Gastrointestinal Pharmacology II

Question 1

What are immunomodulators and what are they used to treat?

Answer 1

• Thiopurines: 6-mercaptopurine and azathioprine
  
  • prodrugs, metabolized to 6-thioguinine (active moiety)
• Used to treat inflammatory bowel disease
• mechanism of action
  
  • inhibit purine synthesis,
    
    • thus produce anti-proliferative side effects & indicue apoptosis in T-cells
  • slow onset of action

Question 2

Mechanism of action for thiopurines?

Answer 2

• 6-mercaptopurine is converted to 6-thoguanine
  
  • further converted to 6-thoguanine monophosphate
    
    • Inhibit purine synthesis enzymes:
      
      • ATP, GTP, dATP, dGTP
        
        • this block RNA & DNA production
          
          • decreases cell proliferation
          • increases cell apopsosis
    • can be futher converted to 6-thioguanine triphosphate
      
      • it can itself be incorporated into DNA & RNA
        
        • decreases cell proliferation
        • increases cell apopsosis

Question 3

What are the clinical uses of thiopurines?

Answer 3

• maintain remission (UC)
• induce and maintain remission (CD)
• Action
  
  • assist steroid tapering
  • treat steroid-dependent and steroid-resistant IBD
  • decrease formation of antibodies TNF inhibitors when combined wtih TNF Ab
  • Prevent CD recurrence after surgical resection
  • Prevent rejection following organ transplant
  • Rheumatoid arthritis

Question 4

Adverse effects of tiopurines?

Answer 4

• AE
  
  • common: nausea, vomiting
  • major:
    
    • bone marrow suppression
    • pancreatisis

Question 5

Pharmacogenetics and drug-drug interaction of thiopurines?

Answer 5

• 6-mercaptopurine is metabolized to its inactive form (6-thiouric acid) by xanthine oxidase
  
  • xanthine oxidase is also responsible for synthesis of uric acid
  • for patients on gout drugs (xanthine inhibitors) thiopurines will not be metabolized to their inactive form
    
    • dose must be reduced for patients on gout drugs
  • this means the serum concentration of 6-mercaptopurine will be high, increasing the chance of adverse effects
    
    • specifically bone marrow suppression
• Some patients genetically have more Thiopurine methyltransferase (TPMT), which converts 6-mercaptopurine to 6-methyl-mercaptopurine
  
  • this is a hepatotoxin, which can lead to abnormal liver function
  • but if patients have very low TPMT activity, more 6-mercaptopurine will be conerted to 6-thioinosinic acid by HGPRT
    
    • then to 6-thioguanine nucleotides, leading to bone marros suppression

Question 6

Methotrexate mechanism of action?

Answer 6

• Methotrexate inhibits the convertion of dihydrofolate to tetrahydrofolate
  
  • therefore decreasign the synthesis of DNA

Question 7

What are the clinical uses and adverse effects of Methotrexate?

Answer 7

• Clinical uses
  
  • induce and maintain remission
    
    • moderate to severe steroid-dependent and steroid-resistant CD
    • cancer
    • rheumatoid arthritis
    • psoriasis
• Adverse Effects
  
  • uncommon for the dosage for IBD
  • folate supplement reduces risk of adverse effects

Question 8

What is the mechanism of action of cyclosporine and tacrolimus?

Answer 8

• Cyclosporin and Tacrolimus can bone & inhibit the function oc calcineurin
  
  • The role of calcineuron is to dephosphorylate T-cell specific transcription factor NFAT
  • NFAT binds to cytokine promoter DNA
    
    • therefore increasing inflammtory response

Question 9

What are the clinical uses of cyclosporine and tacrolimus?

Answer 9

• cyclosporine
  
  • severe steroid-resistant UC to induce remission
• Tacrolimus
  
  • alternative to cyclosporine

Question 10

What are the biologics that are used to treat IBD?

Answer 10

• Anti-TNF-alpha – given by injection
  
  • Infliximab
  • adalimumab (CD and UC)
  • golimumab (UC)
  • Certolizumab (CD)

Question 11

What is the mechanism of action for Anti-TNF-alpha agents?

Answer 11

• The TNF_alpha antibodies bind to the TNF_alpha preventing its interaction with its receptor;
  
  • ​inhibiting its induction of transcription factor NFkB, which modulates
    
    • proinflammaotry cytokine release
    • T-cell activation proliferation
    • Fibroblast collagen production
    • Endothelial adhesion molecules
    • hepatic acute phase reactants

Question 12

Clinical uses of Anti-TNF-alpha agents?

Answer 12

• induce & maintain remission
  
  • moderate to severe CD and/or UC

Question 13

Adverse effects and contraindications of Anti-TNF-alpha agents?

Answer 13

• Adverse effects
  
  • serious infections
  • injection site reactions (antibody development)
  • co-administration with immunomodulators: lymphoma
  • rare but serious: acute hepatic failure
• Contraindication
  
  • hypersensitivity
  • uncontrolled infection
  • concomitant administration of other biologics
  • patients with moderate or severe heart failure

Question 14

What is the mechanism of action of Anti-_{alpha 4} integrin?

What are the other two drugs in this category?

Answer 14

1. Natalizumab
2. vedolizumab

• MOA
  
  • on leukocyte surface there are alpha4 integrins that interact with endothelial cells
  • this interaction will let the leukocytes migrate through the endothelial cells, causing inflammation
  • so, by inhibiting the alpha4 integrin via antibodies, it prevents the leukocytes from migrating through the endothelial cells into the tissue
    
    • decreases inflammation

Question 15

Clinical use and adverse effects of Anti-alpha₄ integrin?

Drug-drug interactions?

Contraindications?

Answer 15

• Clinical use
  
  • induce and maintain remission
    
    • moderate to severe CD (Natalizuman) adn UC (Vedolizuman) who do not respons to or could not toldrate anti-TNF_alpha
• Adverse effects
  
  • progressive multifocal leukoencepalopathy
  • severe hepatic toxicity
• Drug interactions
  
  • with othe rimmunosuppressants risk of infection
• contraindications
  
  • hypersensitivity, current or history of PML, immunocompromised patients

Question 16

What is the mechanism of action fo Interleukin-12/23 inhibitor: Usterkinuman (stelara) mechism of action and clinical uses?

Adverse effects?

Answer 16

• Mechanism of Action
  
  • bind to subunit of p40 of IL-12 and IL-23
  • prevents them from binding to their specific receptors
    
    • no intracellular signaling of TH1 and TH17 respectively
  • prevents them from activating those T cells
• Clinical uses
  
  • induce and maintain remission in patients with moderately to severely active IBD who failed or intolerant to treatment with immunomodulators or corticosteroids
• Adverse Effects
  
  • see ibooks

Question 17

What is the mechanism of action and clinical uses of inhibitor of janus kinase 1-3 (Tofacitinib)?

adverse reaction

drug-drug interactions?

Answer 17

• Mechanism of Action
  
  • Tofacitinib inhibits the JAK 1-3 receptor (that responds to cytokines)
  • inhibiting the STAT transcription factor that induces inflammatory response
• Clinical use
  
  • adults with moderately to severely UC
• Adverse effects
  
  • see ibook
• Drug-drug interactions
  
  • tofacitinib is a substrate of CYP3A4 and interacts with CYP3A4 inhibitors and inducers

Question 18

What is the hypothesis behind usign antibiotics of probiotics to treat IBD?

Answer 18

• imbalance of enteric bacteria and fungi play a rold in IBD
• Antibiotics:
  
  • induce and maintain (?) remision of CD
• Probiotics
  
  • maintain remission of UC, especially pouchitis.
  • should not be used with antibiotics or antifungal medications

Question 19

What are the 2 general pharmacological approaches to treatment of IBD?

Answer 19

1. Step-up therapy
   
   • mild to moderate IBD, starts wtih medications that are less potent and have few adverse effects
     
     • advance to more potent medications if needed
2. Top down therapy
   
   • severe IBD
     
     • start with more potent therapies to induce remission adn step down to less potent drugs if needed

Question 20

Question

Answer 20

1. NaHCO₃ is an antacid, so it can directly neutralize acid & reduce the symptoms
2. He has a peptic ulcer
   
   1. need to us a more serious drug – PPI

Question 21

Answer 21

A. antibiotics – address the bacterial infection

Question 22

Answer 22

1. Symptoms are not controlled by the less potent drugs
   
   1. advance her to oral corticosteroids (prednisone or prednisolone) to induce remission
   2. or, TNF-alpha antibody
2. Long-term management options
   
   1. Use another drug to maintain remission (6-mercaptopurine)

Question 23

What are the two general targets for drugs desigend to modulate GI motility?

Answer 23

• neutrotransmitter
• directly acting on GI tract

Question 24

Which drugs increase GI motility?

Which drugs decrease GI motility?

Answer 24

• increase GI motility
  
  • Laxatives
  • prokinetic agents
  • emetics
• Drugs decreasing Gi motility
  
  • antidiarrheals
  • antiemetics

Question 25

What are the clinical uses of drugs tht increase GI motility?

Answer 25

* GERD (increase lower esophageal sphincter pressure) * gastroparesis and postsurgical gastric emptying delay (increase gastric motility) * postsurgical ileus or chronic pseudo-obstruction (increase small intestine motility) * constipation (increase colon transit)

Question 26

What are the D₂ Dopamine receptor antagonists? What is their mechanism of action?

Answer 26

* (Gastroprokinetic agents) Mainly increase upper GI motility * metoclopramide: reglan * domperidone: molax * Mechanism of Action * dopamine is an inhibitory neurotransmitter in the GI tract * binds to D₂ receptors and decreases * gastroesophagela peristalsis * lower esophageal sphincter pressure * D₂ receptor antagonists bind to the receptor & prevent dopamine from binding -- inhibiting dopamines inhibitory effects (increasing gastric motility) * Central action (CTZ): antiemetic action

Question 27

Clinical uses of D₂ Dopamine receptor antagonists? Adverse effects? contraindications?

Answer 27

* Clinical uses * treat impaired gastric emptying * gastroparesis, postsurgical disorders * prevent emesis * Adverese effects * metoclopramide: * neuropsychiatric and extrapyramidal symptoms * tardive dyskinesia * parkinsonism (parkinson's is due to lack of dopamine) * both drugs: * prolonged QT interval * Contraindication * seizure * GI obstruction * hemorrhage * Parkinson disease

Question 28

What is the mechanism of action for macrolide antibiotics? Clinical uses? Special considerations?

Answer 28

Motilin agonists * Mechanism of action * directly stimulate motilin receptors on GI smooth muscle * Clinical uses * gastroparesis * patients who failed to respond to D₂ receptor antagonists * Upper GI bleeding * empty blood before endoscopy * Tolerance develops rapidly

Question 29

What are examples of cholinomimetic agents? Mechanism of action? Clinical use? Adverse effects?

Answer 29

* Acetylcholineesterase (AChE) inhibitor: * neostigmine: increase entire GI motility * Mechanism of Action * inhibits the metabolism of Acetylcholine * increases GI motility * Clinical uses * IV neostigmine to treat acute colonic pseudo-obstruction * Adverse effects * excessive parasympathetic nervous system activity

Question 30

Wat are the goals for laxatives mainly used for constipation?

Answer 30

* stimulate intestine peristalsis and soften bowel contents

Question 31

Examples of bulk-forming laxatives? Mechanism of action? Clinical effects? Adverse effects?

Answer 31

* Fiber-rich products: natural plant and synthetic fibers- indigestible * Mechanism of action: in colon * fermented by bacteria * fatty acids, increase bacterial mass * fermentation --\> reduces stool water * short-chain fatty acid --\> prokinetic effect * increased bacterial mass --\> stool volume * stimulate stretch receptors in the colon & promote peristalsis * non-fermented * retain water--\> expand fecal volume * onset of action is slow * clinical uses * prevent constipation * Adverse effect * bloating * warning * drink lots of fluid ot prevent the intestine blockade

Question 32

What type of drugs are docusate (Colace, oral or enema) or glycerin suppository? administration? mechanism of action? clinical uses?

Answer 32

* Stool surfactant agents (Stool softeners) * orally or rectally administered * mechanism of action * permit water and lipids to penetrate feces and soften it * clinical uses * prevent constipation in patients who should avoid strain (MI and surgery)

Question 33

What type of drug is mineral oil? administration? mechanism of action? clinical uses? Side effects?

Answer 33

* Stool softener * lubricant * administration * orally or rectally administered * mechanism of action * lubricate stool and inhibit water absorption * clinical uses * treat and prevent constipation in young children and debilitated adult * Side effects * youngh children: * severe lipid pneumonitis due to aspiration * long-term use: * malabsorption of lipid-soluble vitamins

Question 34

What is an example of a chlorid channel activator? Mechanism of Action? Clinical uses? Adverse effects?

Answer 34

* Lubiprostone (Amitiza) * Mechanism of Action * stimulate chloride channels on small intestine lumen * promote cloride to enter the lumen, causing water to follow the ion * Clinical uses * chronic idiopathic and opioid-induced constipation * constipation-predominant IBS * Adverse effects * nausea * diarrhea * abdominal pain

Question 35

What are examples of osmotic laxatives? Mechanism of Action?

Answer 35

* Nonabsorbable sugars or salts * active components: * magnesium hydroxide * sodium phosphate * sorbitol * lactulose * magnesium citrate * lacitol * Mechanism of Action * draw water into intestine and prevent water absorption, thus increase fecal fluid, and stimulate colonic peristalsis

Question 36

Clinical uses and adverse effects of osmotic laxatives? Cautions and contraindications?

Answer 36

* Clinical uses * treat acute constipation or prevent chronic refractory constipation * magnesium hydroxide (Milk of Magnesia): commonly used * high dose: purgation * commonly used: magnesium citrate and sodium phosphate (Fleet Enema) * Adverse effect * flatus and cramps, water and electrolyte loss * Caution & contraindications * frail or elderly patients, renal insufficiency, significant cardiac disease * unable to maintain hydration * on diuretics

Question 37

The osmostic laxatives lactulose and lacitol are used to treat what specific condition? Mechanism of Action?

Answer 37

* hepatic encephalopathy * Mechanism of Action * ingested proteins will be converted to ammonia * with normal liver function * ammonia is converted to gluatmine, which is excreted in the urine * patients with cirrhosis * cannot convert ammonia to glutamine * ammonia levels increase in circulation * diffuses into central nervous system * causes hepatic encephalopathy * lactulose or lacitol can be metabolized by bacteria to produce an acidic pH * in this acidic pH, ammonia is converted to amonium * it can also draw ammonia from circulation into the intestine * decreasing the toxicity to the central nervous system

Question 38

What are examples of stimulant laxatives? Mechanism of Action? Clinical uses? Adverse effects?

Answer 38

* Examples * anthraquinone derivatives * senna, aloe, cascara * diphenylmethane derivatives * bisacodyl * Mechanism of Action * stimulate smooth muscle contraction * increase secretion * Clinical uses * treat acute and chronic constipation * diphenymethane derivatives + PEG: colic cleansing * Adverse effects * severe abdominal pain * water and electrolyte loss * anthraquinone derivatives * melanosis coli (brown pigment in coli)

Question 39

What are the opioid receptor antagonist drugs? Mechanism of action? Adverse effects? Contraindications?

Answer 39

* drugs * methylnaltrexons (Relistor) * alvimopan (Entereg) * naloxegol (movantik * nademedine (symproid) * Mechanism of Action * block neuroreceptors in the GI tract * therefore increase activity of GI smooth muscle * Adverse effects * mainly GI related * abdominla pain * nausea * flatulence * vomiting * diarrhea * contraindications * GI obstruction

Question 40

Opoid receptor antagonists in treating opioid-induced constipation

Answer 40

Question 41

What are the FDA approved drugs used to treat opioid-induced constipation

Answer 41

* Opioid receptor antagonists * methylnaltrexone * naldemedine * naloxegol * Chloride channel activator * lubiprostone

Question 42

What is the 5-HT₄ receptor agonist? Mechanism of Action? Clinical use? Adverse effects? Contraindications?

Answer 42

* Prucalopride (resotrans) * Mechanism of Action * activate seratonin receptors * increase the release of ACh release * leads to GI motility * Clinical use * chronic functional constipation in adults who fail to respond to at least two other laxatives * Adverse Effects * headache, abdominal pain, nausea, and diarrhea * Contraindications * previous hypersensitivity reaction to it * intestinal perforation or obstruction dueto a gut wall disorder * obstructive ileus * severe inflammatory intestinal disease (ie. Chrohn's disease)

Question 43

What is the most common use of polyethylene glycol electrolyte solution (1~4L): Mechanism of Action? Active components?

Answer 43

* Clinical use (safe for all patients b/c does not cause significant fluid shift) * bowel preparation * small dose (miralax): treat or prevent occasional chronic constipation * Active components * polyethylene glycol (PEG3350) balanced with sodium and potassium salts * Mechanism of Action * draw water into intestine adn prevent water absorption, thus increase fecal fluid, and stimulate colonic peristalsis

Question 44

What is the clinical use of sodium picosulfate-based preparation (320ml)? Types? contents?

Answer 44

* used for bowel preparation * Powder * Prepopik * solution * Clenpiq * Contains * sodium picosulfate: stimulant laxative * magnesium oxid adn anhydrous citric acid: form magnesium citrate, and osmotic laxative