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38 Cards in this Set
- Front
- Back
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Physiology of acid production
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KNOW THIS PIC TO KNOW HOW DRUGS ACT.
Parietal cells produce acid and superficial epithelial cells produce mucus. Cephalic phase: think about good food, u smell good food, or taste good food, u start producing acid. This is mediated by vagus nerve. Vagus nerve acts on the muscarinic receptors M3 by releasing ACH which stimulate the parietal cells that stimulate the proton pump (H/K ATPase). This pump is the final pathway, secreting H+ into lumen and K+ into cell. Once the food goes into stomach u have second phase called gastric phase: here, there is production of gastrin from the G-cells; gastrin then act on gastrin receptors (CCK2 receptors) to increase acid production. A certain type of cell, stimulated by gastric distention due to food entering it, ECL cells, which produce histamine that act on H2 receptors, causing H+ secretion. Ach, gastrin, and histamine are 3 to remember. H2 is mainly acted on by histamine. Allergic reaction caused by histamine is mediated through H1. Ach can act directly on the muscarinic receptors, and also work on ECL cells. Gastrin can act directly through CCK2, or through histamine. The drug that blocks the proton pump is most effective because u’re blocking the final pathway. The next most effective way is blocking histamine; hence u won’t have the some effects of gastrin, and also histamine. 1st most potent: proton inhibitors 2nd is H2 receptor antagonist: rarely used. PGEs directly inhibit parietal cells to decrease Acid production directly by inhibiting proton pump; directly stimulate superficial epithelial cells which produce mucus and bicarbonate; they are vasodilators, increasing blood flow, hence increasing healing. |
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A loss of balance between cytoprotective factors and risk factors causes peptic ulcer disease.
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Aggravating factors
H. pylori NSAIDs Acid Pepsin (protease) Bile Smoking Alcohol Stress Cytoprotective factors Mucus Bicarbonates Prostaglandins Blood flow Restitution (repair) |
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Drugs for peptic ulcer disease and dyspepsia
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Anti-secretory drugs
Proton pump inhibitors (PPI's) Histamine-2 receptor antagonists Antacids Cytoprotective agents sucralfate / bismuth prostaglandin analogues Antibiotics: eradication of Helicobacter pylori amoxicillin claritromycine |
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Proton pump inhibitors
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Major class
e.g: (es)omeprazole, lansoprazole, pantoprazole, rabeprazole Unstable in acidic environment (stomach), lipophilic weak bases (pKa 4-5), BA decreased by food (50%): take on empty stomach, approximately 1 hour before a meal Prodrugs: converted to sulfonamide which forms a covalent disulfide bond with the active proton pump. Inhibits final common pathway of acid secretion Irreversible therefore long action: plasma t½ ≠ tissue t½ 90% acid reduction for 24 hours (while plasma t½ = 1-2 h) 3-4 days until max effect, 3-4 days after stopping secretion normal again Hepatic metabolism, large FPE, negligible renal clearance |
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Proton pump inhibitors
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Indications:
Gastric ulcer and duodenal ulcer Part of H.pylori eradication therapy (Pantopac) Gastroesophagal reflux disease; in case of especially severe or stricturing disease, Barret's oesophagus NSAID induced gastritis: lansoprazole FDA approved for treatment and prevention Zollinger – Ellison syndrome: gastrinoma = gastrin producing tumor Gastroprotection: NSAIDs + one or more of: corticosteroids, acetylsalicylic acid or anticoagulant, SSRIs, age > 70yrs, CHF, DM, invalidating rheumatoid arthritis, positive anamnesis GU, untreated H. pylori |
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Proton pump inhibitors
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Adverse effects
GI upsets diarrhoea most common nausea and vomiting Interactions Omeprazole: inhibits CYP450 and increases concentration of phenytoin, nifedipine, clarithromycin and disulfiram. Usually not clinically relevant. Decrease absorption of drugs that depend on acidic pH for absorption, e.g. itraconazole |
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H-2 receptor antagonists
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Ranitidine, famotidine, nizatidine
Cimetidine: known for its drug interactions. Inhibits several P450 enzymes. Interactions with coumarins, theophyllin, fenytoin, sildenafil. All: pH effects on absorption Less potent than PPIs, suppress acid secretion by about 70% Use has declined markedly since introduction of PPIs. Predominantly inhibit basal acid secretion (predominantly histamine mediated): prevention of nocturnal acid formation and nocturnal complaints. |
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H-2 receptor antagonists
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Diarrhoea
Confusion Cimetidine only: gynaecomastia inhibits cytochrome P450 coumarin, theophylline, fenytoin interactions not seen with other H2RA’s Careful with hepatic / renal dysfunction H2 receptor antagonist used as second line drug for most of peptic ulcer disease. |
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Antacids
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Examples: aluminium(hydr)oxide, magnesiumhydroxide, sodiumbicarbonate.
Mechanism of action neutralise acid (Mg faster) Taken after food Poor absorption (but not necessary for action) Adverse effects GI upset magnesium salts: diarrhoea aluminium salts: constipation carbonates: belching, gastric distention systemic alkalosis (high doses only) In dialysis patients, aluminium salts may cause metabolic bone disease encephalopathy |
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Antacids
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Drug interactions:
Formation of insoluble complexes prevents absorption of: Iron salts Tetracyclines Fluoroquinolones Itraconazole Easily prevented by dose shifting: 2 hours before or 4 hours later pH effect on absorption Contraindicated in severe kidney failure |
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Cytoprotective agents
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Sucralfate
Bismuth salts Prostaglandin analogues |
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Sucralfate
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Basic aluminium salt of sucrosesulfate
Reacts with stomach acid, at pH < 4 Binds to ulcer base (proteins) Gel like paste forms protective layer Stimulates PGE2, epidermal growth factors and mucus Not absorbed Constipation, dry mouth, bloated feeling Rare “bezoar” formation (especially in reduced GI motility) Needs acidic pH to work, so do not combine with antisecretory drugs Reduces absorption of tetracyclines and ciprofloxacin |
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Bismuth salts
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Example: bismuthsubsalicylate (Pepto-Bismol)
Mechanism of action Dissociates in salicylate (absorbed) and bismuth (<1% absorbed) Precipitates in acid Binds to glycoprotein in ulcer base, may also stimulate PG, mucus, bicarbonate Antimicrobial against H.pylori (might be added to antibiotic regimen) Uses: dyspepsia, acute diarrhoea, prevention and treatment of travellers diarrhoea Side effects Black tongue and stools Contraindicated in advanced renal failure |
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Prostaglandin analogues
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Misoprostol: synthetic analog of PGE1
Can be used to prevent NSAID related ulceration in those who can not avoid drug (e.g. rheumatism) Effects Increased gastric mucus production Increased duodenal bicarbonate secretion Increased mucosal blood flow Inhibition of gastric acid secretion Contractions of uterus |
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Prostaglandin analogues
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Short half life
Hepatic metabolism Adverse effects Diarrhoea and colicky cramps, often seen in therapeutic doses. Uterine contractions: lead to abortions Contraindicated in pregnancy Available as combination with diclofenac Expensive, limited use |
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NSAID induced gastritis, ulcera and bleeding
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--> inhibits prostaglandin sythesis, INCREASED BLOOD FLOW
REDUCED ACID SECRETION INCREASED MUCUS SECRETION |
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H. pylori eradication therapy
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Gram-negative, microaerophilic helical bacterium colonizing stomach and duodenum
Over 50% of population “infected”, 80% of those asymptomatic Nobel Prize 2005 awarded to guinea pig Diagnosis: blood Ab, feces Ag, breath urea test, biopsy (culture) Indications for eradication: Confirmed peptic ulcer with H. pylori detected Severe gastritis Post resection for gastric neoplasia Mucosal gastric lymphoma |
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H. pylori eradication
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Triple therapy b.i.d.
A PPI b.i.d. Plus 2 of: amoxicillin 1g, clarithromycin 500mg, metronidazole 500mg (b.i.d) Quadruple therapy A PPI b.i.d. tetracycline 500mg q.i.d. bismuth q.i.d. metronidazole 500mg t.i.d. Duration 7 to 14 days Eradication rates 85-95% |
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Chemoreceptor Trigger Zone and Emetic Center
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The CNS vomiting centers have specific emetogenic receptors.
Area postrema is rich in serotonin (5-hydroxytryptamine or 5-HT; a serotonin subtype assoc with nausea and vomiting); opioid; and dopamine D2 receptors. CTZ includes serotonin receptors. Nucleus of the solitary tract has histamine, cholinergic, muscarinic, and enkephalin receptors. Hypotension or pharmacologic stimulants can cause the release of these neurochemicals in the brain, initiating the vomiting reflex. Blockade of these CNS receptors is hypothesized to be the mechanism of action of the commonly used antiemetics. |
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Antiemetics: by class
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5-HT3 antagonists
dolasetron, granisetron, ondansetron Antihistamines dimenhydrinate, hydroxyzine Anticholinergics scopolamine Antidopamines metoclopramide droperidol (haloperidol) Phenothiazines chlorpromazine, prochlorperazine, promethazine Othersa dexamethasone dronabinol : is a cannabinoid (9-THC), acts on CB1 receptors. |
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Metoclopramide
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Dopamine receptor antagonist: central and peripheral (D2)
5-HT4 agonist, muscarinic agonist Increases LES tone and motility of upper GIT Uses: antiemetic, GERD, gastroparesis Adverse effects: extrapyramidal symptoms, muscle dystonia, Parkinsonism, galactorrhea Interactions: antipsychotics (EPS), reduces absorption of digoxin, increases ciclosporin, PSL and opiates antagonize. |
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5-HT3 antagonists
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Ondansetron (Zofran®), granisetron (Kytril®), tropisetron (Navoban®), and dolasetron (Anzemet®)
No sedation, extrapyramidal reactions, adverse effects on vital signs or laboratory tests, or drug interactions with other anesthetic medications. Peripheral & central 5-HT3 antagonism. Highly efficacious in chemotherapy induced emesis and radiotherapy induced emesis, post operative nausea and vomiting, hyperemesis gravidarum Adverse effects: headache (very often), dizziness, constipation Interactions: phenytoin, carbamazepine and rifampicine increase it's clearance |
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Anti-histamines
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Competitive antagonists of H-1 receptors
Weak antimetics, but useful in motion sickness First-generation or sedating antihistaminics: Examples: promethazine, hydroxyzine, chlorpheniramine, diphenhydramine, cyclizine, meclizine. Often also anticholinergics. (adverse effects) Sedation can be desired side effect (itching) Second-generation / non-sedating: greater specificity, less BBB passage. Less anticholinergic activity Examples: cetirizine, fexofenadine, (des)loratidine Dimenhydrinate (Gravol) safe in pregnancy |
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Anti-diarrheals
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Priority is to prevent water and electrolyte loss: ORS
Use in mild to moderate acute diarrhoea, IBS, IBD May be harmful in infective cases (bloody diarrhoea, high fever) Antibiotics only used in confirmed infective cases Non-specific anti-motility and anti-secretory agents: Opioids: loperamide and diphenoxylate act on opioid receptors in the GIT and cause decrease in secretions, reduced motility of GIT and increased tone of rectal sphincter. Loperamide does not cross BBB, diphenoxylate can in higher doses Colloidal bismuth compound like bismuthsubsalicylate Absorbents: kaolin, pectin, activated coal: limited efficacy in diarrhoea Bile salt-binding resins cholestyramine and colestipol in diarrhoea due to malabsorption of bile salts in Crohn's or resection of terminal ileum |
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Laxatives
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Normal defecation frequency is between three times daily and once every three days
Lifestyle: fibers, exercise, fluids Bulk forming laxatives: bran, psyllium, methylcellulose Stool surfactant agents (softeners): docusate, paraffin Stimulants: bisacodyl, aloe, senna, cascara, castor oil Osmotics: Magnesium salts (-citrate, oxide) lactulose: preferred in hepatic encephalopathy treatment. |
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Drugs used in GI disorders: must know
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Peptic ulcer: remember PPIs (omeprazole, pantozole) are DOC for ZE syndrome, NSAIDs induced ulcer. Omeprazole is an enzyme inhibitor.
Cimetidine: H2 receptor antagonist. Adverse effects gynecomastia, impotence, also microsomal enzyme inhibitor: can increase concentration of warfarin and digoxin. Sucralfate requires acidic pH to activate. So do not combine with H2 receptor antagonist and PPI / antacids Misoprostol is CI in pregnancy Metoclopramide is a central and peripheral dopamine receptor antagonist used to treat vomiting and gastroparesis. Can cause extrapyramidal symptoms Ondansetron is 5HT3 antagonist. Preferred for chemotherapy, radiotherapy induced emesis. Lactulose preferred in management of hepatic encephalopathy. Other drug is oral Neomycin. Avoid acetazolamide in hepatic encephalopathy. |
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Irritable bowel syndrome
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Idiopathic chronic relapsing disorder
Abdominal discomfort (pain, bloating, distention, cramps) Altered bowel motility (diarrhoea or constipation) Symptomatic treatment: laxatives and / or antidiarrheals Spasmolytics anticholinergics dicyclomine hyoscyamine musculotropic mebeverine |
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Irritable bowel syndrome
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5-HT3 receptor antagonist
Alosetron acts on receptors in the GIT (part central effect) Inhibits nausea, bloating, pain and reduces GI motility Approved for treatment of women with severe IBS where diarrhea is the predominant symptom Less safe than the antiemetic 5-HT3 RA: rare but severe adverse effects: Ischemic colitis (constipation) 5-HT4 receptor agonist Tegaserod, partial agonist for 5-HT4 receptors Promotes peristaltic reflex and gastric emptying, reduces bloating, stool hardness Approved for treatment of chronic constipation and IBS where constipation is the predominant symptom Few side effects: diarrhea (headache) |
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Inflammatory bowel disease
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Crohn's disease and ulcerative colitis (colitis ulcerosa)
Auto-immune diseases (?) with unknown pathogenesis and etiology. Crohn's may occur from mouth to anus Abdominal pain, vomiting, weight loss, (bloody) diarrhea Extraintestinal: arthritis, skin rashes, eye: uveitis and episcleritis Complications: obstructions by adehesions and strictures, fistulae, abscesses, malnutrition, cancers of the GIT Colitis ulcerosa: ulcers in the colon Bloody diarrhea often with mucus of gradual onset, pain, weight loss Same extraintestinal symptoms as Crohn's may occur |
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Inflammatory bowel disease
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Although there is no consensus whether these are true auto-immune diseases, similar treatment has proved effective
Glucocorticoids hydrocortisone, prednisone, budesonide Systemic and topical: enemas, suppositories, foams and time release oral formulations Aminosalicylates: 5-aminosalicylic acid (5-ASA) containing prodrugs mesalazine sulfasalazine olsalazine Slow release topical formulations Adverse effects: more in slow acetylators: nausea, GI upset, headaches, artralgias, myalgias, malaise, bone marrow suppresion DOC for mild to moderate UC, efficay in Crohn's less well established |
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Inflammatory bowel disease
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Anti-metabolites: purine analogs and methotrexate (MTX)
Immunosuppressive agents that inhibit formation of purines and thymidine, thereby inhibit DNA synthesis and repair Purine analogs: azathioprine 6-mercaptopurine (6-MP) Clinical uses: UC and CD, corticoid sparing agents Adverse effects: nausea, vomiting, bone marrow suppression Methotrexate : inhibitor of DHFR lower doses than in cancer don't have antiproliferative effects Oral, subcutaneously or intramuscular Clinical uses: CD, UC uncertain Adverse effects: bone marrow suppression, megaloblastic anemia, alopecia, mucositis. Give folic acid to prevent. |
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Inflammatory bowel disease
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“Biologicals”: monoclonal antibodies against TNF-α reduces Th1 response
infliximab adalimumab certolizumab Very expensive drugs, given as intravenous infusion (infliximab) or subcutaneous (adalimumab, certolizumab). Adverse effect due to immunosuppresive effects: reactivation of latent tuberculosis, pneumonia, sepsis, pneumocystosis, histoplasmosis, listeriosis, reactivation of hepatitis B. Other: fever, headache, dizziness, urticaria, mild cardiopulmonary symtoms (chest pain, dyspnea, hemodynamic instabilty). Delayed serum sickness-like infusion reaction: myalgia, arthralgia, fever, rash, urticaria, edema. Lymphoma, acute hepatic failure, worsening of CHF (infliximab) |
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Prokinetics
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Stimulate gastric emptying and bowel peristalsis.
domperidon D2 receptor antagonist Use: GERD, impaired gastric emptying, antiemetic, nonulcer dyspepsia, postpartum lactation stimulation Adverse effects: rare: EPS (young children) metoclopramide D2 receptor antagonist GERD, impaired gastric emptying, antiemetic, nonulcer dyspepsia Adverse effects: restlessness, drowsiness, insomnia, anxiety, EPS cisapride Dangerous cardiac effects (QT), reserved pediatric use |
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Emetics
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Clinical use: intoxications, when indicated (risks of aspiration, erosion of the oesophagus). Abuse: bulimics.
Ipecac: mixture of alkaloids derived from ipecacuanha plant Oral (syrup), induces vomiting within 20 minutes in 85% of people. Rarely used due to adverse effects: cardiac toxicity |
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Appetite enhancers / inhibitors
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Appetite inhibitors: anorexigenics
Clinical use: adjunct (!) treatment of obesity amphetamine, methamphetamine No longer DOC: dependence Contraindicated in pregnancy amphetamine derivatives: phentermine Mechanism: Act centrally, elevate catecholamines and dopamine: reduction in food-seeking behaviour Adverse effects: CNS stimulation, insomnia Sibutramine: MAO-inhibitor (NE, 5-HT): reduces appetite and may enhance basic metabolism Orlistat (Xenical): lipase inhibitor. AE: steatorrhoea rimonabant: cannabibnoid (CB-1) RA. (Temporarily?) withdrawn due to adverse effects (depression, panic disorders, hallucinations) |
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Appetite enhancers / inhibitors
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Appetite enhancers:
Clinical use: cachexia, loss of appetite in AIDS, chemotherapy Dronabinol: cannabinoid receptor agonist, inhibits vomiting centre Megestrol: progestational agent with increased appetite as side effect |
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Digestive enzyme replacements
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Mixtures of enzymes (pig pancreas): lipase, trypsin, amylase
Clinical use: cystic fibrosis, exocrine pancreatic insufficiency, steatorrhea Lactase in lactose-intolerant individuals Drugs used to dissolve gallstones Ursodiol (ursodeoxycholic acid), effective against cholesterol gallstones. Reduces cholesterol secretion into bile and may gradually (months to years) dissolve existing stones. Therefore often combined with lithotripsy. |
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Octreotide (sandostatin)
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Synthetic analogue of somatostatin
Uses: severe diarrhea by excessive release of GI hormones (gastrin, motilin,VIP, glucagon): carcinoid, VIPoma. Parenteral use. Very expensive |
