PCOL Block 7: Laxatives and Antidiarrheal

Opioids used for diarrhea

- Loperamide -Diphenoxylate +atropine

Use of opioids in GI

- given orally, penetrates CNS poorly (low addictive potential) - traveler's diarrhea -Adjunctive tx in almost all forms of chronic diarrheal disease

Senna use

-occasional constipation -chronic management of opioid induced constipation

How long will it take for a full dose of mineral salts to work?

1-2 hours

ADRs of mineral salts

1. Diarrhea and dehydrated--> electrolyte imbalances (esp in patients with bulimia) 2. Systemic effects due to absorption of cations when igh enough concentration are used--> Mg intoxication (hypotension, impaired cognition)

List 2 compounds classified as emollients (stool softeners)

1. Docusate 2. Mineral oil

ADRs of Castor oil

1. GI distress (N/V/D, pain cramps rectal irritation) 2. Prolonged use can cause laxative dependence

ADRs of senna

1. GI upset (diarrhea, cramping, pain) 2. Melanosis coli 3. May color urine/feces brown (warn patient)

ADRs of PEG

1. PEG alone is well tolerated and not absorbed systemically 2. Bowel prep formulations often cause GI distress

Examples of polyethylene glycol

1. Polyethylene glycol (miralax): occasional or chronic constipation 2. Polyethylene glycol; electrolytes: Bowl prep for colonoscopy and occasional constipation 3. Polyethylene glycol; electrolytes; ascorbic acid: bowel prep for colonoscopy

What are the two situations where castor oil should be avoided?

1. Pregnancy- uterine contraction 2. Fecal impaction, intestinal obstruction

3 main Tx of Diarrhea

1. Rehydration therapy 2. Antidiarrheal Agents 3. Antibiotics

General GI ADRs of opioids

1. constipation from excessive dose 2. nausea

CI's of mineral salts

1. renal impairment (esp in elderly) 2. Electrolyte imbalances 3. Na-salts: heart failure and hypertension

What is the structure of linaclotide?

14 amino acid peptide homologous to the heat stable enterotoxins that cause diarrhea

When does the max effect of bulk laxatives occur?

2-3 days

When should suppositories be given?

30 min after breakfast to synchronize the pharm agent w/ gastrocolic reflex

How long does oral mineral oil take to work?

6-8 hours

How can mineral salts act as a saline diuretic?

Absorbed salts are excreted by kidney

MOA of opioids in GI

Act on ENS neurons, epithelial cells and smooth muscle via agonism at µ-opioid receptors resulting in - decreased peristalsis - increased fluid absorption

MOA of Linaclotide

Activates guanylate cyclase C on brush boarder of enterocytes from duodenum to rectum cGMP opens the CFTR chloride channel and produces a net efflux of ions and water into the intestinal lumen

MOA of lubiprostone?

Activates the ClC-2 in apical membranes of enterocytes of the small intestine this promotes Cl- rich intestinal fluid secretion without altering sodium and potassium concentrations in the blood increased mass of stool stimulates intestinal motility

This class of drugs should not be given w/in a few hours of administration of other drugs

Bile Acid-Binding Agents Can also cause constipation, abd. discomfort, nausea

This class of drugs is useful in bile-salt-induced diarrhea

Bile Acid-Binding Agents Eg. pts. w/ resection of distal ileum

This drug, when given as an enema, can cause local mucosal irritation that promotes accumulation of water and electrolytes, thus increasing distention and motility

Bisacodyl Also has same effect when given as a suppository

Three examples of Bile Acid-Binding Agents

Cholestyramine Colesevelam Colestipol Prefix Choles-/Coles-

Uses for mineral salts

Constipation Antacid Bowel prep for colonscopy

MOA of castor oil

Contains ricinoleic acid triglyceride--> lipases in the small intestine release ricinoleic acid--> stimulates the myenteric plexus, has direct action on mucosa, and alters water and electrolyte secretion

What GI opioid produces CNS effects at higher doses and has the potential for abuse and/or addiction?

Diphenoxlate -formulations contain subtherapeutic doses of atropine to discourage abuse - other anticholinergic effects from atropine

This drug is contraindicated w/ mineral oil bc it increases absorption of mineral oil

Docusate

Cardiac ADRs of loperamide

Excessive dose can cause cardiac events (QT prolongation)

T or F Lubiprostone alters the Na and K concentration in the blood

FALSE Does not alter

T or F Lactulose can cure liver disease

FALSE Helps to improve mental status

T or F Antidiarrheals are a first agent for pts. w/ acute diarrheal illnesses cause by invasive organisms

FALSE Should actually be AVOIDED in scenarios like this They mask the clinical picture, delay clearance of organisms, and increase risk of systemic invasion

This class of drugs alter stool viscosity and the perception of decreased stool fluidity

Fiber supplements

These drug classes may bind bacterial toxins and bile salts

Fiber supplements Bile Acid-Binding Agents

Three types of non-specific anti-diarrheal agents for empirical therapy of acute diarrhea

Fiber supplements Bile-acid binding agents Opiates

ADRs of Linaclotide

GI upset (Diarrhea, abdominal pain, flatulence)

ADRs of lactulose

GI upset (bloating, gas, diarrhea)

This suppository is inert and provides lubrication

Glycerine Good to know ;)

This agent, if given as an enema, can lead to dangerous hyperphosphatemia and hypocalcemic tetany

Hypertonic sodium phosphate (osmotically active agents)

Preferred Tx for rehydration therapy for severe dehydration

IV normal saline or lactated Ringer's solution

Why can't you take Castor Oil at bed time?

Intense cathartic action w/ water evacuation w/in 3-6 hrs.

Why is polyethylene glycol safe for pregnancy and lactation?

It is not absorbed systemically NOTE: allergic rxns. rarely occur and it is well tolerated

This drug is used by mouth or rectally to treat to or prevent hepatic encephalopathy

Lactulose

What is cathartic colon?

Laxative dependence - loss of bowel motility, chronic constipation, structural damage to myenteric plexus -constipation occurs when drug is stopped

(Linaclotide/Lubiprostone) is a prodrug

Linaclotide

This drug is taken on an empty stomach 30 min prior to first meal

Linaclotide

This drug should be avoided in patients 17 and under

Linaclotide

This orally active derivative is effective against Traveler's diarrhea

Loperamide

This drug is a bicyclic FA derived from PGE1

Lubiprostone

Examples of mineral salts

Magnesium- 1. sulfate 2. hydroxide 3. citrate

Example of bulk laxatives (5)

Methylcellulose Pysllium Polycarbophil Bran

This drug is a mixture of liquid hydrocarbons from petroleum

Mineral oil

When are emollients prescribed?

OTC to prevent/treat constipation When straining at stool is not desirable

What class of drug does Loperamide fall under?

Opioid

MOA of polyethylene glycol

Osmotic agent that binds water and retains it in the stool- increased bulk simulates peristalsis

This drug is used w/ a stimulant laxative for opioid-induced constipation

Polyethylene glycol

What initiates the defecation reflex?

Rectal distention

This drug may appear in milk during lactation to affect the nursing infant

Senna

chronic management of opioid induced constipation

Senna - Daily use of an osmotic laxative (PEG) and a stimulant laxative (senna) at least 2-3 times a week

For mild-moderate fluid loss, what is recommended rehydration therapy

Sports beverages (the more sodium the better) Rehydration solutions Balanced clear liquid diet Dissolving salts in water

T or F Mineral oil has the potential to disrupt defecating reflexes

TRUE

T or F Bisacodyl can be given at bedtime

TRUE Action > 6 hrs.

MOA of saline cathartics

Water is retained in stool (osmosis) and this increased bulk stimulates peristalsis

ADRs of Docusate?

Well tolerated Nausea, anorexia, diarrhea, sometimes cramping pain

MOA of docusate

anionic surfactant agent that facilitates incorporation of water and fat into stool so that stool becomes softer

What is the MOA of a bisacodyl suppository?

local mucosal irritation that promotes accumulation of water and electrolytes, thus increasing distention and motility

Milk of magnesia is classified as a _______

mineral salt (osmotic laxative) Magnesium hydroxide

Use of castor oil

occasional constipation

What is melanosis coli?

pigmentation of the colonic mucosa (senna)

T/F Senna DOES NOT produce laxative dependence

true

MOA of bulk laxatives

- Absorbs water from gut lumen, more moves in by osmosis -Fiber + water forms a gel that keeps stool hydrated and promotes peristalsis (because of added bulk) -Prebiotic

This class of drugs can be used as a fiber supplement to support digestive health and decrease occasional constipation

Bulk Laxatives

This drug class is difficult to swallow

Bulk laxatives

Which laxative class modestly lower plasma cholesterol with chronic use?

Bulk laxatives (too much bulk, no room for chol)

3 CIs for bulk-forming agents

Intestinal ulceration Stenosis Adhesions (USA - cellulose)

Which drug can cause hypo-prothrombinemia?

Mineral Oil Decreased Vit K absorption

Two examples of fiber supplements

Psyllium (this was also a bran laxative) Polycarbophil

Regardless of laxative or cathartic effect, laxatives and cathartics should only be prescribed in doses to product a (cathartic/laxative) effect

Regardless of laxative or laxative or cathartic effect, laxatives and cathartics should only be prescribed in doses to product a LAXATIVE effect

When given as an enema, this can cause rectal mucosal damage and necrosis and can lead to hyperphosphatemia and other electrolyte disturbances if the enema is retained

Soapsuds

MOA of bisacodyl

alters intestinal fluid and electrolyte absorption, causing net fluid accumulation

Examples of stimulant laxatives

bisacodyl, senna, castor oil

Why does bisacodyl have prolonged action?

entero-hepatic cycle

Onset of action of docusate

1-3 days

ADRs of Bisacodyl

1. Abdominal pain/cramping 2. Hypokalemia and other electrolyte imbalances 3. Laxative dependence 4. May stimulate uterine contractions

Classes of Laxatives/Cathartics

1. Bulk-forming laxatives 2. Osmotic laxatives 3. Stimulant laxatives 4. Emollients 5. Cl- channel activators

What vitamin deficiencies may be seen with mineral oil use?

ADEK -- fat soluble vitamins (because decrease absorption of fat soluble substances)

This drug class is used to lower cholesterol

Bulk Laxatives

Why must bulk laxatives be taken with water?

If not can cause intestinal obstruction, impaction, and esophageal obstruction

MOA of senna

Irritant (stimulant) of luminal sensory nerves; causing contraction of colon and reducing colonic water absorption

Examples of Cl channel activators

Lubiprostone Linaclotide

What makes up suprep for bowel prep for colonoscopy?

MgSO4 + K2SO4 + Na2SO4; Na2PO4; Mg-citrate

This drug may cause pruritis

Mineral Oil

This drug may interfere in healing of post-operative wounds causing hemorrhage

Mineral Oil

This drug may result in foreign-body rxn if regularly used

Mineral Oil

Rectal enema of this drug produces a stool w/in 2-15 minutes

Mineral oil

examples of osmotic laxatives

Mineral salts Polyethylene glycol lactulose

ADRs or Lubiprostone

Minimal systemic absorption GI upset (N/D)

Are mineral salts completely absorbed?

No- they are incompletely absorbed in the GI tract

MOA of Lactulose

Non-absorbable sugar that is broken down by gut flora into acetic acid and lactic acid when it reaches the colon Colon contents are acidified which ion-traps ammonia as NH4+ in the colon (decreasing amount in blood)

MOA of mineral oil

Softens the stool by decreasing colonic reabsorption of water

MOA of chloride channel activators

stimulate net efflux of ions and water into intestinal lumen to accelerate transit and facilitate ease of defecation