Drugs and the Gastrointestinal Tract PDF

Drugs and the Gastrointestinal Tract Dr Maria M Buckley Learning resources READ: Dave et al., 2015 Gastroenterol Clin North Am. 2014 September ; 43(3): 405–424 Immunology of Inflammatory Bowel Disease and Molecular Targets for Biologics Learning objectives Outline the pharmacologi...

Drugs and the Gastrointestinal Tract Dr Maria M Buckley Learning resources READ: Dave et al., 2015 Gastroenterol Clin North Am. 2014 September ; 43(3): 405–424 Immunology of Inflammatory Bowel Disease and Molecular Targets for Biologics Learning objectives Outline the pharmacological management of: ▪ Peptic ulceration & gastro-oesophageal reflux disease ▪ Diarrhoea & constipation ▪ Liver ascites ▪ Irritable bowel syndrome (IBS) & inflammatory bowel disease (IBD) List the main drug groups used & describe their mechanism of action Identify the main limitations of each  Clinical indications -H. pylori -peptic ulceration -reflux oesophagitis -gastrin producing tumours (Zollinger- Ellison syndrome) -NSAID-induced ulceration Treatment rationale -decrease gastric acid secretion Gastric acid secretion Gastric parietal cell & drug targets  Mechanism of action -irreversibly inhibit the H+/K+ ATPase (proton pump) -accumulation of the drug in canaliculi of the parietal cell Proton pump (specificity) -more specific inhibition of acid secretion that H2r or Mr inhibitors antagonism -inhibit basal and stimulated acid secretion (PPIs) Pharmacokinetics Omeprazole, -inhibitory effect on acid secretion can increase bioavailability -single dose can inhibit acid secretion for 2-3 days esomeprazole Unwanted effects (omeprazole) -inhibits the 2C family of cytochrome P450 -decreased metabolism of warfarin, carbamazepine, phenytoin -gastric neoplasia (long term use); increased gastrin production Histamine H2 receptor antagonists Cimetidine, ranitidine (low dose available OTC) Competitively inhibit histamine H2 receptors -inhibit histamine-, gastrin- and ACh-stimulated acid secretion -inhibit acid secretion by 70% Unwanted effects affinity for androgen receptors cimetidine inhibits cytochrome P450 -gynaecomastia, decreased sexual function -potentiate action of oral anticoagulants and tricyclic antidepressants Limitations -relatively short duration of action -development of tolerance  Histamine H2 receptor antagonists Tolerance exageratted response to a smaller stimuli ❑Nocturnal acid breakthrough “NAB”; H2 receptor antagonists and PPI -short serum half-life of PPIs (2-4 hours) -not all proton pumps are active at the same time -generation of new proton pumps is a continuous process Hs2RA-> blocks any future proton pumps Antacids Magnesium & aluminium salts Neutralise acidity (removal of the H+ ion by the antacid) Sodium bicarbonate: NaHCO3 -Na+ + HCO3- → Na+ + Cl- + CO2 + H2O (alkalosis & bloating) Magnesium hydroxide: Mg(OH)2 -Mg(OH)2 + 2HCl → Mg2+ + 2Cl- + 2H2O (diarrhoea) Aluminium hydroxide: Al(OH)3 - Al(OH)3 + 3HCl → AlCl3 + 3H2O (constipation) Adverse effects -Al3+ and Mg2+ antacids can bind other drugs, alter GI transit or pH Helicobacter -> penicillin allergy pylori infection bismuth (increase protective layer) forms a protective layer across the gastric lumen  Constipation and diarrhoea Constipation Purgatives Bulk laxatives -methylcellulose, bran, ispaghula husk (bulking agents) -polysaccharide polymers that are not broken down in upper GI tract Osmotic laxatives -lactulose, magnesium sulfate, magnesium hydroxide -increase luminal fluid volume -accelerate small intestinal transit > distension and purgation in colon Adverse effects -abdominal cramps, diarrhoea, electrolyte disturbances Faecal softeners i.e. docusate sodium Stimulant laxatives: interact with lumenal epithelium and enteric nerves -bisacodyl, glycerol, sodium picosulfate (prep. surgery & colonoscopy) patient should not take laxatives long term -> lazy bowel syndrome + dehydration Constipation: ClC-2 activator Lubiprostone (+) Lubiprostone ❑Lubiprostone -selective chloride channel activator -efflux of chloride through the ClC-2 channels -sodium ions follow through a paracellular pathway & water passively follows -increase intestinal motility and softens the stool Cuppoletti et al, Am J Physiol Cell Physiol 2004; 287(5): C1173–83  Constipation and diarrhoea Diarrhoea Oral rehydration therapy -cotransport of glucose of Na+ in the small intestine Spasmolytic agents Antimuscarinics reduce contractions -atropine, hyoscine, propantheline, dicycloverine (RDR, 10, pp153-154) Mebeverine -does not posses anti-cholinergic activity  Anti-diarrhoeal: Mu opioid agonists Codeine, loperamide Morphine Loperamide HO HO ❑Adverse effects 2 2 -may cause respiratory depression in babies or small children do not prescribe -paralytic ileus in patients with active IBD De Luca and Coupar, 1996 Liver ascites  Liver Ascites Mild/moderate ascites Sodium restriction Diuretic therapy Spironoloctone -potassium sparing diuretic -aldosterone antagonist Unwanted effects hyperkalaemia effects at androgen receptors -testicular atrophy, gynaecomastia Spironoloctone & loop diuretic -disappearance of ascites in ~90% of patients with cirrhosis & ascites Irritable Bowel Syndrome IBS  Irritable Bowel Syndrome Functional gastrointestinal ~20% of the population Often described as a 3 subtypes: disorder worldwide biopsychosocial disorder Constipation predominant Diarrhoea predominant Mixed/alternating subtype.  Rome criteria. These criteria include abdominal pain and discomfort lasting on average at least one day a week in the last three months, associated with at least two of these factors: Pain and discomfort are related to defecation, the frequency of defecation is altered, or stool consistency is altered. Manning criteria. These criteria focus on pain relieved by passing stool IBS: Diagnosis and on having incomplete bowel movements, mucus in the stool and changes in stool consistency. The more symptoms you have, the greater the likelihood of IBS. Type of IBS. For the purpose of treatment, IBS can be divided into three types, based on your symptoms: constipation-predominant, diarrhea- predominant or mixed. IBS: Treatment FIBER SUPPLEMENTS: PSYLLIUM LAXATIVES: MAGNESIUM ANTI-DIARRHEAL MEDICATIONS: FODMAP DIET: (METAMUCIL) WITH FLUIDS MAY HYDROXIDE ORAL (PHILLIPS' MILK LOPERAMIDE (IMODIUM), CAN DIET LOW IN FERMENTABLE HELP CONTROL CONSTIPATION. OF MAGNESIA) OR POLYETHYLENE HELP CONTROL DIARRHEA. OLIGO-, DI-, AND GLYCOL (MIRALAX). MONOSACCHARIDES AND POLYOLS (FODMAPS) less healthy diets are better for these patients  Tricyclic antidepressants. relieve depression as well as inhibit the activity of neurons that control the intestines to help reduce pain. diarrhea + abdominal pain without depression ➔lower dose of imipramine (Tofranil), desipramine (Norpramine) or nortriptyline (Pamelor). Side effects can include drowsiness, blurred vision, dizziness and dry mouth. Anticholinergic medications: dicyclomine (Bentyl), propantheline can help relieve painful bowel spasms. IBS: Treatment generally safe but can cause constipation, dry mouth and blurred vision. Contraindicated in patients with glaucoma, prostatism or GERD. Pain SSRI antidepressants: Selective serotonin reuptake inhibitor (SSRI) antidepressants, such as fluoxetine (Prozac, Sarafem) or paroxetine (Paxil) for depression + pain and constipation. Pain medications. Pregabalin (Lyrica) or gabapentin (Neurontin) for severe pain or bloating. all anti muscarinic (we have no specific drugs) so huge amount of S/E IBS: Treatment Alosetron (Lotronex): potent selective 5-HT3 receptor Eluxadoline (Viberzi): opoid mu (µ) & antagonist blocks the actions of serotonin at 5-HT3 sites in Kappa (κ) receptor agonist the peripheral nervous system, particularly on Decreased intestinal motility. enteric and nociceptive sensory neurons, thereby affecting the regulation of visceral pain, Side effects can include nausea, decreasing gastrointestinal contraction and abdominal pain and mild motility, & decreasing gastrointestinal secretion constipation. Side effects: Severe adverse effects including ischemic Eluxadoline has also been colitis, severely obstructed or ruptured associated with pancreatitis. bowel, and death. Withdrawn in 2000, but received FDA approval 2002 with restrictions. do not give it to patients with severe IBS  Linaclotide (Linzess): IBS: Lubiprostone (Amitiza): Agonist of intestinal guanylate cyclase type C (GC-C). Secretagogue, analgesic and Treatment laxative activities Treatment for IBS-C Activates GC-C receptors located on the luminal Poorly absorbed after oral administration surface of the intestinal epithelium. Increases intestinal motility via direct Increases the concentration of intracellular cyclic activation of chloride channels on guanosine monophosphate (cGMP), which is derived from guanosine triphosphate (GTP). luminal membrane of intestinal epithelium cGMP activates CFTR & stimulates the secretion of chloride and bicarbonate into the intestinal This results in secretion into the lumen. intestinal lumen, stimulating peristalsis. Promotes sodium excretion into the lumen and results in increased intestinal fluid secretion. Accelerates GI transit of intestinal contents, Rifaximin (Xifaxan): improves bowel movement and relieves constipation. This antibiotic can decrease bacterial Increased extracellular cGMP levels may also overgrowth and diarrhoea. exert an antinociceptive effect, through an as of yet not fully elucidated mechanism, that may involve modulation of nociceptors found on colonic afferent pain fibers. minimal S/e/ Inflammatory Bowel Disease Ulcerative colitis & Crohns Ulcerative Colitis  An inflammatory disorder of the colonic mucosa characterised by relapses & remissions 90-170:100,000 population (more common than crohns) 7-22:100,000 new cases per year Most patients present at age 15-30 yrs 15% have a family member with UC HLA genes are more strongly linked to UC Vs Crohns Ulcerative Colitis 3X as common in ex-smokers or non-smokers The cause is unknown, but some factors have been implicated: deficient immunoregulation NSAIDs Cell-wall deficient bacteria Diet (low fibre, milk) Stress can exacerbate the disease but does not cause it  Relieved by defecation Crampy abdominal pain Left iliac fossa Blood ++ Diarrhoea Mucous Urgency Ulcerative Tenesmus Colitis Weight loss Fever Anaemia Treatment/ Management of UC 5-ASA Sulfasalazine, Mesalazine, Balsalazide, Olsalazine Inhibits COX and 5-lipo oxygenase – decrease arachadonic acid- decreased PGs – decreased inflammation. Side Effects: agranulocytosis; Hepatitis; Nausea; Diarrhoea; Abdo pain Treatment/ Management of UC: Corticosteroids Treatment/ Management of UC: Corticosteroids Prednisolone Treatment/ Management UNSURE ABOUT MOA of UC: Mercaptopurine One of a large series of purine analogues which interfere with nucleic acid biosynthesis Has been found active against human leukemias. An analogue of the purine bases adenine and hypoxanthine. Not known exactly which of any one or more of the biochemical effects of mercaptopurine and its metabolites are directly or predominantly responsible for cell death Treatment/ Management of UC: ciclosporin/cyclosporine is a calcineurin inhibitor lowers the activity of T-cells; inhibits calcineurin in the calcineurin–phosphatase pathway & prevents the mitochondrial permeability transition pore from opening. Binds to the cytosolic protein cyclophilin of lymphocytes, especially of T cells. Cyclosporin—cyclophilin complex inhibits calcineurin, which is normally responsible for activating the transcription of interleukin 2. Activation of the T-cell receptors  intracellular calcium, which acts via calmodulin to activate calcineurin. Calcineurin then dephosphorylates the transcription factor NF-AT (nuclear factor of activated T-cells) & increases the transcription of genes for IL-2. side effects include high blood pressure, headache, kidney problems, increased hair growth, and vomiting Treatment/ Management of UC Biologicals: Crohn’s Disease Crohns Idiopathic, chronic, transmural inflammatory process of the bowel that can affect any part of GI tract from mouth to anus Most cases involve the small intestine, particularly the terminal ileum Prevelance 70-100:100,000 population 4-11:100,000 new cases per year Incidence has doubled sine 1950 but stabilised since 1990 Males & females equally affected Smokers 3X more likely to develop crohns Presents at any age: 15-40yrs 15% have a relative with IBD  Inflammation; fibrosis; bowel Crampy abdominal pain obstruction Blood Diarrhoea Steatorrhea Weight loss Fever Crohns Anaemia Obstruction: Distension, Vomiting Abscesses Fistulae: Enteroenteral; Anorectal; Vesicointestinal; Rectovaginal  5-ASAs: first port of call Inhibits COX and 5-lipo oxygenase – decrease arachadonic acid- decreased PGs – decreased inflammation. Side Effects: agranulocytosis; Hepatitis; Nausea; Diarrhoea; Abdo pain. Azathioprine: metabolised to 6-mercaptopurine (by thiopurine methyl transferase) –inhibits purine production - decreased leucocyte proliferation. IBD: Methotrexate – folate antagonist (inhibits dihydrofolate reductase): essential for DNA sysnthesis. Treatment Stop 3 months prior to conception. Not for patients that have effusions (pleural; ascitic)-drug accumulates and stores then becomes toxic. Given weekly – give with folic acid. Infliximab: -> Biologics Use if severe acute crohns + immunosuppressants not effective/not tolerated + surgery inappropraite Monoclonal antibody against TNF alpha (proinflammatory cytokine) – attached to tnf alpha receptors on t lymphocytes and blocks it- stops the cell from working = decreased inflammation. Give infusion over 2 hours – have obs every 30 mins and resus equipment nearby. Avoid pregnancy for 6 months after stopping.  Acute bowel rest is very effective! Bowel rest; Analgesia (not NSAIDs); Steroids: IV; oral; rectal Antibiotics 5-ASAs Chronic Crohns: 5-ASAs Treatment Per rectum steroids Immunosuppressant's Azathioprine Methotrexate (Crohn’s) Anti-TNF: Infliximab (Remicade), Adalimumab (Humira) Vedolizumab Surgery: Resection Emerging Therapies Al-Bawardy B, Shivashankar R, Proctor DD. Novel and Emerging Therapies for Inflammatory Bowel Disease. Front Pharmacol. 2021 Apr 14;12:651415. doi: 10.3389/fphar.2021.651415. PMID: 33935763; PMCID: PMC8080036.  Inflammatory bowel disease (IBD) https://www.mims.co.uk/summaries-nice-bowel-disease-guidance-published- mims/gi-inflammatory-bowel-disease/article/1405299