Pharm of Drugs in Upper GI Disease Flashcards by Bryn Longcroft-Harris

How is H+ secreted into the lumen of the stomach?

Via a H/K ATPase (H out, K in)

Constitutive activation via histamine release from enterochromaffin-like cells

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Prostaglandin E2

Mediates mucus and bicarb secretion from mucus cells

Via EP receptors

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2 general ways to treat acid-related disorders

Neutralize or reduce gastric levels of H+/ H pylori

Strengthen/enhance protective factors

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5 options for acid neutralizing/lowering drugs

3 main ones, 2 others

Antacids
Histamine H2 receptor antagonists
Proton pump inhibitors
Antimuscarinics
Gastrin receptor antagonists

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Antacids

3 examples and MOA

Al(OH)3, Mg(OH)2, CaCO3
Direct neutralization of already secreted stomach acid
Increased gastric pH
No receptor interaction (direct chemical interaction)

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Pharmacokinetics of antacids

Counter ions (Al, Ca, Mg) are poorly absorbed
They may chelate other drugs, affecting their absorption
Altered pH may affect drug absorption

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Indications for antacids

Heartburn/mild GERD

Dyspepsia

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Side effects from antacids

Carbonate based salts: belching (CO2 is produced)
Ca: hypercalcemia
Al: constipation, hypophosphatemia (impaired absorption)
Mg: diarrhea

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H2 receptor antagonists

Competitive, selective block of histamine H2 receptors
The -tidine drugs (ranitidine)
Reduced (but not eliminated) acid secretion
ACh and gastrin pathways in response to a meal are still active
Most effective in reduction of nocturnal acid secretion

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Pharmacokinetics in H2 receptor antagonists

Oral, intramuscular, and intravenous formulations
Bioavailability is 50%, need a twice daily administration (except nizatidine - oral, minimal 1st pass metabolism)
Renal elimination

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Indications for H2 receptor antagonists

GERD
Peptic ulcer disease
Dyspepsia
Prevention of bleeding from stress-related gastritis

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Some common and some rare side effects from H2 receptor antagonists

Common: diarrhea (or constipation), headache, drowsiness/fatigue, muscle pain
Rare: confusion/agitation, delirum/hallucinations, slurred speech

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Proton pump inhibitors

The -prazole drugs (ex: omeprazole)
Irreversible inactivation of proton pump common to ALL triggers of gastric acid secretion (inhibits the H/K ATPase)
Restoration of function requires new proton pump synthesis (takes 18-24 hours)
Relatively selective for parietal cell proton pumps

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Pharmacokinetics of PPIs

Parietal cell access requires systemic absorption (oral formulations require enteric coating)
Prodrug molecules activated by acid (best if taken within 30-60 mins of meal)
Drug interactions: altered pH (reduced absorption of some drugs), competition for certain cytochrom P450 enzymes

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Indications for a PPI

Gastric/duodenal ulcer (H pylori associated or NSAID induced)
GERD
Prevention of bleeding from stress-related gastritis
Gastric hypersecretory conditions

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Common side effects of PPIs

Generally well-tolerated
Nausea
Diarrhea (or constipation)
Abdominal pain
Flatulence

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Antimuscarinics

Work on food induced pathways
Ex: pirenzipine
Utile and effective, but side effects!

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Gastrin receptor antagonists

Ex: proglumide
Work on food induced pathways
Pathway inhibited at pH < 2.5 (won’t give you tangible benefits)
Blocks the CCK2/B receptor

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Treatment for H pylori

PPI and two antibiotics and 14 days (triple therapy)
Clarithromycin and amoxicillin or metronsazole
Or PPI alone for 6 weeks

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Misoprostol

Prostaglandin E1 analogue (emulates endogenous PGE2)

Direct effects on parietal cells (inhibitory) or mucus cells (stimulatory)

Pharmacokinetics of misoprostol

Short half-life
Frequent dosing
No impact on cytochrome P450

Indication for misoprostol

NSAID-induced ulcers

Contraindication of misoprostol

Pregnancy

Its a strong uterine stimulant so there is a huge uterine stimulant

Side effects from misoprostol

Diarrhea
Abdominal cramping
Uterine contraction
All because prostaglandin E1/E2 to stimulate GI/uterine smooth muscle

Sucralfate

``` Al(OH)3-sucrose sulfate complex Acid release anionic sulfated sucrose Binds to charged proteins in ulcer Viscous, sticky, protective barrier Indirect stimulation of PGE2 production ```

Pharmacokinetics of sucralfate

Localized action, minimal systemic absorption Short effect (6 hours) Take on empty stomach

Indications for sucralfate

Gastric and duodenal ulcer

Side effects of sucralfate

Al-induced constipation | May reduce absorption of some other drugs (Direct binding, or impaired membrane crossing)

Bismuth subsalicylate

Coat ulcers to form a physical protective barrier Increased PGE2, HCO3 and mucus production Antimicrobial against H pylori Reduces stool frequency

Pharmacokinetics of bismuth subsalicylate

Dissociated in stomach, acts locally | Only salicylate substantially absorbed

Indications for bismuth subsalicylate

Adjuvant to triple therapy for H pylori-induced ulcers | Acute diarrhea

Contraindications of bismuth subsalicylate

Children with viral infections (Reye's syndrome) | Allergies to ASA

Side effects as bismuth subsalicylate

Black stool (reaction with hydrogen sulfide in colon, may be confused with GI bleeding) Blackening of tongue Constipation

Prokinetic drugs

Ex: metoclopramide and domperidone Both dopamine D2 receptor antagonists Metoclopromaide has additional activity as agonist of serotonin receptors Relieve basal dopamine inhibition of upper GI tract, stimulating peristalsis and facilitating gastric emptying Move things along the tract faster (less material in the GI tract that can splash up into the esophagus)

Pharmacokinetics of prokinetics drugs

Metoclopromide is available in oral and parenteral formulations Domperiodone has greater first-pass metabolism Short duration of action Hepatic metabolism

Indications of prokinetic drugs

GERD Impaired gastric emptying Nausea and vomiting Postpartum lactation stimulation

Contraindications of prokinetic drugs

Situations where GI motility is harmful

Side effects of prokinetic drugs

GI crampings Diarrhea Hyperprolactinemia Metoclopromide (not domperidone) crosses BBB

Anti-emetic pharmacology

Based on receptor expression in brainstem vomiting center and/or chemoreceptor trigger zone Ex: Ondansetron, Dimenhydrinate, Scopolamine

Ondansetron

Antagonist of serotonin 5-HT3 receptors | Vomiting center, chemoreceptor trigger zone, vagal afferents

Indications for ondansetron

Chemotherapy-induced nausea and vomiting | Postoperative and postradiation nausea and vomiting

Side effects for Ondansetron

Headache Dizziness Constipation

Dimenhydrinate

Antagonist of histamine H1 receptors (some anticholinergic activity) Relatively weak anti-emetic activity (can be used as adjuvant)

Indications for dimenhydrinate

Motion sickness (prevention or treatment)

Side effects of dimenhydrinate

Dizziness Sedation/drowsiness Dry mouth Urinary retention

Scopolamine

Antagonist of muscarinic receptors Comparable efficacy to dimenhydrinate Best administered as transdermal patch

Indication for scopolamine

Motion sickness (prevention and treatments)

Side effects of scopolamine

Antagonist of muscarinic receptors when given orally Comparable efficacy to dimenhydrinate Best administered as transdermal patch