Pharmacology of Common Agents Used in Gastrointestinal Conditions
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1 Pharmaclgy f Cmmn Agents Used in Gastrintestinal Cnditins Cmmn agents used in GERD/Hyperacidity Prtn Pump Inhibitrs (PPI) - They are pr-drugs that require activatin in an acidic envirnment. They get activated in gastric parietal cells and inhibit the H + /K + ATPase enzyme system (prtn pump), thereby inhibiting acid secretin Generally well tlerated Pssible rebund increase in gastric acidity upn discntinuatin f medicatin Assciated with an increased risk fr develping acute gastrenteritis and cmmunity acquired pneumnia Lansprazle (safety/efficacy in children under 1 years f age has nt been studied) Omeprazle (FDA apprved fr children ver 1 years f age) Pantprazle (limited data fr use in children) Rabeprazle (safety/efficacy in children under 18 years f age has nt been studied) H2 receptr antagnists - They reduce acid secretin by acting as cmpetitive, reversible inhibitrs f the H 2 receptr. They als decrease the acid-secretry respnse f the parietal cell t stimulated acid secretin frm chlinergic agents, gastrin, fd and vagal stimulatin - Tlerance t acid suppressing effects f H 2 blckers is cmmn with cntinued drug administratin (can be as early as 3 days int curse f treatment). This is nt seen with the PPIs Abdminal pain, bradyarrhythmia (rare) Pssible rebund increase in gastric acidity upn discntinuatin f medicatin Assciated with an increased risk fr develping acute gastrenteritis and cmmunity acquired pneumnia Ranitidine Famtidine - Dsing Dse adjustments need t be made fr patient with renal impairment
2 Cmmn Agents Used fr Bwel Mtility Dpamine receptr antagnists - Dpamine reduces lwer esphageal sphincter and intragastric pressures. This is mediated by suppressin f acetylchline (Ach) release frm myenteric mtr neurns - By antagnizing the inhibitry effect f dpamine f myenteric mtr neurns, dpamine receptr antagnists are effective as prkinetic agents. They als help relieve nausea and vmiting by antagnizing dpamine receptrs in the chemreceptr trigger zne - Direct activatin f muscarinic receptrs is nt a very effective strategy fr treating GI mtility disrder because they enhance cntractins in an un-crdinated fashin. This prduces little prpulsive activity - Dpamine receptr antagnists dn t have significant effects n lwer GI mtility (eg: small bwel dysmtility) Extrapyrimidal symptms (EPS), headache, fatigue, asthenia, neurleptic malignant syndrme (rare) Metclpramide (useful in gastrparesis, as it accelerates gastric emptying and als has antiemetic effects) Dse adjustments needed fr patients with renal impairment Dmperidne Predminantly antagnizes D 2 receptrs. It is less likely t cause EPS, as it desn t readily crss the bld-brain barrier Use in children is nt recmmended unless in chemtherapy r radiatininduced nausea/vmiting Cmmn Agents Used fr Cnstipatin Osmtically active agents - They prduce an smtic effect in the cln t cause water retentin, distensin and prmtin f peristalsis Abdminal distensin and discmfrt, flatulence Saline laxatives such as magnesium citrate (need t be used with cautin in patients with renal insufficiency) Nndigestible sugars and alchls (eg: lactulse) Stl sfteners and emllients - Reduces surface tensin f the il water interface f the stl. This leads t enhanced incrpratin f water and fat int the stls t sften them - Patients taking these medicatins need t have adequate fluid intake Dcusate salts
3 Cntraindicated in cncmitant use f mineral il, intestinal bstructin, acute abdminal pain, nausea, vmiting Mineral il Rare lipid pneumnitis due t aspiratin can ccur, s heavy mineral il shuld nt be taken at bed time, and light (tpical) mineral il shuld never be administered rally Cntraindicated in patients with a clstmy, ilestmy, appendicitis, ulcerative clitis, diverticulitis, dysphagia, r hiatal hernia Stimulants - They have direct effects n entercytes, enteric neurns and GI smth muscle. They likely induce lw-grade inflammatin in the small and large bwel t prmte accumulatin f water an electrlytes and stimulate intestinal mtility - Prlnged use f these medicatins shuld be avided, as it can lead t dependence - Cntraindicated in patients with undiagnsed abdminal pain, appendicitis, intestinal bstructin r perfratin Senna, castr il, bisacdyl Enemas and Suppsitries - Enemas cause direct bwel distensin, and prduces an evacuatin reflex in mst peple. Sme enemas have additinal substances that are either smtically active r irritant - Glycerin acts a hydrscpic agent and lubricant when given rectally. The resultant water retentin stimulates peristalsis and usually prduces a bwel mvement in less than 1 hur. Glycerin is fr rectal use nly, as the ral frm is absrbed, and desn t reach the bwel t exert this effect Cmmn Anti-diarrheal agents Bismuth subsalicylate (Pept-Bisml) - It adsrbs extra water in large intestine, as well as txins. It frms a prtective cat n the intestinal mucsa, and appears t have antisecretry and antimicrbial effects - It is cntraindicated in children r teenagers with r recvering frm influenza r varicella (risk f Reye s syndrme). It is als cntraindicated in patients with a histry f severe GI bleeding r cagulpathy - Use cautin in children < 3 years f age - Adverse effect: dark stls (smetimes mistaken fr melena), impactin may ccur in infants and debilitated patients Opiids - They act by several different mechanisms, mediated mainly thugh either u r delta piid receptrs n enteric nerves, epithelial cells, and muscle. Tgether, they inhibit intestinal mtility (μ receptrs), intestinal secretin (δ receptrs), r absrptin (μ and δ receptrs) - Opiids that d nt penetrate the CNS are preferred ver nes that d Drwsiness (unlikely), risk f txic megacln, xerstmia, urinary retentin
4 Lperamide (acts mainly via peripheral μ piid receptrs) Increases small intestinal and muth t cecum transit time, and increases anal sphincter tne Use cautin in patients with active inflammatry bwel disease invlving the cln because f the risk fr txic megacln Cntraindicated in children < 24 mnths f age; ulcerative clitis; infectius diarrhea that results frm rganisms that penetrate the intestinal mucsa; bldy diarrhea Antinausseants and antiemetic agents - Vmiting is cntrlled by the vmiting center f the medulla, and has input frm at least 4 surces (chemreceptr trigger zne, crtex, vestibular apparatus, GI tract). These pathways mediated by neurtransmitters (eg: 5HT) - Since multiple neurtransmitters are invlved in vmiting, a number f agents frm varius drug classes can be used t treat vmiting - Varius clinical factrs (eg: emetgenic ptential f chem drugs) determine efficacy f antiemetics Dpamine receptr antagnists - Prmethazine Blcks pstsynaptic meslimbic dpaminergic receptrs in the brain Cautin: avid use in children <2years f age due t ptential fatal respiratry depressin. Als avid use with any medicatins that may have respiratry depressant effects Adverse effects: risk f neurleptic malignant syndrme (esp. when used with antipsychtic drugs), phttxicity, xerstmia, CNS depressin, lwered cnvulsive threshld, respiratry depressin - Phenthiazines (eg: prchlrperazine, chlrprmazine) They are D 2 receptr antagnists at the CTZ. They are nt as effective in cancer r chem induced emesis as ndansetrn r metclpramide They als have antihistamine and antichlinergic prperties which are useful in ther frms f nausea such as mtin sickness - Metclpramide Dse adjustment needed fr patients with renal impairment : drwsiness, EPS, hallucinatin, cnvulsin, neurleptic malignant syndrme (rare), phtsensitivity Antihistamine - Dimenhydrinate Cmpetes with histamine fr H 1 receptr sites n effectr cells in the GI tract, bld vessels, and respiratry tract. This diminishes vestibular stimulatin and depresses labyrinthine functin thrugh central antichlinergic activity Cautin in nenates (gasping syndrme: metablic acidsis, respiratry distress, gasping respiratins, CNS dysfunctin, hyptensin, cardivascular cllapse) because f benzyl alchl in the IV frmulatin Apprved fr children 2 years f age Use f the IV rute in children is nt recmmended (use IM instead)
5 : drwsiness, xerstmia, blurred visin (rare) Gluccrticids and anti-inflammatry agents - They can be useful in patient with widespread cancer, pssibly by suppressing peritumral inflammatin and prstaglandin prductin Sertnin antagnist - They inhibit 5HT 3 receptrs present bth centrally (medullary chemreceptr zne) and peripherally (GI tract) t inhibit visceral afferent stimulatin f the vmiting center : Ondansetrn Effective in preventing chem r radiatin induced nausea and vmiting, with very few adverse effects Oral ndansetrn therapy, as a single dse, can be used fr infants and children wh present t the emergency department with vmiting related t suspected acute gastrenteritis, and wh have mild t mderate dehydratin There is n FDA apprved dse fr children < 4 years f age, but dsing based n bdy surface area has been used Adverse effects: Mst cmmn is diarrhea (thus it is nt recmmended in patients wh are cmplaining f diarrhea), anxiety, drwsiness, headache Ptential t blck cardiac sdium r ptassium channels, resulting in prlngatin f QRS/QTc interval respectively Granisetrn, dlasetrn, palnsetrn References 1. Cheng A. Emergency department use f ral ndansetrn fr acute gastrenteritisrelated vmiting in infants and children. Paediatr Child Health 2011;16(3): Taketm CK, Hdding JH, Kraus DM. Pediatric Dsage Handbk. 16 th ed. Lexi- Cmp; Bruntn LL (ed). Gdman and Gilman s The Pharmaclgical Basis f Therapeutics. 11 th ed. New Yrk: The McGraw-Hill Cmpanies Inc; Repchinsky C (ed). Cmpendium f Pharmaceuticals and Specialties. 46 th ed. Canadian Pharmacists Assciatin; Acknwledgements Written by: Daniel Li RPh., BScPhm., Rui Chen Edited by: Dianna Luie
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