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Flashcards in Pharm 2 Deck (26)
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1

Irritable Bowel Syndrome (IBS)

  • 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

2

IBS is characterized by:

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

3

IBS is treated with

  • Changes in diet
  • Drugs

4

Serotonin Signaling for IBS-C

  • 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 

5

Linaclotide: uses

  • 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

6

Linaclotide: General info

  • 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

7

Linaclotide Mechanism in IBS-C

  • 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

8

IBS-D: 5HT3 antagonists

  • 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

9

IBS-D: Mixed Opioid Agonists/Antagonist

  • 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

10

IBS-D: Eluxadoline mechanism

  • 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 

11

IBS-D: Eluxadoline DDI

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

12

IBS-D: Eluxadoline side effects

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

13

IBS-D: Rifaximin

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

14

IBS-D: Rifaximin Side Effects

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

15

IBS-D: Anticholinergics

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

16

Miscellaneous GI Drugs

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

17

Pancreatic Enzyme Supplements

  • 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

18

Bile Acid Theray

  • 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

19

Gallstones consist of

Cholesterol

bilirubin

calcium carbonate

20

Bile Acid Therapy: Ursodiol Pharmacodynamics

  • 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

21

Bile Acid Therapy: Ursodiol Other uses

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

22

Variceal Hemorrhage

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

23

Variceal Hemorrhage: Drugs

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

24

Variceal Hemorrhage: Stomatostatin, Octreotide (synthetic somatostatin)

  • 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 

25

Variceal Hemorrhage: Vasopressin

  • 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

26

Variceal Hemorrhage: Non-selective B-blockers

  • 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