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Drug Action II > Block 1: GERD and PUD Pharm > Flashcards

Block 1: GERD and PUD Pharm Flashcards

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1
Q

What is the cause of GERD?

A

Retrograde reflux of gastric content (acid-pepsin) coupled with imcompetent esophagi-gastric junction → esophageal mucosa erosion

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2
Q

What are the mechanisms of esophago-gastric junction incompetence?

A
  1. Abnormal lower esophageal sphincter (LES) relaxations caused by gastric distention
  2. LES hypotension
  3. Anatomic distortion of the esophagi-gastric junction → hiatus hernia
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3
Q

What are exacerbating factors for reflux?

A
  1. Abdominal obesity
  2. Pregnancy
  3. Defective clearance of reflux from the esophagus
  4. Impaired esophageal mucosal defense
  5. Disruption of esophageal peristalsis
  6. Delayed gastric emptying
  7. Gastric hypersecretory states
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4
Q

What mechansims do we target to treat GERD?

A
  1. Neutralizing and suppressing gastric acid to treat GERD
  2. Enhancing esophago-gastric peristalsis
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5
Q

Why do we neutralize and suppress gastric acid to treat GERD?

A

Most sx stem from injury to esophageal epithelium with acid-pepsin content, however, gastric acid is not the only cause.

Pepsin, bile, and pancreatic enzymes can also cause damage

Harmful properties are more prominent in an acidic environment and require acid for activation

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6
Q

How do we neutralize acid for GERD?

A

Acid reducing agents: Antacids, H2-blockers, PPIs

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7
Q

Why do we enhance esophago-gastric peristalsis to treat GERD?

A

Increasing LES tone improves reflux clearance and gastric emptying

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8
Q

How do enhance esophago-gastric peristalsis?

A

Prokinetic drugs/motility enhancers: Bethanechol (Cholinomimetic), Metoclopramide (D2 + 5-HT3 receptors antagonist)]

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9
Q

What is PUD?

A

Chronic and recurrence disease that compases GU and DU

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10
Q

What protects the stomach from ulcers?

A

Mucosal defense

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11
Q

What is DU?

A

Occurs in the duodenum in which patients produces more acid mainly at night (basal secretion)

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12
Q

What is GU?

A

Occurs in the stomach in which patient produce more or diminished acid with a weakened mucosal defence and reduced bicarb production

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13
Q

PUD are an imbalance between what 2 factors?

A
  1. Mucosal defensive
  2. Damaging

Damaging factors such as acidity, pepsin secretion, infection, NSAIDs outweigh defensive mechanism (bicarb, mucus, epithelial regeneration, PG, mucosal BF)

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14
Q

What factors cause PUD? How do you fix the imbalances?

A

1. Hypersecretion of acid (pepsin): Acid Reducing Agents → [Antacids, H2-Blockers, Proton-pump inhibitors (PPIs)]
2. GI infection by H. pylori: Antibiotics → [Amoxicillin, Clarithromycin, Metronidazole]
3. Chronic use of ulcerogenic drugs: Gastric mucus/Cytoprotective agents → Prostaglandin analogue [Misoprostol], Sucralfate

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15
Q

Describe how gastric acid gets secreted?

A
  1. Input from Postganglionic cholinergic fibers and gastrin on the CCK2 on the parietal cells -> Gq-PLC-IP3 -> Ca2+ dependent pathway -> K,H ATPase
  2. Input from postganglionic cholinergic fibers to ENS -> ECL cel that releases histamine to H2 receptors -> Gs-cAMP-PKA pathway -> K,H ATPase
  3. Neural input from vagus nerve on M1 the superficial epithelial cell (gut) -> mucus and bicarb secretion
Enterochromaffin-like (ECL) cell, Enteric nervous system (ENS), Cholecystokinin receptor 2 (CCK2)
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16
Q

Identify where factors and pharm target in gastric secretion?

A
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17
Q

What histamine receptors are found in the gut?

A

H2

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18
Q

What are the components of mucus?

A

Consists of water (95%), phospholipids, and glycoproteins (mucin)

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19
Q

What cell contains a mucus-bicarb phosphilipid layer?

A

Mucus and bicarbonate are secreted by gastroduodenal surface epithelial cells.

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20
Q

What are the precursors of prostaglandins?

A

From phospholipid-arachidonic acid that is formed by phopholipase A2

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21
Q

What PGs strains are the gastrium?

A

PGI1 and PGE2

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22
Q

What is the function of gastric PG?

A
  1. Regulate the release of mucosal bicarb and mucus, inhibit parietal cell secretion, maintain mucosal bloof flow
  2. Directly inhibit gastric acid secretion by parietal cells
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23
Q

What is the most potent suppresor of Acid-reducing agent? Where does it target?

A

PPIs block the final step in acid production

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24
Q

What the clinically used PPIs?

A
  1. Prilosec (Omeprazole) and S-isomer, Nexium (Esomeprazole)
  2. Prevacid (Lansoprazole) & its R-enantiomer, Dexilant (Dexlansoprazole)
  3. Aciphex (Rabeprazole)
  4. Protonix (Pantoprazole)
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25
What is the MOA for PPIs?
1. Prodrug diffuses into parietal cells and accumulates in acidic secretory canaliculi 2. Activated by acid-catalyzed formation of a tetracyclic sulfenamide -> drug becomes trapped by ionization 3. Activated form then binds covalently with sulfhydryl groups of the H+/K+-ATPase, irreversibly inactivating the pump
26
How should you administer PPIs?
1. Several doses are required for max suppression because pumps are not active simultaneously 2. Pumps increase after fasting so PPIs should be given before meals 3. Drugs that inhibit acid secretion decrease PPI effectiveness
27
What PPIs are given are enteric coated gelatin capsules?
1. Prilosec (Omeprazole) 2. Dexilant (Dexlansoprazole) 3. Nexium (Esomeprazole) 4. Prevacid (Lansoprazole)
28
What PPIs are given as enteric-coated granules powder for suspension?
Prevacid (Lansoprazole)
29
What PPIs are given as an enteric coated tablet?
1. Prilosec (Omeprazole) 2. Protonix (Pantoprazole) 3. Aciphex (Rabeprazole)
30
What PPI is given with bicarb? Dosage form?
Omeprazole as a capsule for oral suspension
31
ADME of PPIs?
Rapidly absorbed Highly protein bound Extensively metabolized by CYPs (CYP2C19 and 3A4) Low F (<90%)
32
What is the dosage adjustment of PPIs?
**Chronic renal failure** -> does not cause drug accumulation with once-a-day dosing **Hepatic disease** -> reduces clearances of Nexium (esomeprazole) & Prevacid (lansoprazole) **Severe hepatic disease require dose reduction**
33
What are the indications of PPIs?
**GERD:** Non-erosive and erusive reflux diseases, esophageal complications of reflux disease **PUDs (both DU and GU):** H.pylori-associated ulcers and NSAID-associated ulcers
34
How does PPIs target H.pylori?
1. Direct antimicrobial properteies are minor 2. Increase intragastric pH 3. Lower MIC of antibiotics against H pylori
35
What is the "triple therapy" for H.pylori?
1. Any PPIs 2. Clarithromycin 3. Amoxicillin or metronidazole
36
What PPIs are indicated for NSAID-associated ulcers?
1. Prevacid (Lansoprazole) 2. Nexium (Esomeprazole)
37
What are the types of ADRs of PPIs?
**Generally, extremely safe** **Reduction in PO B12 absorption** because it requires an acid environment **Respiratory and enteric infections** due to lack of acid that prevent colonization and infection **Hypergastremia** → hyperplasia of ECL and parietal cells → transient rebound acid hypersecretion
38
What are the DDIs of that prevent PPI effectiveness?
Decreased gastric acid may alter absorption of those drugs which require acidic environment for absorption Ketoconazole, itraconazole, digoxin, atazanavir, ampicillin
39
How are PPIs metabolized? How does it afftect it ADME?
**CYP2C19 & CYP3A4** 1. Short half-lives -> lower ADR 2. Clopidogrel requires CYP2C19 for activation
40
What are the approved H2RAs? Dosage forms?
1. Tagamet (Cimetidine) 2. Zantac (Ranitidine) 3. Pepcid (Famotidine) 4. Axid (Nizatidine) PO, Nizatinidine is also available as IV or IM
41
Rank the potency of H2RAs?
Famotidine >>>> Ranitidine = Nizatidine >> Cimetidine
42
What is more potent, H2RA or PPIs?
PPIs
43
What is the MOA of H2RAs?
1. Reduce acid secretion stimulated by histamine release from ECL cell and by gastrin and Ach 2. Inhibit basal acid secretion (useful for DU)
44
Describe the ADME of H2RAs?
**Absorbed** rapidly in the intestine and undergoes first pass metabolism (50% F) -> Cimetidine, Zantac (ranitidine), Pepcid (famotidine) **Duration of action** depends on the dose given **Poorly bound** to plasma proteins **Eliminated** renally (glomerular filtration & renal tubular secretion) with a small fraction of hepatic metabolism clearance
45
How should H2RAs be dosed?
**Moderate-severe renal insufficiency:** Dose reduction required **Hepatic insufficiancy:** No adjustment required
46
What is H2RA has little first-pass metabolism?
Nizatidine
47
What are the minor ADRs of H2RAs?
1. Diarrhea 2. HA 3. Drowsiness 4. Fatigue 5. Muscular pain 6. Constipation
48
What are the ADRs associated with long-term cimetidine use? Why?
**Men:** Gynecomastia or impotence **Women:** Galactorrhea 1. Inhibits binding of dihydrotestosterone to androgen receptors 2. Inhibtis metabolism of estradiol and increases prolactin
49
What H2RAs fetal toxic?
Can cross the placenta and secreted in breast milk. Showed no harm in fetus, but may in nursing infants
50
What are the downsides of using H2RAs chronically?
**Tolerance** may develop leading to **secondary hypergastrinemia** that stimulates more histamine release from ECL cells
51
What are the indications for H2RA?
GERD and PUD
52
What are the DDIs of H2RAs?
**Cimetidine inhibits CYP1A2, CYP2C9, CYP2D6, CYP3A4** interfering with a large number of drugs
53
What produces most of the PG?
Gastric mucosa
54
Why are PGE2 considered gastroprotective?
**Cytoprotective** 1. Increase mucin and bicarb secretion 2. Increase mucosal blood flow 3. Suppress acid
55
What are the PG analogs?
Cytotec (Misoprostol) - synthetic analog of PGE1
56
What is the MOA of Cytotec?
Misoprostol binds to EP3 receptor on parietal cells → stimulates Gi pathway → decreasing icAMP → decreasing gastric secretion Inhibition of gastric acid secretion is dose-dependent
57
Describe the ADME of Misoprostol?
**Rapidly absorbed** after oral administration **Metabolized** to free acid **Short half-life** therefore T-QID Excreted in **urine** → NO reduction in renal insufficiency
58
What are the DDIs of Cytotec?
Food and antacids → ↓ absorption rate → delayed effect and ↓ plasma concentration of the active metabolite
59
What are the ADRs of Misoprostol?
1. Diarrhea (dose-related) w/ or w/o abdominal pain and cramps 2. Exacerbations of IBD → CI 3. ↑ uterine contractility → CI in pregnancy
60
Indications of Cytotec?
1. NSAID-induced mucosal injury 2. Rarely used
61
What is Sucralfate?
Carafate is a sucrose salt complexed as a sulfated aluminum hydroxide
62
What is the MOA of Carafate?
1. Acidic environment separates sucrose salt from aluminum → undergoes crosslinking to produce a viscous, sticky polymer that adheres to epithelial and ulcers for 6hr 2. Negatively charged sucrose sulfate binds to positively charged proteins in the base of ulcers or erosion → forming a physical barrier 3. Stimulates mucosal prostaglandin and bicarbonate secretion.
63
What contributes to mucosal erosion and ulcerations?
Pepsin mediated hydrolysis of mucosal proteins
64
What are the indications of carafate?
Prevention of stress-related bleeding to prevent the nosocomial pneumonia in critically ill patients by acid inhibitory therapies
65
What are the ADRs of Carafate? CI
No systemic ADR due to limited absorption Constipation from slight aluminum salt absorption Not used long term in patients with renal insufficiency → due to aluminum.
66
What are the DDIs of sucralfate?
May bind to other meds impairing its absorption Phenytoin, digoxin, cimetidine, ketoconazole, fluoroquinolone antibiotics
67
What are the indications of antacids?
Mainstay for treatment of acid-peptic disorders until H2RAs and PPIs Heartburn, dyspepsia
68
What is the MOA of antacids?
1. Weak base that ↓ intragastric acidity, neutralizing HCl forming a salt and water 2. Acid-neutralization capacity (ANC) of antacids → highly variable
69
What are examples of antacids?
1. Sodium bicarb (Alka Seltzer) 2. Calcium carbonate (Tums) 3. Antacids containing Mg(OH)2 or Al(OH)3
70
How does Sodium bicarb work as an antacids? What products does is produce?
Reacts with HCl → produce CO2 and NaCl: **CO2** → gastric distention and belching **Unreacted alkali** → absorbed → metabolic alkalosis in patients with high doses or renal insufficiency **NaCl** → Exacerbate fluid retention in patients with HF and renal insufficiency
71
How does calcium carbonate differ from Alka Seltzer?
1. Less soluble and reacts more slowly with HCl 2. Forms CO2 and CaCl2
72
How does Magnesium and aluminum differ from calcium and sodium antacids?
1. No gas, belching, metabolic alkalosis 2. Unabsorbed Mg2+ salts → Osmotic diarrhea & Al3+ salts → Constipation 3. Absorbed and excreted by the kidneys (not for renal insufficiency)
73
What are the DDIs of antacids?
1. Bind to other drugs and reduce its absorption 2. ↑ intragastric pH → altering dissolution or solubility of drugs
74
What are the Prokinetic / Motility Enhancing Drugs?
Bethanechol (Cholinomimetic agents) Reglan (Metoclopramide)
75
What is the MOA of Bethanechol (Cholinomimetic agents)? Indication?
Stimulate muscarinic M3 receptors on muscle cells and at myenteric plexus synapses GERD and Gastroparesis, but rarely used
76
What is the MOA of Reglan (Metoclopramide)? Indication?
D2-receptor + 5-HT3 receptor antagonist 1. ↑ esophageal peristaltic amplitude, ↑ lower esophageal sphincter pressure, ↑ gastric emptying → Treat GERD 2. Blocks dopamine D2 receptors in chemoreceptor trigger zone (CTZ) of the medulla (area postrema → Antinausea and Antiemetic action
77
GIT activity with dopamine receptors?
Inhibits cholinergic smooth muscle stimulation

Drug Action II (28 decks)

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