “waking amine”, acting by “increasing the sensitivity of large cerebral areas to excitation inputs”by increasing excitatory transmitters acetylcholine and glutamine. 2.Cardiovascular system Stimulation of H1 receptors which present in smooth muscle of vessels, promotes vasodilation accompanied by a fall in blood pressure., This effect cannot be adequately reversed by antihistaminic agents but by adrenaline. While in bronchus, histamine causes broncho-constriction; patients of asthma are highly sensitive. Histamine-induced bronchospasm is effectively antagonized by adrenaline. Note: histamine produce contraction of all smooth muscles ,except those of smooth muscles of vessels , cause VD. 3. Exocrine Glands: lacrimal, nasal ,bronchial (lacrimation, nasal discharge, bronchial secretion ). These effects are by activation of H1 receptors. 4. At nerves ending : actions include induction of itching and swelling (due to VD). 3  Activation of H2 receptors which present mainly in stomach (responsible for HCl), causes marked increase in gastric secretion, primarily of acid but also of pepsin. This is a direct action exerted on parietal cells through H2 receptors , and this effect is blocked by H2 blockers such as cimetidine. Histamine has no valid therapeutic use currently. But it plays very important role in anaphylaxis and other forms of allergic reactions. Betahistine: It is an orally active, somewhat H1 selective histamine analogue, which is used to control vertigo in patients of Meniéré’s disease: possibly acts by causing vasodilatation in the internal ear. It is contraindicated in asthmatics and ulcer patients. How can we fight against Histamine Histamine antagonists 1- Physiological antagonist ( adrenaline ) which produces 2 important effects that antagonized histamine, bronchodilation and vasoconstriction. 2- Preventing histamine release from the mast cells during immunological reactions, by preventing Ca ion influx in mast cells and therefore prevent the degradation of MC to release histamine. These called Mast cells stabilizers (ketotifen and cromoglycon. 3- Antihistaminc Drugs: These compounds do not influence the formation or release of histamine, they block the receptor-mediated response of a target tissue. These drugs are of two types: The H1- receptor blockers, and H2-receptor blockers. The term antihistamine, without a modifying adjective, refers to the classic H1-receptor blockers. H3 and H4 antagonist still under investigations. 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 4 with other receptors, producing a variety of unwanted adverse effects, By contrast, the second-generation agents are specific for H1 receptors, and because they do not penetrate the blood-brain barrier, they show less CNS toxicity than the first-generation drugs. Among these agents desloratadine , fexofenadine , and loratadine. 1. H1 receptor antagonists Pharmacokinetics: The conventional H1 antihistaminics are well absorbed from oral and parenteral routes, metabolized in the liver and excreted in urine. They are widely distributed in the body and enter brain. Pharmacological actions and clinical applications The action of all the H1-receptor blockers is qualitatively similar. However, most of these blockers have additional effects unrelated to their blocking of H1 receptors; these effects probably reflect binding of the H1 antagonists to cholinergic, adrenergic, or serotonin receptors. 1. Antagonism of histamine: - They effectively block histamine effects such as bronchoconstriction, and others effects of histamines. - Cyproheptadine had additional 5-HT2 receptor blocking activity. 5 2.Antiallergic action: Many manifestations of immediate hypersensitivity (type I reactions) are suppressed. Urticaria, itching and angioedema are well controlled. Anaphylactic fall in BP is only partially prevented. 3. CNS: The older antihistamines produce variable degree of CNS depression. This appears to depend on the compound’s ability to penetrate the blood- brain barrier.The second generation antihistaminics are practically nonsedating. Certain H1 antihistamines are effective in preventing motion sickness, morning sickness, drug induced and postoperative vomiting, vomiting of pregnancy and radiation sickness.. Promethazine and few other antihistaminics reduce tremor, and rigidity of parkinsonism. Some older antihistamines, especially cyproheptadine, have appetite stimulating effect. And can be used in carcinoid syndrome. Some H1 antihistamines are also effective Antitussives. 4. Anticholinergic action: Some have central antimuscarinic actions which is useful in the treatment of Parkinsonis. 5. Local anaesthetic : Some drugs like pheniramine, promethazine, diphenhydramine have strong while others have weak membrane stabilizing property. SIDE EFFECTS AND TOXICITY Sedation, diminished alertness and concentration, light headedness, motor incoordination, fatigue and tendency to fall asleep are the most common. Dryness of mouth, alteration of bowel movement, urinary hesitancy and blurring of vision can be ascribed to anticholinergic property ( atropine like action ). Epigastric distress and headache may be felt. 6 Hypotension : Most antihistaminics cause a fall in BP on i.v. injection (direct smooth muscle relaxation or α adrenergic blockade as in promethazine). However, this is not evident on oral administration. Overdoses: 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. SECOND GENERATION ANTIHISTAMINICS Have the following properties. Absence of CNS depressant property. Not causing sedation. Higher H1 selectivitiy: no anticholinergic side effects.. Have long duration of action and more potent.. Not having antimuscarinic and antiserotonine action Their principal indications are: (i) Allergic rhinitis and conjunctivitis. (ii) Urticaria, dermographism, atopic eczema. (iii) Acute allergic reactions to drugs and foods. They have poor antipruritic, antiemetic and antitussive actions. Individuals drugs : Loratadine A long-acting selective peripheral H1 antagonist which lacks CNS depressant effects and is fast acting. Desloratadine It is the major active metabolite of loratadine effective at half the dose. Noninterference with psychomotor performance and cardiac safety are documented. Cetirizine It is a metabolite of hydroxyzine with marked affinity for peripheral H1 receptors; penetrates brain poorly, but mild sedation and subjective 7 somnolence. It attains high and longer lasting concentration in skin, which may be responsible for superior efficacy in urticaria/atopic dermatitis, It is indicated in upper respiratory allergies, pollinosis, urticaria and atopic dermatitis; also used as adjuvant in seasonal asthma. Cinnarizine is the H1 antihistamine having additional anticholinergic, anti-5-HT, sedative and vasodilator properties which has been widely used in vertigo. Histamine H2-Receptor Blockers Histamine H2-receptor blockers have little, if any, affinity for H1 receptors. Although antagonists of the histamine H2 receptor (H2 antagonists) block the actions of histamine at all H2 receptors, their chief clinical use is as inhibitors of gastric acid secretion in the treatment of ulcers and heartburn. The four drugs used are ”cimetidine, ranitidine, famotidine, and nizatidine”. 8