GI pharmacology

Question 1

Factors controlling acid secretion

Answer 1

• Gastrin (from G cells) and histamine (from enterochromaffin-like cells, ECL) both stimulate H/K ATPase on the parietal cells and increase acid secretion
• ACh from vagus directly increases H/K ATPase activity and also stimulates ECL/G cells to release histamine/gastrin
• As the pH drops in the stomach the D cells sense it and release somatostatin which inhibits gastrin release
• ACh from vagus will decrease somatostatin release from D cells

Question 2

Antacids

Answer 2

• Provide the stomach lumen w/ hydroxyl ions to neutralize the H+
• Various forms: Ca carbonate (tums), NaHCO3 (aka seltzer), Mg/Al hydroxide (maalox)
• Main side effects depend on the content of the antacids
• Antacids w/ high Mg cause diarrhea, and those w/ high Al cause constipation

Question 3

H2 receptor antagonists

Answer 3

• Block the H2 receptor on parietal cells and thus reduce acid secretion (slower than antacids but last longer)
• H2 antagonists: cimetidine, ranitidine (all the “tidines”)
• Only cimetidine has side effects: it reduces activity of CYP450 and increases the T1/2 of drugs metabolized by CYP450
• Cimetidine also binds to androgen receptors, leading to increased metabolism of testosterone and thus increased estradiol production (it also inhibits estradiol metabolism)
• This can lead to erectile dysfxn/impotence/decreased libido and gynecomastia in men
• Cimetidine can cause galactorrhea and amenorrhea in women

Question 4

PPI 1

Answer 4

• Most effective in reducing acid secretion by parietal cell
• Block H/K ATPase activity directly, thus work independently from the source of acid stimulation
• Are not absorbed until SI, then once in bloodstream they concentrate at the gastric pits
• For the PPI to be active at the ATPase it must be exposed to H+ (low pH)
• Names: lansoprazole, esomeprazole (all the “prazoles”)

Question 5

PPI 2

Answer 5

• Major side effects: lead to hypoCa and osteopenia due to interfering w/ Ca pumps (new evidence suggests it inhibits Mg pumps, leading to hypoCa and osteopenia secondary to hypoMg)
• It is necessary to give Mg citrate and Ca w/ long term PPI Rx (but high Mg will cause diarrhea)
• There is a compensatory increase in gastrin release, due to hyperplasia of G cells which can lead to hyperplastic polyps (no risk for malignancy)

Question 6

Protection of GI mucosa

Answer 6

• Sucralfate: activated by low pH and binds to mucous layer at ulcer and erosion sites
• Protects the mucosa from further damage
• Should not be given w/ PPIs/H2 antagonists/antacids
• Misoprostol is a PG analog that stimulates mucus formation in gastric mucosa
• It is an abortifacient (causes contractions of myometrium) and should never be used in pregnant women

Question 7

Promoting GI motility

Answer 7

• Metoclopramide acts by blocking sympathetic input and stimulating parasympathetic input
• It is a D2 receptor antagonist, can be used to treat N/V
• D2 receptors on PsNS Ach neurons inhibit Ach release, thus blocking the D2 receptors will increase ACh release on the GI tract
• Other drugs that stimulate GI motility: erythromycin (binds to motilin receptors in gut) and neostigmine (cholinesterase inhibitor that increases ACh in gut)

Question 8

Anti N/V drugs 1

Answer 8

• Vomiting center (in ponto-medullary junction) has various inputs: sight/smell/thought (cerebral), vestibular, chemosensory, sensory from gut
• Antihistamines (diphenylhydramine) block histamine and cholinergic receptors and reduce N/V
• Cholinergic antagonists (scopolamine) reduce N/V (sea sickness)
• D2 receptor antagonists: metoclopramide blocks D2 receptors in CNS (chemo-sensing center) and helps w/ N/V

Question 9

Anti N/V drugs 2

Answer 9

• 5HT receptor antagonists (main use in chemoRx N/V): blocks action of 5HT in chemo-sensing center and vagal afferents
• 5HT antagonist drugs: odansetron, dolasetron (all the “setrons”)
• 3 drugs can be used in combination w/ 5HT antagonists to potentiate their effects: corticosteroids (dexameth), neurokinins (aprepitant), cannabinoids (dronabinol)

Question 10

Rx of constipation

Answer 10

• Change in lifestyle/diet (increased fiber and fluids, increased exercise)
• Bulking laxatives: psyllium
• Stimulant laxative: bisacodyl (dulcolax)
• Osmotic laxatives: MgOH (milk of magnesia, SE is diarrhea), polyethylene glycol (used for bowel cleansing prior to colonoscopy)
• Chloride channel activator: lubiproston used in Rx of constipation from IBS
• Stool softeners: glycerin and dioctyl sodium sulfosuccinate
• Opioid antagonists: naltrexone and alvinopan

Question 11

Rx of diarrhea

Answer 11

• Opioid agonists: diphenoxylate and loperamide both work by blocking ACh release to decrease motility and allow for more water absorption
• Somatostatin agonists (octreotide) for reducing tumor-induced diarrhea (thru action of GH)
• H2O absorbing drugs: colloidal bismuth (kaopectate, pepto bismol)

Question 12

IBS Rx

Answer 12

• Rx is directed at cramping pain and diarrhea/constipation Sx
• Cramping and pain is Rx w/ cholineragic antagonists such as dicyclomine and hyoscyamine
• Blocking ACh activity means less SmM constriction of bowel
• Constipation Rx: see constipation card
• Diarrhea: can be so severe than a 5HT receptor antagonist is used (alosetron specific for IBS diarrhea)
• Alosetron blocks cholinergic input to the colon, slowing motility and allowing time for more water absorption
• Alosetron only used in women and only if they have IBS associated diarrhea