Drugs Used in the Treatment of Gastrointestinal Diseases PDF

C H A P T E R 7 Drugs Used in the Treatment of Gastrointestinal Diseases Emetics and Antiemetics PH1.34 Nausea and vomiting are protective reflexes that help to remove toxic substances from the gastrointestinal tract (GIT). They...

C H A P T E R 7 Drugs Used in the Treatment of Gastrointestinal Diseases Emetics and Antiemetics PH1.34 Nausea and vomiting are protective reflexes that help to remove toxic substances from the gastrointestinal tract (GIT). They are symptoms of altered function but are not diseases. Nausea denotes the feeling of impending vomiting, whereas vomiting refers to forceful expulsion of the contents of stomach and upper intestinal tract through mouth. Retching is the laboured rhythmic respiratory activity that usually precedes vomiting. MECHANISM OF VOMITING The act of vomiting is controlled by vomiting centre in the medulla. Stimuli are relayed to this centre from peripheral areas, i.e. gastric mucosa and other parts of GIT. Sensory stimuli also arise within the central nervous system (CNS) itself (i.e. cerebral cortex and vestibular apparatus) – the impulses are transmitted to vomiting centre (Fig. 7.1). The lack of blood–brain barrier (BBB) at the chemoreceptor trigger zone (CTZ) al- lows it to be directly stimulated by blood-borne drugs and toxic substances. Nausea and vomiting may be the symptoms of pregnancy, serious organic disturbances of almost any of the viscera or may be produced by infection, drugs, radiation, painful stimuli, motion sickness, metabolic and emotional disturbances. The main neurotransmitters involved in the control of vomiting are acetylcholine (ACh), histamine, 5-hydroxytryp- tamine (5-HT) and dopamine. EMETICS The drugs that cause vomiting are called emetics, e.g. mustard, common salt, ipecac and apomorphine. They cause emesis either by stimulation of CTZ or gastric irritation or both. Mustard and common salt are commonly used household emetics. Syrup ipecac is a safer emetic than apomorphine. Emetics are indicated in certain cases of poisoning. Contraindications for the use of emetics: 1. Unconscious patients because of risk of aspiration. 2. Corrosive and caustic poisoning – further damage to oesophageal lining occurs. 3. Poisoning due to CNS stimulants because of risk of precipitation of seizures. 4. Kerosene poisoning as aspiration may occur. ANTIEMETICS The drugs that are used to prevent or control vomiting are called antiemetics (Table 7.1). 263 264 PHARMACOLOGY FOR MEDICAL GRADUATES CNS Smell, pain, sight, psychogenic + stimuli Cortex + Vomiting Cerebellum centre + STN M 5-HT3 D2 H1 CTZ Blood–brain barrier M1 5-HT3 D2 H1 + Vestibular apparatus (during motion) + + GIT Drugs + Radiation Infection Blood GI irritation vessel 5-HT3 Periphery Fig. 7.1 Central and visceral structures involved in emesis. CTZ, chemoreceptor trigger zone; STN, solitary tract nucleus. (Source: Adapted from Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 12e.) Classification 1. 5-HT3-receptor antagonists: Ondansetron, granisetron, dolasetron, palonose- tron, ramosetron. 2. Prokinetic agents: Metoclopramide, domperidone, levosulpiride. 3. Antihistamines (H1-blockers): Dimenhydrinate, diphenhydramine, cyclizine, meclizine, hydroxyzine, promethazine, doxylamine. 4. Anticholinergics: Scopolamine (hyoscine), dicyclomine. 5. Neuroleptics: Chlorpromazine, fluphenazine, prochlorperazine, haloperidol. 7—DRUGS USED IN THE TREATMENT OF GASTROINTESTINAL DISEASES 265 Table 7.1 Antiemetics with their uses and side effects Drugs Uses Important side effects 1. 5-HT3-receptor Cancer chemotherapy–induced Headache, dizziness and antagonists vomiting, radiation sickness diarrhoea and postoperative vomiting 2. Prokinetic drugs Drug-induced, disease- Drowsiness, dizziness, Metoclopramide induced, postoperative, diarrhoea, acute Domperidone cancer chemotherapy– dystonias and other induced vomiting and extrapyramidal symp- radiation sickness toms (EPS) Preferred antiemetic in Dryness of mouth, children and levodopa- diarrhoea and induced vomiting headache 3. Antihistamines Motion sickness, morning Drowsiness and dryness sickness, Meniere disease, of mouth drug induced, postoperative, radiation sickness and cancer chemotherapy– induced vomiting 4. Anticholinergics Motion sickness Sedation, dryness of (scopolamine) mouth, blurred vision and urinary retention 5. Neuroleptics Drug-induced, disease- EPS, sedation, dystonic induced, postoperative, reactions and ortho- cancer chemotherapy– static hypotension induced and radiation- induced vomiting 6. Neurokinin (NK1)- Cancer chemotherapy– Dizziness, diarrhoea receptor antagonist induced vomiting and fatigue 7. Dronabinol Vomiting due to cytotoxic drugs Sedation, dysphoria, and radiation sickness hallucinations and drug dependence 8. Glucocorticoids Adjuvant antiemetic along Metabolic disturbances (adjuvant antiemetics) with ondansetron or metoclopramide in cancer chemotherapy-induced vomiting 9. Benzodiazepines Psychogenic and anticipatory Sedation and drowsiness (adjuvant antiemetics) vomiting 6. Neurokinin (NK1)-receptor antagonists: Aprepitant, fosaprepitant. 7. Cannabinoids: Dronabinol. 8. Adjuvant antiemetics (a) Glucocorticoids: Betamethasone, dexamethasone, methylprednisolone. (b) Benzodiazepines: Lorazepam, alprazolam. 5-HT3-Receptor Antagonists. Ondansetron is the prototype drug. Other drugs are granise- tron, dolasetron, palonosetron and ramosetron. Their antiemetic effect is mainly due to 266 PHARMACOLOGY FOR MEDICAL GRADUATES blockade of 5-HT3-receptors on vagal afferents in the gut (peripheral action). In addition, they also block 5-HT3-receptors in the CTZ and solitary tract nucleus (central action). Anticancer drugs and radiotherapy Tissue damage (in the gut) Release of serotonin (5-HT) from enterochromaffin cells of intestinal mucosa Stimulates vagal afferents in the gut through 5-HT3 receptors 5-HT3 -antagonists block Impulses to CTZ and STN Induce vomiting Pharmacokinetics. 5-HT3 antagonists are well absorbed after oral administration. The metabolites are excreted in urine and faeces. These agents are also available for intravenous administration. Ondansetron can also be administered intramuscularly. Granisetron is more potent and longer acting than ondansetron. Transdermal patch of granisetron is available for prevention of cancer chemotherapy-induced vomiting. Palonosetron has the longest duration of action among (half-life is 40 hours) the 5-HT3 antagonists. Uses 1. 5-HT3 antagonists are the most effective agents for prevention and treatment of chemotherapy-induced nausea and vomiting (CINV). They are effective for prevention and control of acute phase vomiting following chemotherapy. Palonosetron is superior to ondansetron in preventing delayed emesis following chemotherapy. Combination with dexamethasone/diazepam/aprepitant enhances the antiemetic efficacy. 2. They are also effective in hyperemesis of pregnancy, postoperative, postradiation and drug-induced vomiting but they are ineffective against motion sickness. 3. Ramosetron can be used in irritable bowel syndrome. Adverse Effects. 5-HT3 antagonists are well tolerated. They may cause headache, dizziness and diarrhoea. Prokinetic Drugs. Drugs that promote coordinated movement of GIT and hasten gastric emptying are called prokinetic drugs. They include metoclopramide, domperidone, mosapride, itopride, cisapride and levosulpiride. Of these, metoclopramide and dom- peridone are used as antiemetics. Metoclopramide. Metoclopramide is a dopamine (D2)-receptor antagonist. It has two important actions – central and peripheral. 7—DRUGS USED IN THE TREATMENT OF GASTROINTESTINAL DISEASES 267 Metoclopramide Blocks Extrapyramidal D2-receptors in symptoms basal ganglia CTZ Blood–brain barrier 5-HT3 , D2 ks Poorly loc.b Bl crosses nc ck s oc co ks igh Blo Ath Metoclopramide Domperidone Prokinetic effect Increase tone of lower oesophageal sphincter Relax the pyloric sphincter and Increase the peristaltic duodenal bulb movement of upper GIT Fig. 7.2 Effects of metoclopramide and domperidone. Central Actions. The antiemetic effect of metoclopramide is mainly due to blockade of D2-receptors in CTZ. At high concentration, it also blocks 5-HT3-receptors in CTZ (Fig. 7.2). Prokinetic Effect on Upper GIT Metoclopramide 5-HT4-agonism D2-antagonism 5-HT3-antagonism in the gut ↑↑ACh secretion from the myenteric motor neurons Metoclopramide enhances release of ACh from myenteric neurons. This effect is due to D2-antagonism and 5-HT4-agonism in the GI tract. Thus, peripherally, it has prokinetic effect on upper GIT (Fig. 7.2) and enhances the rate of gastric and duodenal emptying. 268 PHARMACOLOGY FOR MEDICAL GRADUATES The effects of metoclopramide on upper GI tract: 1. Increase in tone of lower oesophageal sphincter (LES). 2. Increase in tone and amplitude of antral contractions. 3. Relaxation of pyloric sphincter. 4. Increase in peristalsis of small intestine. Thus, it promotes forward movement of contents in the upper GIT. It does not have significant effect on motility of colon. Pharmacokinetics. Metoclopramide is rapidly absorbed after oral administration. It can also be administered by i.m. or i.v. routes. Onset of action is within half an hour after oral dose; a few minutes after parenteral administration. It has a short half-life of 4 hours; poorly bound to plasma proteins; crosses blood–brain barrier. The drug is partly metabolized and excreted in urine. Uses 1. As an antiemetic: Metoclopramide is effective for prevention and treatment of: (a) Disease-associated vomiting. (b) Drug-induced vomiting (not used to control levodopa-induced vomiting). (c) Postoperative vomiting. (d) Cancer chemotherapy-induced vomiting. It is used in combination with 5-HT3 antagonists/dexamethasone/promethazine/diazepam. (e) Vomiting due to radiation sickness. It is less effective against motion sickness. 2. Gastroesophageal reflux disease (GERD): Metoclopramide produces symptom- atic relief in patients with reflux oesophagitis by increasing the tone of LES. By prokinetic effect, it also reduces the volume of gastroduodenal contents that reflux into oesophagus. It is less effective than proton-pump inhibitors (PPIs) and H2-blockers. 3. To alleviate symptoms associated with gastric stasis in patients with diabetes, postoperative or idiopathic gastroparesis: Gastric stasis is characterized by upper abdominal discomfort, distension, bloating, nausea, vomiting, etc. By prokinetic effect, it controls the above symptoms. 4. To stimulate gastric emptying before general anaesthesia in emergency surgeries. 5. Metoclopramide has been used in the treatment of intractable hiccups. Adverse Effects. They are drowsiness, dizziness and diarrhoea. Acute dystonias (spasm of muscles of face, tongue, neck and back) can occur. Other extrapyramidal symptoms (EPS: tremor, rigidity, etc.) are due to blockade of D2-receptors in basal gan- glia (drug-induced parkinsonism). Acute dystonias can be treated with centrally acting anticholinergics (e.g. benzhexol and benztropine) or antihistamines with anticholiner- gic action (e.g. promethazine and diphenhydramine). Long-term use may lead to gynaecomastia, galactorrhoea and menstrual irregulari- ties due to blockade of inhibitory effect of dopamine on prolactin release. Drug Interactions. Metoclopramide and levodopa: Metoclopramide crosses BBB, blocks D2-receptors in the basal ganglia, thus interfering with the anti-parkinsonian effect of levodopa. Hence, it is not used to treat levodopa-induced vomiting. Metoclopramide accelerates the absorption of diazepam but reduces digoxin absorp- tion by its prokinetic effect. Domperidone. It is a butyrophenone derivative (related to haloperidol) and has effects almost similar to metoclopramide. Its antiemetic and prokinetic effects are due 7—DRUGS USED IN THE TREATMENT OF GASTROINTESTINAL DISEASES 269 to blockade of D2-receptors (Fig. 7.2). It is less potent and less efficacious than metoclo- pramide. It poorly crosses BBB; hence, extrapyramidal side effects are rare. Atropine blocks the prokinetic effect of metoclopramide but not that of domperidone. It is usually administered orally, but its oral bioavailability is low because of extensive first- pass metabolism; metabolized in liver and metabolites are excreted in urine. Domperi- done is a preferred antiemetic in children, as it rarely produces EPS. It counteracts vomiting induced by levodopa or bromocriptine without affecting their anti-parkinso- nian effect as it poorly crosses BBB. Hence, it is preferred over metoclopramide to treat vomiting induced by these drugs. It increases prolactin levels. The important side effects are dryness of mouth, diarrhoea, headache, skin rashes, galactorrhoea and menstrual irregularities. Other prokinetic agents Cisapride, prokinetic agent, was banned because of its dangerous side effect – ventricular fibrillation (torsades de pointes). Mosapride The prokinetic effect is due to 5-HT4-agonism; also has weak 5-HT3 antagonistic effect Does not cause EPS, hyperprolactinaemia (no D2-blocking action) May be useful in dyspepsia, diabetic gastroparesis, GERD Side effects are dizziness, diarrhoea, headache, etc.; QT prolongation has been reported Itopride Prokinetic effect is due to D2-antagonism and anticholinesterase activity Drug interactions are rare and does not cause EPS Cinitapride It blocks 5-HT2 and D2-receptors in the gut. It is useful in GERD. Levosulpiride It blocks D2-receptors – has prokinetic and antiemetic effects. It is useful in irritable bowel syndrome. Anticholinergics. Scopolamine (hyoscine) is the drug of choice to prevent motion (travel) sickness. It blocks afferent impulses from vestibular apparatus to the vomiting centre by its anticholinergic action. Its sedative effect also contributes to its antiemetic effect. Scopolamine is administered orally, intramuscularly or as transdermal patch (see Chap. 2, p. 67). Antihistamines (H1-Blockers). H1-blockers are mainly useful for the prevention of motion sickness. They are also effective in morning sickness, postoperative and other types of vomiting (Table 7.1). Dimenhydrinate, diphenhydramine, doxylamine, pro- methazine, cinnarizine, cyclizine and meclizine are some of the H1-blockers that have antiemetic properties. Their antiemetic effect is due to sedative, H1 blockade and central anticholinergic actions. Cyclizine and meclizine have less sedative effect. Meclizine has a long duration of action (24 hours). Neuroleptics. They are potent antiemetics. Their antiemetic effect is due to blockade of D2-receptors in the CTZ. In addition, they have anticholinergic and antihistaminic actions. Among these, prochlorperazine is commonly used as an antiemetic. They are effective in the treatment of vomiting due to drugs, uraemia and systemic infections. Prochlorperazine, in low doses, may be used in hyperemesis gravidarum. They are also useful for the treatment of chemotherapy and radiation-induced vomiting. They are less 270 PHARMACOLOGY FOR MEDICAL GRADUATES effective in motion sickness. The common side effects are sedation, muscle dystonia and other EPS, dryness of mouth, hypotension, etc. Neurokinin (NK1)-Receptor Antagonists. Aprepitant (orally) and fosaprepitant (infused intravenously) are neurokinin-receptor antagonists. They block action of substance P in CTZ and NTS. They are highly effective in prevention of delayed emesis following moderately or highly emetogenic chemotherapy and increase the efficacy of standard antiemetic regimens (e.g. 5-HT3 antagonist ! dexamethasone). They are well tolerated; flatulence can occur. Cannabinoids Dronabinol. It is either obtained from marijuana plant or synthesized and is used to prevent cancer chemotherapy–induced vomiting not responding to other antiemetics. It is effective orally. It produces serious side effects such as sedation, central sympathomi- metic effects (tachycardia, palpitations and hypotension), hallucinations, disorientation and drug dependence – hence kept as a reserve antiemetic. Adjuvant Antiemetics Glucocorticoids. Glucocorticoids, such as dexamethasone, betamethasone and meth- ylprednisolone are used as adjuvant antiemetics. These agents are commonly used in combination with ondansetron or metoclopramide in the treatment of anticancer drug-induced acute and delayed vomiting. The beneficial effect of steroids is due to their anti-inflammatory property. Benzodiazepines. Lorazepam, diazepam and alprazolam are used to control psycho- genic and anticipatory vomiting. The beneficial effect is mainly due to their sedative, amnesic and antianxiety effects. Antidiarrhoeal Agents PH1.34 Generally, the term ‘diarrhoea’ denotes passage of unusually loose or watery stools at least three times or more in a 24-hour period (WHO). Based on the pattern of onset, there are two types of diarrhoea, i.e. acute and chronic. In most of the cases, acute diarrhoeas are caused by infectious agents. In acute diarrhoea, irrespective of the aetiol- ogy, emphasis is given to prevent dehydration, which is responsible for most of the mortalities. Diarrhoea is called chronic when it persists for more than 2 weeks. In chronic diarrhoea, finding out the cause is important for effective management. MANAGEMENT OF DIARRHOEA 1. Oral and parenteral rehydration 2. Antimotility agents: Opioids: codeine, loperamide, diphenoxylate 3. Antisecretory agents: Racecadotril, octreotide. 4. Probiotics 5. Antimicrobial agents Oral Rehydration Solution (ORS). In acute diarrhoea, it is important to maintain water and electrolyte balance with proper fluid replacement (rehydration). Oral rehydration seems to be the simplest, safest and least expensive method of choice for acute diarrhoea. WHO-ORS contains sodium chloride 2.6 g, potassium chloride 1.5 g, sodium citrate 2.9 g 7—DRUGS USED IN THE TREATMENT OF GASTROINTESTINAL DISEASES 271 and glucose 13.5 g. It has to be dissolved in 1 L of water. This provides sodium 75 mM, potassium 20 mM, chloride 65 mM, citrate 10 mM and glucose 75 mM. The total osmo- larity is 245 mOsm/L. Amount of sodium and glucose is lower than older preparations; this promotes better absorption of water from the solution. Sodium and potassium are administered to replace the losses. Sodium is transported along with glucose by sodium- glucose cotransporter in the ileum. Citrate, a base, corrects acidosis. ORS decreases stool volume and vomiting. It is also effective in cholera. ORS is also useful in heat stroke and maintenance of hydration in burn patients. In case of severe diarrhoea with dehydra- tion, intravenous fluids are indicated. WHO recommends the use of zinc supplement (10–14 days) with ORS in acute diar- rhoea in children. It decreases intestinal secretions, promotes regeneration of intestinal epithelium and reduces duration and severity of diarrhoea. Antimotility and Antisecretory Agents Codeine. It is a natural opium alkaloid. It decreases GI motility and produces consti- pation. It has abuse potential. Diphenoxylate. It is related to pethidine. In high doses, it has abuse liability, hence is usually available in combination with a small dose of atropine to discourage abuse or overdosage. The side effects are constipation, paralytic ileus and drug addiction. This drug has been banned in many countries. Loperamide. It is an opiate analogue and has more potent antidiarrhoeal effect than morphine. By interacting with µ-opioid receptors in the gut, loperamide reduces GI mo- tility and increases the anal sphincter tone. It decreases secretion induced by cholera toxin and some toxins of Escherichia coli. It is orally effective and has a rapid onset of action. It poorly penetrates BBB and has no abuse potential. The usual dose of loperamide is 4 mg stat and then 2 mg after each loose stool, but the maximum dose should not exceed 16 mg in 24 hours. It has been used in both acute and chronic diarrhoeas. It can also be used in travellers’ diarrhoea. The toxic effects are skin rashes, headache and paralytic ileus. It should not be used in children younger than 4 years. Antimotility drugs produce only symptomatic relief in diarrhoea and should be avoided in acute infectious diarrhoeas, as it can lead to penetration of organisms into bloodstream. These drugs also increase intraluminal pressure; hence, they should be avoided in inflammatory bowel disease (IBD). Clonidine. It has an antisecretory as well as antimotility effect. It has been used to control diarrhoea due to opioid withdrawal and in diabetes patients with autonomic neuropathy. The side effects are depression and hypotension. Octreotide. It is an analogue of somatostatin which is useful in secretory diarrhoea due to hormone-secreting tumours of the GIT and pancreas. It inhibits secretion of 5-HT, vasoactive intestinal peptide (VIP), gastrin, insulin, etc. It is administered either intravenously or subcutaneously. It can be used to treat diarrhoea in patients with AIDS. Racecadotril. Racecadotril (prodrug) active metabolite enkephalinase inhibi- tor inhibits degradation of enkephalins ("/# agonists) in intestinal mucosa increases the concentration of enkephalins in intestinal mucosa decrease in intestinal secretion. It is used in acute secretory diarrhoeas. It can be used in children. Side effects are nausea, vomiting and drowsiness. Probiotics They consist of either bacteria or yeast like Lactobacillus, Bifidobacterium and Saccharomy- ces boulardii. They may produce beneficial effect by competing with pathogens in the gut. 272 PHARMACOLOGY FOR MEDICAL GRADUATES Table 7.2 List of commonly used chemotherapeutic agents for specific treatment of infectious diarrhoea Preferred drug with route Organism and dose Alternative drugs 1. Shigella Ciprofloxacin 500 mg b.d. Ofloxacin, ampicillin and species $ 5 days cotrimoxazole 2. Salmonella Ciprofloxacin 500 mg b.d. Ceftriaxone, cefoperazone, $ 10 days ofloxacin and levofloxacin 3. Campylobacter Ciprofloxacin 500 mg b.d. Erythromycin and doxycycline jejuni $ 5 days 4. Vibrio cholerae Doxycycline 100 mg b.d. Ciprofloxacin $ 5 days 5. Escherichia coli Ciprofloxacin 500 mg b.d. Cotrimoxazole and rifaximin $ 5 days 6. Clostridium Metronidazole 800 mg t.d.s. Vancomycin difficile $ 10 days 7. Entamoeba Metronidazole 400 mg t.d.s. Tinidazole, secnidazole and histolytica ! Diloxanide furoate ornidazole 500 mg t.d.s. $ 7 days 8. Giardia lamblia Metronidazole 200 mg t.d.s. Tinidazole, paromomycin and $ 5 days nitazoxanide Antimicrobials Irrational use of antimicrobials should be avoided. They are indicated in acute bloody diarrhoea. They are also useful in cholera, pseudomembranous enterocolitis and amoebic dysentery. A list of antimicrobials is provided in Table 7.2. Pharmacotherapy of Inflammatory Bowel Disease PH1.34 IBD includes Crohn disease and ulcerative colitis, which are characterized by diarrhoea, bleeding, abdominal discomfort, anaemia and weight loss. COMMONLY USED DRUGS 1. Aminosalicylates: Sulphasalazine, mesalamine, olsalazine, balsalazide. 2. Glucocorticoids: Prednisolone, methylprednisolone, hydrocortisone, budesonide. 3. Immunomodulators: Azathioprine, 6-mercaptopurine (6-MP), methotrexate, cyclosporine. 4. Biological response modifiers: Infliximab. 5. Antibiotics: Metronidazole, ciprofloxacin, clarithromycin. 6. Others: Probiotics. Aminosalicylates (Fig. 7.3) Sulphasalazine. It is a prodrug and is composed of sulphapyridine and 5-aminosalicylic acid (5-ASA). On oral administration, sulphasalazine reaches the colon, where it is 7—DRUGS USED IN THE TREATMENT OF GASTROINTESTINAL DISEASES 273 Inhibits production of inflammatory Sulphasalazine, Beneficial effect mediators – interleukin (IL-1), olsalazine, Mesalamine in inflammatory tumour necrosis factor (TNFα), balsalazide bowel disease leukotrienes (LTs), etc. Fig. 7.3 Aminosalicylates and their mechanism of action. broken down by colonic bacteria to 5-ASA and sulphapyridine. The released 5-ASA acts locally by inhibiting the production of inflammatory mediators. Sulphapyridine gets absorbed and causes side effects like nausea, vomiting and headache. Allergic side effects are skin rashes, fever, hepatitis, pancreatitis, pneumonitis, etc. To avoid the side effects of sulphapyridine, several 5-ASA compounds have been developed which can be directly targeted to the colon. Mesalamine, Olsalazine and Balsalazide. Mesalamine (mesalazine) is 5-ASA. Mesalamine is well absorbed in the upper GIT; therefore, it has to be given as special formulations (delayed release capsules or pH-dependent tablets). It can be administered as supposi- tory or enema. Olsalazine is composed of two molecules of 5-ASA with an azo linkage. It is poorly absorbed after oral administration. In the colon, it is cleaved into two molecules of 5-ASA by colonic bacteria. Balsalazide is split into 5-ASA and a metabolite in the colon. Mesalamine, olsalazine and balsalazide have a lower incidence of side effects than sulphasalazine. They may cause headache and skin rashes. Diarrhoea is common with olsalazine. 5-ASA agents are mainly effective for mild to moderate ulcerative colitis. Glucocorticoids Glucocorticoids are used for the short-term treatment of moderate to severe IBD. Various glucocorticoids used in IBD are prednisolone (oral), methylprednisolone (oral, parenteral), hydrocortisone (enema, suppository) and budesonide (oral). Prolonged use of glucocorticoids can lead to hypothalamic–pituitary–adrenal axis suppression and other side effects like osteoporosis, peptic ulcer, infections and hyperglycaemia. Antibiotics Metronidazole, ciprofloxacin and clarithromycin are used as adjuncts in patients with active Crohn disease. Immunosuppressants Azathioprine, 6-mercaptopurine, methotrexate and cyclosporine are used in severe dis- ease or in patients with steroid-dependent/steroid unresponsive IBD. Biological Response Modifiers Infliximab, adalimumab (TNF-% inhibitors) and certolizumab can be used in severe cases of Crohn disease and refractory ulcerative colitis. The main disadvantages of bio- logics are their cost and increased susceptibility to infections. Probiotics Probiotics (e.g. Lactobacillus, Bacteroides, etc.) are used to restore the intestinal flora; useful as adjunct therapy in patients with severe IBD. 274 PHARMACOLOGY FOR MEDICAL GRADUATES Laxatives (Purgatives, Cathartics) PH1.34 Laxatives are drugs that facilitate evacuation of formed stools from the bowel. Purgatives cause evacuation of watery stools. The terms laxatives, purgatives and cathartics are often used interchangeably. CLASSIFICATION (ACCORDING TO MECHANISM OF ACTION) 1. Bulk laxatives Dietary fibre – Bran, methylcellulose, ispaghula (isabgol) 2. Stimulant or irritant laxatives Bisacodyl, sodium picosulphate, senna, cascara sagrada, lubiprostone, prucalo- pride 3. Osmotic laxatives Magnesium sulphate, magnesium hydroxide, sodium phosphate, sodium sulphate, lactulose, lactitol, polyethylene glycol 4. Stool softeners (emollient laxatives) Docusates, liquid paraffin Bulk-Forming Laxatives They are indigestible, hydrophilic substances like bran, methylcellulose, agar and ispa- ghula, which absorb water, swell up and increase the bulk of stools. They cause me- chanical distension, so stimulate peristalsis and promote defaecation. It takes 1–3 days for the evacuation of formed stools. Ispaghula is obtained from the seed of Plantago ovata. Large amount of water should be taken with bulk purgatives to avoid intestinal obstruction. Dietary fibres like pectin-bind bile acids increase their excretion in faeces and lower plasma LDL. Fibre diet should be encouraged in patients with irritable bowel syndrome, but should be avoided in those with megacolon or megarectum. The side effects include abdominal discomfort and flatus. Stool Softeners (Emollient laxatives) Docusates. Common docusate salts are dioctyl sodium sulphosuccinate (DOSS) and dioctyl calcium sulphosuccinate. They are anionic surfactants. They lower the surface tension of stool, thereby cause accumulation of fluid and fatty substance, thus softening the stools. These agents act within 1–3 days. They are administered orally or as a reten- tion enema. Docusates increase the absorption of liquid paraffin, hence should not be given together. Liquid Paraffin (Note the ‘Ls’). Liquid paraffin is a mineral oil and is administered orally. It softens stools. It also has a Lubricant effect which helps in smooth defaecation. It is useful in patients with cardiac disease because it prevents straining during defaeca- tion. Adverse Effects of Liquid Paraffin 1. Lipid pneumonia may occur due to entry of drug into lungs; hence, liquid paraffin should not be given at bed time and in lying down position. 2. Long-term use may cause malabsorption of vitamins A, D, E and K (fat-soluble vitamins). 3. Leakage of faecal matter through anal sphincter may lead to soiling of clothes. 7—DRUGS USED IN THE TREATMENT OF GASTROINTESTINAL DISEASES 275 Stimulant (Irritant) Laxatives These agents have direct action on enteric neurons and GI mucosa. They increase pros- taglandin (PG) and cyclic adenosine monophosphate (cAMP) levels, but inhibit Na!, K!-ATPase activity in the intestinal mucosa. This causes an increased secretion of water and electrolytes by the mucosa thus stimulating peristalsis. They cause evacuation of semifluid stools. Chronic use of stimulant laxatives may cause atonic colon. Large doses may cause loss of fluid and electrolytes. They are contraindicated in pregnancy as they cause reflex stimulation of uterus. Bisacodyl. The major site of action is colon. It is available as an enteric-coated oral tablet and also as a rectal suppository. It is poorly absorbed after oral administration and undergoes activation by esterases in the bowel. Hence, the effect is seen only after 6–8 hours of oral administration. Therefore, it is usually given at bed time. Rectal suppositories act more rapidly within an hour by irritation of rectal mucosa. Bisacodyl is used in constipation and to empty the bowel before endoscopy, surgery and radio- logical investigations. The side effects are local irritation and inflammation. Sodium Picosulphate. It is a stimulant purgative given orally at bed time. It can be used to evacuate the bowel before surgery or colonoscopy. Prucalopride. Prucalopride, a prokinetic drug, is a 5-HT4 agonist. It is useful in chronic constipation not responding to laxatives. It increases colonic motility. Lubiprostone. Lubiprostone, a PG analogue, is useful in chronic constipation and irri- table bowel syndrome. It increases intestinal secretion. Anthraquinone Derivatives. The popular anthracene purgatives are senna and cascara. They take 6–8 hours to act, hence are usually administered at bed time to produce their effect in the morning. They are poorly absorbed in the small intestine. The unabsorbed portion reaches the colon, where it is reduced by bacteria to anthrol that acts locally and induces purgation. They should not be prescribed to lactating mothers, as they are secreted in milk. The side effects are skin rashes, black pigmentation of the colonic mucosa and discolouration of urine. Prolonged use can cause colonic atony. Osmotic Laxatives They are salts of magnesium, sodium or potassium. Those having magnesium or phos- phate are known as saline laxatives. Osmotic purgatives are given orally, Act on the small and early morning on large intestine Not absorbed in the gut empty stomach (within 1–3 hours) with plenty of water Draw fluid into the lumen by osmotic activity Evacuation of watery Stimulate peristalsis Distend the bowel stools in 1–3 hours 276 PHARMACOLOGY FOR MEDICAL GRADUATES Colonic bacteria Lactulose Acidic products Ammonia is converted into Blood ammonia an ammonium ion (not Reduces luminal level decreases absorbed in the gut) pH in the colon Fig. 7.4 Action of lactulose in hepatic coma. In addition, magnesium salts cause release of cholecystokinin. To mask the bitter taste, they are often administered with fruit juice. The important osmotic laxatives are magnesium sulphate (Epsom salt), magnesium hydroxide (milk of magnesia), sodium phosphate, lactulose, etc. They should be avoided in young children and patients with renal failure, as they may cause CNS or cardiac depression. Sodium phosphate is commonly used orally for colon preparation before surgery or colonoscopy. It can also be used as an enema. Sodium salts should be avoided in cardiac patients. Lactulose. Lactulose is a disaccharide of fructose and galactose. Lactulose is available as liquid and powder. On oral administration, it is not absorbed through GI mucosa. Colonic bacteria convert it into acidic products, which exert osmotic effect – draw fluid into the lumen and distend it, thus useful in constipation. It produces soft to loose stools. It can be used to treat constipation in children and pregnant women. Lactulose is used in hepatic coma to reduce blood ammonia levels (Fig. 7.4). The side effects include abdominal discomfort and flatulence. Lactitol. Its actions are similar to lactulose. It is useful in constipation and hepatic encephalopathy. Polyethylene Glycol. It is an osmotic laxative which is used to evacuate the bowel prior to surgical, radiological and endoscopic procedures. It is available as powder and solution. The powder should be mixed with water or fruit juice. USES OF LAXATIVES WITH PREFERRED PREPARATIONS 1. Acute functional constipation (atonic or spastic) – bulk laxatives. 2. To prevent straining during defaecation in patients with cardiovascular disease, eye surgery, hernia, etc. – docusates or bulk laxatives. 3. In patients with hepatic coma to reduce the blood ammonia level – lactulose. 4. Preoperatively in bowel surgery, colonoscopy and abdominal X-ray – osmotic laxatives or bisacodyl. 5. Following anthelmintics (e.g. for Taenia solium) – saline laxatives are used to expel the worm segments. 6. In drug poisoning to wash out the poisonous material from the gut – saline laxatives. 7. To treat constipation in children and pregnant women – lactulose. Treatment of opioid-induced constipation Laxatives are the preferred drugs. If patient does not respond to laxatives, opioid antagonists like methylnaltrexone and naloxegol can be used. Methylnaltrexone (s.c.), 7—DRUGS USED IN THE TREATMENT OF GASTROINTESTINAL DISEASES 277 naloxegol (oral) are peripherally acting µ-opioid receptor antagonists. They are devoid of central effects; used to treat opioid-induced constipation in cancer patients. Adverse effects are nausea, vomiting and diarrhoea. Pharmacotherapy of Peptic Ulcer and Gastroesophageal Reflux Disease PH1.34 Physiology of gastric secretion The stomach secretes roughly about 2–3 litres of gastric juice per day. The chief or peptic cells secrete pepsinogen, which is converted to pepsin by gastric acid. Parietal or oxyntic cells secrete acid and intrinsic factor (IF). Superficial epithelial cells secrete alkaline mucus and bicarbonate ions. Regulation of gastric acid secretion The secretion of gastric acid by parietal cells is regulated by ACh, histamine, gastrin and prostaglandin E2 (PGE2). Binding of histamine, ACh and gastrin to their specific recep- tors on the parietal cell results in increased secretion of gastric acid. In contrast, the binding of PGE2 to its receptor decreases gastric acid secretion. There are various phases of gastric acid secretion – basal, cephalic and hormonal. A membrane-bound proton pump H!, K!-ATPase plays an important role in the final step of gastric acid secretion. Damage to the mucosa and deeper tissue exposed to acid and pepsin is known as peptic ulcer. The exact cause of peptic ulcer is not clear. In most of the cases, peptic ulcers are caused by Helicobacter pylori infection or the use of nonsteroidal anti-inflam- matory drugs (NSAIDs). CLASSIFICATION OF DRUGS USED IN PEPTIC ULCER Drugs used in peptic ulcer are classified as follows (Fig. 7.5): 1. Drugs that inhibit gastric acid secretion (a) PPIs: Omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole. (b) H2-receptor antagonists (H2-blockers): Cimetidine, ranitidine, famotidine, rox- atidine, nizatidine. Antacids Neutralize PPIs ACID Decrease H2-blockers secretion of Prostaglandins r ce Ul Protect Sucralfate CBS Fig. 7.5 Drugs used in peptic ulcer. PPIs, proton-pump inhibitors; CBS, colloidal bismuth subcitrate. 278 PHARMACOLOGY FOR MEDICAL GRADUATES (c) Antimuscarinic agents (anticholinergic agents): Pirenzepine, telenzepine. (d) Prostaglandin analogues: Misoprostol. 2. Ulcer protectives Sucralfate, colloidal bismuth subcitrate (CBS). 3. Drugs that neutralize gastric acid (antacids) (a) Nonsystemic antacids: Magnesium hydroxide, magnesium trisilicate, alumin- ium hydroxide, calcium carbonate. (b) Systemic antacids: Sodium bicarbonate, sodium citrate. 4. Anti-H. pylori agents Amoxicillin, tetracycline, clarithromycin, metronidazole, tinidazole, bismuth subsalicylate, H2-antagonists, PPIs. Drugs That Inhibit Gastric Acid Secretion Proton-Pump Inhibitors (PPIs). Proton pump (H!, K!-ATPase) is a membrane-bound enzyme that plays an important role in the final step of gastric acid secretion (basal and stimulated; Fig. 7.6). Omeprazole is the prototype drug. The other PPIs are lansoprazole, pantoprazole and rabeprazole. PPIs (prodrugs) nabsorbed in small intestine n blood n diffuse into parietal cells n canaliculi of the cell (acidic pH) n converted to sul- phenamide (active, charged form). The activated form (sulphenamide) binds covalently with SH group of the proton pump and irreversibly inactivates it. PPIs are the most powerful inhibitors of gastric acid secretion. They inhibit both fasting and stimulated acid secretion. As PPIs act in the final step of acid secretion, they are effective in inhibit- ing acid production following any stimulation. PPIs are administered orally about 30 minutes before food because food stimulates secretion of acid (in the canaliculi of parietal cell), which is necessary for activation of PPIs. Food decreases absorption of PPIs. Though the half-life of PPIs is short (!1.5 hours), acid secretion is suppressed for up to 24 hours as they cause irreversible inhibition of proton pumps. In the commonly used doses, PPIs suppress acid production by about 80%–98%. PPIs are available as enteric coated form or as powder containing sodium bicarbonate to prevent their acti- vation by acid in the stomach. Esomeprazole, pantoprazole and lansoprazole have higher oral bioavailability than omeprazole. Ilaprazole is more potent than omeprazole. Parenteral (i.v.) formulations are available for esomeprazole, lansoprazole, pantoprazole Canaliculi Blood Parietal cell (acidic pH) PPIs PPIs PPIs Sulfenamide Proton ! pump Fig. 7.6 Mechanism of action of proton-pump inhibitors. 7—DRUGS USED IN THE TREATMENT OF GASTROINTESTINAL DISEASES 279 and rabeprazole. They are highly bound to plasma proteins; extensively metabolized in liver and metabolites are excreted in urine. Therapeutic Uses 1. Peptic ulcer: PPIs are the most powerful acid suppressive agents. They inhibit all phases of gastric acid secretion. PPIs are superior to H2-blockers as their onset of action is rapid and cause faster ulcer healing. The standard dose of omeprazole is 20 mg, lansoprazole 30 mg and pantoprazole 40 mg once daily. Duodenal ulcers require 4 weeks’ therapy and gastric ulcers require 6–8 weeks’ therapy for healing. In acute bleeding ulcers, intravenous PPIs are preferred. By suppressing acid secretion, they promote healing of ulcer. H. pylori–associated ulcers: Combination therapy of two or three antimicrobials and a PPI is the most effective regimen for these ulcers. Stress ulcers (Curling ulcer): Prophylactic use of intravenous PPIs reduce the incidence of stress ulcers in critically ill patients. NSAID-induced ulcers: PPIs are more effective than H2-blockers for prevention and treatment of NSAID-induced ulcers. 2. PPIs can be used preoperatively to reduce the risk of aspiration pneumonia. 3. Zollinger–Ellison (Z–E) syndrome: Z–E syndrome is characterized by hypergas- trinaemia with multiple peptic ulcers. PPIs are the preferred agents for Z–E syndrome. Higher doses of PPIs are needed for healing of ulcers. Surgery is the definitive treatment. In inoperable cases, prolonged therapy with PPIs has been recommended. 4. Gastroesophageal reflux disease: In GERD, the goal of therapy is to produce symptom relief, heal erosive oesophagitis and prevent complications. PPIs are the preferred agents for the treatment of GERD and are usually given once daily. They are more effective than H2-blockers. Patients with erosive oesophagitis or peptic ulcer with stricture need prolonged maintenance therapy with PPIs. Adverse Effects. PPIs are generally well tolerated. The side effects are headache, nausea, diarrhoea and abdominal pain. Skin rashes and arthralgia can rarely occur. Long-term use of PPIs can decrease vitamin B12 absorption, increase the risk of infections (e.g. hospital-acquired pneumonia) and osteoporosis. Chronic use also results in hypergastri- naemia which may predispose to gastric tumours. Gynaecomastia and erectile dysfunc- tion with omeprazole therapy have been reported. Drug interactions. Omeprazole can inhibit the metabolism of drugs like phenytoin, warfarin and diazepam. PPIs decrease the bioavailability of itraconazole, iron salts, etc. Drug interactions are minimal with pantoprazole. H2-Receptor Antagonists (H2-Blockers) Ranitidine Parietal cell Famotidine Histamine H2-receptors Nizatidine (Agonist) Cimetidine (Antagonists) Mechanism of Action. H2-receptor antagonists competitively block H2-receptors on parietal cell and inhibit gastric acid production. They suppress all phases (basal, cephalic and gastric) of acid secretion. They are mainly effective in suppressing nocturnal acid secretion. H2-blockers also reduce acid secretion stimulated by ACh, gastrin, food, etc. 280 PHARMACOLOGY FOR MEDICAL GRADUATES They are less potent than PPIs – 24-hour acid secretion is suppressed by 60%–70%. Cimetidine is the prototype drug and was the first H2-blocker developed. It is seldom used now because of its adverse effects (Table 7.3). H2-blockers are usually administered orally and are well absorbed; metabolized in liver and the metabolites are excreted in urine. Cimetidine, ranitidine and famotidine are also available for intravenous administration. Nizatidine: All the features are similar to ranitidine but it has higher bioavailability (almost 100%). Famotidine: Most of the features are similar to ranitidine. It is more potent and longer acting than ranitidine. It has no antiandrogenic effect. Drug interactions are negligible. Lafutidine: It is an H2-receptor blocker and decreases acid secretion. It increases mucosal blood flow and mucin synthesis. Nitric oxide production is increased. Therapeutic Uses 1. Peptic ulcer: H2-blockers are one of the commonly used drugs in peptic ulcer. H2-blockers produce symptomatic relief within days and ulcer healing within weeks. The duration of treatment for duodenal ulcer is 4–6 weeks. Gastric ulcer requires prolonged therapy for 6–8 weeks. But, PPIs are more frequently used because they have higher efficacy and are well tolerated. H. pylori–associated ulcers: H2-blockers can be used along with antimicrobial agents to treat H. pylori infection. Stress ulcers are commonly seen in critically ill patients with severe medical or surgical illness. They may be associated with upper gastrointestinal bleeding. Intravenous H2-blockers are used to prevent and treat stress-related ulcer and bleeding. NSAID-induced ulcers: H2-blockers can be used for healing of NSAID-induced ulcers but they are less effective than PPIs. Table 7.3 Comparison of cimetidine and ranitidine Cimetidine Ranitidine 1. H2-blocker (competitive blocker) H2-blocker (competitive blocker) 2. Less potent More potent 3. Has shorter duration of action (6–8 hours) Has longer duration of action (24 hours) 4. Cimetidine is an enzyme inhibitor, hence Has less affinity for hepatic cytochrome increases the plasma concentration of P450 enzymes, hence drug interac- many co-administered drugs, such as tions are rare phenytoin, digoxin, theophylline, warfarin and propranolol 5. Increases plasma prolactin level; can cause Has no antiandrogenic effect; does not menstrual irregularities and galactorrhoea in increase prolactin secretion women; gynaecomastia, oligospermia and impotence in men 6. Crosses BBB and produces CNS side Poorly crosses BBB, CNS side effects effects like confusion, headache and are rare hallucinations 7—DRUGS USED IN THE TREATMENT OF GASTROINTESTINAL DISEASES 281 2. Gastroesophageal reflux disease: In GERD, H2-blockers are effective and produce symptomatic relief. PPIs are more effective than H2-blockers. 3. Zollinger–Ellison syndrome: In Z–E syndrome, surgery is the definitive therapy. PPIs or H2-blockers are used to control the hypersecretion of acid. PPIs are the preferred agents in Z–E syndrome. 4. H2-blockers are used preoperatively to reduce the risk of aspiration pneumonia. Anticholinergic Agents. Pirenzepine and telenzepine, selective M1-receptor blockers, in- hibit acid secretion. They are not commonly used because of their low efficacy and an- ticholinergic side effects. Prostaglandin Analogues. Misoprostol, a synthetic PG analogue (PGE1), is effective orally for prevention and treatment of NSAID-induced gastric and duodenal ulcers. PGs inhibit gastric acid secretion, increase mucus and bicarbonate secretion; they also increase mucosal blood flow (cytoprotective effect). The common side effects are diarrhoea and abdominal cramps. Misoprostol is contraindicated in pregnancy, as it may cause uterine contractions. Because of its adverse effects and need for frequent dosing, it is rarely used. Ulcer Protectives Sucralfate. It is a complex of aluminium hydroxide and sulphated sucrose. In the acidic environment of stomach (pH & 4), sucralfate undergoes polymerization to form a sticky polymer that adheres to the ulcer base and protects it. It also precipitates proteins at the ulcer base – forms a barrier against acid–pepsin. It stimulates the release of PGs and epidermal growth factor locally, thus produces cytoprotective effect. It also increases mucus and bicarbonate secretion – enhances mucosal defence and repair. Sucralfate is given orally on an empty stomach at least 1 hour before meals. It reduces the absorption of drugs, such as digoxin, tetracyclines, ketoconazole and fluoroquino- lones. Since it requires pH & 4 for activation, concurrent administration of antacids, H2-blockers or PPIs should be avoided. Constipation is a common side effect. Nausea may occur. Aluminium toxicity can occur in patients with renal failure. After the introduction of PPIs, sucralfate is seldom used in peptic ulcer. Sucralfate is effective for prevention of bleeding from stress ulcers and to reduce the risk of aspiration pneumonia. It is also useful in GERD with oesophagitis, as it is a mucosal protector. Other uses are oral mucositis, radiation proctitis, rectal ulcer, burns, bed sores, etc. Bismuth-Containing Preparations. Bismuth subsalicylate and CBS are the most commonly used oral bismuth preparations. Their mode of action is not clear. They probably: 1. Precipitate proteins and protect ulcer base. 2. Stimulate the secretion of PGE2, mucus and bicarbonate. 3. Have antimicrobial effect against H. pylori. They are one of the components in certain anti-H. pylori regimens. The side effects are blackening of the tongue and stools. Drugs that Neutralize Gastric Acid (Antacids) Antacids are weak bases that neutralize gastric acid and raise the gastric pH. They do not affect acid production. Acid neutralizing capacity reflects the potency of an antacid. An Ideal Antacid 1. should be insoluble and capable of neutralizing acid. 2. should not liberate CO2. 282 PHARMACOLOGY FOR MEDICAL GRADUATES 3. should be nonabsorbable. 4. should not disturb the acid–base balance of the body. Types of Antacids 1. Nonsystemic: Magnesium hydroxide, magnesium trisilicate, aluminium hydrox- ide gel and calcium carbonate. 2. Systemic: Sodium bicarbonate and sodium citrate. Nonsystemic Antacids. Magnesium hydroxide, magnesium trisilicate, aluminium hydroxide, calcium carbonate, etc. form respective chloride salts in stomach. When this reaches the intestine, the chloride salt reacts with bicarbonate, so HCO3– is not available for absorption; hence, there is no systemic alkalosis. Combination of antacids produces various beneficial effects. They are as follows: 1. Aluminium salts cause constipation and magnesium salts cause diarrhoea, so combination of these two can counteract the adverse effects of each other. 2. Magnesium hydroxide has a rapid onset of action, but aluminium hydroxide acts slowly – the combined product produces rapid and sustained effect. 3. Dose of individual antacid is reduced; hence, systemic toxicity is minimized. Calcium may be absorbed from its salts resulting in hypercalcaemia and hypercalciuria. Systemic Antacids Sodium bicarbonate (NaHCO3). It rapidly neutralizes gastric acid, but the duration of action is short. The disadvantages of NaHCO3 are that (i) it is highly water soluble and rapidly absorbed from the gut; (ii) it releases CO2 that can cause abdominal distension and belching; (iii) it may cause metabolic alkalosis; and (iv) it produces rebound acidity. Sodium bicarbonate is also used to alkalinize urine and to treat acidosis. It should be avoided in patients with hypertension and congestive cardiac failure (CCF), as it causes sodium retention. Formulations. Antacids are available as suspension, tablet and powder. Tablet should be chewed and swallowed for better effect. Suspensions have better neutralizing capacity than other formulations. Drug Interactions. All antacids increase the pH of stomach and form insoluble and nonabsorbable complexes with many drugs – iron, tetracyclines, fluoroquinolones, keto- conazole, etc.; thus, antacids reduce the absorption of these drugs. There should be a gap of 2 hours between administration of these drugs and antacids. Antifoaming Agents Methylpolysiloxane (simethicone and dimethicone): They are antifoaming agents, usu- ally present in some antacid preparations. They decrease foaming and relieve flatulence. Oxethazaine: It is a topical anaesthetic and is used to anaesthetize gastric mucosa. It produces symptomatic relief in gastritis and GERD. It is available in combination with antacids. Sodium alginate: It forms froth on the contents in the stomach – prevents effects of gastroesophageal reflux. Anti-H. pylori Agents H. pylori, Gram-negative, rod-shaped bacterium, is associated with gastritis, duodenal ulcer, gastric ulcer and gastric carcinoma (Fig. 7.7). The mechanism by which H. pylori causes mucosal inflammation and damage is not clear. The ammonia produced by urease activity may directly damage the cells. 7—DRUGS USED IN THE TREATMENT OF GASTROINTESTINAL DISEASES 283 Urease Urea NH3 Fig. 7.7 Helicobacter pylori (H. pylori). Many regimens are available for the eradication of H. pylori. Combination therapy (triple/quadruple) is always recommended. The objectives of combination therapy are as follows: 1. To prevent or delay the development of resistant organism. 2. To prevent relapse. 3. To promote rapid ulcer healing. 4. To eradicate H. pylori infection. The duration of treatment could be 1 week or 2 weeks, of which 14-day therapy is more effective. The antimicrobials used in H. pylori infection are amoxicillin, tetracycline, clarithro- mycin, metronidazole and tinidazole. Resistance develops rapidly to metronidazole and clarithromycin but not to amoxicillin. Amoxicillin should be avoided in patients with history of penicillin allergy. Other anti-H. pylori drugs are PPIs, H2-blockers and CBS. Some of the recommended regimens are listed below: Triple Therapy ! 14 Days (2 Weeks) Lansoprazole 30 mg b.d ! Clarithromycin 500 mg b.d. ! Amoxicillin 1 g b.d. Quadruple Therapy ! 14 Days (2 Weeks) Omeprazole 20 mg b.d. ! CBS 120 mg q.i.d. ! Tetracycline 500 mg q.i.d.! Metronidazole 400 mg t.i.d. After completion of the above-recommended regimen, PPI should be continued for 6 more weeks to enhance ulcer healing. DRUGS USEFUL IN GASTROESOPHAGEAL REFLUX DISEASE PH1.34 1. PPIs and H2-receptor blockers: They decrease acid secretion n pH of gastric contents rise n relief of symptoms and healing of esophageal lesions. PPIs are more effective than H2-blockers. They do not affect LES tone. 284 PHARMACOLOGY FOR MEDICAL GRADUATES 2. Antacids are used occasionally in GERD. They are rapid acting. 3. Prokinetic drugs, e.g. metoclopramide and mosapride increase tone of LES, enhance gastric emptying but do not affect acid secretion. DRUGS FOR DISSOLVING GALLSTONES. PH1.34 Ursodiol decreases biliary secretion of cholesterol and helps to dissolve cholesterol stones. It is administered orally. A functional gall bladder is required. Elevation of liver enzymes may occur. It is used in those patients with gallstones in whom surgery cannot be done.