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OS 214 [B]: Digestion and Excretion 2 Lec 11: Gastrointestinal Pharmacology October 9, 2013 Maria Concepcion C. Sison, MD, FPPS, FPCC TOPIC OUTLINE I. II. Rational Prescribing Acid Peptic Disease A. Peptic ulcer disease B. Gastric acid secretion C. Drug therapy in peptic ulcer disease D. Antacids E. Histamine (H2) receptor antagonists F. Proton pump inhibitors G. Drugs that protect the mucosa H. Treatment of H. pylori III. Gastrointestinal Motility A. Drugs affecting GI motility B. Prokinetic Agents IV. Constipation A.Stool Formation B. Pathophysiology C. Laxatives V. Diarrhea A. Pathophysiology B. Treatment VI. Vomiting A. The Reflex Mechanism of Vomiting B. Emetic Drugs C. Antiemetic Drugs VII. Irritable Bowel Syndrome A. Pharmacologic Therapy VIII. Inflammatory Bowel Disease A. Pharmacologic Therapy IX. Biliary Tree A. Bile Acids B. Drugs Affecting the Biliary System Objectives: Enumerate the classes of drugs used for common GI symptoms and disease Discuss the pathophysiology of the following GI diseases relevant to drug therapy o Acid peptic disease o Vomiting o Diarrhea o Constipation o Irritable bowel syndrome o Inflammatory bowel disease State the targets of therapy for these common GI problems Legends: From the Powerpoint presentation From the lecturer and other sources Figure 1. Acid peptic disease. This results from an imbalance between the aggressive and defensive factors in the GIT. Treatment should reduce aggressive factors and stimulate formation of protective factors. A. PEPTIC ULCER DISEASE Note: First two (H. pylori and NSAIDs) comprise more than 90% of the causes of acid peptic disease. B. GASTRIC ACID SECRETION Establish diagnosis Know the problem (pathophysiology) Address the problem (solution / therapeutic objective): pharmacologic or non-pharmacologic Choose drug Monitor drug action (re-evaluate effectiveness / toxicities) Determine endpoint of therapy and plan a program for patient education Gastric acid secretion is a complex continuing process which culminates in the secretion of H+ by parietal cells The most important mechanism of ion-gradient generation is through the K+/H+-ATPase Pump or the Proton Pump (most hardworking pump in the body); this generates the largest known ion gradient in vertebrates with intracellular pH of 7.3 and intracanalicular pH of 0.8 Logical to target the proton pump itself if you want to prevent gastric acid secretion. o Proton pump inhibitors are widely used because of its efficacy and safety in decreasing gastric acid secretion Note: Refer to figure 7 for the complete diagram of gastric acid secretion. C. DRUG THERAPY IN PEPTIC ULCER DISEASE I. RATIONAL PRESCRIBING The most common cause are as follows: o Helicobacter pylori o Nonsteroidal anti-inflammatory drugs (NSAIDs) o Alcohol and drug abuse o Trauma and stress Reduce gastric acidity o Antacids o Histamine (H2) receptor antagonists o Proton pump inhibitors Promote mucosal defense (prevent ulceration) Eradicate H. pylori infection (if present) Example of drugs used in PUD: o Antacids – to neutralize the secreted acid o Sucralfate – coats ulcer base when theres already an ulcer o PPI – inhibits K+H+ATPase pump o H2 blockers – block histamine receptors to decrease secretion of gastric acid Note: We should not be satisfied with just giving the drug, we should also educate the patient. II. ACID PEPTIC DISEASE Q: All of the following drugs protect gastrointestinal tract from ulceration, EXCEPT a. Cimetidine b. NSAIDs c. Calcium carbonate d. Omeprazole Figure 2. Sites of action of some drugs used in Peptic Ulcer Disease. Gastrin (G), Histamine (H2) and Muscarinic (M3) receptors are the most important sites of action. QUINIO, RAMOS, REYES Page 1 / 10 Lec 11: Gastrointestinal Pharmacology Q: D. ANTACIDS A patient takes 30 mL Maalox (Aluminum magnesium hydroxide) per orem 1 hour and 3 hours after meal (height of gastric acid production) and bedtime for treatment of duodenal ulcer. Why does she take this antacid so frequently? a. It has a slow onset of action b. It has a short duration c. It has a prolonged half-life d. It is highly metabolized Used for centuries for acid peptic diseases Neutralize gastric acid since they are weak bases o Weak bases + gastric acid salt + water Stimulates mucosal prostaglandin formation increases mucus production May cause increased acid production, must be used repeatedly to reduce acidity 156 meqs antacid given 1 hour after a meal neutralize gastric acid for up to 2 hours Can be used in diagnosis: if relief is felt after intake, then it is probably a case of peptic acid disease Highly variable acid-neutralization capacity of various formulations Differ mainly in absorption and effects on stool consistency If patient has abdominal pain in the ER & acute abdomen has been ruled out, you may give antacid as it has fast onset of action of approximately 30 minutes PREPARATIONS Sodium bicarbonate (baking soda, Alka Seltzer) o Produces CO2 (can cause bloating and increased burping capacity), and NaCl (may aggravate sodium retention and cause fluid overload) by coupling with your hydrochloric acid Calcium carbonate (Tums) o CO2 and CaCl2 o Both sodium bicarbonate and calcium carbonate cause metabolic alkalosis if reabsorbed Magnesium hydroxide, Aluminum hydroxide: weak bases PHARMACOKINETICS Onset: 5-15 minutes Duration: 2 hours Faster symptom relief, though short-lived, than H2 antagonist Should be given 1 and 3 hours after meals (when gastric acid production is at its peak) May affect (decrease) absorption of other medications (tetracycline, fluoroquinolones, itraconazole, iron) since it alters the pH of the stomach; these drugs must be given at least 1-2 hours after you give the antacid E. HISTAMINE (H2) RECEPTOR ANTAGONISTS Used for fast relief of gastric discomfort, often in combination with other therapies Dyspepsia Symptomatic relief in peptic ulcer, esophageal reflux ADVERSE EFFECTS Antacids can affect absorption, bioavailability, or urinary excretion of other drugs by altering gastric and urinary pH or by delaying gastric emptying Can cause hypokalemia Overuse can also cause the following problems o Aluminum hydroxide – may cause constipation and hypophophatemia, proximal muscle weakness, osteodystrophy, seizures Aluminimum amount of feces o Magnesium hydroxide – may cause diarrhea, hyporelexia, hypotension, cardiac arrest Mg = Must go to the bathroom *Commonly used: salts of magnesium (Mg) with aluminium (Al) is a good combination because they offset each other’s side effect (eg. Maalox) o Calcium carbonate – hypercalcemia, increased rebound acid Can chelate and decrease effectiveness of other drugs (eg. Tetracycline) Has the probability of being absorbed so not frequently used QUINIO, RAMOS, REYES Competitively, reversibly inhibit histamine actions at all H2 receptors o Block histamine release from ECL cells via gastrin or vagal stimulation o Diminish gastrin- or Ach-stimulated acid secretion (decreased cAMP, attenuate protein kinase activation) Inhibit 60-70% of total 24-hr acid secretion (vs PPI’s which decreases as much as 90-98% of acid secretion), mostly during meal time Decrease both basal and food-stimulated acid secretion (linear, dose-dependent); less on food-stimulated acid secretion Especially effective in inhibiting nocturnal acid secretion (90%) Recommended prescription doses maintain >50% inhibition for 10 hours Cimetidine (prototypic drug, but lots of side effects and drug reactions), Ranitidine, Nizatidine, Famotidine (most potent) o Take H2 blockers before you DINE o Think table for 2 to remember H2 (it’s best to eat with someone else) PHARMACOKINETICS Given orally and is well-absorbed Peak effect: 1-3 hours With intravenous preparations as well Cleared by hepatic metabolism, glomerular filtration and renal tubular secretion Except for Nizatidine, there is decreased (50%) bioavailability due to first-pass metabolism Dosage: BID (twice a day) or at HS (bedtime) Table 1. Clinical comparison of H2 blocker Drug Relative >50% acid Frequency inhibition (10h) Cimetidine 1 400-800 mg Ranitidine 4-10x 150 mg Nizatidine 4-10x 150 mg Famotidine 20-50x 20 mg Acute duodenal / gastric ulcer 800 mg HS 400 mg BID 300 mg HS 150 mg BID 150 mg BID 300 mg HS 20 mg BID 40 mg HS Usual dosage for GERD 800 mg BID 150 mg BID 150 mg BID 20 mg BID Note: Potency does not equate with efficacy, it just means some drugs need to be given at a higher dose CLINICAL USE CLINICAL USE OS 214 Peptic ulcer disease o Nocturnal acid suppression o Healing >80-90% after 6-8 weeks (uncomplicated) o NSAID-induced Gastroesophageal reflux disease Erosive esophagitis Non-ulcer dyspepsia (questionable benefit) Prevention of bleeding from stress-related gastritis (especially when patient is put on nothing per orem) If you are going to use H2 receptor antagonist for NSAIDs-induced peptic ulcer disease, you have to discontinue use of NSAIDs. In using PPI’s, you can still use NSAIDs and expect healing. ADVERSE EFFECTS Extremely safe drugs <3% of patient: diarrhea, headache, fatigue, myalgias, constipation, mental status changes (elderly, cimetidine) Crosses palcenta, secreted in breastmilk (not administered in pregnancy) CIMETIDINE First found but least used due to adverse effects Inhibits binding of dihydrotestosterone and metabolism of estradiol ( testosterone + estrogen galactorrhea in women, gynecomastia and impotence in men; decreased sperm count, diminished libido) *Hardly anyone uses this drug. Fortunately, there are alternatives. Inhibits cytochrome P450 (1A2, 2C19, 2D6) o 2C19 is important in the metabolism of Warfarin and Coumadin. If patient is on anticoagulants, watch out because they may bleed. o Drug interaction: oral anticoagulants, tricyclic antidepressants, lidocaine, quinidine, metoprolol, ethanol, CCBs, others Page 2 / 10 Lec 11: Gastrointestinal Pharmacology o o Fatal if it causes arrhythmia, and potent if it can causes bleeding that can be fatal as well Ranitidine binds 4-10x less avidly to cytochrome P450 Negligible binding with nizatidine and famotidine CLINICAL USE F. PROTON PUMP INHIBITORS (PPI) First choice drug for acid peptic disease Major role for the treatment of acid-peptic diseases (most effective of them all) Outstanding efficacy and safety (most widely-used now) Omeprazole (first PPI – prototypic drug), lansoprazole, pantoprazole, rabeprazole, esomeprazole Irreversibly inhibit K+/H+ ATPase (proton pump) – a noncompetitive inhibitor; inhibits synthesis of new pumps Lipophilic weak bases Inactive at neutral pH but accumulated in the acid environment of the canaliculi of parietal cell (ie. where the action is) Effectively inhibits meal-stimulated acid secretion during the day as well as basal secretion overnight Inhibits 90-98% of 24-hour acid secretion H2 antagonists are more effective than PPIs in nocturnal acid secretion OS 214 GERD o Most effective agents o Once daily dosing provides symptom relief and tissue healing (85-90%) o Empiric treatment – symptom relief in 70-80% PUD o More rapid symptom relief and faster ulcer healing o H. pylori associated ulcers o NSAID-associated ulcer – healing despite continued therapy; in acute coronary syndrome, osteoarthritis, etc. Non-ulcer dyspepsia (10-20% > placebo) Prevention of stress gastritis Hypersecretory conditions (gastrinoma) SIDE EFFECTS Not common Headache, diarrhea, rashes, dizziness, somnolence, mental confusion, impotence, gynecomastia, myalgia, arthralgia have been reported Chronic treatment – hypergastrinemia, since body tries to compensate May affect (decrease) absorption of other drugs (digoxin, ketoconazole); iron, Ca, zinc, vitamin B12 (cobalamin deficiency) Inhibits metabolism of Coumadin, diazepam and phenytoin (CYP2C19) but not to the same extent cimetidine would G. DRUGS THAT PROTECT THE MUCOSA Sucralfate, Bismuth chelate, Carbenoxolone, Misoprostol (not freq used anymore) Enhance mucosal protection mechanisms specifically increase in bicarbonate production Provide physical barrier over the surface of the ulcer SUCRALFATE Figure 3. PPI shows consistent inhibition of acid formation. Spikes in the graph of H2 block indicate periods where Ach or gastrin released, such as during meal times. PHARMACOKINETICS Administered as inactive prodrugs (acid-labile – if they are released in the gastric acid, they will be immediately inactivated) o Is only active in the canaliculi Formulated for delayed release as acid-resistant, enteric coated capsules/tablets Bioavailability decreased to 50% by food intake Ideally given approximately 1 hour before meals Absorbed in the small intestine blood diffuse readily into acidified compartment (parietal cell canaliculus) protonated (and trapped, being a weak base that is ionized) and concentration increases 1000-fold thiophillic sulfonamide cation covalent (thus irreversible, with long duration of action) disulfide linkage with H+K+ATPase Given orally Short half-life: 1-2 hours (serum concentration, because they are concentrated at the target site of action) Long duration of acid inhibition (because it is an irreversible inhibitor): 24 hours (because it will take at least 18 hours to synthesize new pumps); diffuses to extracellular space immediately and is protonated, which does not allow it to cross back Full acid-inhibiting potential is achieved after 3-4 days o In a fasting state, not all pumps will be immediately inhibited since not all are active Hepatic metabolism, negligible renal clearance Ideal drug (from a pharmacokinetic perspective) because of short half-life (leaves the serum readily), long duration of action (irreversible binding) and concentrated at the target site of action, where it is most needed Table 2. PPIs: Pharmacokinetics Drug Bioavailability Omeprazole 40-60% (20) Esomeprazole 50-89% (20) Lansoprazole 80-90% (20) Rabeprazole 52% (20) QUINIO, RAMOS, REYES Half-life 0;5-1 1.2 1.9 0.7-2.0 Tmax 1-3.5 1.5 2.0-4.0 2.0-5.0 Complex of aluminium hydroxide and sulphated sucrose Coats the ulcer base and stimulates mucus, bicarbonate and prostaglandin production (defensive factors) In the presence of acid, sucralfate forms an insoluble amorphous complex that binds to base of ulcers and erosions for up to 6 hours o Short duration, problems in compliance Given orally, requires acid environment for activation 30% is still present in the stomach 3 hours after administration Reduces absorption of a number of drugs including: o Fluoroquinolone antibiotics o Theophylline o Tetracycline o Digoxin o Amitryptilline Increases defensive factors Clinical use o Gastric, duodenal and oral ulcers, GI bleed, stress ulcer prevention, critically-ill patients o Minimal absorption o Dosing: 1g QID, 1 hr before meals & HS (compliance is an issue) o Side effects: constipation (Al); less commonly, dry mouth, nausea, vomiting, headache, rashes o Caution to renal insufficiency (if Al is absorbed) Note: Any drug that acts locally can alter absorption of other drugs. Thus, if drugs for bleeding and arrhythmia are involved, take note of possible drug interactions because these can be lethal. BISMUTH CHELATE Colloidal bismuth subcitrate (Europe), bismuth subsalicylate (US) Mucosal protecting actions (binds to ulcer base, promote mucin and bicarbonate production) Used in combination regiments to treat H. pylori infection in peptic ulcer (bismuth chelate is a 2nd choice regimen in treatment of H. pylori peptic ulcers) Has toxic effects to bacillus (bactericidal; compared to sucralfate), prevents its adherence to mucosa, inhibit its proteolytic enzymes Small amount absorbed with raised amount of bismuth Side effecs: nausea and vomiting, irreversible blackening of the tongue and feces Also used in diarrhea because of its anti-bacterial effect Avoided in patients with renal insufficiency Page 3 / 10 Lec 11: Gastrointestinal Pharmacology MISOPROSTOL Q: This drug is used for prevention and treatment of gastric ulcers but has been withdrawn from the market because it has been used by many as abortifacient (and has teratogenic effects) a. Rioprostil b. Carbenoxolone c. Misoprostol (prostaglandin analogue) d. Sucralfate Stable analogue of PGE1 (prostaglandins are protective) Decreases gastric acid secretion Augments secretion of mucus and bicarbonate Uses: very effective prostaglandin analogue for prevention and treatment of NSAID-related ulcers Half-life < 30 minutes; given 3-4x daily Side effects: diarrhea and abdominal cramps; uterine contractions can also occur Absolute contraindication: pregnancy (since it can cause uterine contractions) premature delivery or miscarriage (abortion) Not readily available due to potential to cause miscarriage and abortion and potential for abuse OS 214 5HT (Serotonin) – main NT 5HT3 receptors – extrinsic afferent nerves stimulate nausea, vomiting, abdominal pain 5HT4 receptors – intrinsic primary afferent neurons (IPAN) enhance release of Ach and cGRP (calcitonin gene-related peptide) increased GI motility Pressure and stimuli will release substances that when coupled with 5HT3 receptor would cause symptoms of nausea, vomiting and abdominal pain So you want something to activate 5HT4 and inhibit 5HT3 A. DRUGS AFFECTING GI MOTILITY Purgatives – accelerate passage of food through the GIT; when you want to empty the bowel (ex. for constipation and surgery preparation) Agents which increase motility without causing purgation Antidiarrheal agents – decrease GIT movement (more absorption of fluid resulting to increase formation of stool) Antispasmodic drugs – decrease GIT movement (relieve abdominal pain) o Do not use antidiarrheals and antispasmodics when you’re not sure. These may mask the symptoms of a greater disease H. TREATMENT OF H. pylori H. pylori infection may be detected in almost 100% of patients with duodenal lcers and 70-80% of patients with gastric ulcers Combination therapy with three drugs is employed o Omeprazole, amoxicillin, metronidazole o Omeprazole, clarithromycin, amoxicillin o Tetracycline, metronidazole, bismuth chelates Give something that will protect the mucosa or inhibit acid production plus two antibiotics (to prevent resistance and recurrence) 10-14 days: PPI 2x a day (for 4-6 weeks), clarithromycin 500 mg 2x/day, amoxicillin 1g 2x/day Bismuth plus triple therapy – decreased treatment to two weeks of quadruple therapy B. PROKINETIC AGENTS DOPAMINE-RECEPTOR ANTAGONISTS III. GASTROINTESTINAL MOTILITY 5HT4 receptor agonists / Serotonin receptor modulators 5HT4 = 4ward = FORWARD Enhance coordinated GI motility and transit of material (propulsive movement) Enhance release of excitatory neurotransmitter without altering physiologic motility pattern and rhythm Dopamine-receptor antagonists Serotonin receptor modulators Motilin agonists GIT is supposedly in a continuous, contractile, absorptive, and secretory state even at rest Control: muscle itself, Enteric nervous System, CNS, humoral pathways Enteric Nervous System (ENS) – autonomous collection of nerves (myenteric/Auerbach’s plexus, submucosal/Meissner’s plexus) Figure 4. Propulsive peristalsis (esophagus, stomach, small intestine) versus mixing segmentation. Contraction from oral end results in propulsion of the bolus distally. Dopamine o Significant amount in the GIT o Suppression of Ach release from myenteric plexus (mediated by D2 receptors) Ach is cholinergic, so suppressing it prevents motility o Inhibitory effects on motility Reduction of lower esophageal sphincter pressure Reduction of intragastric pressure o D2 receptor antagonist – prokinetic agent Metoclopromide (e.g. plasil; also a serotonin receptor modulator) and domperidone o Dopamine receptor (D2) blockade Ach release primary prokinetic mechanism of action o Esophageal peristaltic amplitude o LES pressure – prevents GER and promote movement towards colon o Gastric emptying GERD where LES is lax, impaired gastric emptying (postsurgical, diabetic gastroparesis), prevention of vomiting METOCLOPROMIDE DOMPERIDONE Figure 5. Control of GI Motility. QUINIO, RAMOS, REYES Serotonin receptor modulator Other receptors involved: 5-HT4 agonist (good!), 5HT3 antagonist (vagal and central) (anti-bad = good, addressing nausea, vomiting and pain), muscarinic receptors sensitization Absorbed rapidly Excreted in the urine Half-life 4-6 hours Peak concentration/effects = within 1 hour Duration 1-2 hours Adverse effects because it crosses the blood-brain barrier o Extrapyramidal effects (dystonias, parkinsonian-like movements) – since it crosses blood-brain barrier causing involuntary movements o Tardive dyskinesia o Galactorrhea D2 receptor antagonist Does not involve other receptors Modest prokinetic activity at 10-20 mg 3x a day Does NOT cross the blood-brain barrier (diference with Metoclopromide) Exerts effect in parts without this barrier o Regulation of emesis, temperature and prolactin release (helps in post-partum lactation) Page 4 / 10 Lec 11: Gastrointestinal Pharmacology OTHER SEROTONIN RECEPTOR MODULATORS Tegaserod o 5HT4 agonist – stimulates motility (see Figure 5) o Female patients with Irritable Bowel Syndrome; mostly used for constipation (proven clinical efficacy) o Removed from the market because of cardiovascular effects Cisapride o Stimualte 5HT4 and Ach release in the myenteric plexus in the UGIT o May directly stimulate smooth muscle o GER, reflux esophagitis o Withdrawn from the market because it prolongs QTc (which may lead to torsades de pointes) especially with erythromycin arrhythmia, specifically torsades de pointes shock Motilin o Potent contractile agent of UGIT (smooth muscles and enteric neurons) o Action mimicked by macrolides (erythromycin, azithromycin, clarithromycin, oleandomycin) Erythromycin o LES pressure o Stimulates gastric and small bowel contractility o Cholinergic facilitation at lower doses o Diabetic gastroparesis o Very hard to tolerate, but it is used as prophylaxis for diphtheria IV. CONSTIPATION STOOL FORMATION Fluid content – principal determinant of stool volume and consistency (70-80% SW). Net fluid content depends on luminal input (I,S) - output (A) o 8-9 L enter small intestine, 1.5 L crosses ileocecal valve and enters colon, 100 mL fecal water excreted. Normally within absorptive capacity. o Factors which may alter processes: neurohumoral mechanisms, pathogens, drugs, altered motility (absorption depends on transit time). Ex: cholera: water and fluid secretion relative decreased absorptive capacity PATHOPHYSIOLOGY Decreased motility, excessive absorption o Constipation: hard, dehydrated stool o Increases strain on defecation (some may tolerate it) o Harmful for a subset of patients May cause dehiscence of wounds (recent episiotomy, colostomy), hemorrhoids. Valsalva due to constipation can activate the vasovagal reflex which can cause shock or death in patients with severe mitral stenosis or any cardiovascular disease. Ex: Patients with mitral stenosis (cvd) are given laxatives to soften stools because straining may cause cardiorespiratory arrest. Their mitral valve area so small that their cardiac output is compromised by vagal insult. Lack of dietary fiber Hormonal disturbances Drugs (opioids, morphine) Neurogenic disorders, systemic illnesses 60% with normal colonic transit. “Decreased motility” of mass action type; “increased motility” of nonpropulsive type. Treatment is empirical and based on non-specific principles. NON PHARMACOLOGIC THERAPY High fiber diet (green vegetables and fruits) Adequate fluid intake Regular exercise Use of alternative drugs Heeding of nature’s call *when you feel it, go for it! LAXATIVES Production of soft formed stool over 1 or more days. Enhance intraluminal fluid retention: o Hydrophilic o Osmotic mechanisms. Decrease net absorption of fluid (fluid and electrolyte transport). Altering motility: QUINIO, RAMOS, REYES o Inhibit nonpropulsive action o Stimulate propulsive contractions. Summary of laxatives o Luminally active agents Bulk-formers Osmotics Stool softeners/lubricants o Stimulants/Irritants (fluid secretion and motility) Bisacodyl, senna o Prokinetic agents 5HT4 receptor agonists Opioid receptor antagonists o Chloride channel activator o Opioid receptor antagonist LUMINALLY ACTIVE AGENTS (LAA) MOTILIN AGONISTS OS 214 Q: Psyllium husk, more popularly known as Metamucil, is used as what type of laxative? a. Lubricant b. Stimulant c. Bulk-forming d. Emollient LAA BULK LAXATIVES Stool Softeners/ Lubricants. Polysaccharide polymers not broken down by the normal digestion in the upper GIT. Capacity to retain water and promote peristalsis by afferent stimulation of the gut (increased sensation of fullness). Onset: 12-24 hours to several days. o Takes a while to take effect because it has to attract water. Methycellulose, psyllium husk Plant gums– sterculia, agar, bran, ispaghula husk Use: chronic constipation, irritable bowel syndrome LAA OSMOTIC LAXATIVES Agents which will attract water faster and that will poorly absorbed solutes. Saline purgatives and lactulose attract water (lactulose is mostly used in cardiac patients). Increased volume of fluid in the lumen through osmosis. Large volume in the colon distension and purgation about an hour later. Can increase motility, causing abdominalc ramps. Colon distention stimulates 5-HT3 abdominal cramps due to distention. Main salts– magnesium sulfate and magnesium hydroxide (Milk of Magnesia; remember ‘Must go to the bathroom’). Minimal absorption and adverse systemic effects. Should be avoided in small children and patients with poor renal function because Mg may accumulate and cause the following: o Heart block o Neuromuscular block o CNS depression. Q: This cathartic is used in cases of portal HPN and hepatic encephalopathy due to its ability to decrease intestinal absorption of ammonia: a. Magnesium citrate b. Magnesium hydroxide c. Milk of magnesia d. Lactulose LACTULOSE o Semisynthetic disaccharide of fructose and galactose – poorly absorbed o Fermented to lactic and acetic acids – osmotics o Takes 2-3 days to act; has side effects if given at high doses: Flatulence, cramps, diarrhea, electrolyte disturbance tolerance can develop LAA STOOL SURFACTANT AGENTS (STOOL SOFTENERS) Docusate sodium (Colace, Doss), glycerin, mineral oil) Given per orem or per rectum Soften stool material allowing water and lipid to penetrate Mineral oil lubricates fecal material retarding water absorption from stool May be mixed with juices - to be more palatable Onset: 24-48 hrs (up to 3-5 days) Side effects: (rare) GI pain, cramping, rash Administer with adequate fluids Page 5 / 10 Lec 11: Gastrointestinal Pharmacology o LAA STIMULANT LAXATIVES Bisacodyl (Dulcolax), senna, sodium picosulfate Increases water and electrolyte secretion by the mucosa Increases peristalsis possibly by stimulating enteric nerves Potent, may cause watery stools and cramping Often used for preprocedure bowel preps, postop Potential for abuse (especially for those trying to lose weight) Long-term use is not recommended because (cause dependence, destruction of myenteric plexus, colonic atony and dilatation) Side effects: abdominal discomfort, nausea, cramps Active in stimulating enteric nerves BISACODYL SENNA CHLORIDE CHANNEL ACTIVATOR OPIOD RECEPTOR ANTAGONIST o Usually given as suppository (especially when Pt has mucosal bleeding in the anus because of the constipation, or when the parent is really worried) o Stimulates rectal mucosa o Peristaltic action and defecation in 15-30 minutes o Tablets: onset is 6-12 hours (bowel preparations) o Contains derivatives of anthracene (e.g. emodin) plus sugars = glycosides o Bacteria hydrolyze the glycoside bond→ direct stimulant effect on the myenteric plexus o Used for simple constipation, postop, etc. o Onset: 6-12 hours (up to 24) o Chronic use: “melanosis coli” (brown pigmentation of the bowel on colonoscopy; reversible) has no clinical significance o Lubiprostone o Chronic constipation and Irritable Bowel Syndrome with predominant constipation o Stimulates type 2 Cl channels in the small intestine o Increased chloride-rich secretion stimulates intestinal motility o Minimal systemic absorption, increased fetal loss in guinea pigs o Effects through µ-opioid receptors o Inhibit peripheral µ-opioid receptors without impacting analgesic effects in the CNS o Methylnaltrexone: opioid-induced constipation in palliative care o Alvimopan: short-term use for postoperative ileus in cases of small or large bowel resection CLINICAL IMPLICATION OF LAXATIVES (FROM 2016) Instruct in diet, adequate fluid intake, activity Promote alternatives when appropriate to minimize laxative dependency Assess for abuse or overuse, especially in the young (eating disorders, purging) and the elderly Always assess bowel pattern before administering laxatives - Hold for loose stools Nursing orders for bowel care common Choose agent according to onset of action, tolerability, patient preference Nonpharmacologic treatment is preferred if possible V. DIARRHEA Frequent passage of liquid feces May be caused by infectious agents, toxins, anxiety, and drugs Consequence: discomfort and inconvenience to a medical emergency Increase in GIT motility Increased secretion and decreased absorption of fluid Loss of electrolytes and water There are three approaches to the treatment of severe acute diarrhea: 1. Maintenance of fluid and electrolyte balance – first priority 2. Use of anti-infective agents (for selected cases like amoebiasis, cholera, giardia) 3. Use of non-antimicrobial anti-diarrheal agents PATHOPHYSIOLOGY TREATMENT REHYDRATION Mainstay of therapy ZINC SUPPLEMENTATION Zinc is lost in large amounts during diarrhea QUINIO, RAMOS, REYES o OS 214 Supplementation decreases duration and severity of diarrhea and lowers incidence of diarrhea in the next 2-3 months Recommended dosage < 6 months : 10 mg once a day for 10/14 days ≥ 6 months: 20 mg once a day for 10/14 days ANTI-MOTILITY AGENTS: OPIATES The most effective antidiarrheal drugs are the opioids and derivatives of opioids. Selected for maximal antidiarrheal and minimal CNS effect. Inhibit presynaptic cholinergic nerves in the submucosal and myenteric plexus leading to constipation Activation of opioid receptors in GI tract decrease motility increased colonic transit time and fecal water absorption Decrease mass colonic movements and gastrocolic reflex Side Effects: o Constipation o Dizziness o Abdominal cramps o Paralytic ileus Diphenoxylate and loperamide: meperidine analogs with very weak analgesic effects. Diphenoxylate is formulated with antimuscarinic alkaloids (eg, atropine) to reduce the likelihood of abuse ATROPINE o o o o o o o o o MORPHINE o o DIPHENOXYLATE o "Hot as a hare”- flushing “Blind as a bat”- mydriasis, blurred vision “Dry as a bone”- dry mouth “Red as a beet”- flushing “Mad as a hatter“- confusion, hallucination OTHERS: arrhythmia, TACHYCARDIA, DIZZINESS, NAUSEA, photophobia, loss of balance Increases tone and rhythmic contractions of the intestine; diminishes propulsive activity Complex effect: overall effect is constipating Does not have morphine-like activity in the CNS in therapeutic dose Large doses (25-fold higher) produce typical opioid effects The pyloric, ileocolic, and anal sphincters are contracted and the tone of the large intestine is markedly increased Lomotil® o Imodium® o Used in Traveler’s diarrhea – enterotoxin producing E. coli, Cyclospora cayetanensis, etc. LOPERAMIDE o Selective action in the GIT o Reduces frequency of passage of feces and duration of illness o Anti-secretory action as well *Muscarinic receptor antagonists – rarely used BISMUTH SUBSALICYLATE Used in Traveller’s diarrhea Recall that this is also a protectant in H. pylori infection for peptic ulcer diseases Prevent up to 65% of cases of diarrhea in areas of high risk Work largely by salicylate component Side effects: tinnitus and blackening of feces ABSORBENTS Act by adsorbing microorganisms or toxins Altering intestinal flora Coating and protecting intestinal mucosa No hard evidence for action Used extensively No properly controlled trials Activated attapulgite, kaolin, pectin, charcoal, methylcellulose RACECADOTRIL (HILDRASEC) Antisecretory agent Enkephalinase inhibitor o Enkephalin Endogenous opioid peptide Inhibits intestinal secretion Increase endogenous enkephalin Decrease intracellular cAMP and secretion of water and electrolytes Does not promote bacterial overgrowth Does not affect basal absorption of water and electrolytes Does not alter motility or duration of intestinal transit Only affects the secretory part (not motility, absorption, transit, and growth of bacteria) Page 6 / 10 Lec 11: Gastrointestinal Pharmacology SUMMARY: ANTIDIARRHEAL AGENTS Replacement and maintenance agents: ORAL REHYDRATION SALTS Antimotility: LOPERAMIDE, diphenoxylate Adsorbents/bulk forming agents: Attapulgite, kaolin, pectin, psyllium, carboxymethylcellulose Antisecretory agent: Racecadotril Bile-Acid binding resins, Octreotide BUTYROPHENONES VI. VOMITING Forceful evacuation of gastric contents through mouth May be valuable – to induce vomiting in toxic ingestion Usually unwanted – during chemotherapy Accompanies pregnancy, motion sickness, numerous disease states THE REFLEX MECHANISM OF VOMITING See figure 8 in appendix Emetic stimuli include o Chemicals in blood o Neuronal input from gastrointestinal tract, labyrinth and CNS Impulses from chemoreceptor trigger zone, and various CNS centers relay to the vomiting center. Chemical transmitters include: histamine, acetylcholine, dopamine and 5-hydroxytryptamine, acting on H1-, muscarinic, D2and 5-HT3-receptors, respectively EMETIC DRUGS Ingestion of toxic substances Should not be attempted when o Patient is not fully conscious o The substance is corrosive o High probability of aspiration (hydrocarbons) IPECACUANHA o Acts locally in the stomach o In case of poisoning, activated charcoal can be given to sequester toxic drug o Irritant due to two alkaloids - Emetine - Cephaeline METOCLOPROMIDE AND DOMPERIDONE METOCLOPROMIDE (REGLAN®) OS 214 o Chlorpromazine, prochlorperazine, trifluoperazine, thiethylperazine Thiethylperazine is an antiemetic alone (never used or licensed as an antipsychotic). o Side effects: sedation, hypotension, extrapyramidal symptoms (tardive dyskinesia, dystonia) o Antipsychotics o Haloperidol (Haldol®), Droperidol (Inapsine®) o Side effects: extrapyramidal effects and hypotension; Droperidol- prolong QTc o Central dopaminergic blockade o Acute chemotherapy-induced emesis “DOLpamine receptor antagonist” o D2 receptor antagonists that act in the CTZ o Important gastric kinetic and antiemetic properties o Domperidone does not penetrate BBB o Vomiting caused by radiation, uremia, gastrointestinal disorders, cytotoxic drugs o o o o o Blocks dopamine receptors elsewhere in the CNS Recall: a prokinetic Given orally Plasma half-life of 4-5 hours; excreted in the urine Side effects: Disorders of mov’t (fatigue, motor restlessness, spasmodic torticollis, Occulogyric crises) Stimulates prolactin release AED ANTICHOLINERGICS – HYOSCINE (SCOPOLAMINE) Most widely used antimuscarinic agent Prophylaxis and treatment of motion sickness Effective in vomiting caused by irritants in the stomach Have little effect against substances that act directly on the CTZ Used in post-op nausea and vomiting AED H1-RECEPTOR ANTAGONISTS Meclizine, cinnarizine, cyclizine, dimenhydrinate, promethazine, diphenhydramine Indications same as hyoscine Not used in chemotherapy-induced emesis Clinical Uses: o Cyclizine – motion sickness o Cinnarazine – motion sickness, vestibular disorders (i.e., Meniere’s Disease) ANTI EMETIC DRUGS (AED) AED AED SEROTONIN (5HT3) ANTAGONISTS Selective 5-HT3-receptor antagonists Ondansetron (Zofran®), Granisetron (Kytril®), Tropisetron, Dolasetron Primary site of action: CTZ (chemoreceptor trigger zone) Prevent and treat radiation therapy- and chemotherapy- induced emesis Given orally Side-effects: headache and gastrointestinal upsets (relatively uncommon) o A carbazole that binds to the serotonin and alpha-1 adrenergic and u-opioid sites o Controls nausea without having the prokinetic action of Metoclopromide ONDANSETRON o Used in vomiting caused by cytotoxic anti-cancer drugs; post-operative vomiting; radiation-induced vomiting (ZOFRAN) o Metabolism: liver o Mechanism: 5-HT3 antagonist. Powerful centralacting antiemetic o Clinical use: Control vomiting post-operatively and in patient s undergoing cancer chemotherapy o Toxicity: Headache, constipation AED YOU WILL NOT VOMIT WITH ONDANSETRON, SO YOU CAN GO ON DANCING. AED DOPAMINE (DA) ANTAGONISTS PHENOTHIAZINES o Antipsychotic agents with potent antiemetic and sedative properties o For severe episodes of nausea and vomiting associated with vertigo, motion sickness, uremia, radiation and viral gastroenteritis, migraine o Prochlorperazine (Compazine®) o Promethazine (Phenergan®) QUINIO, RAMOS, REYES CANNABINOIDS No receptor involved For vomiting caused by cytotoxic anti-cancer drugs Effectiveness initially anecdotal Since then, synthetic derivatives have been found to decrease the vomiting caused by agents which stimulate the CTZ Action antagonized by naloxone Opioid receptors important in the action of these drugs Utilizes CB1 type of cannabinoid receptor Tetrahydrocannabinol (THC) o Active ingredient in marijuana o Dronabinol (Marinol®) o Nabilone (Cesamet®) (half life = 120 mins.) Given orally, well absorbed Side Effects: o Common: Drowsiness, dizziness, dry mouth o Frequent: mood changes and postural hypotension o Hallucinations, psychotic reactions STEROIDS No receptor involved, no effect on receptors High dose glucocorticoids may have anti-emetic action Includes Dexamethasone, methylprednisolone o Dexamethasone enhances efficacy of 5-HT3 receptor antagonists o 8-20mg IV before chemo followed by 8 mg/d orally for 24 days MOA not clear o Action may involve inhibition of prostaglandin synthesis Neurokinin I (substance P) antagonist: vofopitant (GR-205171) may be effective in the control of both chemotherapy-induced and post-operative nausea and vomiting Can be used alone or in combination with a phenothiazine or ondansetron Page 7 / 10 Lec 11: Gastrointestinal Pharmacology AED NEUROKININ RECEPTOR ANTAGONIST Example is Aprepitant o Combined therapy with aprepitant, HT3 receptor antagonist and dexamethasone prevents acute emesis in 8090% (vs. 70% without aprepitant) o Prevention of delayed emesis (70% vs. 30-50%) Adverse effects: o Fatigue o Dizziness o Diarrhea Metabolized by CYP3A4 (metabolism of drugs are impaired -> can affect plasma levels) SIDE EFFECTS OF ANTIEMETICS Drowsiness and anti-parasympathetic effects (hyoscine, nabilone > cinnarizine) Dystonic reactions (thiethylperazine > metoclopramide) General CNS disturbances (nabilone) Headache, gastrointestinal tract upsets (ondansetron). SUMMARY: ANTIEMETIC AGENTS Anti-emetic Drugs Example Vomiting most effective against 5-HT3 ANTAGONIST Ondansetron Cytotoxic drug emesis D2 ANTAGONIST Metoclopromide Promethazine Cytotoxic drug emesis H1 ANTAGONIST Cyclizine Vestibular (motion sickness) MUSCARINIC ANTAGONIST CANNABINOID AGONIST NEUROKININ ANTAGONIST Hyoscine (Scopolamine) Dronabinol Nabilone Aprepitant OS 214 VIII. INFLAMMATORY BOWEL DISEASE The two major important entities are o Crohn’s disease - Can affect intestines from the mouth down to the anus. - Systemic manifestation. o Ulcerative colitis - Affects the colon. There is dysregulation of TH1 response and regulatory T-cells. PHARMACOLOGIC THERAPY 1. 2. 3. 4. 5. Treatment involves different drug classes with anti-inflammatory action: Aminosalicylates Glucocorticoids Immunomodulators/immunosuppressives Anti-tumor necrosis therapy Anti-integrin therapy. PHARMACOTHERAPEUTIC GOALS 1. Control acute exacerbation 2. Maintain remission 3. Treat complications like fistula (more common in Crohn’s disease) *Dampen generalized inflammatory response Motion sickness Cytotoxic drug emesis Cytotoxic drug emesis VII. IRRITABLE BOWEL SYNDROME Incidence of irritable bowel syndrome is not really high. Idiopathic chronic, relapsing disorder. Abdominal discomfort associated with alterations in bowel habits. Relief or abdominal pain and discomfort Improving bowel function PHARMACOLOGIC THERAPY ANTISPASMODIC AGENTS Muscarinic receptor antagonists inhibit parasympathetic activity. Of value in irritable bowel syndrome and diverticular disease, mainly for abdominal pain. DICYCLOVERINE (dicyclomine) – direct relaxant effect on smooth muscle. (dec. contraction dec. spasm dec. abdominal pain) Mebeverine – direct relaxant effect on GI smooth muscle. Side effects: light-headedness, drowsiness, nervousness, anticholinergic effects (dry mouth, urinary retention, constipation). SEROTONIN 5HT3 RECEPTOR ANTAGONISTS 5HT3 receptors activate visceral afferent pain sensation inhibition of receptors will inhibit unpleasant sensation. Used to inhibit colonic motility via enteric cholinergic neurons. Alosetron – severe IBS and diarrhea. o Adverse effects – constipation (1/1000-surgical), ischemic colitis (3/1000). SEROTONIN 5HT4 RECEPTOR AGONISTS: TEGASEROD IBS with predominant constipation. Increased number of cardiovascular deaths. Removed from the market. CHLORIDE CHANNEL ACTIVATOR: LUBIPROSTONE For women, IBS with predominant constipation. Increase chloride ion secretion, thus increasing motility. If IBS + constipation, increase bowel movement. If IBS + vomiting and diarrhea (which are related to 5HT3 receptor), give Alosetron to inhibit unpleasant sensation. QUINIO, RAMOS, REYES Figure 6. Algorithm for treatment of inflammatory bowel disease; for milder diseases, drugs with relatively less side effects are given. (One side effect is immunosuppression, which could make one more prone to infection and sepsis, because the drugs modulate the inflammatory system.) AMINOSALICYLATES (5-ASA) The most popular for IBD Sulfasalazine, olsalazine, balsalazide – contain 5-ASA bound by an azo (N=N) bond to an inert compound or to another 5-ASA molecule (azo compounds), various mesalamine. 5-ASA (released in the large intestine) – works “topically” in areas of diseased GI mucosa, formulations have been designed to deliver 5-ASA to various distal segments of the small bowel or the colon since up to 80% of unformulated 5-ASA is rapidly absorbed in the proximal small intestine. Mechanism is not certain. o Modulates inflammatory mediators. o Interfere with production of inflammatory cytokines. o Inhibit NK cells, lymphocytes, macrophages. o Scavenge oxygen metabolites. Sulfasalazine o First Aminosalicylate made o 5-ASA and sulfapyridine linked by azo bond. o Induce and maintain remission in UC. o For mild or moderately active UC. o High incidence of adverse effects attributed to coupled sulfapyridine molecule. o Side effects (treats inflammation, but causes other inflammation): - Nausea, GI upset, headaches, myalgia, arthralgia, bone marrow suppression; hypersensitivity results in fever and exfoliative dermatitis, pancreatitis, pericarditis, pneumonitis, hepatitis - Interstitial Nephritis - Impairs folate absorption. 2nd generation- 5-ASA bound to 1) 5-ASA or to 2) inert material. (The 5-ASA of these drugs are not bound to Sulfapyridine molecule anymore unfavorable effects decreased) Page 8 / 10 Lec 11: Gastrointestinal Pharmacology GLUCOCORTICOIDS Inhibit formation of inflammatory cytokines, reduce expression of ICAM, and inhibit gene transcription of NO synthase, PA2, COX2, NF-κB. Prednisone and prednisolone are most commonly used. Hydrocortisone enemas, foams, suppositories. Moderate to severe active inflammatory bowel disease: o If disease in only mild, use topically. o If severe, administer orally or IV. Prednisone 40-60 mg/day (~1-2 weeks, then taper) Not useful to maintain remission. Major side effects: immunosuppression and suppression of the pituitary release of ACTH, GH, TSH and LH; stunted growth in children. PURINE ANALOGS 6-mercaptopurine and azathioprine Antimetabolites with immunosuppressive properties causing anti-inflammation. Induction and maintenance of remission of IBD. Allow steroid dose reduction or elimination of steroids in the majority (long term therapy). Remission achieved in 50-60% of patient; maintained in 80%. Side effects: Nausea, vomiting, BM depression, hepatic toxicity 6-mercaptopurine undergoes a complex biotransformation via competing catabolic enzymes that produce inactive metabolites and anabolic pathways that produce active thioguanine nucleotides → side effects. ANTI-TNF THERAPY TNF- key proinflammatory cytokine in IBD. Three monoclonal antibodies to human TNF approved in IBD. Bind to soluble and membrane-bound TNF preventing binding to its receptor. Reverse-signalling suppressing cytokine release. Infliximab, Adalimumab (Fc portion)- antibody mediated apoptosis, complement activation, cellular cytotoxicity of activated Tlymphocytes and macrophages. Most important adverse effect: o Suppression of TH1 inflammatory response infection such as bacterial sepsis, tuberculosis, invasive fungal organisms, reactivation of Hepatitis B and other opportunistic infections. Mechanism: a monoclonal antibody to TNF, proinflammatory cytokine Clinical use: Crohn’s disease, rheumatoid arthritis Toxicity: respiratory infection (including reactivation of latent TB), fever, hypotension OS 214 Since cholesterol cholesterol stones, give bile acids to inhibit cholesterol synthesis (and decrease cholesterol stones). DRUGS AFFECTING THE BIILIARY SYSTEM Litholytic bile acids (for cholesterol cholelithiasis) Dissolve non calcified cholesterol gallstones. Chenodeoxycholic acid (CDCA) Ursodeoxycholic acid (UDCA) / Ursodiol o Naturally occurring bile acid. o Reduce hepatic cholesterol secretion by negative feedback. o Stabilizes hepatocyte canalicular membranes. o For patients with symptomatic gallbladder disease who refuse cholecystectomy or are poor surgical candidates. o 10 mg/kg/d x 12-24 mos → dissolution in half of the patients (small non-calcified stones). o May have cytoprotective effects on hepatocytes and effects on the immune system – cholestatic liver disease. o Absorbed → conjugated in the liver with glycine or taurine → excreted in the bile. o Extensive enterohepatic circulation. o Serum half-life = 100 hrs = long! o Practically free of adverse effects. o In primary biliary cirrhosis reduces concentration of bile acids and improves biochemical and histological features. o Greater efficacy and less frequent side effects (hepatotoxicity) than chenodiol. o basically decrease the sizeof cholesterol stones so they can be small enough to be sent out of the body system. END OF TRANSCRIPTION Lean: Saan nga ulit related ang 6-mercaptopurine? Baka lumabas sa exam haha. Konting push nalang, 2017 Nikki: Hi 2017!! Last trans for the sem, last module exam, finals, tapos sembreak naaaaa! Finally. Enjoy the break boys and girls! Aldric: AFTG! INFLIXIMAB, INFLIX PAIN ON TNF ANTI-INTEGRIN THERAPY Integrin: adhesion molecules in leukocytes. o Allows movement through vessel wall into tissue. Used in moderate to severe Crohn’s disease – not in mild cases because of its side effects. Natalizumab - humanized IgG4 against the α4 subunit. o Leukocyte cannot go through the vessel wall and into the tissue because of absence of integrin. Adverse Effect: progressive multifocal leukoencephalopathy, acute infusion reactions, small risk of opportunistic infections. SA NATALIZUMAB…NATALIZUD SI LEUKOCYTE, KAYA DI NA MAKAGALAW (THROUGH THE VESSEL WALL AND INTO THE TISSUE). IX. THE BILIARY TREE BILE ACIDS Essential component of bile. Induce bile flow. Feedback-inhibit cholesterol synthesis. Promote intestinal excretion of cholesterol. Facilitate absorption of lipids and ADEK. Undergoes enterohepatic circulations. *NEGATIVE FEEDBACK MECHANISM Cholesterol synthesized by hepatocyte (either incorporated in membranes OR secreted in bowel OR ) enters enterohepatic circulation in the form of bile acids the body will sense bile acids in enterohepatic circulation decreased cholesterol synthesis. QUINIO, RAMOS, REYES Page 9 / 10 Lec 11: Gastrointestinal Pharmacology OS 214 Figure 7. Gastric acid secretion. Acid in the GIT is secreted by the parietal cell. Acid secretion is stimulated by: (1) Ach from the vagus preganglioni nerve, though the muscarinic repector (M3), (2) Histamine from the ECL (enterochromaffin-like) cell through the H2 receptor and (3) Gastrin from G cell through the gastrin receptor, increasing gastric acid secretion. (4) Somatostatin from D cells is generally a GIT inhibitor, preventing gastrin and histamine release. The H 2 and gastrin receptors are targets of drugs inhibiting drug release, M2 receptors are not targeted because of the myriad of side effects that may result from its inhibition. H. pylori is said to inhibit the release of somatostatin from D cells leading to increase in the secretion of gastrin, hence increased acid secretion. Figure 8. Reflex mechanism of vomiting QUINIO, RAMOS, REYES Page 10 / 10