Gi System- Laxatives By Maloney

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GI System- Laxatives by Maloney

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GI System- Laxatives by Maloney

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Bulk-forming Laxatives Agents

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Methylcellulose
Psyllium (Derived from the plantago seed)

-Nonabsorbable polysaccharide and cellulose derivatives

-go into colon, suck up water and get bigger. some are food for bacteria in the colon, so the more bacteria, the more mass, hence stimulate mechanical distention of the colon, and this distention is stimulus for peristalsis.

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Mechanism of Action - Summary for Bulk-forming laxatives

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Swell in water and increase bacterial mass
Increase fecal mass
Mechanical distention of the intestinal wall
Activate stretch receptors and increase peristalsis
Decrease transit time

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What may happen if you take
most fiber laxatives without water?

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it can form a plug, creating bowel or esophageal obstruction

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Bulk-forming Laxatives therapeutic use

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-acute/chronic constipation
-effect within 12 to 24 hours
-acute diarrhea
--absorb water and provide mass

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Adverse Effects

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Flatulence and bloating: Varies with how well the agent is fermented by colonic bacteria

psyllium has significant fermentation so there's more flatulence. methycellulose is poorly fermented so there's less flatulence
gross.

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Osmotic Laxatives Agents

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Saline laxatives:
Magnesium citrate
Magnesium hydroxide
Magnesium oxide
Magnesium sulfate
Sodium phosphate (Also given as an enema)

Nondigestible sugars and alcohols:
Lactulose
Sorbitol
Glycerin – rectal only

Polyethylene glycol (PEG):
electrolyte solutions
powder

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Mechanism of Action - Summary

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Thought to cause an osmotic effect that increases intraluminal volume and pressure in the small intestine and/or colon

The increased mass activates stretch receptors and stimulates peristalsis

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BLACK BOX WARNING FOR ORAL SODIUM PHOSPHATE!!!

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Oral sodium phosphate for bowel cleansing can cause acute phosphate nephropathy!

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Acute Phosphate Nephropathy

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Large amount of phosphate taken (and absorbed by the GI tract) without enough water

Hypovolemia-induced avid salt and water reabsorption in the proximal tubule of the kidney

Delivery of a large phosphate load to the distal nephron

Precipitation of calcium phosphate in the distal tubule and collecting duct

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Magnesium salts

How quickly does magnesium citrate work?

What would be the biggest problem with magnesium citrate?

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works in a couple hours (relatively quickly)..and the more you take, the faster it works

the biggest problem is (if you take it every day) you can get hypermagnesemia and that's not so good. not recommended for chronic constipation.

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Lactulose

Lactulose is metabolized by colonic bacteria. How quickly will it work?

What would be the main side effect of lactulose?

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used for acute or chronic constipation... not for bowel prep.

works 24-48 hrs. much slower than other laxatives bc you have to wait for it to get to the colon to do its thing.

main side effect of lactulose (metabolized by colonic bacteria) is cramps and flatus

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Polyethylene glycol (PEG) for constipation and bowel prep.

How quickly will low dose PEG work when used for constipation?

How quickly will high dose PEG work when used as a cathartic?

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acts as an osmol to sit in GI tract and suck in water.

bowel movement in one to three days; but will work very quickly for bowel prep

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Why are electrolytes added to PEG when used in high dose to evacuate the bowel?

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you're drinking like 4 liters of water for the prep, so you may cause electrolyte imbalance if you don't add electrolytes to it.

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Stimulant Laxatives

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Bisacodyl
Castor oil
Anthraquinone derivatives:
-Senna or sennosides
-Aloe Vera

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Stimulant Laxatives Mechanism of Action - Summary

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-Exact mechanism of action in unclear

-One theory - act as a local irritant in the small intestine or colon. This activates the enteric nervous system to increase peristaltic contractions.

-Another theory - alter fluid and electrolyte absorption, producing net intestinal fluid accumulation which causes distension and peristalsis.

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Clinical Use

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Acute or chronic constipation
Work in about 8-10 hours
Bisacodyl can be used in conjunction with PEG for bowel prep

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Possible Problems with Chronic Use?

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Cathartic colon:
-A gradually increasing desensitization of the bowel to normal stimuli which forces the laxative user to employ larger and larger doses

Damage the enteric nervous system

Recent evidence suggest they are safe for chronic use

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Stool Softeners.. how do they work? name one. what is it used for?

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Docusate sodium
Anionic surfactants that lower the fecal surface tension in vitro, allowing water and lipid penetration

Marginal, if any, efficacy in most cases of constipation
Major use is to avoid straining during defecation

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Selective type 2 chloride channel (ClC-2) activator...name it. what does it do?

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Lubiprostone (Amitiza)

Increases intestinal fluid secretion and motility

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Lubiprostone (Amitiza) clinical use

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Chronic constipation

Constipation predominant irritable bowel syndrome

AE: nausea and diarrhea

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Antidiarrheals

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Antimotility and Antisecretory Agents
-Opioids

Intraluminal Agents:
-Bismuth subsalicylate

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Opioids agents...why do you use Loperamide and why do they work well?

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Tincture of opium and paregoric

Codeine

Diphenoxylate + Atropine (Lomotil)
-High doses cross BBB

Difenoxin + Atropine (Motofen)

Loperamide (Imodium)
-Does not cross the BBB

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Why is atropine a
component of Lomotil?

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to prevent drug abuse (atropine is an M blocker) b/c high doses cross the BBB

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clinical use of opioids? Adverse Effects?

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Can control diarrhea due to almost any cause

Diphenoxylate and loperamide are the opioid agonists with the greatest ratio of intestinal smooth muscle activity to CNS activity

AE:
Drowsiness
Dizziness
Abdominal cramps
Constipation

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OTC Prep:
Bismuth Subsalicylate

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-Pepto-Bismol
-Kaopectate

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Mechanism of Action in Diarrhea
for bismuth and salicylate

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Bismuth-> antimicrobial effect binds enterotoxins -> prevent/treat traveler's diarrhea

Salicylate-> inhibits production of PG's -> decrease intestinal secretions

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How effective is bismuth subsalicylate in treating diarrhea?

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not as good as the opioid in treating diarrhea

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Drugs for Irritable Bowel Syndrome

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Visceral hypersensitivity
-Bloating
-Abdominal pain
Constipation predominant IBS (IBS-C)
Diarrhea predominant IBS (IBS-D)
Mixed symptoms of constipation and diarrhea (IBS-M)
Alternating symptoms of constipation and diarrhea (IBS-A)


*key thing is the abdominal pain from visceral sensitivity

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What is the difference between chronic constipation and constipation predominant IBS?

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the visceral hypersensitivity. IBS is characterized by chronic abdo pain and altered bowel habits

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IBS Tx

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Problem:
There is no well defined drug target because it involves multiple receptors or mediators

There is a very high placebo response:
Range 5% to 84%
Average of 47%


huge placebo response!

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IBS Treatment – Brief Summary

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constipation-> OTC laxatives

diarrhea-> loperamide

Pain-> anticholinergics, antidepressants

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If those don’t work, then bring out the big guns

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-Lubiprostone – IBS-C
-Drugs that affect serotonin receptors

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Serotonin

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5% in brain, 95% in the gut

5HT3 for visceral perception and GI motility

5HT4 are for peristalsis and secretion

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Alosetron (Lotronex) MoA

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block serotinin receptors

5-HT3 receptor antagonist
Reduces visceral sensations in the gut
Reduces colonic transit and secretion

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Alosetron (Lotronex) clinical use, Adverse Effects

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SEVERE IBS with diarrhea in women

Clinical studies have shown:
Relieves abdominal pain and discomfort
Increases colonic compliance
Decreases diarrhea urgency

Adverse Effects:
Constipation
-Can be serious causing ileus, bowel obstruction, toxic megacolon, fecal impaction or perforation

Ischemic colitis
-Reason unclear; Animal studies show that blocking 5HT3 receptors causes mesenteric vascular constriction

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Tegaserod (Zelnorm) MoA

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-Selective 5-HT4 partial agonist
-Increases motility and promote fluid secretion

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Clinical use

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Clinical studies have shown that in IBS-C:
-Decreases abdominal discomfort, pain, bloating
-Increases stool frequency and consistency

Emergency treatment of IBS-C and chronic idiopathic constipation in women (<55 years of age) in which no alternative therapy exists

Diarrhea
-Can cause hypovolemia, hypotension and syncope

Increased risk of heart attack, stroke, and worsening chest pain