Gastrointestinal Pharmacology III

Question 1

What strategies are utilized by antidiarrheals?

Answer 1

• thicken stool and reduce intestinal smooth muscle contraction
• treat symptoms
• should be avoided in infection-caused acute diarrhea
  
  • can mask symptoms and delay the treatment of infection

Question 2

What opioids are used as antidiarrheals?

mechanism of action?

clinical uses?

Adverse effects?

drug-drug interactions?

Answer 2

• drugs
  
  • Loperamide (diamode)
  • diphenoxylate
• mechanism of action
  
  • stimulate opiate receptors (micro and delta) on enteric neurons and inhibiting presynaptic cholinergic action
    
    • suppress smooth muscle contraction
    • enhance mucosal absorption
  • decrease gastrocolic reflex
• metabolism
  
  • substrate of CYP2C8, CYP3A4, and pg-protein
• Clinical uses
  
  • treate travelers diarrhea and chronic diarrhea
    
    • Loperamide: nonprescription drug
      
      • High dose: arrhythmia
    • Diphenoxylate: prescription drug
      
      • higher dose: central nervous effects
      • long-term use: dependence
      • commercial preparations: combined with atropine (lomotil) to prevent overdose
• Adverse effects
  
  • constipation and dry mouth (b/c decrease effects ACh)
• Drug-drug interactions
  
  • loperamide with inhibitors of CYP3A4, 2C8, and pg-protein
    
    • some patients will take high dose of loperamide to achieve euphoria & take inhibitors of CYP3A4, 2C8, and pg-protein, purposefully reducing the metabolism & achieve euphoric effects
      
      • will results in arrhythmia

Question 3

What type of drugs are Kaolin & Pectin?

Mechanism of Action?

Clinical use?

additional considerations?

Answer 3

• Adsorbents
  
  • Kaolin: hydrated magnesium aluminum silicate
  • Pectin: indigestible carbohydrates
• Mechanism of Action
  
  • adsorbents of bacteria, toxin, and fluid
• Clinical use
  
  • often administered to kids to treat acute diarrhea
• Additional considerations
  
  • should be taken within 2 hours of other drugs

Question 4

What type of drug is bismuth subsalicylate?

Mechanism of Action?

Use?

Answer 4

• Adsorbents
• mechanism of action: not clear
  
  • salicylate: reduce chloride secretion
  • bismuth: binds to bacteria and enterotoxin
• clinical use
  
  • prevent and treat traveler’s diarrhea
  • short term

Question 5

What type of drug is bile salt-binding resins

Mechanism of Action?

Use?

Answer 5

• Adsorbent
  
  • colestipol: colestid
  • cholestyramine: loCHOLEST
• Mechanism of Action
  
  • bind to bile
• Clinical use
  
  • reat bile malabsorption-caused diarrhea

Question 6

What is the synthetic somatostatin drug?

Mechanism of Action?

Adminstration?

Answer 6

• Octreotide (sandostatin)
• Mechanism of Action
  
  • Inhibit secretion of 5-HT, gastrin, glucagon, growth hormone, insulin, secretin, pancreatic polypeptide, VIP, cholecytokinin, adn pituitary hormones
  • reduce fluid secretion
  • slow GI motility and inhibits gallbladder contraction
• Route: IV, subQ, or IM

Question 7

Clinical uses of octreotide?

Answer 7

• Synthetic somatostatin
• Clinical uses
  
  • treat secretory diarrhea caused by endocrine tumor (carcinoid, VIPoma)
  • high dose (100-250 micrograms): treat diarrhea caused by vagotomy or dumping dyndrome, short bowel syndrom or AIDS
  • treat pancretic fistula
  • treat pituitary tumors
• Adverse effects
  
  • lipid-soluble vitamin deficiency
  • gallstones
  • nausea, abdominal pain, flatulence, and diarrhea
  • hyper- and hypo-glycemia
  • hypothyroidism, bradycardia

Question 8

What is the Tryptophan hydroxylase inhibitor drug?

Mechanism of Action

Clinical use?

Adverse effects?

Answer 8

• Drug: telotristat ethyl (Xermelo)
• Mechanism of Action
  
  • Inhibit the enzyme that converts L-tryptophan to 5-hydroxy-tryptophan (tryptophan hydroxylase)
    
    • leads to a subsequent decrease in seratonin
• Clinical use
  
  • combined witha somatostatin analogue
    
    • carcinoid syndrome diarrhea that is not adequately controlled by a somatostatin analogue alone
• Adverse effects
  
  • most common
    
    • nausea, headache, depression, flatulence, decreased appetite, peripheral edema, fever, adn liver enzyme elvations
  • large dose: constipation

Question 9

What is the name of the chloride channel inhibitor?

Mechanism of action?

clinical uses?

Adverse effects?

Answer 9

• crofelemer
• Mechanism of Action
  
  • inhibit the secretion of chloride ions into the intestine
• Clinical uses
  
  • antiretroviral-induced diarrhea
  • provide symptom relief
• Adverse effects
  
  • upper respiratory infection
  • flatulence
  • and increased bilirubin

Question 10

Identify the location of receptors for antemetic drugs

• Chemoreceptor trigger zone
• CNS
• Vestibular system
• Pharynx
• Vagal adn spinal afferent nerves in GI

Answer 10

• Chemoreceptor trigger zone
  
  • D₂
  • NK₁
  • 5-HT₃
• CNS
  
  • H₁
  • M₁
  • NK₁
  • 5-HT₃
• Vestibular system
  
  • M₁
  • H₁
• Pharynx
  
  • M₁
• Vagal and spinal afferent nerves in GI
  
  • 5-HT₃

Question 11

What drug classes are used to prevent and treat nausea and vomiting?

Answer 11

• antagonists for
  
  • NK₁
  • 5-HT₃
  • D₂
  • M₁
  • H₁
• others
  
  • benzodiazepines
  • CB₁ agonists

Question 12

What are the causes of emesis?

Answer 12

• Chemotherapy
  
  • Acute (24 hrs, 5-HT₃)
  • delayed (48 hrs to several days, neurokinin)
  • anticipatory
• motion sickness
• others
  
  • non-chemotherapy drug-induced emesis
  • infections
  • PONV (postoperative nausea and vomiting)
  • Radiation
  • Pregnancy
  • Disease

Question 13

What are the 5-HT₃ antagonists?

mechanism of action?

clinical uses?

Adverse effects?

Answer 13

• Drugs (-setrond)
  
  • ondabsetron
  • dolasetron
  • grabisetron
  • palonosetron
• Mechanism of action
  
  • blocking both central and perioheral 5-HT₃ receptors
• Clinical uses
  
  • 5-HT₃ antagonist + dexamethasone (corticosteroid)
    
    • the most effective therapy for prevention of chemotherapy-induced acute severe vomiting
  • prevent and treat acute emesis caused by radiation and postoperation
• Adverse effects
  
  • headache
  • constipation
  • dizziness
  • prolonged QT intercal (antibiotics?)

Question 14

What are the NK₁-antagonists?

mechanism of action?

clinical uses?

Adverse effects?

Answer 14

• drugs (-pitants)
  
  • Aprepitant (Emend)
  • fosaprepitant
  • rolapitant (Varubi)
• MOA
  
  • blocking central NK₁ receptors
• Clinical uses
  
  • NK₁ antagonists + dexamethasome
    
    • prevent delayed emesis caused by chemotherapy
  • NK₁ antagonists + 5-HT₃ antagonists + dexamethasone
    
    • prevent acute adn delayed emesis caused by chemotherapy
• Adverse Effects
  
  • all drugs are the substrates of CYP3A4, interact wth CYP3A4 inducers and inhibitors
  • Rolapitant: also a substrate of p-gp, interacts with p-gp inhibitors adn inducers
  • Cmmon adverse effects: hiccups, decreased appetite, and dizziness
    
    • Rolapitant also causes neutropenia and allergic reactions

Question 15

What are the benzodiazepines?

Mechanisms of Action?

Clinical use?

Answer 15

• Drugs
  
  • Lorazepam (Ativan)
  • diazepam
• Mechanisms of Action
  
  • enhance GABA’s effect on chloride ion conductance leading to sedation, hypnosis, anesthesia, etc.
• Clnical uses
  
  • prevent anticipatory nausea and vomiting prior to the initiation of chemotherapy

Question 16

What are the synthetic cannabinoids?

Mechanism of action?

clinical use?

Adverse effects?

Answer 16

• Drugs
  
  • Dronabinol (marinol schedule III)
  • Nabilone (cesamet: schedule II)
• Mechanism of action
  
  • stimulate CB1 adn block 5-HT₃ receptor in vomiting center
• Clinical uses
  
  • chemotherapy-induced emesis
    
    • reserved for patients who are intolerant or refractory to first-line therapy
    • combined with phenothiazines
      
      • provides synergistic antiemetic action
• Adverse effects
  
  • cannabinoids-like effects

Question 17

What drugs are used to treat motion sickness?

Answer 17

• M₁ receptor antagonists
  
  • scopolamine transdermal patch
  • one of the best agents for prevention of motion sickness
• H₁ receptor antagonists
  
  • MOAs and uses
    
    • meclizine (antivert): block H₁ receptors, motion sickness and vertigo
    • diphenhydramine and doxylamine: block both H₁ and M₁ receptors

Question 18

What drugs are used to treat morning sickness?

Answer 18

• doxylamine + pyridoxine:
  
  • who dont’ resond to conservative management
• diphenhydramine + other antiemetics
  
  • chemotherapy-induced vomiting

Question 19

What are the D₂ dopamine receptors antagonist antiemetic drugs?

Mecanisms of action?

Clinical uses?

Adverse effects?

Answer 19

• Drugs
  
  • Antipsychotics
    
    • phenothiazine (prochlorperazine)
    • butyrophenonones (droperidol)
  • substituted benzamides
    
    • metoclopramide
• Mechanism of Action
  
  • phenothiazine
    
    • block central D, M and H₁ receptors
  • Butyrophenones and substituted benzamides
    
    • block central D₂ receptors
• Clinical uses
  
  • Phenotiazines: general emesis
  • Butyrophenones: postoperative and anticipatory nausea and vomiting
  • Substituted benzamides (high dose): treat radiation, chemotherapy, and infection-induced nausea and vomiting
• Adverse effects
  
  • apply to all: extrapyramidal effects
  • droperidol and metoclopramide: prolonged QT interval

Question 20

What drugs are used to treat diarrhea-predominant irritable bowel syndrome?

Answer 20

• Opioid receptor agonist
  
  • loperamide
  • eluxadoline
    
    • micro -opioid receptor agonist and delta-opioid receptor antagonist
      
      • micro receptor stimulation: decrease muscle contractilty, inhibit water and electrolyte seretion
      • delta receptor blocking: reduce the risk of constipation and pain
      • contraindication: patients without a gallbladder — serous pancreatitis
      • a lof ot drug-drug interactions
• bile acid sequestrants
• 5-HT₃ receptor antagonists (Alosetron)
  
  • approved for women with severe IBS with diarrhea predominant
• Antibiotic: rifamixin
  
  • MOA
    
    • alter gut microbiota and may reduce mucosal inflammation adn visceral hypersensitivity
  • use
    
    • refractory IBD, relieve bloating, abdominal pain, stool frequency
  • drug interaction
    
    • interact with inhibitors or inducers of p-gp

Question 21

What drugs are used to treat constipation-predominant IBS?

Answer 21

• Fiber-rich laxatives
• stool softeners
• osmotic laxatives
• chloide channer activator
  
  • lubiprostone, approved for women with IBS in whom constipation is predominant
• Guanylate cyclase type-C agonists (linaclotide, plecanatide)

Question 22

What are the guanylate cyclase type-C agonist drugs?

Mechanism of action?

Clinical uses?

Adverse effects?

Contraindication?

Answer 22

• Drugs
  
  • linaclotide
  • Plecanatide
• Mechanism of Action
  
  • can activate guanylcyclase-type C (GC-C) receptors
    
    • increasing the cGMP levels
      
      • increase levels of intestinal fluid
      • and decrease gastrointestinal transit time
        
        • increase frequency of bowel movement
  • increase extracellular cGMP levels
    
    • activity of pain-sensing nerves decreases
      
      • indestinal pain decreases
• Clinical uses
  
  • chronic idopathic constipation
  • IBS with constipation dominant
• Adverse effects
  
  • diarrhea, abdominal pain and distention, and flatulence
• Contraindication
  
  • patients <6
  • mechanical GI obstruction

Question 23

What is the partial neuronal 5-HT₄ agonist?

Mechanism of action?

Clinical uses?

Adverse efects?

Contraindications?

Answer 23

• tegaserod
• mechanism of action
  
  • activates 5-HT₄ receptors
    
    • activate seratonin receptors increase the release of ACh release
    • leads to GI motility
  • also activates 5-HT_1B and 5-HT_2A – coronary artery and intracranial artery spasm
• clinical uses
  
  • severe IBS-C in women younger than age 65 ith no history of CV ischeic diseases
• Adverse effects
  
  • headache, abdominal pain, diarrhea, serious cardiovascular events (MI, Stroke, angina)
• Contraindications
  
  • history of MI, stroke, TIA, or angina

Question 24

What drugs are used to abdominal pain?

Mehcniasm of action?

Adverse effects?

Contraindications?

Answer 24

• drugs
  
  • low dose of antidepressants
    
    • selective serotonin reuptake inhibitors (SSRI, fluoxetine)
    • tricyclic antidepressants (TCA, amitriptyline)
  • anticholinergics (antispasmodics) dicyclomine and hyoscyamine
• Mechanism of action
  
  • can increase endorphin release
  • decrease norepinephrine reuptake
  • decrease serotonin uptake
    
    • therefore inhibit pain pathways
• GI adverse effects
  
  • SSRI: diarrhea
  • TCA adn anticholinergics: constipation
• Contraindication
  
  • SSRI: diarrhea
  • TCA adn anticholinergics: constipation

Question 25

Answer 25

• Anticipatory nausea and vomiting
  
  • Lorazepam (benzodiazepine)

Question 26

Answer 26

• delayed nausea and vomiting (increased release NK₁)
  
  • acute is more associated w/ seratonin
• B - combinaiton of ondansetron, aprepitant and dexamethasone

Question 27

List the drugs used to treat peptic ulcer

Answer 27

1. H⁺/K⁺-ATPase inhibitors
2. H₂ antagonists
3. antacids
4. mucosal defenders
5. antibiotics (H. pylori infection)

Question 28

list the drugs used to treat IBD

Answer 28

• 5-ASAs
• oral corticosteroids
• immunomodulators
• biologis

Question 29

List the drugs that increase GI motility

Answer 29

• D₂ antagonists
• AChE inhibitor
• laxatives
  
  • bulk-forming
  • stool softener
  • lubricant
  • chloride channel activator
  • osmotic laxatives
  • stimulant laxatives
  • opioid receptor antagonists
  • 5-HT₄ receptor agonist

Question 30

list the drugs that decrease GI motility

Answer 30

• antidiarrheals
  
  • opiates
  • adsorbents
  • synthetic somatostatin
  • chloride channel inhibitor
• antiemetics
  
  • 5-HT₃, NK₁, M₁, D₂, and H₁ antagonists
  • benzodiazepines
  • synthetic cannabinoids

Question 31

List the drugs used to treat IBS

Answer 31

• Diarrheal
  
  • opioid receptor agonists
  • 5-HT₃ antagoinst
• constipation
  
  • laxatives
  • GC-C receptor agonist
  • 5-HT₄ agonist
• Pain
  
  • SSRI
  • TCA
  • anticholinergic agents