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LOCAL HORMONES January, 2012

LOCAL HORMONES January, 2012. Local Hormones. Includes: - Histamine serotonin ( 5-HT ) Prostaglandins vasoactive peptides- platelet activating factor (PAF), bradykinin, nitric oxide neuropeptides, cytokines. HISTAMINE - Synthesis, Storage & Release.

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LOCAL HORMONES January, 2012

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  1. LOCAL HORMONESJanuary, 2012

  2. Local Hormones • Includes:- • Histamine • serotonin ( 5-HT ) • Prostaglandins • vasoactive peptides- platelet activating factor (PAF), bradykinin, nitric oxide neuropeptides, cytokines

  3. HISTAMINE-Synthesis, Storage & Release • Is a basic amine formed from amino acid histidine by histidine decarboxylase. • It is found in most tissues but is present in high concentrations in the lungs and the skin, and in particularly high concentration in the gastrointestinal tract. • At cellular level, it is stored in high concentrations in mast cells. • But non-mast cell histamine occurs in ‘histaminocytes’ in the stomach and in histaminergic neurons in the brain.

  4. HISTAMINE-Synthesis, Storage & Release…. • In mast cells and basophils, histamine is complexed in intracellular granules with an acidic protein and a high-molecular-weight heparin termed macroheparin • It is released from mast cells by exocytosis during inflammatory or allergic reactions

  5. Histamine-……. • It is metabolized by amine oxidase enzymes • Histaminase and/or by methylating enzyme imidazole N-methyltransferase • Excess production of histamine in the body can be detected by measurement of imidazole-acetic acid, its major metabolite, in the urine.

  6. Histamine… • Because it is released from mast cells in response to immunoglobulin E (IgE)-mediated ( immediate ) allergic reactions, this autacoid plays an important pathophysiologic role in seasonal rhinitis ( hay fever ), urticaria, and angioneurotic oedema. • Histamine also plays an important role in control of acid secretion in the stomach.

  7. Histamine Receptors and Effects • Produces its action by an effect on specific histamine receptors which are of three main types:- • H1, H2 and H3- receptors, distinguished by means of selective antagonist drugs. • H1 and H2 receptors mediate most of the well-defined peripheral actions

  8. Histamine Receptors and Effects… a) H1 receptor: This receptor is important in smooth muscle effects, especially those caused by IgE-mediated responses. • Causes contractions of the smooth muscles of (the ileum, the bronchi, bronchioles and uterus) • Typical responses include bronchoconstriction and vasodilation, the latter by release of endothelium-derived relaxing factor (EDRF).

  9. Histamine Receptors and Effects… • Capillary endothelium, in addition to releasing endothelium-derived relaxing factor (EDRF), also contracts, opening gaps in the permeability barrier and resulting in the formation of local oedema. • These effects are manifested in allergic reactions and in mastocytosis, a rare neoplasm of mast cells.

  10. b) H2 receptors: has three actions which are:- mediates gastric acid secretion by parietal cells in the stomach. Clinically, this is the most important action of histamine, since it is implicated in the pathogenesis of peptic ulcer. It also has cardiac stimulant effect. A third action is to reduce histamine release from mast cells:-a –ve feedback effect. These actions are mediated by activation of adenylyl cyclase, which increases intracellular cAMP.

  11. Histamine Receptors and Effects… c) H3 receptor: • This receptor appears to be involved mainly in presynaptic modulation of histaminergic neurotransmission in the CNS . • In periphery, it appears to be a presynaptic heteroceptor with modulatory effects on the release of other transmitters.

  12. CLINICAL USE • Histamine has no therapeutic applications, but drugs that block histamine’s effects are very important in clinical medicine

  13. HISTAMINE H1 ANTAGONISTS • A wide variety of antihistaminic H1 blockers are available from different chemical families. • Diphenhydramine and Chlorpheniramine may be considered prototypes. • Because they have been developed for use in chronic conditions, H1 blockers are all active by the oral route. • Most are metabolized extensively in the liver.

  14. HISTAMINE H1 ANTAGONISTS… • Half-lives of the older H1-blockers vary from 4 hours to 12 hours. • Several newer agents (“ second generation “ antihistamines, e,g. Terfenadine, Fexofenadine, Astemizole, Loratadine ) have half lives of 12-24 hours and decreased CNS penetration.

  15. MECHANISM AND EFFECTS • H1 blockers are competitive pharmacologic antagonists at H1receptor, these drugs have no effect on histamine release from storage sites. Because their structure closely resembles that of muscarinic blockers and alpha blockers, many of these agents are also pharmacologic antagonists at these receptors. A few also block 5HT receptors. However, they have negligible effects at H2 receptors.

  16. MECHANISM AND EFFECTS… • H1-blocking drugs have sedative and anti-motion sickness effects in the CNS. In periphery, they competitively inhibit the effect of histamine ( especially if given before histamine release occurs ). • Many H1 blockers are potent local anaesthetics.

  17. Clinical Use of Histamine H1-antagonists • Have many application in allergies of immediate type ( i.e. those caused by antigens acting on IgE antibody-sensitized mast cells ). • These conditions include hay fever and urticaria. • The drugs have a broad spectrum of adverse effects that limit their usefulness but can sometimes be used to good effect ( e.g. the sedative effect is used in over-the-counter (OTC) sleep aids ).

  18. TOXICITY AND INTERACTIONS • Sedation is common, with Diphenhydramine and Promethazine. • It is less common with newer agents that do not enter the CNS readily ( e.g. Terfenadine, Astemizole ). • Antimuscarinic effects such as dry mouth and blurred vision occur with some drugs in some patients.

  19. TOXICITY AND INTERACTIONS… • Alpha-blocking actions may cause orthostatic hypotension. • Interaction occur between older antihistamines and other drugs with sedative effects, e.g. benzodiazepines and alcohol.

  20. Drugs that inhibit hepatic metabolism may result in dangerously high levels of non sedating antihistaminic drugs that are taken concurrently . For e.g. Ketoconazole inhibits metabolism of astemizole and terfenadine. In the presence of this anti-fungal drug, the plasma concentration of either antihistamine may increase and precipitate lethal arrhythmias. Cardiac arrhythmias are effects of excessive concentrations of terfenadine and astemizole.

  21. Terfenadine is the pro-drug of the active antihistaminic molecule Fexofenadine. • It is not subjected to the interaction described above and has become available as a prescription drug.

  22. HISTAMINE H2 ANTAGONISTS • Cimetidine is the prototype. • These drugs do not resemble H1 blockers structurally. • They are orally active, with half-lives of 1-3 hours. • Because they are relatively non-toxic, they can be given in large doses, so that the duration of action of a single dose may be 12-24 hours.

  23. HISTAMINE H2 ANTAGONISTS MECHANISM AND EFFECTS • These drugs produce a surmountable pharmacologic blockade of histamine H2 receptors. • They are relatively selective and have no significant blocking actions at H1 or autonomic receptors.

  24. HISTAMINE H2 ANTAGONISTS MECHANISM AND EFFECTS… • The only therapeutic effect of clinical importance is the reduction of gastric acid secretion, but this is a very useful action. • Blockade of cardiovascular H2 receptor-mediated effects can be demonstrated but has no clinical significance.

  25. HISTAMINE H2 ANTAGONISTS CLINICAL USE • In acid-peptic disease, especially duodenal ulcer, these drugs reduce symptoms, accelerate healing, and prevent recurrences. • Acute ulcer is usually treated with 2 or more doses per day, while recurrence of the ulcer can often be prevented with a single bed-time dose.

  26. HISTAMINE H2 ANTAGONISTS TOXICITY • Cimetidine is a potent inhibitor of hepatic drug metabolizing enzymes and may reduce hepatic blood flow. • It also has significant anti-androgen effects in many patients. • Ranitidine has weaker inhibitory effect on hepatic drug metabolism; neither it nor the newer H2 blockers appear to have endocrine effects.

  27. SEROTONIN ( 5-Hydroxytryptamine, 5-HT ) Revision: • Discuss the distribution, biosynthesis, storage, release, re-uptake and degradation of 5-HT • What are the actions and functions of 5-HT? • Classify the main 5-HT receptor subtypes; in each state the location, main effects, agonists and antagonists

  28. 5-HT-Revision… • What are the important drugs that act on 5-HT receptors in the periphery?

  29. SEROTONIN ( 5-Hydroxytryptamine, 5-HT ) and Related Agonists • Serotonin is produced from tryptophan and stored in the enterochromaffin cells of the gut and in the CNS. • Degradation of 5-HT occurs mainly through oxidative deamination, catalysed by monoamine oxidase (MAO), followed by oxidation to 5-hydroxy-indoleacetic acid (5-HIAA), which is excreted in urine.

  30. Excess production of serotonin in the body can be detected by measuring its major metabolite, 5-hydroxy-indoleacetic acid ( 5-HIAA ), in the urine.

  31. Serotonin (5-HT)… • 5-HT appears to play a physiologic enteric role as a neurotransmitter in both the CNS and the nervous system and perhaps as a local hormone that modulates gastrointestinal tract activity. • 5-HT is also stored ( but synthesized to only a minimal extent ) in platelets. • Only one drug is in use for its 5-HT agonist effects i.e. specific agonist. (Revision-What is it? Its use??)

  32. Serotonin (5-HT)… • Answer: The drug is Sumatriptan, a 5-HT1D receptor agonist used to treat migraine. • Others include: Buspirone used in anxiety; • 5-HT4 receptor agonist metoclopramide used to stimulate gastric emptying. • Ergotamine is a partial agonist

  33. Serotonin (5-HT)… • Several drugs are in use or under investigation as 5-HT antagonists. (Revision- E.g??? Use???

  34. 5-HT Receptor Antagonists Revision • 5-HT3-receptor antagonists (e.g. ondansetron, granisetron; tropisetron) used as anti-emetic drugs particularly for controlling the severe nausea and vomiting that occurs with many forms of cancer chemotherapy.

  35. 5-HT Receptor Antagonists Revision… • 5-HT2-receptor antagonists (e.g. dihydroergotamine, methysergide, cyproheptadine, kentanserin, ketotifen, pizotifen). These ‘classical’ 5-HT antagonists act mainly on the 5-HT2-receptors. They are, however non-selective, and act also on targets, such as alpha-adrenoceptors andhistamine receptors.

  36. 5-HT Receptor Antagonists Revision… • Dihydrergotamine and methysergide belong to the ergot family and are used mainly for migraine prophylaxis. Ketotifen is sometimes used to treat asthma but the role of 5-HT receptors in this condition is unclear. Other 5-HT2 antagonists are used to control the symptoms of carcinoid tumours.

  37. RECEPTORS AND EFFECTS • 5-HT1 receptors:-Are most important in the brain and mediate synaptic inhibition via increased potassium conductance. • Peripheral 5-HT1 receptors mediate both excitatory and inhibitory effects in various smooth muscle tissues.

  38. 5HT2 receptors: Are important in both brain and peripheral tissues. These receptors mediate synaptic excitation in the CNS and smooth muscle contraction ( gut, bronchi, uterus, vessels ) or dilation ( vessels). The mechanism involves ( in different tissues ) decreased potassium conductance, decreased cAMP, and increased inositol triphosphate (IP3). In carcinoid tumor, this receptor probably mediates some of the flushing, diarrhoea, and bronchoconstriction characteristic of the disease.

  39. 5HT3 receptors: Are found in the CNS, especially in the chemoreceptive area and vomiting centre, in peripheral sensory and enteric nerves. These receptors mediate excitation via a 5-HT-gated cation channel ( i.e, the mechanism of serotonin at the 5-HT3 receptors resembles that of Ach at nicotinic cholinergic cation channels ). Antagonists acting at this receptor have proved to be of useful anti-emetic drugs.

  40. CLINICAL USE • Serotonin has no clinical applications. NB • Clinical conditions in which 5-HT plays a role: there are two situations in which the peripheral actions of 5-HT are believed to be important, are migraine and carcinoid syndrome

  41. OTHER SEROTONIN AGONISTS • Sumatriptan, a receptor agonist: It is a 5-HT1D agonist. • Effective in the treatment of acute migraine and cluster headache attacks- an observation that supports the association of 5-HT abnormalities with these headache syndromes. • It is available for oral, nasal, or parenteral administration.

  42. SEROTONIN RE-UPTAKE INHIBITORS • Used for treatment of depression. • Dexfenfluramine, a reuptake inhibitor with other effects, was used exclusively for its appetite-reducing effect. While effective as an anorexiant, it is toxic: cardiac disease in patients and neurological damage in animals were reported.

  43. 5-HT-ANTAGONISTS • Ketanserin is a 5HT2 and alpha-adrenoceptor blocker. • Phenoxybenzamine- an alpha-adrenoceptor blocker and Cyproheptadine a H1-blocker are also good 5-HT2 blockers. • Ondansetron is a 5-HT3 blocker.

  44. MECHANISMS AND EFFECTS of 5-HT-ANTAGONISTS • Ketanserin and Cyproheptadine are competitive pharmacological antagonists. • Phenoxybenzamine is an irreversible blocker.

  45. CLINICAL USE • Used in the treatment of carcinoid tumour, a neoplasm that secrete large amount of 5-HT ( and peptides ) and causes diarrhoea, bronchoconstriction, flushing. • Ondansetrone is extremely useful in the control of post-operative vomiting associated with cancer chemotherapy.

  46. TOXICITY • Adverse effects of Ketanserin are those of alpha blockade and H1 blockade. (H/W what are they?) • The toxicity of Ondansetron include diarrhoea and headache.

  47. ERGOT ALKALOIDS • The ergot alkaloids are partial agonists at alpha adrenoceptors and 5-HT receptors. • The balance of agonist-versus-antagonist effect varies from compound to compound. • Some are also agonists at the dopamine receptor.

  48. CLASSIFICATION AND PROTOTYPES • The ergot alkaloids may be subdivided into 3 major groups on the basis of the organ or tissue in which they have their primary effects. • This division is not absolute, since most of the alkaloids have some effects on several tissues.

  49. The brain is a target organ for several natural ergot alkaloids that cause the hallucinations and chemical psychoses associated with epidermics of ergotism. • The most important derivatives acting in the CNS are the semisynthetic drugs lysergic acid diethylamide-LSD and Bromocriptine. • The uterus is very sensitive to ergot alkaloids as term pregnancy nears but less so at other times.

  50. Ergonovine is a prototypical oxytocic ergot alkaloid. • Blood vessels are sensitive to ergonovine and other ergot drugs ergotamine is a prototype

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