Autacoid - Histamine PDF

Autacoid (Hormones like substances)  Forms of chemical signaling 1) Autocrine signaling: A cell signals to itself, releasing a ligand binding to receptors on its surface. 2) Paracrine signaling: Cells communicate with each other over a short distance. 3) Endocrine sign...

Autacoid (Hormones like substances)  Forms of chemical signaling 1) Autocrine signaling: A cell signals to itself, releasing a ligand binding to receptors on its surface. 2) Paracrine signaling: Cells communicate with each other over a short distance. 3) Endocrine signaling: Signals are produced by specialized cells and released into the bloodstream, which carries them to target cells in distant parts of the body. 4) Cell-cell contact signaling: Gap junctions in animals and plasmodesmata in plants are tiny channels that directly connect neighboring cells  Paracrine example Synaptic signaling Hormones Organic regulatory substances that produced in one part of an organism and transported by the blood or the lymph to another part of the organism where it stimulate specific cells or tissues into action a) Circulating hormones Reach the bloodstream. b) Local hormones ( Autocoid): Act locally first. 1. Paracrine 2. Autocrine  Autacoids Auto = self acos (relief or remedy for example, drug). Local hormones do not usually circulate. They act locally at the site of synthesis and release. They have a diversity of pharmacological and physiological activities. They have short duration of action  Classification Amine derived: Histamine which is derived from amino acid histidine, Serotonin Peptide derived: Angiotensin, Bradykinin Lipid derived: Eicosanoids Histamine Histamine locations Almost found in all types of tissues. Found at high concentrations in basophils and mast cells. Occurs as a component of venom and in secretion from insect bites. Also, a high amount of histamine exists mainly in: 1. Lungs 2. Skin 3. GIT. Histamine Histamine is stored in granules after synthesis. synthesis If histamine is not stored, it is rapidly inactivated by the enzyme amine oxidase.  Histamine release 1. Immunologically: Histamine is released from cells in response to an antibody called immunoglobulin E (IgE). This antibody may be secreted in response to an invading pathogen such as a virus, bacteria, or an allergenic substance such as pollen 2. Chemically: Like morphine. 3. Destruction of the cells: As a result of cold, toxins, venom, and trauma.  Histamine mechanism of action Histamine is released in response to certain stimuli. Histamine binds to various types of histamine receptors (H1, H2, H3, and H4) Both H1 and H2, are widely expressed and are the targets for clinically useful drugs.  Mechanism of action of Histamine Histamine H1 H2 H3 H4 Smooth muscle Increase gastric contraction Decrease acid secretion CNS (↑Ach & histamine Increase glutamate level) release Immunomodulator capillary Vasodilatation Decrease permeability Sensory nerve secretion Vasodilatation ending pain and itching Histamine mechanism of action Actions mediated by H1 and H2 receptors Histamine reactions 1. Local reaction If the histamine release is slow enough to permit its inactivation before it enters the bloodstream. Dilation and increased permeability of the capillaries resulting in leakage of protein and fluid into the tissue in the skin. Results in Triple Response of Lewis: 1. Red spots/ line. 2. Flare (Redness around the line). 3. Wheal formation (edema). Histamine reaction 2. Anaphylactic shock: If the release of histamine is too fast for efficient inactivation, a full-blown anaphylactic reaction occurs. Antihistamine  Histamine antagonists Drugs preventing Physiological Pharmacological the release of Immunotherapy antagonism: antagonism: histamine Nedocromil, Inhibit H1 and H2 cromolyn antigen- Adrenaline receptor sodium and antibody antagonists Ketotifen reaction. Histamine receptor blocking agents  H1 receptor antagonists 1. First generation: Advantage: Effective, inexpensive Disadvantages: Cross BBB, causes sedation, and interacts with other receptors (serotonin), causing side effects (Cognitive Impairment and increase the appetite). Short duration 2. Second generation Advantage Specific H1 blockers, less sedation Pharmacokinetics: The oral duration of action is at least 24h which facilitates once-daily dosing. Most effective when used before allergen exposure rather than as needed conjunctivitis (pink eye) Urticaria or hives Allergic rhinitis Therapeutic uses 1. Allergy and inflammation  Therapeutic uses 2. Motion sickness and Morning sickness (pregnancy) 3. To induce sleep (they might help patients with insomnia)  First-generation antihistamines are contraindicated in patients working in jobs where wakefulness is critical  Side effect 1. Sedation Less with 2nd generation drugs 2. Atropine like – effect: Dry mouth, urinary retention, blurring of vision, tachycardia Less with 2nd generation drugs  H2 receptor antagonists Competitive antagonists of histamine and are fully reversible. They have no effect on H1 receptors. Mechanism: Competitively blocking histamine binding to H2 receptors and reducing the intracellular concentrations of cAMP leads to decreased gastric acid secretion. Mechanism of gastric acid secretion  Inhibit HCl secretions H2 receptor antagonists Used in the treatment of peptic ulcer Cimetidine Ranitidine Famotidine Nizatidine  Therapeutic uses Heal Heal gastric and duodenal ulcers (for 4-8 weeks). Treat Treat gastroesophageal reflux disease (GERD) Prevent the occurrence of stress ulcers (given I.V. Prevent because of limited oral administration of drugs). Prevent Prevent recurrence of peptic ulcer. Reduce the aspiration of acidic gastric contents Reduce during anesthesia in emergency operations and so, given before anesthesia. Side effects Most side effects are related to cimetidine: 1. Antiandrogenic effects:  Long-term use of cimetidine at high doses a. Decreases androgen binding to the androgen receptors. b. Inhibits estradiol hydroxylation by inhibiting CYP 450 enzymes (inhibition of estrogen metabolism) Both effects result in:  Galactorrhea in women  Gynecomastia, reduced sperm count, and impotence in men. Side effect 2. CNS adverse effects: Dizziness, headache, confusion. 3. Drug interactions: Due to the enzyme-inhibiting activity of cimetidine. 4. Hepatitis and elevated serum creatinine.  CASE STUDY A healthy 45-year-old physician attending a reunion in a vacation hotel developed dizziness, redness of the skin over the head and chest, and tachycardia while eating. A short time later, another physician at the table developed similar signs and symptoms with marked orthostatic hypotension. The menu included a green salad, sauteed fish with rice, and apple pie. 1. What is the probable diagnosis? 2. How would you treat these patients?  Answer These patients demonstrate typical symptoms and signs caused by histamine. Fortunately, neither patient in this episode of food poisoning had significant laryngeal edema or bronchospasm. Certain types of fish, if improperly preserved, contain large quantities of histamine, due to the conversion by bacteria contaminating the muscle tissue of histidine to histamine. If consumed in a sufficient amount, enough histamine can be absorbed to cause the clinical picture described. This syndrome is termed scombroid poisoning. Treatment with maximal doses of histamine blockers, especially H1 blockers, is usually sufficient to control the symptoms. Because this is not an allergic reaction, administration of epinephrine is not necessary unless hypotension or airway obstruction is severe.