Reacts slowly to form CaCl2 and CO2 to cause belching
Calcium carbonate (
Reacts with HCl to produce NaCl and CO2 which causes belching and gastric distention.
Reacts with HCl to form water and aluminum chloride or magnesium chloride. Magnesium salts not absorbed can cause osmotic diarrhea and aluminum salts can cause constipation so often used together.
Magnesium hydroxide & Aluminum hydroxide
H2 receptor Antagonists \?
Pk H2 All but ____ under go? resulting in? Cleared by both?Reduction in?
All but nizatidine under-go first pass metabolism resulting in 50% bioavailability. Cleared by both metabolism and excretion so need for dose reduction with severe renal dysfunction.
PD H2 antagonists Highly selective ________ ___ which inhibit___ ___ but especially basal ____ gastric acid secretion and pepsin. Inhibit ___ - ___ of acid secretion per day.
Highly selective H2 competitive antagonists which inhibit meal-stimulated but especially basal nocturnal gastric acid secretion and pepsin. Inhibit 60-70% of acid secretion per day.
Uses for H2 antagonists?
Can be used for infrequent dyspepsia/heartburn or prophylactically before meals. Rarely used for peptic ulcers. For critically ill pts with stress-related mucosal disease and upper GI ulcers used via continuous iv infusion. Available over the counter and as prescription.
AEs of H2 antagonsits
Extremely safe, < 3% diarrhea, constipation, headache fatigue, myalgias In elderly in intensive care or renal or hepatic dysfunction- mental status perturbation Cimetidine inhibits binding of dihydrotestosterone to androgen receptors and estradiol metabolism so increases serum prolactin resulting in possible male gynecomastia or impotence and female galactorrhea. Cross placenta and excreted in breast milk
DIs for H2 Antagonists
Competes with creatinine and with some drugs for renal tubule secretion Cimetidine inhibits P450 drug metabolism
What type of drugs are PPIs? What type of Coating? Dissolve where? Converted to a reactive? What does it do to the enzymes?
Administered as a prodrug. Acid resistant coating to protect from destruction by gastric acid, dissolves in intestine where drug is absorbed (weak base) and is concentrated in parietal cell canniculus. Converted to a reactive thiophilic sulfonamide which forms a covalent bond with active proton pumps irreversibly inactivating the enzyme. If taken 1 hr before a meal drug, there is maximal activation of pumps when drug is available for inactivating the pumps. Although t1/2 = 1.5 hrs, inhibition lasts about 1 day due to synthesis of new pumps. 3-4 days for full effect due to acid inhibition as well as 3-4 days for full recovery after cessation of treatment. Absorption diminished by food so must be taken on an empty stomach.
PD of PPIs
Inhibit both basal and meal-stimulated HCl secretion 90-98%/day Similar clinical efficacy among drugs in class
Uses for PPIs
Gastroesophageal reflux disease (GERD)-provide symptom relief and tissue healing but symptoms often recur after discontinuation of drug resulting in the need for long term or intermittent therapy Peptic Ulcer -Rapid relief of symptoms and ulcer healing in 4-8 wks Useful for NSAID-associated ulcers and treatment of bleeding ulcers
AEs of PPIs
Safe, 1-5% diarrhea, headache, abdominal pain Reduction in gastric acidity- Can reduce release of vitamin B12 from food and reduce absorption of minerals such as iron, calcium, zinc and magnesium. Associated with increase hip fracture so for those at risk, monitor bone density and provide calcium supplements. Increased risk for respiratory and enteric infections since low pH is protective against bacteria. Increased risk of chronic kidney disease and mortality from it
DIs for PPIs
Alter absorption of drugs from stomach that depend on low pH
Mucosal Protective agents Sucralfate PD and PK
Sucrose complexed to sulfated aluminum In water or acid forms viscous paste that binds to the ulcer forming a barrier and stimulates mucosal prostaglandin and bicarbonate secretion < 3% absorbed
Sucralfate limited uses?
Upper Gi bleeding in critically ill and stress related bleeding
AEs of Sucralfate
Constipation in 2% due to aluminum Not absorbed systemically so no systemic adverse effects
Mucosal Protective Agents Prostaglandin analog Misoprostol analog of? PK and PD
Pharmacokinetics Orally available, rapidly absorbed and metabolized to active form t1/2 < 30min so 3-4 doses/day Pharmacodynamics Stimulates mucus and bicarbonate secretion Enhances mucosal blood flow Binds to prostaglandin receptors on parietal cells to reduce histamine-stimulated acid production
Uses for Misoprostol
Prophylactic use for NSAID induced ulcers
Misoprostol AEs and DIs
10 -20% diarrhea and cramping Causes uterine contractions so contra-indicated during pregnancy No significant drug interactions
Mucosal Protective Agents Bismuth compounds PK and PD
PK- Salicylate rapidly dissociates and is absorbed Bismuth excreted in the stool PD- Bismuth coats ulcers for physical protection Stimulates prostaglandin, mucus and bicarbonate secretion Direct antimicrobial effects, binds enterotoxins Antimicrobial effects against Helicobacter pylori Reduces stool frequency and liquidity in acute infectious diarrhea
Treatment of dyspepsia and acute diarrhea and prophylactically against traveler’s diarrhea Used in combination with antibiotics and proton pump inhibitors for H. pylori infection
Extremely safe Harmless blackening of stool and if liquid formulation also tongue
Abx for the Tx of H. Pylori only need to know 2
Clarithromycin and Metronidazole
Natural laxative product 1 What is it?
Psyllium- Indigestible hydrophobic colloid that absorb water to form a bulky gel that distends the colon and advances peristalsis, bacteria in colon can cause bloating and fart from nat product
Stool softener only one How does it work?
Docusate Surfactants allowing water and lipids to penetrate stool
Osmotice laxatives Mg Oxide Should be used in patients with?
should not be used in pts with renal insufficiency due to hypermagnesemia
Balanced polyethylene glycol What is it? Whats in it? No change in? Not associated with? Used for what?
Inert non-absorbable sugar balanced with isotonic solution of sodium sulfate, sodium chloride, sodium bicarbonate, potassium chloride No change in intravascular volume or electrolyte balance Not associated with cramps or flatus Used for colonic cleansing before GI endoscopic procedures and chronically for constipation at lower doses
Stimulant laxatives Diphenylmethane derivatives Biscodyl- Used for?
used for acute and chronic constipation, and in conjunction with PEG for colonic cleansing prior to endoscopy
Chloride channel activator?
Lubiprostone MOA? Used for?
Stimulates type 2 chloride channels in small intestine. Used for the tx of chronic constipation and IBS with constipation
Opioid receptor Antagonists
Methylnaltrexone Selective for? does cross? Used for?
alvimopan and naloxegol are selective mu opioid antagonists that do not cross the blood brain barrier. Used for the treatment of opioid-induced constipation and post-operatively.
cross the BBB
Bile salt binding resins
Conjugated bile salts are absorbed in the terminal ileum. Diseases of terminal ileum such as Crohn’s disease or surgical resection disturb bile salt absorption and may cause colonic secretory diarrhea. Bile salt binding resins bind bile salts to decrease diarrhea due to excess fecal bile acids.
Bloating, flatulence, constipation, fecal impaction Further removal of bile acids may cause fat malabsorption
Cholestryanine and colestipol may bind other drugs and decrease their absorption, so do not take other drugs within 2 hrs. Colesevelam does not alter absorption of other drugs.
Antiemtic Drugs 5-HT3 receptor antagonists
Palonosetron PK and PD
Anti-emetic actions through blockade of 5-HT3 receptors on extrinsic intestinal vagal and spinal afferent nerves and perhaps on the vomiting center and chemoreceptor trigger zone.
Palonosetron- 2nd generation with a?
longer t1/2 and higher binding affinity Selective- no antagonism at dopamine or cholinergic muscarinic receptors May slow colon transport but no effect on esophageal or gastric motility.
Anti-emetic effects for emesis due to vagal stimulation such as post-operative or chemotherapy. Chemotherapy induced emesis- primary agents for use alone but can also be used in combination with dexamethasone or NK1 antagonist Used for nausea and vomiting induced by radiation therapy to the abdomen or whole body and post-operatively.
1. 5-HT3 Receptor Antagonists AEs
Well-tolerated and generally safe Most common side effects are headache, dizziness and constipation.
Neurokinin 1 receptor antagonists PK PD Uses AEs DIs
Aprepitant has 65% oral bioavailability.
Fosaprepitant is an iv infusion formulation that is rapidly converted to aprepitant.
Rolapitant- long half-life prolongs therapeutic effects
Selective neurokinin 1 receptor antagonist with antiemetic properties via central blockade of receptors in the area postrema.
Prevent and treat post-operative and chemotherapy-related nausea & vomiting
Less effective for motion sickness related nausea & vomiting
Used alone or in combination with 5-HT3 receptor antagonist and dexamethasone (corticosteroid).
Safe, well tolerated, few adverse effects reported but include fatigue, dizziness and diarrhea.
Inhibit P450 metabolism (CYP3A4) and metabolism of drugs including some chemotherapeutic agents.
- Dopamine 2 receptor antagonists
D2 receptor antagonists
Antipsychotics with antiemetic effects via dopamine & muscarinic receptor antagonism (phenothiazines) or for butyronphenones via central dopaminergic antagonism.
Sedative effects via antihistamine activity
In the past, used extensively for post-operative antiemetic and sedative effects.
Extrapyramidal effects and hypotension
- Substituted benzamides
Mechanism of antiemetic effect- dopamine receptor antagonisms
Trimethobenzamide also has weak antihistamine effects
Via central dopaminergic antagonism- restlessness, dystonia, parkinsonism
H1 antihistamine anticholinergics
Diphenhydramine and dimenhydramine have both antihistamine and anticholinergic properties
Meclizine has antihistamine effects but limited anticholinergic effects so less sedating.
Hyoscine is a muscarinic antagonist.
Used to prevent and treat motion sickness.
Diphenhydramine and dimenhydramine used in combination with other agents for treatment of chemotherapy caused emesis.
Meclizine is used for preventing motion sickness and treatment of vertigo caused by labrynth dysfunction.
Hyoscine in a transdermal patch used extensively for motion sickness.
Use limited by side effects- sedation, dizziness, confusion, dry mouth, cycloplegia, urinary retention
Enhance GABAergic neurotransmission
Used to reduce vomiting associated with anxiety or anticipatory vomiting related to chemotherapy
Used as an appetite stimulant and antiemetic
Used with other antiemetics, synergistic with phenothiazines and decrease adverse effects of both drugs.
Euphoria, dysphoria, sedation, hallucination, dry mouth, increased appetite, tachycardia, orthostatic hypotension
Drugs for the Tx of IBS with diarrhea
- Anti-diarrheal agents especially loperamide
- Mu and kappa opioid agonist, delta opioid antagonist
Decreases abdominal pain and diarrhea
Adverse effects: constipation, nausea, abdominal pain
- Tricyclic anti-depressants at low doses
Normalize GI motility and secretions to reduce frequency and volume
No effects on mood
- 5-HT3 receptor antagonists
Alosetron approved for treatment of women with severe IBS with diarrhea
Efficacy of other 5-HT3 antagonists not examined
5-HT3 receptors in GI modulate visceral pain and intestinal motility
Alosetron- rare but serious GI toxicity limits use to women refractory to other therapies
- Bile salt binding resins
About 1/3 of people with IBS-D have bile acid malabsorption and can be treated with bile salt binding resins
Used to reduce colon muscle spasms and pain
Rifaximin- GI specific broad spectrum antibiotic
Drugs for tx of IBS with Constipation
- Polyethylene glycol and osmotic laxatives used to soften stools and increase frequency, but no impact on pain.
- Guanylate cyclase agonist
diarrhea, upper respiratory tract infection, abdominal pain or distention, flatulence, headache
- Chloride channel activators
Stimulates type 2 chloride channels in small intestine, low systemic absorption
Used for the treatment of chronic constipation and women with IBS with constipation
Nausea (29%),< 12 % headache, diarrhea, stomach pain or bloating, gas, vomiting, dizziness, swelling of the hands, feet, ankles, or lower legs, discomfort in chest, tiredness
Drugs for the Tx of IBD
5-aminosalicylic acid differs from salicylic acid by addition of an amino group at the 5 position
Mechanism of action uncertain but thought to alter inflammation and immune responses.
Thought to work topically in the GI mucosa so several formulations used to limit absorption and aid in delivery to small bowel or colon.
An aza bond to another 5-aminosalicylate or inert compound reduces absorption until drug reaches the terminal ileum and colon where an azoreductase cleaves the azo bond to achieve high concentrations of active compound at site of action.
Formulations designed to deliver 5-aminosalicylic acid to various segments of the small and large bowel.
Mild to moderate ulcerative colitis and Crohn’s disease.
Sulfasalazine has high incidence of adverse effects especially in slow acetylators due to sulfapyridine, up to 40% cannot tolerate.
Olsalazine causes stimulatory diarrhea in 10% of pts.
Some of the common side effects of aminosalicylates include abdominal pain, diarrhea, headaches, heartburn, nausea and vomiting.
Prednisone and prednisolone are the most commonly used oral glucocorticoids.
Hydrocortisone enemas, foam and suppositories used to maximize colon effects and diminish systemic absorption.
Budesonide is a high affinity synthetic prednisolone analog with high first pass effect, available in controlled release formulation for delivery to distal ileum and colon.
Via interaction with glucocorticoid receptors:
Decrease production of inflammatory cytokines and chemokines.
Decrease inflammatory cell adhesion molecules.
Decrease transcription of nitric oxide synthase, phospholipase A2, cyclooxygenase-2 and NFB.
Treatment of moderate to severe IBD.
Budesonide for mild to moderate Crohn’s disease since slightly less effective but with significantly fewer adverse effects.
For treatment less than 2 weeks, very well tolerated, occasional peptic ulcer, and rare pancreatitis.
Extensive adverse effects for treatment lasting longer than 2 weeks
- Immune Modulators
Bioavailability of azathioprine better than 6-MP, azathioprine converted to 6-MP
Short half-life but active 6-thioguanine nucleotide metabolites have a long half-life and are concentrated in cells
Immunosuppressive properties through an unknown mechanism
6-thioguanine inhibits purine nucleotide metabolism and DNA synthesis and repair leading to decreased cell division and proliferation
Induction & maintenance of remission of ulcerative colitis and Crohn’s disease
Help maintain remission in up to 80% of pts
Used to reduce dose or eliminate glucocorticoid treatment
Nausea, vomiting, hepatotoxicity, bone marrow suppression
Monitoring of complete blood count and liver function tests needed
Leukopenia and liver dysfunction usually reverse with dose reduction
Hypersensitivity characterized by fever, rash, pancreatitis, diarrhea & hepatitis in 5%
Reduce the dose of azathioprine and 6-MP by half in patients taking allopurinol because
allopurinol reduces purine analog catabolism.
Anti-metabolite used for a number of chronic inflammatory diseases.
Primary mechanism of action is inhibition of dihydrofolate reductase, an enzyme important in production thymidine and purines.
Induce and maintain remission of IBD
At high doses- bone marrow suppression, megaloblastic anemia, alopecia and mucositis.
At doses used for IBD, uncommon but if occur, reduce dose
Folate supplements reduce the risk of adverse effects without reducing anti-inflammatory effects.
- Anti-Tumor Necrosis Factor (TNF) therapy
Due to a long half-life, these drugs are given at bi-weekly or longer intervals for induction and maintenance of remission.
Monoclonal antibodies to human TNF approved for the treatment of IBD.
TNF is a pro-inflammatory cytokine dysregulated via TH1 T cell response in IBD, esp. Crohn’s disease.
Acute and chronic treatment of moderate to severe Crohn’s disease with inadequate response to other therapies.
Infliximab approved for acute and chronic ulcerative colitis with inadequate response to other therapies.
Median clinical response time is 2 weeks.
Serious adverse effects occur in 6% of pts
Infection due to suppression of TH1 inflammatory response such as pneumonia & sepsis, fungal infections, viral infections, reactivation of latent TB and other opportunistic infections.
Acute adverse infusion reactions in ~10% characterized by fever, chills, pruritis, urticaria, cardiopulmonary symptoms, dyspnea or hemodynamic instability
Antibody production against the antibodies which eliminate the clinical response and increase the risk for infusion reactions.
Delayed(1-2 wks) infusion reaction in 1% characterized by myalgia, arthralgia, fever, rash, urticaria and edema. Usually requires discontinuation of therapy.
Rare adverse effects include hepatic failure, demyelinating disorders, hematological reactions congestive heart failure in pts with heart disease and lymphoma
- Anti-Integrin therapy
Integrins are adhesion molecules that allow circulating leukocytes to enter tissue
Natalizumab is a monoclonal antibody against α4 integrin that prevents circulating leukocytes from entering tissues targeting brain and gut.
Vedolizumab humanized monoclonal antibody directed against α4β7 integrin. The α4ß7 integrin is expressed on the surface of a discrete subset of memory T-lymphocytes that preferentially migrate into the GI tract providing increased selectivity.
Approved for the treatment of moderate to severe Crohn’s refractory to other treatments.
Acute infusion reactions and opportunistic infections.
Progressive multifocal leukoencephalopathy a rare infection of the brain that cannot be treated, prevented, or cured and that usually causes death or severe disability. The risk for PML is higher with one or more of the following risk factors: treatment for longer than 2 years, previous treatment with immunosupressants (azathioprine, cyclophosphamide, methotrexate, mitoxantrone, and mycophenolate mofetil), exposure to JC virus.
Hepatotoxicity with jaundice in 0.1% -discontinue if occurs
Vedolizumab- no PML reported
Used to treat infections resulting from IBD
Tx of Celiac Disease
Life-long gluten-free diet accomplished by excluding wheat, rye and barely from the diet, oats should also be excluded due to contamination issues.
Initial supplements with iron, calcium, phosphorous, folate, B12 and fat-soluble vitamins as needed.
Refractory disease can be treated with corticosteroids such as budesonide or anti-inflammatory drugs such as azathioprine.
Untreated celiac disease damages the small intestine and interferes with nutrient absorption.
Without treatment, people with celiac disease can develop complications such as osteoporosis, anemia, and cancer.