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Drugs for Acid-Peptic Disorders Eradication of Helicobacter pylori (Antibiotic/Inhibition of Acid) Proton Pump Inhibitors (Omeprazole) Histamine (H2) Receptor Antagonists (Cimetidine, Ranitidine) Anticholinergics Prostaglandins (Misoprostol) Antacids Mucoprotective Drugs (Sucralfate) Drugs for Motility Disorders Prokinetics (Metoclopramide) Laxatives (Bran) Antidiarrheals (Opioids)
A benign lesion of gastric or duodenal mucosa occurring at a site where the mucosal epithelium is exposed to acid and pepsin;
pylori
Not all of those infected with H. pylori develop
ulcers
H. pylori MAY result in a weakening of the
mucosal defense systems, allowing for development of ulcer subsequent to acid/pepsin aggression;
Duodenal Ulcer
HP NSAID Cancer (ZE)
Gastric Ulcer
Other
Helicobacter pylori
Thought to be spread by fecal-oral route; Possible ?oral-oral transmission?; Infection thought to occur between parents and young children;
Additional Notes:
Correlated with socioeconomic status; Almost universal infection in developing countries; Most of those infected are asymptomatic.
Vagal Nucleus
Ach
Parietal Cells
Cholinergic Neuron
Antral G Cell
G
G G G G G
Ac h
H H
Ac h
Ac h
Parietal Cell
Acid
G
Circulation
Vagal Nucleus
Parietal Cell
Ach
Ach
H+ G-cell
Histamine
Gastrin
Each Secretagogue Binds to its Own Receptor and Interacts with the Others
CCK2
Gastrin
H2 Histamine
cAMP dep. pathway PP
H+
Gastric Lumen
M Acetylcholine
3
Cimetidine Inhibit Omeprazole secretion Prostaglandins Muscarinic antagonists Prevent contact Neutralize acid Sucralfate Antacids
H+
H+
H2
Histamine Antagonists M
cAMP PP
H+ Gastric Lumen
Muscarinic Antagonists
Apical
Histamine
(+)
ATP EP3
K+
H+
(-)
cAMP
PGI2 PGE2
EP3
Mucus
M?
HCO3pH 6.7 pH 2
Ca2+ (-)
cAMP
2
EP3
(+)
ATP M3
Protein Kinase
PP
H+
Ca2+
H+, K+-ATPase (the proton pump) is the final transport pathway for parietal cell hydrogen ion secretion
H+, K+-ATPase is located in the apical membrane
The pump requires large amounts of energy that is supplied by intracellular ATP;
Inhibition of H+, K+-ATPase blocks both basal and stimulated acid secretion.
Omeprazole (Prilosec)
Prototype H+, K+-ATPase inhibitor; A prodrug that needs
a low pH to be active;
Irreversible (forms a covalent bond with the proton pump) - long lasting inhibition of acid production; Profound reduction of gastric acid - elevates gastric pH significantly (20mg/day for 7days will decrease acid by 95%); Highly protein bound; Metabolized by CYP2C & CYP3A; plasma half life of 1 to2 hours but long duration of action; Should be taken just prior to a meal and should NOT be taken with other acidsuppressing agents.
Ca2+ (-)
cAMP
EP3
Histamine Antagonist
Protein Kinase
PP K+
H+
ATP
M3
Ca2+
Histamine Receptors
H1 receptors
Smooth muscle Nerves
H2 receptors
Parietal cells
Histamine
Protein Kinase
K+
PP
H+
ATP
Histamine Antagonist
Time (hr) 1
Histamine H2 Antagonists
Cimetidine (Tagamet) Ranitidine (Zantac)
Famotidine (Pepcid)
Nizatidine (Axid)
Esomeprazole (Nexium)
Simply the S-isomer of omeprazole; H+, K+-ATPase inhibitor; Given orally.
Pantoprazole (Protonix)
H+, K+-ATPase inhibitor; An acid-stable form and can be given by i.v.
Drugs for Acid-Peptic Disorders - Ranitidine (Zantac), Famotidine (pepcid), Nizatidine (Axid)
Same mechanism of action as Cimetidine but a longer duration of action (8 to 12 hrs); Can be given less frequently;
Ca2+ (-)
cAMP
EP3
Protein Kinase
PP K+
H+
ATP
Acetylcholine
M3
Ca2+
Drugs for Acid-Peptic Disorders - Anticholinergics Blockade of acetylcholine at muscarinic (M3/M1) receptors
Effectively blocks acid secretion (30 to 40%) Limited by side-effects
Stimulates:
Mucus secretion Bicarbonate secretion Mucosal blood flow
These compounds act by both inhibition of acid production and by increasing defense mechanisms
These compounds are also effective against direct damage produced by alcohol, aspirin and NSAIDs, and are therefore termed
Side Effects
stomach;
They do not decrease the secretion of acid, and in
Magnesium-aluminum
mixtures
Calcium carbonate
Sodium bicarbonate
ions dissociate and the resulting negatively charged molecule polymerizes to form a viscous paste-like substance;
This substance adheres strongly to gastric and duodenum
mucosa and adheres even more strongly to partially denatured proteins such as those found at the base of the ulcer.
Drugs for Acid-Peptic Disorders - Sucralfate (Carafate) This compound does not decrease the concentration or total amount of acid in the stomach; Sucralfate protects the gastric and duodenal mucosa from acid/pepsin attack. Side effects:
The compound is not really absorbed and, therefore, side-effects are minimal:
constipation diarrhea nausea
H. pylori Eradication Rates with Either Dual, Triple or Quad Therapy (1999)
GENERIC NAME Dual therapies omeprazole amoxycillin ranitidine clarithromycin lansoprazole amoxycillin 500 mg TID 14 days 1,000 mg TID 14 days 400 mg BID 500 mg TID 30 mg TID 1,000 mg TID 28 days 14 days 14 days 14 days 70-80 73-84 66-77 DOSING DURATION CURE RATE (%)
Gastrointestinal Pharmacology Acid production: 2.5 L per day Isotonic HCl solution pH < 1 Produced by parietal cells Mucus production: Produced by mucus-secreting cells Also produce bicarbonate, which becomes trapped in the mucus layer => pH gradient across the mucus layer (can become destroyed by alcohol)
Antacids: Weak bases: Aluminum hydroxide Cause constipation Magnesium hydroxide Cause diarrhea => often combined Usally taken 5-7 times per day
Gastrointestinal Pharmacology Antacids: Histamine stimulates acid production by parietal cells Mast cells produce a steady basal level of histamine, which increases in response to gastrin or acetylcholine Parietal cells express histamine H2 receptors => H2 receptor blockers: Cimetidine (Tagamet) First H2-blocker available Inhibits P450 => Drug interaction Ranitidine (Zantac) Does not inhibit P450 => fewer side effects Nizatidine (Axid) Famotidine (Pepcid)
Gastrointestinal Pharmacology Gastroesophageal reflux disease (GERD): Backflow of stomach acid into the esophagus Esophagus is not equipped to handle stomach acid => scaring Usual symptom is heartburn, an uncomfortable burning sensation behind the breastbone (MI often mistaken for GERD !) More severe symptoms: difficulty swallowing, chest pain Reflux into the throat can cause sore throat Complications include esophageal erosions, esophageal ulcer and narrowing of the esophagus (esophageal stricture) In some patients, the normal esophageal lining or epithelium may be replaced with abnormal (Barrett's) epithelium. This condition (Barrett's esophagus) has been linked to cancer of the esophagus. Primary treatment option are proton pump inhibitors
Mucosal protective agents: Misoprostol Prostaglandin E1 analog (PG stimulate mucus and bicarbonate production) Used when treatment with NSAIDs inhibits endogenous PG synthesis Sucralfate Complex of aluminum hydroxide and sulfated sucrose Forms complex gels with mucus => mucus stabilized => diffusion of H+ impaired Not absorbed => essentially free of side effects Must be taken every 6 hours
Peptic Ulcer Disease Imbalance between defenses and aggressive factors Defensive factors: Prevent the stomach and duodenum from self-digestion Mucus: continually secreted, protective effect Bicarbonate: secreted from endothelial cells Blood flow: good blood flow maintains mucosal integrity Prostaglandins: stimulate secretion of bicarbonate and mucus, promote blood flow, suppress secretion of gastric acid Aggressive factors: Helicobacter pylori: gram negative bacteria, can live in stomach and duodenum, may breakdown mucus layer => inflammatory response to presence of the bacteria also produces urease forms CO2 and ammonia which are toxic to mucosa Gastric Acid: needs to be present for ulcer to form => activates pepsin and injures mucosa Decreased blood flow: causes decrease in mucus production and bicarbonate synthesis, promote gastric acid secretion NSAIDS: inhibit the production of prostaglandins Smoking: nicotine stimulates gastric acid production
Peptic Ulcer Disease (~25 mill. Americans will have an ulcer in their life) Most common cause (> 85%): Helicobacter pylorii (not stress or hot sauce!) Treatment options: Antibiotics Antisecretory agents Mucosal protectants Antisecretory agents that enhance mucosal defenses Antacids
Antibiotic ulcer therapy: Combinations must be used: Bismuth (PeptoBismol) disrupts cell wall of H. pylori Clarithromycin inhibits protein synthesis Amoxicillin disrupts cell wall Tetracyclin inhibits protein synthesis Metronidazole used often due to bacterial resistance to amoxicillin and tetracyclin, or due to intolerance by the patient Standard treatment regimen for peptic ulcer: Omeprazole + amoxicillin + metronidazole
Antiemetic drugs: Vomiting: Infection, pregnancy, motion sickness, adverse drug effects, Triggered by the vomiting center or chemoreceptor trigger zone (CTZ) in the medulla (CTZ is on the blood side of the blood-brain barrier). Treatment options: H1 antagonists: Meclizine, promethazine, dimenhydramine Muscarinic receptor antagonists: Scopolamine (motion sickness) Benzodiazepines: Lorazepam (during chemotherapy) D2 antagonists: have also peripheral prokinetic effects => increase motility of the GI tract => increases the rate of gastric emptying. Caution in patients with Parkinsons disease! Metoclopramide Domperidone Cannabinoids: Marihuana ? Synthetic cannabinoids: during chemotherapy Nabilone Dronabinol
Laxatives: Laxative production of a soft formed stool over a period of 1 or more days Catharsis prompt, fluid evacuation of the bowel, more intense Indications for laxative use: Pain associated with bowel movements To decrease amount of strain under certain conditions Evacuate bowel prior to procedures or examinations Remove poisons To relieve constipation caused by pregnancy or drugs Contraindications: Inflammatory bowel diseases Acute surgical abdomen Chronic use and abuse
Laxatives: Stimulate peristalsis Soften bowel contect Classification: Bulk laxatives Non-absorbable carbohydrates Osmotically active laxatives Irritant laxatives = purgatives Small bowel irritants Large bowel irritants Lubricant laxatives Paraffin Glycerol
Laxatives: Bulk laxatives:Increas e in bowel content volume triggers stretch receptors in the intestinal wall => causes reflex contraction (peristalsis) that propels the bowel content forward Carbohydrate-based laxatives Insoluble and non-absorbable Non digestable; take several days for effect Expand upon taking up water in the bowel Must be taken with lots of water Vegetable fibers (e.g. Psyllium, lineseed) Bran (husks = milling waste product) Osmotically active laxatives Partially soluble, but not absorbable Saline-based (mostly sulfates) Effect in 1-3 hrs => used to purge intestine (e.g. surgery, poisoning) MgSO4 (= Epsom salt) Na2SO4 (= Glaubers salt)
Laxatives: Irritant laxatives: Cause irriatation of the enteric mucose => more water is secreted than absorbed => softer bowel content and increased peristaltic due to increase volume Small bowel irritants Ricinoleic acid (Castor oil) Active ingredient of Ricinus communis The oil (triglyceride) is inactive Ricinoleic acid released from oil through lipase activity Ricin: Lectin from the beans of R.communis Potent toxin: inhibits protein synthesis Potential bioterrorism agent (LD ~100g) In 1978, ricin was used to assassinate Georgi Markov, a Bulgarian journalist who spoke out against the Bulgarian government. He was stabbed with the point of an umbrella while waiting at a bus stop near Waterloo Station in London. They found a perforated metallic pellet embedded in his leg that had presumably contain rich toxin
Laxatives: Irritant laxatives: Large bowel irritants Anthraquinones Active ingredient of Senna sp. (Folia and fructus sennae), Rhamnus frangulae (cortex frangulae) and Rheum sp. (rhizoma rhei): contain inactive glycosides => active anthraquinones released in colon take 6-10 hours to act
Laxatives: Irritant laxatives: Large bowel irritants Diphenolmethanes Derivatives of phenolphtalein Bisacodyl Oral administration: effect in 6-8 hrs Rectal administration: effect in 1 hr Often used to prepare for intestinal surgery Sodium picosulfate
Laxative abuse: Most common cause of constipation! Longer interval needed to refill colon is misinterpreted as constipation => repeated use Enteral loss of water and salts causes release of aldosterone => stimulates reabsorption in intestine, but increases renal excretion of K+ => double loss of K+ causes hypokalemia, which in turn reduces peristalsis. This is then often misinterpreted as constipation => repeated use
Antidiarrheal drugs: treat only symptoms! Diarrhea is usually caused by infection (Salmonella, shigella, campylobacter, clostridium, E. coli), toxins, anxiety, drugs In healthy adults mostly discomfort and inconvenience In children (particularly mal-nourished) a principal cause of death due to excessive loss of water and minerals. Antimotility agents: Muscarinic receptor antagonists (not useful due to side effects) and opiates: Morphine Codeine Diphenoxylate All have CNS effects - NOT useful for diarrhea treatment Loperamide Selective action on the GI tract Does not produce CNS effects First choice antidiarrheal opoid Combined with Dimethicone (Silicon-based gas-absorbent)
Prokinetic Drugs Act on Enteric Nerves to Increase Muscarinic M2 (stimulated by Bethanechol ) Cholinergic Stimulation
Dopaminergic Neuron 5HT4 Stimulated by Metoclopramide (+) Cisparide Cholinergic Neuron
Ach
(+)
(+)
Motilin
(+)
Stimulated by Erythromycin
Motilin
Indirect effects are mediated by M2 muscarinic receptor Metoclopramide crosses the blood-brain barrier
Ach
(-) (+)
Domperidone is an antiemetic and improves gastric emptying Not very effective for GERD Actions
Dopamine receptor antagonist Ganglionic stimulant Pharmacokinetics Low oral bioavailability Does not cross blood-brain barrier Adverse Side-effects Headaches Gynecomastia Galactorrhea
Serious cardiovascular problems including arrhythmias (i.e., ventricular tachycardia, ventricular fibrillation and QT prolongation As of December 1999, 80 deaths Janssen Pharmaceutical Inc. has stopped making cisapride in the US as of 2000