Drugs used in GIT disorders

1. Mgr. Petra Hirsova Dept. ofPharmacology 2011 Drugsused in GIT disorders

2. Overview Pharmacotherapy ofpepticulcer Drugsthatincrease GIT motility Purgatives Antidiarrhealagents Spasmolyticagents

3. Pepticulcer Lesion ofgastricorduodenalmucosa: Chronic and recurrent Lesiondeeperthanmuscularis mucosae(x erosion) In proximity of acidigastricjuice → autodigestionofmucosa Imbalancebetweenaggressiveandprotectivefactors Incidence ofpepticulcer: 5-10 % ofpopulation

4. Pepticulcer - etiology Primary ulcer Helicobacter pylori being the main or the only factor Secondary ulcers: Stress-related(burns, trauma) Drug-related(NSAID, ASA) Endocrine(Zollinger-Ellison syndrome) Age-related(vascular and trophicfactors) Ulcerlocalization: Gastric x duodenal

5. Peptic ulcer - symptoms Abdominalpain (in 90 % ofcases) Ulcerperforation and bleeding(melena, hematemesis) in 10 % of c. Gastriculcer Painaftermealorwithin 1 hour(up to ulcerlocalization) Frequentdyspepsia (lackofappetite, nausea, weightloss, belch) Duodenalulcer Painwhenfasted (>2 h aftermeal), during night Painrelievedwithmeal! Waterbrush, regurgitation)

6. Regulationofgastric acid secretion - 1 • Nervous • ACH, M1/3rcp. • Endocrine • Gastrin • Paracrine • Histamine n.vagus

7. Regulationofgastric acid secretion

8. Aggressivea protectivefactors- 1 Aggressivefactors: Endogenous: Chloric acid (HCl) Activatedpepsin Duodenalsecretion– reflux (bileacids, pepticenzymes…) Exogenous: Helicobacterpyloriinfection Alcohol(especial. spirits) Smoking & nicotine Coffee & coffein Drugs (NSAID a glucocorticoids!!!) Stress!

9. Aggressive a protectivefactors - 2 Protectivefactors: Mucus(rightcomposition and amount) Intactmicrocirculation in gastricmucosa Alkalicsecretionofbicarbonate (HCO3-) Normalsynthesis and secretionof prostaglandin E2 and I2 ↑ Mucus and bicarbonatesecretion ↑ Mucosaperfusion (dilationeffect) ↓ HClsecretion

10. Therapeuticaims No pain and dyspepsia To healtheulcer To preventulcerrecurrence Possiblepharmacologicalintervention ↑ gastricpH ↓ HClsecretion EradicationH. pylori Gastrointestinalmucosaprotection Cytoprotectiveagents– enhancementofendogenousfactors

11. Antacids- 1 NeutralizegastricHCl (chemicalreaction) Immediate and shorteffect(usedbeforeeverymeal) Most ofthemover-the-counter Local x systemeffect NaHCO3= Sodiumbicarbonate, CaCO3are absorbedfrom GIT → alkalosis Someformprotectivelayer on thestomachsurface Al(OH)3= Aluminium hydroxyde, Mg2(SiO3)3 = Magnesium trisilicate

12. Antacids- 2 Otherdrugs: MgO/Mg(OH)2= Magnesium hydroxide Adverseeffects: Constipation (CaCO3, Al3+) x diarrhea (Mg2+) Drug-druginteractions: May decreaseabsorption and BAV ofco-administereddrugs Indication: Symptomatictreatmentofdyspepsiarelated to excessivegastric acid secretion, heartburn, waterbrash Gastroesophageal reflux disease (GERD)

13. Drugsused to inhibitgastric acid secretionSelectiveparasympatholytics Lowclinicalsignificance – not in use (lowerantisecretionefficacy /adverseeffects) Pirenzepine (Gastrozepin) M1-selective parasympatholytic(competitiveantagonist) Adverseeffects– typicalanticholinergiceff. Contraindication– e.g. glaucoma, urine retention… Replaced by PPi

14. Drugsused to inhibitgastric acid secretionHistamine H2rcpantagonists– 1 Ranitidine, famotidine, nizatidine,cimetidine (withdrawn) Selectivecompetitiveantagonistsof H2 histaminereceptors Inhibitbasal, night and inducedsecretion (by histamine) Administered per os (possiblyparenterally), goodabsorptionfrom GIT Adverseeffects: Rare (ranitidine, famotidine)- headache, confusion (espec. theold), GIT disturbaces; very rarelybradycardia and negative inotropicefefect Cimetidine– inhibitor of CYP450! – frequentdrug-druginteractions AE: as above + gynecomastia, decrease in sexualfunction

15. Drugsused to inhibitgastric acid secretionHistamine H2rcpantagonists – 2 H2 rcpantagonistscure most ulcers (80-90 %) within 6 weeksx recurrenceis very frequent!!! Indication: Lightdyspepsia, waterbrash… Pepticulcerprophylaxis Pepticulcertreatment – not a choiceoftreatment (x iPP) !!! Contraindication: pregnancy, lactation, malignantulcer

16. Proton pump inhibitors - 1 Omeprazole, pantoprazole, lansoprazole, esomeprazole Irreversibleproton pump inhibition (H+/K+-ATPasa) Final step in HClproduction→ inhibitionofsecretionis independent ofinducing stimulus! Long-term effect – synthesisofnewH+pump isneeded(functionrecoveredafter ~4 days) Drugs of choice for peptic ulcers!!! When combined with H.pylori eradication , therecurrence of peptic ulcer is 0 – 10 %

17. Proton pump inhibitors - 2 Unstable in acids – decomposed in stomach→ enterosolvent capsules Parenterally in urgent situations (ulcerperforation) Prodrug Absorbedfromtheintestine → systemiccirculation → weak base = accumulation in acidic pH ofparietalcells(= plasma Cssisminimal) → bioactivation and proton acceptance (“ion-trap“) → covalent bond to proton pump Utmosteffect– aftermaximalstimulationofparietalcells→ used in themorning (fastedstomach)

18. Proton pump inhibitors - 3 • Indication: • Pepticulcer • Zollinger-Ellison syndrome (adenoma→ hypergastrinemia)‏ • Gastroesophageal reflux disease • H. pylorieradication • Prophylaxis in high-risk patientstreatedwithNSAIDs • Pregnancy & lactation: yesafterbalancingrisks and benefits • (excretedintothemilk – 6% of plasma level) • Adverseeffects: • Very welltolerated (headache, dyspepsia; very rarelyalterationofbloodformation)‏ Combinationwith histamine H2 rcpantagonistsis not rationalbecause Ppi actdirectlyagainstthe cause

19. Drugsprotectingthemucosa - 1 Produceprotectivebarrier on gastric and duodenalmucosa →protectulcerlesionsagainsttheaggressivegastricjuice Sucralfate – aluminium hydroxid + sulfatedsucrose Indication: Stress-relatedulcers, prophylaxis in high-risk patients and in patiens in remission Not absorbedfrom GIT AcidicpHneededfortheeffect – don’t use togetherwithantacids! Formprotectivebarrier, binds pepsin and bileacids StimulatessecretionofPGE2and I2 AE:mostlyconstipation Drug-drug I:decreasesabsorptionofotherdrugs

20. Drugsprotectingthemucosa - 2 Alginates Polysaccharidefromseaalgae Becomesviscous (protectsesophagusmucosa) Forms gel in thestomach (floating – blockesophageal reflux) Alsocombinedwithantacids Bi3+compounds: Bismuthchelate Antibacterialaction(in combinationforH.pylorieradication) Coatingoftheulcer base Stimulatessecretionof PGE2 and I2 AE:headache, dyspepsia, constipation, vomiting Not recommended in pregnancy

21. Cytoprotectivedrugs Misoprostol, enprostil Stablesynthetic prostaglandin derivatives (PGE2 a PGI2) PGE2cannotbeused – highlyunstable Indication: Prophylaxisfor NSAID adverseeffects (long-term therapy, highdoses, high-risk patients) Adverseeffects diarrhea, colic, nausea, flatulence Contraindication Pregnancy(risk ofabortion)‏ Expensive – not in use (not registered in Czech)‏

22. Helicobacterpylorieradication Eradicationiscrucialforrecurrencefrequency Successfuleradication: 0-9% CombinationofPPi(omeprazoleorpantoprazole) and two ATB (amoxicillin, clarithromycin, metronidazole) Most commoncombinations(2 x daily, 7 days) Omeprazole+amoxicillin+clarithromycin(up to 96%) Omeprazole+metronidazole+clarithromycin(up to 95%) Omeprazole+amoxicillin+metronidazole(up to 79%) Possible to use bismuthchelates, histamine H2rcpantagonists(↓ effect)

23. Drugsincreasing GIT motility - 1 ↑ sphincter tonus ofesophagus(blocksesophageal reflux) ↑ gastricemptying(improvesymptomsofgastroparesis, dyspepsia, etc.) ↑ gut motility Antiemeticaction Mechanismofaction: D2-rcp antagonism entericneurons- disinhibition→ ↑ acetylcholine secretion area postrema pituitary – adverseeffect– hyperprolactinemia within CNS – extrapyramidaladverseeffects Inhibitionof acetylcholine esterase (AChE) Stimulationof 5-HT receptorů (5-HT4, 5-HT1)

24. Drugsincreasing GIT motility - 2 Domperidone Competitive D2-antagonist Doesn’t cross HEB– effect on centers outside ofHEB Rare AE: GIT disorders, hyperprolactinemia Don’t combinewithstrong CYP3A4inhibitors (ketokonazole, erythromycin– QT interval prolongation ) Not recommendedduringpregnancy and lactation Metoclopramide D2-antagonist, agonist on 5-HT4rcpand sensitizationofM-rcpto ACh Crosses HEB→ possibleextrapyramidaladverseeffects inCNS Rare AE: acutedyskinesia (children), parkinsonismsa latedyskinesia(olderpatients), malignanthypertermia, hyperprolactinemia Strongantiemeticaction(more thandomperidone) Don’t use in1sttrimester of pregnancy andduring lactation

25. Drugsincreasing GIT motility - 3 Itopride D2-antagonist andinhibitor of AChE Contraindicated during pregnancy and lactation AE: rarely diarrhea, ↑ salivation and epigasticpain, headache, prolactinemia Cisapride– withdrawn Agonist on 5-HT4 rcp Metabolized by CYP450 – drug-druginteractions Serious AE: QT interval prolongation Risk offatalcardiacarrhythmias – „torsadesde pointes“

26. Purgatives - 1 Hastenthe transit of food throughtheintestine Mainindication: Symptomatictreatmentofacuteconstipation (individualsuitabilitymustbeassessed) Prior to GIT surgeryorexamination Constipation Lowfrequenceofbowelmovements(hugeinterindividual variability) Change in consistency, painfuldefecation Effectof diet and lifestyle Lackoffiber, pectins, liquids, lackofexercise/moving

27. Purgatives - 2 Risk factors: Pregnancy Higherage(lackofmoving, worse diet) Immobility Constipation as a symptom ofotherdisease: ! Malignanciesobstructingthe GIT ! Constipationas a consequentof pharmacotherapy: Opioids (no tolerance develops) Anticholinergicagents, antidepressants, histamine rcpantagonists Ifpossible, changethe pharmacotherapy

28. Purgatives - 3 Bulklaxativesorfecalsofteners Saline and osmoticlaxatives Stimulant laxatives Non-pharmacologicalmeasurements are part ofthetherapy Not for long-term use – often OTC drugsoverused Contraindications: Bowelobstruction Pregnancy(exceptforbulklax.) and lactation(stimulant laxativesexcretedintothemilk)

29. Bulklaxatives Semisynthetic:methylcelulose, carboxymethylcelulose Natural:agar, psyllium Indigestible polysaccharides attract water→ swell and from bulky gel mass→ gut distension and stimulation ofmotility Effect within 1-3 days! Sufficient liquid intake is critical (guidance to patients) – complications when dehydrated! Other beneficial effects: binding of bile acids, carcinogen protection… AE: minimal – well tolerated (depletion of minerals)… OK for long-term use; safe in pregnancy

30. Osmotic and salinelaxatives - 1 Non-absorbable, osmoticallyactive Stay in the gut lumen and attractwater Increasemass → gut distension and peristalsispromotion Actwithin 1-3 hours Adverseeffects: Spasms, colic, dehydration, electrolyteloss Often prior gut surgery and examination Salinelaxatives: Magnesium sulfate, sodiumsulfate Specialmineralwaters (Šaratica, Zaječická...)

31. Osmotic and salinelaxatives - 2 Osmotic: Lactulose Cleaved by intestinalbacteria to lactate and acetate→ decreases pH→ improvedintestinal flora Decreasedproductionof NH3 by intestinalbacteria(usefulfor liver encephalopathy) Lactitol, sorbitol Glycerol In suppositories, relativelygentle and safelaxative to renew a lostdefecation reflex Makrogol 4000 (polyethylenglycol4000) Similar to glycerol, prior to endoscopy...

32. Stimulant laxatives- 1 Absorbedfromthe GIT, metabolized – effectafter6 h Irritate gut mucosa Decreaseabsorptionofwater and electrolytes Increasesecretion and gut motility (direct stimulationofmyentericnerves?) Not for long-term use!!! Canlead to irreversibledamageor gut amyotonia ↑ absorptionoftoxins Contraindication: Pregnancy(risk ofabortion), lactation(excretedintothemilk) Adverseeffects: spasms, colics,dehydration, electrolyteloss

33. Stimulant laxatives - 2 Natural drugs: Foliumsennae, Rhizomarhei, Aloe, Cortexfrangulae glycosidsabsorbedfromtheproximal GIT → activeformssecretedintolarge gut Dye urine (darkred-brown) Excretedintothemilk(diarrhea in babies) Syntheticdrugs: Bisacodyl, sodium picosulfate AE: allergy, fotosensitivity

34. Fecalsofteners Nonabsorbable→ soften Facilitatemovements Liquidparaffin Mineraloil = mixtureofnonabsorbablehydrocarbons Adverseeffects: Longertreatmentcanlead to vitamini A, D, E, K deficiency(due to theirdecreasedabsorption) Smallpercentagecanbeabsorbed (deposition in the liver) In highdoses – colicpain

35. Antidiarrhealagents Diarrhea Higherfrequencyofbowelmovements(waterystools) Abdominaldiscomfort, evenspasms and pain Risk ofdehydration and electrolyteimbalance Varied etiology: Infection(salmonella, shigella, campylobacter…) Yeasts Toxins Drugs(Mg2+, damage to intestinal flora by broad-spectrum ATB, cytostatics, anticholinergics, verapamil, digoxine)

36. Intestinaladsorbents Charcoal(Carboadsorbens, medicinalis), diosmectite (kaolin) Act on basicsofphysics– unselective Adsorptionoftoxins, bacteria on itssurface Indication:diet errror, yeastovergrowth, intoxication Rareadverseeffects: Low toxicity, for a limited timecanbeadministered in relativelyhighdoses (at least grams) Drug-druginteractions: Unselectiveaction– adsorbdrugson thesurface

37. Intestinaldesinfectionagents Broad-spectrumaction(bacteria, yeasts, some protozoa) Don’t interferewithnormalintestianl flora No resistancedevelop! Cloroxin- OTC Not for more than 10 days (otherwise risk of GIT toxicity) Nifuroxazide - Rx Nonabsorbablefromthe GIT! Indication: Diarrheawithanticipated etiology ofinfection Traveler’s diarrhea

38. Antidiarrhealagents – Opioids - 1 Significantly decreased GIT motilityandincreased water absorption Effect on μ- a δ-receptors in enteric nervous system Indication: Acuteexhaustingdiarrhea(lossofelektrolytes) Non-infectiousdiarrhea Tinctura opii Strongeffect Morfine, codeine and papaverine (spasmolytics) Not forkids! (respirationdepression)

39. Antidiarrhealagents – Opioids – 2 In today’s use: Low risk of abuse and dependencydevelopment Diphenoxylate In normaldoses has no opioideffects in CNS, onlyreallyhighdoses (orwhencombinedwithalcohol) Combinationwith atropine („Reasec“) Loperamide Does not crossHEB No risk ofdependency and abuse Rareadverseeffects – safe in general Oftenused (OTC – „Imodium“)

40. GIT spasmolytics Smoothmusclespasmrelief Combinedwithanalgetics(pethidine, codeine, metamizole, tramadol) Indication: Irritablebowel syndrome, flatulance, otherspasms in GIT Colics– intestinal, bililary, renal Contraindications: paralyticileus Neurotropicspasmolytics(anticholinergics, parasympatholytics) Myotropicspasmolytics(papaverine and similar) Oftentheircombination

41. Neurotropicspasmolytics Parasympatholytics (M-rcpantagonists) Atropine, tolterodine and trospium Paradoxically cause spasmofsphincters – SphincterofOddie! AE: typicalanticholinergic– xerostomia, mydriasis, cycloplegia, glaucom!, urine retention, psychotropiceffect… Anticholinergics(both M and N rcpantagonists) Otilonium, fenpiverinium Effect on sphincters Very strongeffect LowerabsorptionfromtheGIT → lower risk of AE in CNS Bettertolerated

42. Myotropicspasmolytics - 1 Act directly on smooth muscles (w/o sign. neuronal regulation) Act partly on vascular smooth muscle → cardiovascular adverse effects Various modes of action: Ca2+channel blocade, K+channel activation Activation of adenylcyclase (production of cAMP, cGMP) → inactivation of proteinkinase, stimulation of NO production Often combined with analgetics Natural opioid alkaloids: Papaverine Quinoline derivativefrom opium (X opioidanalgetics) Spasmolysis of smooth muscles - both vascular and other i.v: strong vasodilation, ↓BP, bradycardia, AV blocs CI: glaucoma, intracranial hypertension, respiratory center depression

43. Myotropicspasmolytics - 2 Synthetic derivatives: Drotaverine, mebeverine, alverine, pitofenone Stronger myotropic effect than papaverine Fewer adverse effects Indication: irritable bowel sy, diverticulosis, spasms (gut, biliary, ureter), intestinal discomfort i.v. – arrhythmogenicandhypotension effects Spasmoanalgetics Short-term and intensive treatment Analgetics withspasmolytic effect (pethidine,tramadol) Combination of spasmolytics with analgetics(, metamizole, acetaminophen, codeine) Metamizole + fenpiverine + pitofenone Indication: Spastic pain, spastic dysmenorrhea Spasmoanalgesia before and after examination, gynecologic surgeries