2/20/20161 LOCAL HORMONES January, 2012

2/20/20162 Local Hormones Includes:-  Histamine  serotonin ( 5-HT )  Prostaglandins  vasoactive peptides- platelet activating factor (PAF), bradykinin, nitric oxide neuropeptides, cytokines

2/20/20163 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.

2/20/20164 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

2/20/20165 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.

2/20/20166 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.

2/20/20167 Histamine Receptors and Effects Produces its action by an effect on specific histamine receptors which are of three main types:- H 1, H 2 and H 3- receptors, distinguished by means of selective antagonist drugs. H 1 and H 2 receptors mediate most of the well-defined peripheral actions

2/20/20168 Histamine Receptors and Effects… a) H 1 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).

2/20/20169 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.

2/20/ b) H 2 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.

2/20/ Histamine Receptors and Effects… c) H 3 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.

2/20/ CLINICAL USE Histamine has no therapeutic applications, but drugs that block histamine’s effects are very important in clinical medicine

2/20/ HISTAMINE H 1 ANTAGONISTS A wide variety of antihistaminic H 1 blockers are available from different chemical families. Diphenhydramine and Chlorpheniramine may be considered prototypes. Because they have been developed for use in chronic conditions, H 1 blockers are all active by the oral route. Most are metabolized extensively in the liver.

2/20/ HISTAMINE H 1 ANTAGONISTS… Half-lives of the older H 1 -blockers vary from 4 hours to 12 hours. Several newer agents (“ second generation “ antihistamines, e,g. Terfenadine, Fexofenadine, Astemizole, Loratadine ) have half lives of hours and decreased CNS penetration.

2/20/ MECHANISM AND EFFECTS H 1 blockers are competitive pharmacologic antagonists at H 1 receptor, 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 H 2 receptors.

2/20/ MECHANISM AND EFFECTS… H 1 -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 H 1 blockers are potent local anaesthetics.

2/20/ 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 ).

2/20/ 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.

2/20/ 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.

2/20/ 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.

2/20/ 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.

2/20/ HISTAMINE H 2 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 hours.

2/20/ HISTAMINE H 2 ANTAGONISTS MECHANISM AND EFFECTS These drugs produce a surmountable pharmacologic blockade of histamine H 2 receptors. They are relatively selective and have no significant blocking actions at H1 or autonomic receptors.

2/20/ HISTAMINE H 2 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.

2/20/ HISTAMINE H 2 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.

2/20/ HISTAMINE H 2 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 H 2 blockers appear to have endocrine effects.

2/20/ 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

2/20/ HT-Revision… What are the important drugs that act on 5-HT receptors in the periphery?

2/20/ 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.

2/20/ Excess production of serotonin in the body can be detected by measuring its major metabolite, 5-hydroxy- indoleacetic acid ( 5-HIAA ), in the urine.

2/20/ 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??)

2/20/ 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

2/20/ Serotonin (5-HT)… Several drugs are in use or under investigation as 5-HT antagonists. (Revision- E.g??? Use???

2/20/ HT Receptor Antagonists Revision 5-HT 3 -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.

2/20/ HT Receptor Antagonists Revision… 5-HT 2 -receptor antagonists (e.g. dihydroergotamine, methysergide, cyproheptadine, kentanserin, ketotifen, pizotifen). These ‘classical’ 5-HT antagonists act mainly on the 5-HT 2 - receptors. They are, however non- selective, and act also on targets, such as alpha-adrenoceptors and histamine receptors.

2/20/ 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-HT 2 antagonists are used to control the symptoms of carcinoid tumours.

2/20/ RECEPTORS AND EFFECTS 5-HT 1 receptors:-Are most important in the brain and mediate synaptic inhibition via increased potassium conductance. Peripheral 5-HT 1 receptors mediate both excitatory and inhibitory effects in various smooth muscle tissues.

2/20/ HT 2 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 (IP 3). In carcinoid tumor, this receptor probably mediates some of the flushing, diarrhoea, and bronchoconstriction characteristic of the disease.

2/20/ HT 3 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-HT 3 receptors resembles that of Ach at nicotinic cholinergic cation channels ). Antagonists acting at this receptor have proved to be of useful anti-emetic drugs.

2/20/ 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

2/20/ OTHER SEROTONIN AGONISTS Sumatriptan, a receptor agonist: It is a 5- HT 1 D 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.

2/20/ 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.

2/20/ HT-ANTAGONISTS Ketanserin is a 5HT 2 and alpha- adrenoceptor blocker. Phenoxybenzamine- an alpha- adrenoceptor blocker and Cyproheptadine a H 1 -blocker are also good 5-HT 2 blockers. Ondansetron is a 5-HT 3 blocker.

2/20/ MECHANISMS AND EFFECTS of 5-HT-ANTAGONISTS Ketanserin and Cyproheptadine are competitive pharmacological antagonists. Phenoxybenzamine is an irreversible blocker.

2/20/ 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.

2/20/ TOXICITY Adverse effects of Ketanserin are those of alpha blockade and H 1 blockade. (H/W what are they?) The toxicity of Ondansetron include diarrhoea and headache.

2/20/ 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.

2/20/ 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.

2/20/ 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.

2/20/ Ergonovine is a prototypical oxytocic ergot alkaloid. Blood vessels are sensitive to ergonovine and other ergot drugs ergotamine is a prototype

2/20/ EFFECTS VESSELS: Ergot alkaloids can produce marked and prolonged alpha receptor- mediated vasoconstriction. An overdose can cause ischaemia and gangrene of the limbs.

2/20/ EFFECTS UTERUS: A powerful contraction occurs in this tissue near term. This is sufficient to cause abortion or miscarriage. After delivery of the placenta, ergonovine or ergotamine can produce a useful contraction of the uterus that reduces blood loss.

2/20/ BRAIN: Hallucinations may be prominent with the naturally occurring ergots and with lysergic acid diethylamide (LSD) but less common with therapeutic ergots. Although LSD is potent 5-HT 2 blocker in peripheral tissues, its CNS effects may be due to actions at dopamine receptors. In pituitary, some ergot alkaloids are potent dopamine-like inhibitors of prolactin secretion. Bromocriptine and Pergolide are among the most potent of the semisynthetic derivatives at these dopamine D 2 receptors and at similar receptors in the basal ganglia.

2/20/ CLINICAL USES Ergotamine is a mainstay of treatment of acute attacks of migraine. Methysergide and ergonovine are used prophylactically. Obstetric bleeding: Ergonovine and ergotamine are effective agents for reduction of postpartum bleeding

2/20/ Hyperprolactinemia and Parkinsonism: Bromocripine and Pergolide are used to reduce prolactin secretion ( dopamine is the physiologic prolactin release inhibitor ). Bromocriptine also reduce the size of pituitary tumours of prolactin-secreting cells. This drug is also useful in the treatment of Parkinson’s disease.

2/20/ OTHER USES Methysergide has been used in carcinoid tumour.

2/20/ TOXICITY VASCULAR EFFECTS Severe prolonged vasoconstriction can result in ischemia and gangrene. The only consistently effective antagonist is Nitroprusside

2/20/ Methysergide produces an unusual hyperplasia of connective tissue. Similar lesions are found in some patients with characinoid, suggesting that this action is probably mediated by agonist effects at serotonin receptors.

2/20/ GASTROINTESTINAL EFFECTS: They cause nausea, vomiting, diarrhoea in many individuals. UTERINE EFFECTS; Marked uterine contractions may be produced. Although abortion due use of ergot for migraine is rare, most obstetricians recommend avoidance.

2/20/ CNS EFFECTS Hallucination resembling psychosis are common with LSD but less common with other ergot alkaloids.

2/20/ VASOACTIVE PEPTIDES Include angiotensin, bradykinin, atrial natriuretic peptide, vasoactive intestinal peptide, substance P, calcitonin gene- related peptide, vasopressin, glucagons, and several opioid peptides

2/20/ MECHANISMS These agents probably all act on cell surface receptors. Most act via G protein-coupled receptors and cause the production of second messengers; a few may open ion channels.

2/20/ ANGIOTENSIN AND ITS ANTAGONISTS SOURCE AND DISPOSITION; Angiotensin I is produced from angiotensinogen by renin, a proteolytic enzyme released from the juxtaglomerular apparatus of the kidney.

2/20/ An inactive decapeptide, angiotensin I is converted into angiotensin II, an octapeptide, by angiotensin-converting enzyme (ACE), also known as peptidyl dipeptidase or kinisase II. Angiotensin II, the active form of peptide, is rapidly degraded by peptidases (angiotensinases ). H/W- Read on Renin-Angiotensin system

2/20/ EFFECTS Angiotensin II is potent arteriolar vasoconstrictor and stimulant of aldosterone release. A-II directly increases peripheral vascular resistance and, through aldosterone, causes renal sodium retention. A-II also facilitates the release of nor- adrenaline from adrenergic nerve endings via pre-synaptic hetero-receptor action.

2/20/ CLINICAL ROLE In the past it was used to control bleeding by intra-arterial in sites difficult to access. Its major clinical significance is as a pathophysiologic mediator in some cases of hypertension ( high-renin hypertension ) and in congestive heart failure.

2/20/ ANTAGONISTS Two types of antagonists are available. Angiotensin II receptor-blockers ( e,g, losartan, valsartan ) are orally active non-peptide inhibitors at the angiotensin II AT1 receptor.

2/20/ Saralasin, a peptide a partial agonist at this receptor, is not used clinically. Angiotensin-converting enzyme inhibitors (e.g, captopril, enalapril ) are important agents for the treatment of hypertension and heart failure.

2/20/ Blocking the effects of angiotensin by either of these drug types is often accompanied by a compensatory increase in renin and angiotensin I.

2/20/ BRADYKININ SOURCE AND DISPOSITION: Is one of several vasodilator kinins produced from kininogen by a family of enzymes, the kallikreins. Bradykinin is rapidly degraded by various peptidases, including angiotensin- converting enzymes.

2/20/ EFFECTS Bradykinin is one of the most potent vasodilator known. The peptide is thought to be inyolved in inflammation and cause oedema and pain when released or injected into tissue. Bradykinin can be found in saliva and may play a role in stimulating its secretion.

2/20/ CLINICAL ROLE Although it has no therapeutic application, bradykinin may play a role in the anti- hypertensive action of angiotensin- converting inhibitors. There are no clinically important bradykinin antagonists.

2/20/ ATRIAL NATRIURETIC PEPTIDE:[ ANP ] SOURCE AND DISPOSITION ANP also known as atrial natriuretic factor is synthesized and stored in the cardiac atria of mammals. ANP is released from the atria in response to distention of the chambers. ( Revision-release of ANP occurs during volume overload in response to stretching of the atria)

2/20/ EFFECTS of ANP ANP activates guanlyl cyclase in many tissues. It is a vasodilator as well as natriuretic (sodium excretion-enhancing ) agent. Its renal action includes increased glomerular filtration, decreased proximal tubular sodium reabsorption, and inhibitory effects on renin secretion.

2/20/ EFFECTS of ANP The peptide also inhibits the action of angiotensin II and aldosterone. Although it lacks positive inotropic action, atrial natriuretic peptide may play an important compensatory role in congestive cardiac failure by limiting sodium retention.

2/20/ CLINICAL ROLE ANP has been studied for possible use in the treatment of congestive cardiac failure. There are no clinically important products that act as agonist or antagonist at ANP receptors.

2/20/ ENDOTHELIN Are peptide vasoconstrictors formed and released by endothilin cells in blood vessels. Endothelins are believed to function as paracrine hormones in vasculature. Three different endothelin peptides [ ET-1, ET-2, and ET-3 ] with minor variations in amino acid sequence have been identified, both of which are G protein-coupled.

2/20/ Endothelin are much more potent than NA as vasoconstrictors and have a relatively long- lasting effect. The peptide stimulates the heart, increase atrial natriuretic peptide release, and activate smooth muscle proliferation. The peptides may be involved in some form of hypertensions and other cardiovascular disorders. Antagonists have recently become available for research use.

2/20/ VASOACTIVE INTESTINAL PEPTIDE, SUBSTANCE P, CALCITONIN GENE-RELATED PEPTIDE AND NEUROPEPTIDE Y Vasoactive intestinal peptide VIP is an extremely potent vasodilator but probably is physiologically more important as a transmitter. It is found in the central and peripheral nervous systems and in the G.I.T. No clinical application has been found for this peptide.

2/20/ Substance P Substance P is another neuro-transmitter peptide with potent vasodilator action on arterioles. However, substance P is a potent stimulant of veins and of intestinal and airway smooth muscle.

2/20/ Substance P… The peptide may also function as a local hormone in the G.I.T. Highest concentrations of substance P are found in those parts of the nervous system that contain neurons subserving pain.

2/20/ Substance P… At the present time, there are no clinical applications for substance P or its antagonists. However, capsaicin, the ‘hot’ component of chilli peppers, release substance P from its stores in nerve endings and depletes the peptide. Capsaicin has been approved for topical use on arthritic joints.

2/20/ Calcitonin Gene Related Peptide Calcitonin gene-related peptide ( CGRP ) is found in high concentrations in the thyroid and is also present in most smooth muscle tissues. The presence of CGRP in smooth muscle suggests a function as a co-transmitter in autonomic nerve endings.

2/20/ Calcitonin Gene Related Peptide CGRP is the most potent hypotensive agent discovered to date and cause reflex tachycardia. There is no clinical application for this peptide at present.

2/20/ Neuropeptide Y Unlike the three peptides described above, (i.e. VIP, Substance P, CGRP), neuropeptide Y ( NPY ) is a potent vasoconstrictor that stimulate the heart. NPY is found in both the CNS and the peripheral nerves. In the periphery, NPY is most commonly localized as a co transmitter in adrenergic nerve endings.

2/20/ Further reading on: Prostaglandins Platelet activating factor Nitric oxide (revision) neuropeptides Cytokines