TU SOND AO ea MULL GON AUTACOIDS- HISTAMINE ™ Autacoids- oooee , Histamine vas 3 AUTACOIDS Classification of Autacoids = aka. “Local hormones” = endogenous substances with biological | 1.Biologically active amines activity. VHistamine = not released or stored in glands. vy Serotonin = not circulated in blood. ire formed at the site of action. j roduce localized action. , b 8Classification of Autacoids Classification of Autacoids 2Lipid derived autacoids 4. Vasoactive tides (Eicosanoids) noes ¥ Prostaglandins BM YAngiotensin VLeukotrienes YEndothetin vy Thromboxanes mm /Natriuretic peptide % Fi, vVasopressin 3.Ergot Alkaloids yy substance P 5. Endothelium derived autacoids Nitric oxide — — A. HISTAMINE Distribution of Histamine Z CHI o Histamine is found L-Hisldine —0H;— CN, decarboxylase iit in many tissues, — ys including the brain. o itis stored and found — Histamine in the highest nisaaine amounts in mast cells and basophils. crs ‘mast cells oration‘Two processes by which HISTAMINE IS RELEASED 1. Energy- and Ca2+ -dependent degranulation] reaction. Immunologic Release 2. Energy- and Ca* - independent release (displacement). Types of Histamine Receptors Receptor] Distibution | _ Post ° Partial ‘Type Receptor Ag ‘Antagonists Mechanism 1, [Smooth muscle, | 193,086 2m Mepyeanine, fendetesum, | (Sq) Fuuoropneny)- | Tprobaine brain histamine Hy | Gastiemucosa, |; GAMP(Gs) [Dimaprt, | Raniane ‘cardiac muscle, Impromine, | Tietaine mast ell, bain ‘Amibamine [Presynaptic | cAMP. | Ra.Methyi | Thoperamide, brain,myenter | Ca (Gi) Hisgmine, | iodophenpropit met. Immepip | Ciobenpront ‘obenpropt. | Theperamae met, Clozapine 2. Energy- and Ca* - release (displacement). Chemical & Mechanical Release Occurs following chemical _ or} independent mechanical injury to mast cells. » Displacement is induced by drugs such morphine, tubocurarine, guanethidine, and amine antibiotics. » does not require energy H1 receptors le H,-receptors. Location: Location: found in the brain, Receptors found inthe bain, heart, bronchi, hear, vasculature, gastrointestinal ‘and parietal tract, and vascular ‘smooth muscles. /\ i we Gee to ' Ineretes watefatnes Increase acid tr nerese a perma aeused in allergy testing to assess histamine sensitivity in the test of gastric secretory function function (they have been largely supplanted for this use by pentagastrin) HISTAMINE AGONISTS = Histamine alpha methylhistamine is an Hy-specific agonist. = Betazole (histalog) tenfold greater activity at Hereceptors than at H-receptors impromidine investigational agent; its ratio of H,:H, activity is about 10,000 Adverse effects of HISTAMINE AGONISTS > Flushing Hypotension Tachycardia Headache Fo Wheals = © Bronchoconstriction © Gastrointestinal upseto Aka : classical ANTIHISTAMINES 1. 15 Generation Antihistamines 2. Ethanolamines: antiemetics » competitive inhibitors at the H1- e Carbonoxamine, Dimenhydrinate, receptor. Diphenhydramine, Doxylamine steping a) [| ». Ethylaminediamines: Pyrilamine, Tripelennamine ‘protuce moderate sedation ‘ean cause gastrointestinal upset CLASSES of Histamine (H1)- receptor antagonists Piperazine: Anemetcs, nt-motion Hydroxyzine, Cyciizine, Meciizine 1. Alkylamines: Brompheniramine, Chlorpheniramine . Phenothiazines: Promethazine antiemetic ‘weak alpha-adrenoceptor antagonist Miscellaneous: Cyproheptadine antihistamine, anticholinergic, 2, 24 Generation Antihistamines a. Piperidines: Terfenadine (Seldane) Fexofenadine Astemizole (Hismanal) A vennetrteryearaa ». Miscellaneous: Loratidine, Cetirizine ‘Poor CNS penetration, less sedatingPharmacokinetic Properties of Hi Blocking ‘A. well absorbed after oral administration. oNormal effects seen in 30 minutes (with maximal effects at 1-2 hours) The duration of action is 215% generation compounds:3-6 hours 22% generation compounds: 3-24 hours. B. lipid-soluble = cross the blood-brain barrier ¢. metabolized in the liver; smany induce microsomal enzymes and alter their own metabolism ¥ ethanolamine, phenothiazines, and ethylenediamines = have ANTICHOLINERGIC activity. block mucus secretion and sensory nerve stimulation. effective local anesthetics Eg. Dimenhydrinate and promethazinePharmacologic Actions - H-receptor antagonists relax histamine-induced contraction of bronchial smooth muscle and have some use in allergic bronchospasm. block the vasodilator action of my histamine. £) inhibit histamine-induced increases in capillary permeability. Therapeutic Uses Pharmacologic Actions- H11-receptor ¥ frequently cause CNS depression Ii (marked by sedation, decreased B alertness, and decreased appetite) ¥ In children and some adults, these agents stimulate the CNS. » Treatment of allergic rhinitis and conjunctivitis. V reat the common cold based on their anticholinergic properties Diphenydramine also has an antitussive effect not mediated by H1-receptor antagonism.Therapeutic uses ‘Treatment of urticaria and atopic dermatitis, including hives Sedatives ‘v Several (doxylamine, diphenhydramine) are marketed as over-the-counter (OTC) sleep aids. Prevention of motion sickness Appetite suppressants © Sedation (synergistic w/ alcohol, other depressants, dizziness, and loss of appetite. CAUTION: drivers and machine operators gastrointestinal upset, nausea, constipation and diarrhea. anticholinergic effects (dry mouth, blurred vision, and urine retention). Effects (significantly reduced with ssecond-generation agents) H2-receptor Antagonists (1) Histamine (H2)-receptor antagonists include ¥ Cimetidine (Tagamet) v Ranitidine (Zantac) v Famotidine (Pepcid AC) fl v Nizatidine (Avid) (2) competitive antagonists at the H2- receptor, which predominates in the gastric parietal cell.USEIS: « treatment of gastrointestinal isorders: 5 \ heartbum and acid-induced indigestion promote the healing of gastric and duodenal ulcers \ hypersecretory states such as Zollinger- Ellison syndrome 1. poorly absorbed salts; ROUTE of admin: inhalation 2. They inhibit the release of histamine and other autacoids from the mast cell "4 ***increase influx of Chloride ions 3. Prophylactic agents in asthma Inhibitors of histamine 8 vcromolyn (Intal) vnedocromil sodium 4, Nedocromil sodium - appears to be more effective in reducing bronchospasm caused by exercise or cold air. 5. adverse effects: sore throat and dry mouth.PART 2 men AGENTS USED IN PEPTIC ULCER DISEASE PHYSIOLOGY OF GASTRIC ACID SECRETION ——— CONTENTS = Physiology of gastric acid secretion «= Introduction to PUD = Anti ulcer drugs Histamine PGE: AcetyichalineGastrina o]More INVA Ntael Ook Peptic Ulcer Exepnaged WY ‘ tler a = a circumscribed y , gastric ulcer Duodenal ulcer system exposed to gastric juices containing acid and pepsin. “EP OECERATION Letter lO eel mailer Ln * Helicobacter pylori Sry TM coc Surgery, Severe medical illness)NSAIDS rout ey Pee ed ott ey Peete et eee ee Seer raland per od eet ee Piccard a): 10 Nel ENCANA ie ato ag aA Se eee oy F Signs and symptoms: rat = gnawing, burning or aching pain (tends to worsen at night and ocours 1-3 hours after More often in meals) ere ete = nausea, vomiting, belching and significant weight loss. Cee er Re eeu EoseS Te a Complications of PUD iy Bleeding — - occurs in 25-33%of patients eS Te a Complications of PUD i ‘Obstruction from edema or scarring — often due to pyloric channel ulcers - most frequent complication and maybe life- - occur with duodenal ulcer threatening - causes incapacitating, crampy abdominal - account for 25% of ulcer deaths pain = may be the first indication of an ulcer = may lead to total obstruction with 2. Perforation intractable vomiting / - accounts for 2/3 of ulcer deaths. hd ieee ae Goal of therapy with anti-ulcer drugs — occurs in about 5% of the patient! ¢ L Intractable pain i 1. reduce gastric acid production 2. neutralize gastric PH 3. protect the walls of the stomach from the acid and pepsin released by the stomach 4. treat peptic ulcer and reflux esophagitis ooeC Ese h H2 receptor antagonists rege en ee o Commerce “tidine” Te eur) Et x Cimetidine Ranitidine Nizatidine Famotidine —_ (“ aMNIGHEFeSFGAStric Acid Production H2 receptor antagonist 1. H2 receptor antagonists Mechanism of ‘\A use; moti os > = GERD . » ~ Duodenal and gastric ulcer decrease gastric — Sroncilcerdyeneneia acid secretion - - prophylaxis for recurrent ulcers in patients through =m - control of reflux esophagitis and bile reflux competitive _— gastritis inhibition of Hz ~ prevent aspiration pneumonia receptors - Hypersecretory states— ae ‘hwy Wve "Ts i> Useless side Prva ey Sila Ook Gti Gxt ea her lee tris fel famosa rs Lam jai ie lemernme a — H2 receptor antagonist A. Cimetidine major adverse effects include : 1 thrombocytopenia 1 gynecomastia and impotence — ise ise few ete ‘ave ‘apres ‘epsenssh = iano (androgen receptor antagonist) = reduces ac Di mental confusion in the elderly Clow incidence of mild gastrointestinal upset, headache — H2 receptor antagonist A. Cimetidine secretion by 70% for 4-5 hours (300mg qid) = bioavailability is reduced by antacids = decreases the absorption of ketoconazole — H2 receptor antagonist A Cimetidine Potent inhibitor of CYP450 CIV: dementation and bradycardia (elderly)—— H2 receptor antagonist « B. Ranitidine — five to ten times more potent than cimetidine - does not bind to androgen receptor ~ secreted in milk therefore it should not be given in lactating mothers - low incidence of headache and cutaneous rash - hepatotoxic _—— H2 receptor antagonist ad. Nizatidine (as effective as ranitidine and may be ‘administered once daily Cimay produce hepatotoxicity but it does. not inhibit drug metabolism in the absence of liver damage does not bind to androgen receptors — H2 receptor antagonist «0c. Famotidine Clapproximately twice as potent as ranitidine tachyphylaxis compromise its long term use -has a longer duration of action -produces fewer side effects similar to those of ranitidine mild cardiotoxig Most Potent H2 blocker Comparison of H2 antagonists cry— QUESTION: » Your friend wants to take H2 blocker before he takes alcohol to avoid gastric irritation. Which H2 blocker is the most appropriate for him to take? Ranitidine Famotidine Cimeti ‘A. Inhibitors of Gastric Acid Production 2. Proton pump inhibitors (PPIs) “prazole” Omeprazole Lansoprazole Rabeprazole Pantoprazole, Esomeprazole — Explanation: «All H, antagonists inhibit gastric first pass metabolism of alcohol increasing its bioavailability except Famotidine |" aaNAIGHOPESFGAStric Acid Production 1. Proton pump inhibitors (PPI’s) USES: -GERD ~ Duodenal and gastric ulcer. H.pyloriulcer, NSAID-induced ulcer Prevention of rebleeding from peptic ulcer - non-ulcer dyspepsia - Prevention of stress-related mucosal bleeding - Gastrinoma and Hypersecretory states_— 2. Proton pump inhibitors (PPI's) «= a, Omeprazole Cigiven as delayed release capsule because of acid lability Cantisecretory effects occurs within 1 hour with the maximum effects occurring within 2 hours | -ciitiotompumpeinhibitors (PPI’s) «= b. Lansoprazole ~ acid labile and administered as an enteric coated tablet prodrug that requires protonation for activation = most effective when given 30 to 60 mins before meals its acid inhibitory effects is greater than 24 hours ~ adverse effects include abdominal pain, nausea and diarrhea it can increase theophylline clearance itis contraindicated in asthma — 2. Proton pump inhibitors (PPI's) = a, Omeprazole lit may produce abdominal pain, nausea, diarrhea, vomiting, rash, constipation, headache, asthenia and back pain may inhibit the metabolism of warfarin, diazepam, and phenytoin iit inhibits the absorption of ketoconazole contraindicated in pregnancy To EO ea) Coe eo ca ee ce Colca uc_ White more poentn reding aed secretion?) ABWIMBREPFaF Gost Aid Production 3. Anticholinergics = Includes propantheline, isopropamide and scopolamine - decrease ACh-stimulated secretion and motilty in the gastrointestinal tract = required doses produce systemic anticholinergic effects - they are rarely used alone but they are useful as adjuncts in patients resistant to H2 blockers a B. Mucosal Protective agents B. Cytoprotective agents = a. Sucralfate ~a salt of sucrose complexed to sulfated aluminum hydroxide - has an affinity for exposed proteins in the crater of peptic ulcer ~ protects ulcerated areas from further damage and promotes healing_—— B. Cytoprotective agents «a. Sucralfate - MOA: stimulates mucosal production of prostaglandins and inhibits pepsin ~ itmay produce constipation and nausea, gastric discomfort, indigestion, dry mouth, rash, pruritus, back pain, dizziness, sleepiness and vertigo, hypophosphatemia Nelle COC Pao vided (as it aus eM U ce ME UC on DCE oe to See et ee eer eet Dee PS Gud - ‘Suerte we » ea ome B. Cytoprotective agents = b, Misoprostol — A prostaglandin E1 analog = more water soluble and it has a half-life than naturally occurring prostaglandin - inhibits gastric acid secretion and increases mucosal resistance———_ 4. Cytoprotective agents = b. Misoprostol MOA - increases mucus and bicarbonate secretion by the gastric epithelium by increasing epithelial regeneration and by enhancing mucosal blood fiow, thus enhancing mucosal protection ***produces uterine contractions therefore contraindicated in pregnancy — Mucosal protective agents Colloidal Bismuth Compounds sbismuth subsalicylate sbismuth subcitrate sbismuth dinitrate 8 Siutue nd pte cet niopal Psa, = MOA: «coats ulcers and erosions, creating a protective layer against acid and pepsin. « It may also stimulate prostaglandin, mucus, and bicarbonate secretion— Bismuth « has direct antimicrobial effects and binds enterotoxins, accounting for its benefit in preventing and treating traveler's diarrhea. « direct antimicrobial activity against H pylori — Bismuth « Adverse Effects = causes blackening of the stool Liquid formulations may cause harmless darkening of the tongue. «= Bismuth agents should be used for only short periods and should be avoided in patients with renal insufficiency. « bismuth toxicity resulting in encephalopathy (ataxia, headaches, confusion, seizures). — Bismuth = Clinical Uses = nonspecific treatment of dyspepsia and acute diarrhea = prevention of traveler's diarrhea (30 mL or 2 tablets four times daily) « for the eradication of H pyloriinfection —— CARBENOXOLONE = synthetic derivative of glycyrrhizic acid = heals both gastric and duodenal ulcers MOA: increases production, secretion and viscosity of intestinal mucus NE: Aldosterone effect——— QUESTION A patient comes to your clinic at midnight complaining of heart burn. You want to relieve his pain immediately. What drug will you choose? C. Antacids (weak bases that are taken orally and that partially neutralizes gastric aci and reduce pepsin activity. (reduce the pain associated with ulcers and may promote healing high doses are required for healing : 40 mEq of base seven times daily —— Answer is = ANTACIDS = Explanation, Antacids neutralize the already secreted acid in the stomach, All other drugs act by stopping acid secretion ‘and so may relive the symptoms at least 45 minutes. —— Antacids = Types of antacids Systemic antacids «Sodium bicarbonate =Calcium carbonate— Antacids (cont'd) eve a = Nonsystemic antacids Aluminum hydroxide (Amphojel) Dihyroxyalumium sodium (Rolaids) Calcium carbonate (Tums) (Magaldrate (Riopan) (Magnesium hydroxide and aluminum hydroxide (Maalox, Mylanta, Gelusil) i Gat — Differences in the types of Neutralizing capacity Antacids = Cation content = ANC = number of mEq of HCI required to maintain 1 Neutralizing capacity ‘mi of an antaced suspension at pH 2 for2 bein = Duration of action + Factors that can cause variation in the rate of + Side effects neutralization [DDegren of eonninion ee (ental frm Preciptants used [Presence of reactne suspending agents—_ Dosing interval « Ideal antacid should be rapid in onset and provide a continuous buffering action » Rapid onset: Mg(OH),, MgO, CaCO, = Slow onset: Mg trisilicate and aluminum compounds —_ Side effects « Systemic antacid: Sodium bicarbonate Soluble and readily absorbed [2Can cause electrolyte disturbance and alkalosis «= Non- systemic antacids: Al, Ca, Mg (Form insol compounds in the GIT —_ Dosing interval Duration of buffering action = determined by the administration of antac = With food: action will last for 2 hr = An additional 3 hr meals will extend the buffering time by 1 hr « Ideal dosing interval: 1 and 3 hr after meals and at bedtime ——_ The patient « Patients with increase risk of antacid toxicity (Heart failure = excess sodium intake (inc. toxicity) Renal failure = should not use magnesium Containing antacids (can cause hypermagnesemia) or sodium bicarbonate ( systemic alkalosis) = given with aluminum containing antacids for their phosphate lowering effect—— Antacids - The Oldest Remedy C. Antacids » Sodium bicarbonate absorbed systemically and should not be used for long-term treatment contraindicated to hypertension due to its high sodium content mea renee tee Eco Ses Ese) SP eee ene ere Sant Ect Ts ee i) _—— C. Antacids C. Antacids = Calcium carbonate pattially absorbed from the gastrointestinal = Magnesium hyurosice tract and have some systemic effects (not absorbed in the GIT therefore should not be used for long term use produces no systemic effects ‘may stimulate gastrin release and thereby ican be used for long term therapy ‘cause rebound acid production Cimay produce diarrhea ‘contraindicated in renal disease = ADR: = Magnesium containing preparation Hypercalcemia, Alkalosis Sbiartee Renal faire (mik-akali syndrome) feripeenagresenal——— C. Antacids = Aluminum hydroxide Chas no systemic effects and causes constipation CAIso hypophosphatemia and osteomalacia = Prolonged Aluminum use Phosphate depletion Osteoporosis, osteomalacia, neurotoxicity —— C. Antacids = Combination products various preparations that combine magnesium hydroxide and aluminum hydroxide «to achieve a balance between agents, adverse effects on the bowel = Examples of which are Maalox, Mylanta and Gelusil. — Therapeutic question « Is it rational to combine aluminum hydroxide and magnesium hydroxide in antacid preparations? —— C. Antacids Combination products ‘Combine fast and slow reacting antacids to obtain a product with a rapid onset and relative even, sustained action. Lower the dose of each component and ‘minimize the possibilty of certain ADR Use one component to antagonize one or more side effects of another component— _——— Simethicone Somatostatin + is.a 14 amino acid peptide that is released ING onl arioee in the gastrointestinal tract and pancreas = Used to defoam gastric juice to decrease from paracrine cells, D-cells, and enteric the incidence of gastroesophageal reflux nerves as well as from the hypothalamus « short hall-ife in the circulation (3 minutes) ‘when itis administered by intravenous injection I phe Itis a key regulatory peptide that has myriad physiologic effects: = 1. Itinhibits the secretion of numerous = 3. It slows gastrointestinal motility and hormones, including gastrin, inhibits gallbladder contraction. cholecystokinin, glucagon, growth «= 4. Itinduces direct contraction of vascular hormone, insulin, secretin, pancreatic ‘smooth muscle, leading to a reduction of polypeptide, vasoactive intestinal peptide, portal and splanchnic biood flow. and 5- HT3. « 5. Itinhibits secretion of some anterior = 2. It reduces intestinal fluid secretion and pituitary hormones. pancreatic secretion._— Octreotide « is a synthetic octapeptide with actions similar to somatostatin. «= When administered intravenously, it has a serum half-life of 1.5 hours. + Italso may be administered by ‘subcutaneous injection, resulting in a 6- to 12-hour duration of action. = A longer-acting formulation is available for ‘once-monthly depot intramuscular injection, aT oem) The BEST among all the Triple therapy regimen is: Cero mer orl Sune — Octreotide Adverse Effects «= Impaired pancreatic secretion may cause steatorrhea, which can lead to fat-soluble vitamin deficiency. «= Alterations in gastrointestinal motility cause nausea, ‘abdominal pain, flatulence, and diarrhea = acute cholecystitis «+ Prolonged treatment with octreotide may result in bypothyroidism, «= can cause bradycardia, CHeiabaer eatin fata eg, shtemtpty / soi’ (2x00 nda 7095, aitronyin® (x 5 mia 75 \ Onepanle (2x Agha Tes “Hl, retin (2 500 nly) 7saT SMe Renee Rg cee ea Se eer Pe aT EO (octvates release (euppression of gare acid {neutralize gastric acid) —e aU eMC) eeeone Rea eC ae — Nonpharmacologic Measures = Avoid tobacco = Avoid alcohol » Weight loss = Avoid hot, spicy, and greasy foods « Take any NSAIDs including aspirin and oral glucocorticoids with food or in deceased dosage « Sit upright = Do not eat before bed = Wear loose-fitting clothing