Drugs Affecting GI Functions ( Summary) Assoc. Prof. Iv. Lambev E-mail: [email protected] .

Drugs AffectingDrugs AffectingGI FunctionsGI Functions

(Summary)

Assoc. Prof. Iv. LambevE-mail: [email protected]

I. Treatment of Peptic Ulcer

Acid-peptic diseases include hyperacidity, GERD(gastro-esophageal reflux disease), stress inducedmucosal erosions and peptic ulcers (gastric or duodenal).A localized loss of gastric or duodenal mucosa leads tothe formation of peptic ulcer. Peptic ulcer arises when the mucosal protective factors are impaired and aggressivefactors dominate. Ulcers occur five times more in theduodenum (predominantly in the duodenal bulb and pyloricchannel). Benign gastric ulcers are located mainly in theantrum.

The Nobel Prize in Physiology or Medicine (2005) was awarded jointly to Barry J. Marshall and J. Robin Warren "for their discovery of thebacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease"

Barry J. Marshall (2005)J. Robin Warren (2005)

A. Antacids (Drugs Neutralizing Gastric Acid)

Antacids are weak bases that neutralize gastric hydro-chloric acid. They raise the pH of the stomach contents, decrease the acid load delivered to the duodenum andreduce the activity of pepsin. Antacids are given betweenmeal and at bed time when symptoms of hyperacidityusually occur; the presence of food in the stomach canprolong their neutralizing capacity.

1.Systemic Antacids: Sodium bicarbonate acts rapidly,has a brief effect and raises the pH of gastric secretion to7.4. On neutralizing gastric asid (HCl), it forms carbondioxide (CO2) and sodium chloride (NaCl).

Formation of CO2 results in gastric distention and belchingthat can be dangerous if ulcer is near perforation. Unreactedalkali is absorbed and can raise the pH of blood (systemicalkalosis) and the urine. Absorption of NaCl may increasesodium load and this may exacerbate fluid retention in patients with hypertension and CHF. The sudden releaseof CO2 can cause “rebound acidity”.

2. Non-systemic Antacids are poorly absorbed from GITa) Buffer Type Non-systemic Antacids

•Aluminium hydroxide•Magnesium trisilicate•Magaldrate

These drugs have slow onset but longer effect and raisethe gastric pH to 3.5–4. The pepsin activity is inhibitedaround pH 4. “Rebound acidity” is not a problem. Aluminium hydroxide and Magnesium trisilicate neut-ralize gastric hydrochloric acid to form aluminium chlorideand magnesium chloride which further react with intestinalbicarbonates to form aluminium carbonate and magnesiumcarbonate. Sodium chloride formed in these reactions getsreabsorbed to compensate the loss of chlorides duringgastric acid neutralization. Buffer type non-systemicantacids do not disturb the acid-based balance of the body.Aluminium hydroxide can cause constipation andMagnesium trisilicate – diarrhoea, as a side effect.

Magaldrate is a hydrated complex of Aluminium andMagnesium hydroxide sulfate.

b) Non-Buffer Type Antacids (Calcium carbonate and Magnesium hydroxide) are powerful drugs with fast onsetof action, and raise gastric pH > 7.Like Sodium bicarbonate Calcium carbonate may causebelching due to liberation of carbon dioxide. It can causeconstipation too, due to formation of calcium stearate. Magnesium hydroxide does not liberate carbon dioxide butcan cause diarrhoea.

c) Other AntacidsSimethicone (dimethyl polysiloxane) is a silicone polymer

•Omeprazole

and therefore has water-repellent properties. It acts asan antifoaming agents and reduces gastric flatulence. It isnot absorbed from GIT.

B. Drugs, Reducing Gastric Acid Secretion

1. Proton Pump Inhibitors (PPIs)•Esomeprazole•Lansoprazole•Pantoprazole•RabeprazolePPIs are the most widely used drugs for peptic ulcer and

related disorders, because of their efficacy and safety.

PPIs are prodrugs. In the parietal cells they undergo amolecular rearrangement to sulfenamide cation (active metabolite). This cation makes a covalentdisulfide bond with –SH group of gastric proton pump H+/K+-ATPase. Thereby PPIs inactivate the proton pumpirreversibly and shut off the acid secretion.PPIs also inhibit gastric mucosal carbonic anhydraseand reduce bicarbonate secretion to mucus.

ADRs: diarrhoea, headacke, inhibition of vitamin B12, hypochlorhydria and risk of enteric infections.

•Cimetidine (? …)•Famotidine •Nizatidine•Ranitidine •Roxatidine

2. Antagonist of H2-receptors (H2-blockers) – for treatment of peptic ulcer:

3. Prostaglandin analogues•Misoprostol (PGE1) and Enprostil (PGE2)

4. Anticholinergics (M1-blockers)•Pirenzepine and Telenzepine

C. Mucosal Protective Drugs•Sucralfate (aluminium salt of sulfated sucrose) in acidicenvironment (pH < 4) polymerizes and forms a gel over ulcer crater which acts as acid resistant physical barrier. Italso stimulates mucosal synthesis of PGE2 and secretionof bicarbonates. Sucralfate is administered orally. It is noteffective in preventing or healing NSAIDs induced ulcer.•Colloidal Bismuth Subcitrate in gastric acidic media converts into bismuth oxychloride and bismuth citrate whichchelate glucoproteins and amino acids at ulcer base to forman acid resistant coating. It stimulates PGE, mucus andbicarbonate secretion. It has also anti-H. pylori activity.

D. Anti-Helicobacter Pylori Drugs

Peptic ulcer, although a multifactorial disease, also occursdue to colonisation of mucosa by H. pylori: in 90% in caseswith duodenal ulcers, 60 to 70% – with gastric ulcers and50% in patients with non-ulcer dyspepsia. H. pylori isaccepted as a cause of chronic atrophic gastritis too. It is arisk factor for gastric adenocarcinoma and to some extent for non-Hodgkin’s lymphoma affecting stomach.H. pylori produces urease which hydrolyses urea intoammonia. Ammonia neutralizes gastric acid to create aneutral protective cloud over the bacteria.

H. pylori infection can be detected by a “urea breath test”,but the test is not used after the treatment with PPIs.Since H. pylori becomes less virulent in absence of acid,a combination of an antibiotic with PPIs (or H2-blockers) ismore efficacious in eradicating this Gram (–) bacterium.

Preferred anti-Helicobacter pylori Combinations

•Dual therapy (7–10 days). Omeprazole (40 mg OD) + Amoxicillin (1000 mg BD)

•Triple therapy (14 days) Omeparzole (or lanzoprazole), plus Clarithromycin, plus Amoxicilin (resp. Metronidazole, or Tetracycline)

II. Antiemetic DrugsVomiting means expulsion of gastric contents throughmouth due to mass antiperistalsis. It is often precededby nausea. Vomiting can be life saving, physiological response to the ingested toxic substances. It also canbe an adverse reaction of radiation and antineoplasticagents. Vomiting also occurs in early pregnancy, duringmigraine attack, in motion sickness, etc. The CTZ at the base of the 4th ventricle has numerousreceptors: D2-, 5-HT3-, M-, H1-, for SP etc. Stimulation ofdifferent receptors are involved in different pathwaysleading to emesis.

Main Antiemetic Drugs

(1) 5-HT3-receptor antagonists (setrons)•Dolasetron, Granisetron, Ondansetron (Zofran – tab. 8 mg), Tropisetron(2) Neurokinine-1 (NK1-, SP1-) receptor antagonists: Aprepitant, Fosaprepitant (prodrug)(3) D2-receptor antagonists Neuroleptics: Chlorpromazine, Prochlorperzine, HaloperidolProkinetics: Domperidone, Metoclopramide(4) H1-blockers: Diphenhydramine, Doxylamine, Promethazine(5) M-cholinolytics: Scopolamine (Scopoderm TTS)(6) Miscellaneous Antiemetic Agents

5-HT3-receptor antagonists block 5-HT3-receptors bothperipherally (on vagal nerve terminals) and centrally (CTZ).Granisetron is the most potent antiemetic compared toondansetron and dolasetron. These drugs are mosteffective when given i.v. 30 min prior to anticancerchemotherapy (granisetron – 10 mcg/kg). These dosesmay be repeated every 24 h.Neurokinine-1 (NK1-, SP1-) receptor antagonists(Aprepitant etc.) have the similar indications.D2-receptor antagonists Phenothiazines (prochlorperazine, thiethylperazine)and butyrophenone group of antipsychotics (droperidol)can be used to treat postoperative nausea and vomiting.

CisplatinCarmustine

CyclophosphamideMitomycin CL-Asparginase

FluorouracilMethotrexateEtoposideVincristine

Emetogenic activity

5-HT3-blockersD2-blockers

GlucocorticoidsH1-blockers

Antiemetic activity

Prokinetic antemeticMetoclopramide is D2-receptor antagonists but in high dosesit also blocks 5-HT3-receptors. It crosses BBB. Its prokineticaction (stimulation of GI motility) is connected with stimulationof 5-HT4-receptors, present on excitatory interneurons, whichenhances ACh release from primary cholinergic neurons inmyenteric plexus. Metoclopramide is used as antiemetic andas gastrokinetic agent to accelerate gastric empting prior togiving emergency general anaesthesia in case the patienthas taken food less than 4 h before. This drug may also besuccessful in stopping persistent hiccups. Being a central andperipheral D2-blocker it produces sedation, muscle dystonia,in high doses – extrapyramidal effects, galactorrhoea infemales and gynecomastia in males.

Domperidone has a similar mechanism of action asmetoclopramide, but it is a peripheral D2-blocker. Itsantiemetic efficacy is lower than metoclopramide. It is alsoused to prevent the emetic side effect of levodopa orbromocriptine without affecting their antiparkinsonian effect.

H1-blockers with anticholinergic properties (Cyclizine,Diphenhydramine) are useful for prevention or treatmentof motion sickness and vertigo due to labirinth dysfunction.Doxylamine can be used in morning sickness (vomitingduring the first trimester of pregnancy, due to the effect ofincreased oestrogen level on CTZ.

Pyridoxine serves as a cofactor for the glutamate decarbo-xylase and thus increases the synthesis of GABA whichacts as inhibitory neurotransmitter at CTZ.Anticholinergic drugs: Hyoscine (Scopolamine) is used in motion sickness as TTS.

Miscellaneous Antiemetic Agents•GCS: Dexamethasone, Methylprednisolone•Canabinoides: Nabilone and Dronabinol stimulate CB1- receptors present on neurons around the vomiting center and are used in oncology. Their hallucinogenic activity is weak.•Anxiolytics: Aprazolam, Diazepam, Lorazepam•Others: Benzocaine, Sodium citrate, T-ra Menthae

III. Laxative and Purgative DrugsLaxatives provide elimination of soft semisolid stooland Purgatives provide more watery evacuation.

Laxatives are used: to treat constipation; to avoid unduestraining at defecation in cases of hernia, haemorrhoids orCVD; before or after surgery of any anorectal disease; inbedridden patients.Lactulose is an osmotic laxative drug. It is nonabsorble-indigestible disaccharide (sugar), which increases fecalbulk by hydrophilic and osmotic action. It is given in doseof 10 g orally. Latency period is 1 to 3 days. Lactulose isalso used for treatment of hepatic encephalopathy.

Liquid paraffin is an inert mineral oil. Liquid pararaffin is a fecal lubricant and stool softneras it retards water absorption from the stool. It is given 15to 30 ml per day at bed time. Latency period is 1 to 3 days.

Purgatives are used for complete colonic cleansing priorto GI endoscopic procedures or before intestinal operation.Purgatives may also be needed to flush out warms after the use of anthelmintic drugs. In low doses purgatives canbe used as laxatives too.Osmotic Purgatives include: Saline purgatives (Magnesiumsulfate) and Electrolyte purgatives (PEG – PolyEthyleneGlycol, which is a nonabsorbable sugar). They act on small

and on large intestine. Saline purgatives are solubleinorganic salts which increase the fecal bulk by retainingwater by osmotic effect, thus increasing peristalsis. Theseagents also release CCK which further helps in increasingintestinal secretion and peristalsis. Saline purgatives shouldbe ingested with enough water to protect vomiting. Thesedrugs can cause electrolyte disturbances and must be avoided in patients with CVD as well as during pregnancy.

Irritant purgatives•Antraquinone group: Senna, Cascara and Aloë•Organic agents: Bisacodyl, Sodium picosulfate•Oils: Castor oils Aloë vera

All irritant purgatives stimulate peristalsis by irritant actionof intestinal mucosa. They also stimulate colonic electrolyteand fluid secretion by altering the absorptive and secretoryactivity of the mucosal cells. Senna, Cascara and Aloë occur naturally in plants. Sennais more commonly used. These plant agents containanthraquinone glycosides with purgative action.The organic irritants are prodrugs. The primary site of action of their active metabolites is in the colon. Bisacodylis activated in the intestine by deacetylation. In the colonSodium picosulfate is converted to the active metabolite.Castor oil is hydrolyzed in the intestine by pancreatic lipaseto ricinolic acid which increases the intestinal motility.

IV. Antidiarrhoeal AgentsDiarrhoea is an abnormal increase in the frequency andthe liquidity of stool. Increased motility of GIT and thedecreased ability of intestine to absorb water from the stool are the major factors, causing diarrhoea.

Osmotic diarrhoea may cause by ingestion of some typeof meal, use of some osmotic substances, lactulose ormagnesium containing antacids, lactase enzyme deficiency.

Secretory diarrhoea occurs when the intestinal wall losesits functional integrity or gets damaged resulting in an increased secretion of electrolyte in the intestinal tract. Thismay be due to some bacterial infection (Schigella, Salmonella),

bacterial endotoxins (from E. coli, V. cholerae, S. aureus),viral infections (rotavirus etc.), protozoal infections (Lambliaintestinalis, E. histolytica), underlying pathology (inflam-matory bowel disease) or due to side effects of drugs (anti-biotics, anticancer agents, colchicine, prostaglandins,orlistat, acarbose). Excess of bile also causes diarrhoea.Motility disorder diarrhoea. Increased motility reduces thecontact time of the stool with the intestinal wall, so thatlesser amount of water is absorbed back from the faces.Motility disorders include IBS, scleroderma, diabetic neuro-pathy, vagotomy etc. Some drugs can increase intestinalmotility: prokinetic antiemetics, bethanechol, digitalis, quinidine, ampicillin (causes disbiosis); neurosis, etc.

Treatment of infective diarrhoeas needs proper diagnosisand suitable antibiotic and/or antiprotozoal drug. Forsymptomatic relief of non-specific diarrhoes are used:

(1) Antimotility and Antisecretory Agentsa) Opioid agonists which does not cross BBB• Loperamide (Imodium®) and Racecadotril (Hidrasec®)These drugs stimulate mu- and delta-receptors, present in the small and large intestines. Activation of mu-receptorsdecreases peristaltic movements. Activation of delta-receptors contributes to their antisecretory effects. Although all opioids such as morphine and codeine haveantidiarrhoeal effects, their CNS effects and dependenceliability limit their usefulness. Loperamide directly stimulates

mu- and delta-receptors. Racecadotril blocks enzymeencephalinase and increases local concentration ofenkephalins in intestinal mucosa which then stimulate mu- and delta-receptors. This drug can be used orally fromchildren under 5 years old (including babies), but Loperamide is contraindicated in children < 5 years old.

b) Miscellaneous Agents•Carbo activatus (absorbent drug)•Bismuth subsalicylate reduces stool frequency and liquidity in acute diarrhoea due to inhibition of PG synthesis. Bismuth has some antimicrobial andmucosal protective effect too.

(2) Fluid and Electrolyte Replacement

During diarrhoea, a glucose-coupled transport continuesin the intestines which causes water and electrolyte lossesthrough the stools.

Ulcerative colitis and Crohn’s disease are two importantinflammatory bowel diseases. The pathogenesis of thesediseases involves autoimmune mechanism and imbalancebetween proinflammatory and anti-inflammatory cytokines.The main drugs, used in the treatment of these diseases areaminosalicylates, GCS and some immunosuppressants.

V. Treatment of Inflammatory Bowel Disease

Antidiarrhoeal agents must be avoided in active andsevere ulcerative colitis as they can lead to dilatation of the colon and its perforation.Aminosalicylates (sulfasalazine, olsalazine) contain a5-aminosalicylic acid (5-ASA) moiety bound by an azo (N=N) bond to an inert moiety or by another 5-ASA molecule. 5-ASA inhibits the synthesis of PGs by inhibitingCOX, like salicylates, as well as inhibiting the production ofcytokines. 5-ASA also inhibits the activity of nuclear factor-kB, which is an important transcription factor forpro-inflammatory cytokines. It suppresses the generationof superoxide free radicals. Aminosalicylates induce andmaintain remission in patients with ulcerative colitis.

GCS (Prednisone, Prednisolone) have been the mainstayof the treatment for acute/severe exacerbations of irritablebowel disease. Moderately severe attacks of ulcerativecolitis should be treated orally with systemic GCS.

Immunosuppressive Agents•Cyclosporine may induce remissions in case of severe ulcerative colitis unresponsive to GCS.•Azathioprine, mercaptopurine•Methotrexate is useful in controlling relapse of Crohn’s diseases unresponsive to GCS or azathioprine•Infliximab is a chimeric (25% mouse and 75% human) anti-TNF-alpha-monoclonal antibody, which inhibits T-cells

and macrophage functions. Consequently, the release ofother proinflammatory cytokines (IL-1, 2, 8; collagenaseand metaloproteinases) is prevented. It is administeredby i.v. infusion. A single dose of infliximab (5 to 10 mg/kg)induces remission in approximately 40% of patients withCrohn’s disease. An additional dose after 8 weeksproduces long-lasting remission.•Adalimumab is a recombinant human anti-TNF-alpha-monoclonal antibody. It is given s.c. and has a longerplasma half life. It has lesser side effectscompared to infliximab.

VI. Drugs used in Pancreatic Insufficiency

Pancreatic enzyme agents contain a mixture of amylase,lipase and proteases. They are the mainstay of the treatmentof the pancreatic enzyme insufficiency which is mostcommonly caused by cystic fibrosis, chronic pancreatitis orpancreatic resection. Exocrine pancreatic enzyme insufficiencyleads to fat and protein indigestionwhich in turn causes steatorrhoea,azotorrhoea, vitamin deficiency andweight loss.

•Festal, Kreon, •Mezym forte, Panzytrat

VII. HepatoprotectorsDrugs which stimulate regenerative processes

•Acidum oroticum, Essentiale, SilymarinDrugs which stimulate fat infiltration

•Thioctic acid (Acidum aphfa-lipoicum)Derivatives of Methionine: Ademethionine Interferons (in viral hepatitis)

•Interferon alfa-2a •Peginterferon alfa-2a•Interferon alfa-2b

Antiviral vaccines: Hepatitis A and B vaccine, •Hepatitis A vaccine, Hepatitis B vaccine

Choleretic Drugs: Cholagol, Cholamin, FebicholCholekinetic Drugs: Oleum olivarum, RowacholDrugs which improve the solubility

of cholesterol gallstones: Ursodeoxycholic acid

IX. Probiotics – regulators of intestinal or other bacterial flora

VIII. Drugs Acting on Biliary tract

BioGaia, Linex, Lactoflor, Lactagyn® (vaginal flora),Normoflor, Probien®®