Gastrointestinal Pharmacology PDF

Reb bound hyp peracidity a2+ and y: with Ca NaH HCO3 containing anta acids. Cattion overlo oad: – Na+ saltss → hyp pertension...

Reb bound hyp peracidity a2+ and y: with Ca NaH HCO3 containing anta acids. Cattion overlo oad: – Na+ saltss → hyp pertension n and ssystemic alkalosis. a – C 2+ Ca saltss → hyperrcalcemia, renal sstones and d milk-alk kali syndro ome. Dec crease ab bsorption of other d drugs: the e metal ion n in some preparatio ons can che elate other drugs esp pecially tetrracycline, digitalis d an nd iron. N.B. wwhen iron or o tetracyccline is pre escribed with w antacid ds, we sho ould make 30 min interval between both drugs to avoid chelationn with the antacid. a █ DEC CREASE HCL H SECR RETION 1. Sellective M1 blocke ers: (Pirenz zepine - Te elenzepine) Mecha anism of action: selectively s astric M1 receptors → ↓ bas block ga sal HCl secretio on. Uses: TThe selecttive M1 blo ockers are hibitors of HCl secreetion and are e weak inh a now replace ed by morre effectivee drugs. T They are sometimes s s used as adjuvant therapy with H2 blockers. Advers s: high do se effects oses prod pine-like effects: dryy mouth, blurred duce atrop vision, tachycardia, urine re etention. N.B. Attropine itse elf is not used u in the e treatment of PU be ecause it iss non-sele ective M blockerr and may y aggravatte esophag geal reflux x. 2. H2 blockerrs: (Cimettidine – Ra anitidine – Famotidi ne - Nizattidine) Mecha anism and pharmac cological e effects  Theey act as competitive c e inhibitorss of histam mine H2-receptors onn the parie etal cell. Thiss results in d ↓ in histam n a marked mine-stimu ulated HCl secretion.  Alth hough othe er agents such as gastrin an nd ACh maym inducee acid seecretion, histtamine is thhe predom minant final mediator that stimulates HCl ssecretion. 254 Therapeutic uses  Duodenal and gastric ulcers.  Prophylaxis & treatment of stress ulcers (e.g. after burn or major trauma).  Prophylaxis against bleeding of esophageal varices.  Reflux esophagitis.  Zollinger-Ellison syndrome (gastrin-secreting tumor of the pancreas which ↑ HCl secretion): usually larger doses are required.  With ulcerogenic drugs (e.g. NSAIDs) to protect the gastric mucosa from injury. Adverse effects (mostly with cimetidine): – Cimetidine has anti-androgenic effects (due to block of androgen receptors) leading to ↓ sperm count, impotence and gynecomastia. – Cimetidine inhibits hepatic microsomal enzymes (P450) leading to ↓ metabolism of other drugs e.g. theophylline, warfarin, sulphonylureas, etc. – Reversible hepatotoxicity and Reversible anemia. – CNS symptoms: headache, slurred speech, delirium, coma, etc. occurs mainly in elderly people with i.v. administration. Precautions of H2 blockers – Avoid sudden withdrawal to prevent rebound ulceration. – Avoid their use in pregnancy and lactation (they cross the placental barrier and secreted in breast milk). – Avoid combination of cimetidine with drugs having narrow therapeutic index (because cimetidine inhibits microsomal P450 and ↑ their toxicity). Cimetidine Ranitidine Famotidine H2 Blocking effect: Weak Potent More potent Anti-anderogenic effect: Strong Minimal No Liver enzyme inhibition Strong Minimal No Adverse CNS effects: Frequent Less frequent Less frequent Duration of action: 8h 12 h 24 h Dose: 800 mg/day for 300 mg/day for 20 mg/day for 6-8 weeks then 6-8 weeks then 6-8 weeks then 400 mg/day for 150 mg/day for 10 mg/day for 6-8 months 6-8 months 6-8 months 255  3. Pro oton pum mp inhibiitors (PP PIs): (Omep prazole – Lansopraz L zole – Panttoprazole) Chemistry: all arre imidazole derivativves. Mecha anism of action a  Theey are pro odrugs. Th hey are co onverted into o the activee form in thhe gastric mucosa andd produce e irreversiible inhib bition of + + gasstric H /K ATPase A ennzyme leadding to ↓ both basal an nd stimula ated HCl se ecretion to o around th he zero levvel for 1-2 days.  Full restoratio on of acid secretion n after stopping the PPI takess about 3--5 days + + (tim me of re-synnthesis of H /K ATP Pase).  Theeir bioavaillability is decreased d significan ntly by food and, id deally, shoould be admministered 1 hour beffore a mea al. Therap peutic usees: The saame as H2 blockers (dose of omeprazo o ole: 20-40 mg/day orally fo or 4-6 wee eks then 10 0-20 mg/d day for 4-6 months to o prevent re recurrence)). Advers se effects – Low w incidenc ce of diarrrhea, abdo ominal colic, dizzine ess, skin rrash, leuco openia, andd transient increase of o liver enzzymes. – Deccrease vitt B12 abso orption aftter > 12 weeks w of therapy t duue to interrference with h intrinsic factor f secrretion by th he stomac ch. – Inhiibition of gastric g acid dity leads to alteratiion of bioavialability ty of somee drugs e.g.. ketocona azole, digox xin, and iro on. – Ommeprazole inhibits microsomall P450 enzymes and decreasses metabo olism of pheenytoin, wa arfarin, and cyclosporrin. Newer PPIs P do noot affect liveer enzymess. – Ommeprazole in n high dos se induced d gastric ca arcinoid tuumor in ratts. █ ENH HANCING MUCOSA AL DEFENS SE MECHANISMS 1. Suc cralfate  It iss an alumin num salt off sulfated ssucrose.  Slig m metal maay accumulate in ghtly (3%) absorbed from the GIT. The aluminum casses of renal failure, so o it should be avoide ed in renal failure. Mecha anism of action a  It n dic medium to be a needs acid esence of aacidic med activated. In the pre dium, it 256  forms a complex with protein debris at the ulcer base and forms a physical barrier (so not taken with antacids, H2 blockers, or PPIs).  It ↓ pepsin secretion and ↑ secretion of endogenous PGs. Adverse effects N.B. Both sucralfate and – Constipation (due to presence of aluminum). bismuth compound are not – ↓↓ absorption of tetracycline, digoxin and given simultaneously with phenytoin. antacids or H2 blockers (at least 30 min must be elapsed in-between). Why? 2. Bismuth compounds: Bismuth subsalicylate and subcitrate Mechanism of action  In acidic pH, it forms a complex with protein debris at the ulcer base and forms a physical barrier.  It ↓ pepsin secretion and ↑ secretion of endogenous PGs.  It has additional antimicrobial activity against H. pylori. Adverse effects – Stool and teeth discoloration. – Encephalopathy in presence of renal failure Contraindications: Chronic renal failure and CNS diseases. 3. Carbenoxolone It is a liquorice derivative having steroid structure. Mechanism of action  It ↑ production and viscosity of gastric mucus and ↑ mucosal resistance.  It ↓ pepsin secretion and ↑ secretion of endogenous PGs. Adverse effects Salt & water retention (aldosterone-like effects) → edema and hypertension especially in cardiac and renal patients. This edema can be treated by thiazide diuretics (not by spironolactone) because both spironolactone and carbenoxolone have steroid structure and can compete with each other. Contraindications: Hypertension and/or renal failure 257  4. Syn nthetic PG GE1 analo ogue: Mis soprostol Mecha anism of action a  It aacts on specific rece eptors on gastric pa s to ↓ histtamine-stim arietal cells mulated HCll secretion n.  ↑m mucus and bicarbonate secretio on (cytopro otective acction).  ↑m mucosal blo ood flow an nd stimulat ates mucossal cellular regeneratiion. Therap peutic use es Preven ntion of peeptic ulcerr in high risk patients e.g. th hose on l ong term use of NSAIDss for chronic inflamm matory disseases. [mmisoprostool 200 g is combined with xen or dicllofenac in single tab naprox blet]. Advers se effects – Diarrhea and cramping pain: due tto ↑ GIT motility m and water seccretion. – Uteerine contraactions during pregnnancy → ab bortion. Contra ns: pregna aindication ancy. █ ERA ADICATION THERAP PY FOR H H. pylori  Infe ection with H. pylori is s a main c cause of re e of PU. ecurrence  Thee following 10 days “sequential proto- p col”” is highly effective for e eradicationn of H. pylo ori: █ THE ERAPY OF F BLEEDIN NG PEPTIC C ULCER  Hosspitalizatio on and Fre esh blood d transfusion.  Acid suppre ession witth high d dose PPIs s by continuous i.vv. infusion is the stan ndard of ca are e.g. om meprazole 80 mg i.v. bolus follo owed by 8 mg/h for 72h. 7  Vita amin K1: 10 mg i.m or o s.c.  Enddoscopic therapy: t several s type es of endo oscopic tre eatments aare available. 258