Autacoids and Autacoid Antagonists PDF

Autacoids and Autacoid Antagonists Presenter: Dr Karishma Jeeboo Introduction Autacoids: Prostaglandins Histamine Serotonin Have different structures and pharmacologic activities Formed by tissues on which they act Function as local hormones except that they are produced b...

Autacoids and Autacoid Antagonists Presenter: Dr Karishma Jeeboo Introduction Autacoids: Prostaglandins Histamine Serotonin Have different structures and pharmacologic activities Formed by tissues on which they act Function as local hormones except that they are produced by tissues rather than specific endocrine glands  Prostaglandins - Autacoid Unsaturated fatty acids – act on tissues in which they are synthesised Abortion: Several of the prostaglandins find use as abortifacients (agents causing abortions). most effective option available - oral administration mifepristone (RU-486, a synthetic steroid with antiprogestational effects) + synthetic prostaglandin E1 analog misoprostol (Cytotec) (24 hrs later, vaginally). Women can self-administer this regimen (both) with complete abortion rates exceeding 95 percent. The overall case-fatality rate for abortion is less than one death per 100,000 procedures. Infection, haemorrhage, and retained tissue are among the more common complications. Misoprostal use in NSAID-induced peptic ulcers Histamines - Autacoid Chemical messenger; Responses - allergic and inflammatory reactions, gastric acid secretion, and neurotransmission in parts of the brain. Found in all tissues, but high amounts are eventually distributed to the lungs, skin, and gastrointestinal tract (sites where the inside of the body meets the outside). Concentrations in plasma and other body fluids generally are very low, but human cerebrospinal fluid (CSF)contains significant amounts. The concentration of histamine is particularly high in tissues that contain large numbers of mast cells, such as skin, bronchial mucosa, and intestinal mucosa. Component of venoms and secretions from insect stings Histamine Histamine is released from storage granules as a result of the interaction of antigen with immunoglobulin E (IgE) antibodies on the mast cell surface. Histamine plays a central role in immediate hypersensitivity and allergic responses. The actions of histamine on bronchial smooth muscle and blood vessels account for many of the symptoms of the allergic response. Histamine - Autacoid 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. wide range of pharmacologic effects are mediated by both H1 and H2 receptors  H1 and H2 receptors - Effects H1 receptors are important for smooth muscle contraction and increasing capillary permeability. Histamine promotes vasodilation by causing vascular endothelium to release nitric oxide. This chemical signal diffuses to the vascular smooth muscle, stimulating cGMP production and causing vasodilation. Histamine H2 receptors mediate gastric acid secretion. Antiallergic activities of H1 antihistamines, such as inhibition of the release of mediators from mast cells and basophils Other actions of H1 antihistamines involve the down-regulation of nuclear transcription factors that regulate the production of proinflammatory cytokines and adhesion proteins. H2 receptors enhance the production of cyclic adenosine monophosphate (cAMP) by adenylyl cyclase.  Histamine - Autacoid Symptoms resulting from intravenous injection of histamine are similar to those associated with anaphylactic shock and allergic reactions. Contraction of smooth muscle, stimulation of secretions, dilation and increased permeability of the capillaries, and stimulation of sensory nerve endings. If the histamine release is slow enough to permit its inactivation before it enters the bloodstream, a local allergic reaction results. However, if histamine release is too fast for inactivation to be efficient, a full-blown anaphylactic reaction occurs. Histamine Within seconds of the intravenous injection of a histamine liberator, human subjects experience a burning, itching sensation. This effect, most marked in the palms of the hand and the face, scalp, and ears, is soon followed by intense warmth. The skin reddens, and the colour rapidly spreads over the trunk. Blood pressure falls, the heart rate accelerates, and the subject usually complains of headaches. After a few minutes, blood pressure recovers, and crops of hives usually appear on the skin. Colic, nausea, hypersecretion of acid, and moderate bronchospasm also frequently occur.  Triple Response of Lewis. If histamine is injected intradermally, it elicits a characteristic phenomenon known as the triple response. This consists of: A localized "reddening" around the injection site, appearing within a few seconds, maximal ~1 min Histamine A "flare" or red flushing extending ~1 cm beyond the original red spot and developing more slowly Response A "wheal" or swelling that is discernible in 12 min at the injection site The initial red spot (a few mm) results from the direct vasodilating effect of histamine (H1 receptor- mediated NO production); the flare is due to histamine-induced stimulation of axon reflexes that cause vasodilation indirectly, and the wheel reflects histamine's capacity to increase capillary permeability (oedema formation). Antihistamines - Autacoid Antagonists Classic H1-receptor blockers Do not influence the formation or release of histamine; rather, they block the receptor-mediated response of a target tissue Contrasts with the action of cromolyn and nedocromil, which inhibit the release of histamine from mast cells and are useful in the treatment of asthma. 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. For example, Cyproheptadine also acts as a serotonin antagonist on the appetite center and is sometimes used off-label as an appetite stimulant and in treating anorgasmia associated with the use of selective serotonin reuptake inhibitors.  Effects on systems: CNS: The first-generation H1 antagonists can stimulate and depress the CNS. Stimulation occasionally is encountered in H1 Receptor patients given conventional doses; they become restless, nervous, and unable to sleep. Antagonists Central excitation also is a striking feature of overdose, which commonly results in convulsions, particularly in infants. Central depression, on the other hand, usually accompanies therapeutic doses of the older H1 antagonists Therapeutic Uses: Allergic and inflammatory conditions: useful in treating allergies caused by antigens acting on immunoglobulin E antibody-sensitized mast cells. antihistamines are DOC in controlling the symptoms of allergic rhinitis and urticaria because histamine is the principal mediator released by mast cells. However, the H1-receptor blockers are ineffective in treating bronchial asthma because histamine is only one of several mediators. Ophthalmic antihistamines, such azelastine, olopatadine, ketotifen, and others, are useful for the treatment of allergic conjunctivitis Motion sickness and nausea: H1-receptor blockers include diphenhydramine and dimenhydrinate, cyclizine, meclizine, and hydroxyzine. antihistamines prevent or diminish vomiting and nausea mediated by both the chemoreceptor and vestibular pathways. The antiemetic action of these medications seems to be due to their blockade of central H1 and muscarinic receptors. Somnifacients: 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 Local Anaesthetic Effects: Promethazine (Phenergan) Antihistamines Cetirizine – Zyrtec Levocetirizine – Xyzal (active enantiomer of cetirizine) Fexofenadine - Allegra Desloratadine – Clarinex (active metabolite of loratidine) Loratadine – Claritin Promethazine – Phenergan (Has strongest anti ACh activity) Doxylamine – Unisom Diphenhydramine – Benadryl Dimenhydrinate – Dramamine/ Gravol  Pharmacokinetics Well absorbed after oral administration Peak serum levels: 2-3 hrs after administration The average plasma half-life is 4 to 6 hours except for meclizine, which has a half-life of 12 to 24 hours. H1-receptor blockers have high bioavailability and are distributed in all tissues, including the CNS (first generation mainly). All first-generation H1 antihistamines and some second-generation H1 antihistamines, such as desloratadine and loratadine, are metabolized by the hepatic cytochrome P450 system. Cetirizine is excreted largely unchanged in the urine, and fexofenadine is excreted largely unchanged in the faeces. After a single oral dose, the onset of action occurs within 1 to 3 hours. The duration of action for many oral H1 antihistamines is at least 24 hours, facilitating once-daily dosing. They are most effective when used prophylactically before allergen exposure rather than as needed. Tolerance to the action of H1 antihistamines has not been observed.  Adverse Effects First-generation H1-receptor blockers have a low specificity interact with histamine receptors and muscarinic cholinergic receptors, adrenergic receptors, and serotonin receptors. Some side effects may be undesirable, and others may have therapeutic value. Sedation: First-generation H1 antihistamines, such as chlorpheniramine, diphenhydramine, hydroxyzine, and promethazine, bind to H1 receptors and block the neurotransmitter effect of histamine in the CNS. Additive effects with alcohol and other CNS depressants – decreased motor skills. The most frequently observed adverse reaction is sedation. Other central actions include tinnitus, fatigue, dizziness, lassitude (a sense of weariness), incoordination, blurred vision, and tremors. Sedation is less common with second-generation drugs, which do not readily enter the CNS. Second-generation H1 antihistamines are specific for H1 receptors and penetrate the CNS poorly. They show less sedation and other CNS effects. Dry mouth: Oral antihistamines also exert weak anticholinergic effects, leading not only to a drying of the nasal passage but also to a tendency to dry the oral cavity. Blurred vision can occur as well with some drugs.  ADRs con’t Because H1 antihistamines cross the placenta, caution is advised for women who are or may become pregnant. Several antihistamines (e.g., azelastine, hydroxyzine, fexofenadine) had teratogenic effects in animal studies, whereas others (e.g., chlorpheniramine, diphenhydramine, cetirizine, loratadine) did not. In acute poisoning with H1 antagonists - syndrome includes hallucinations, excitement, ataxia, incoordination, athetosis, and convulsions. Fixed, dilated pupils with a flushed face, together with sinus tachycardia, urinary retention, dry mouth, and fever, lend the syndrome a remarkable similarity to that of atropine poisoning. Terminally, there is deepening coma with cardiorespiratory collapse and death usually within 2 - 18 h. Treatment is along general symptomatic and supportive lines.  ADRs Second-generation antihistamines are recommended for elderly patients (>65 years of age), especially those with impaired cognitive function, because of the sedative and anticholinergic effects of first-generation drugs. First-generation antihistamines are not recommended for use in children because their sedative effects can impair learning and school performance. The FDA has approved the second-generation drugs for use in children and are available in appropriate lower dose formulations (e.g., chewable or rapidly dissolving tablets, syrup). Use of over-the-counter cough and cold medicines (containing mixtures of antihistamines, decongestants, antitussives, expectorants) in young children has been associated with serious side effects and deaths. In 2008, the FDA recommended that they not be used in children