Pharm 2

Question 1

Irritable Bowel Syndrome (IBS)

Answer 1

• Very common problem
  
  • accounts for 3% of doctor visits
• Can’t make up its mind:
  
  • associated with constipation
    
    • IBS-C
  • associated with diarrhea
    
    • IBC-D
  • Associated with both:
    
    • alternating courses
    • complicates treatment

Question 2

IBS is characterized by:

Answer 2

• Abdominal pain
• Disordered bowel habits
  
  • constipation or diarrhea
• Often relieved by defecation
  
  • implicating colonic involvement

Question 3

IBS is treated with

Answer 3

• Changes in diet
• Drugs

Question 4

Serotonin Signaling for IBS-C

Answer 4

• 5HT₄ and 5-HT₁ Receptors
  
  • intrinsic serotonin signaling
    
    • activation=contraction and secretion
    • selective 5-HT₄ agonists are no longer available
      
      • tegaserod
    • Nonselective 5HT4 agonist=metaclopramide=only one readily available
• 5HT3 receptors:
  
  • extrinsic signaling via visceral afferents
    
    • ​responsible for GI pain and reflex contraction

Question 5

Linaclotide: uses

Answer 5

• used for:
  
  • IBS-C and CIC
    
    • CIC=chronic idiopathic consitaption
      
      • Constipation feels like bricks piling up
      • Belly pain and constipation feel like a giant knot
  • IBS-C

Question 6

Linaclotide: General info

Answer 6

• Peptide, 14 amino acids
• PO capsule administration
• Contraindicated in children <6 y.o.
  
  • young mice: 1-3 weeks old were very sensitive
    
    • dehydration caused by diarrhea=death
  • Not yet elvaluated for 6-17 y.o.
• Most common Side effect=Diarrhea
• Guanylate cyclase agonist increases cGMP
• Decreases pain transmission
• Stimulates secretion of intestinal fluid
• accelerates GI transit

Question 7

Linaclotide Mechanism in IBS-C

Answer 7

• Guanyl Cyclase Agonist
  
  • Increases [cGMP] in intestinal epithelial cells
  • cGMP activates chloride channels
  • Intestinal chloride attracts sodium
    
    • creates osmotic gradient
  • Water enters intestine
• cGMP also inhibits extrinsic pain signaling

Question 8

IBS-D: 5HT3 antagonists

Answer 8

• Alosetron
  
  • FDA approved IBS-D
    
    • indication: only women
    • Phase II trials:
      
      • significant efficacy in women not men
  • High Affinity Ligand
    
    • long duration of action
  • Adverse events limit usefulness
    
    • serious constipation may occur
    • fatal ischemic colitis has occured
• Ondansetron, granisetron, dolasetron
  
  • are under investigation

Question 9

IBS-D: Mixed Opioid Agonists/Antagonist

Answer 9

• Eluxadoline
  
  • u- and k-opioid agonist, S-antagonists
    
    • mu opioid receptor:
      
      • reduces pain, gastric propulsion
    • Delta opiod receptor
      
      • restores G-protein signaling
      • removes mu agonist-related desensitization

Question 10

IBS-D: Eluxadoline mechanism

Answer 10

• initial u agonist therappy
  
  • u opioid receptor signals G-proteins
  • produces analgesic effect
• Chronic u agonist therapy=Putative mechanism
  
  • u/S heterodimer signal via B-arrestin
    
    • instead of G-protein
• Eluxadoline binds both u and S receptors
  
  • restores G-protein signaling and analgesic activyt

Question 11

IBS-D: Eluxadoline DDI

Answer 11

• other constipating agents
  
  • other opiods
  • -setrons
  • anticholinergics
• OAT inhibitors
  
  • involved in eluxadoline elimination
  • -statins, promote rhabdomyolysis
  • rifampin
  • cyclosporine
  • gemfibrozil

Question 12

IBS-D: Eluxadoline side effects

Answer 12

• Constipation, N&V
• non-serious side effect
• low disconinuation rates
• 5 cases of mild pancreatitis

Question 13

IBS-D: Rifaximin

Answer 13

• FDA approved in 2015
  
  • Tx of Travelers diarrhea and hepatic encephalopathy
• Targets E. Coli
• Reduces bloating, pain

Question 14

IBS-D: Rifaximin Side Effects

Answer 14

• WELL TOLERATED
• N/V
• Constipation
• Bloating
• Stomach pain

Question 15

IBS-D: Anticholinergics

Answer 15

• aka antispasmodics
• -mine
• Dicyclomine and hyoscyamine
  
  • not used for IBS-D anymore
    
    • used for severe spasms
  • anti-muscarinic side effects limit usefulness

Question 16

Miscellaneous GI Drugs

Answer 16

• Pancreatic enzyme supplements
• Bile acid for gallstones
• Drugs for variceal hemorrhage

Question 17

Pancreatic Enzyme Supplements

Answer 17

• Pancreatin & Pertzye
• For pancreatic insufficiency
  
  • Cystic Fibrosis
  • Chronic Pancreatitis
  • Pancreatic resection
• Must be formulated to avoid enteric exposure
  
  • delayed release
  • enteric coating
• Well tolerated
  
  • replacing endogenous enzymes
    
    • amylase
    • liipase
    • protease

Question 18

Bile Acid Theray

Answer 18

• For Gallstones
• Ursodiol
  
  • naturally occuring BA make up <5% in humans
    
    • more common in bears
  • Long term dosing increases to 30-50% of circulating pool
  • Reduces cholesterol secretion
    
    • promotes dissolution of cholesterol gallstones
  • Safe

Question 19

Gallstones consist of

Answer 19

Cholesterol

bilirubin

calcium carbonate

Question 20

Bile Acid Therapy: Ursodiol Pharmacodynamics

Answer 20

• Dosage: 5-25 mg/kg/day
• 12-24 m onths of Tx resulted in disolution of small stones in 50% of patients
• Few adverse events
  
  • rare salt laxative effect=diarrhea

Question 21

Bile Acid Therapy: Ursodiol Other uses

Answer 21

• Prophylaxis to prevent stone formation related to rapid weight loss
• improved liver function in biliary cirrhosis

Question 22

Variceal Hemorrhage

Answer 22

• Serious condition-20% mortality
• Bleeding from submucosal veins in esophagus and/or stomach
• Related to liver cirrhosis
  
  • fibrosis increases :
    
    • portal BP
    • intrahepatic vasoconstriction

Question 23

Variceal Hemorrhage: Drugs

Answer 23

• Somatostatin, octreotide (synthetic somatostatin)
• Vasopressin
• Non-selective B-Blockers

Question 24

Variceal Hemorrhage: Stomatostatin, Octreotide (synthetic somatostatin)

Answer 24

• aka growth hormone inhibiting hormone
• also antidiarrheal
• reduce:
  
  • release of secondary hormoones
  • protal blood flow and variceal pressure
• AEs related to inhibition of insulin/glucagon release
  
  • caution with diabetics

Question 25

Variceal Hemorrhage: Vasopressin

Answer 25

• Hypothalamic peptide hormone
• Potent arterial vasoconstrictor
• Reduces portal pressure and splanchic perfusion
• Adverse Events=significant
  
  • Serious HTN, MI, Mesenteric infarction
• important in acute bowel bleeding

Question 26

Variceal Hemorrhage: Non-selective B-blockers

Answer 26

• Propanolol (hydrochloride)
• decreased venous inflow–>reduces portal pressure
• B1 receptor antagonist
  
  • decreases CO
• B2 receptor antagonist
  
  • produces spanchic vasconstriction
• Good for prophylaxis
• Dose: 80-160 mg BID
• Common adverse events
  
  • hypotension
  • bradycardia
  • fatigue