Module 4: Laxatives, Antidiarrhea Digavalli

Question 1

Definition of Constipation

Answer 1

< 3 Bowel movements per week !!!

-too little mass
-too dry (reabsorption)
-incomplete evacuation
-too little dietary fiber, too little physical activity

-women 2x as prone
-older adults (25-50%)

Question 2

What are neuro or endocrine disorders causing constipation?

Answer 2

-Neuro: Parkinson’s disease
-Endocrine: diabetes (degeneration of neurons in the gut system), hypothyroidism
-drug-induced

Question 3

Drugs causing constipation

Answer 3

-Anticholinergics (e.g. atropine, dicyclomine )
-Antihistaminics (first gen only)
-Tricyclic antidepressants (e.g. )
-Ca++ channel blockers
-NSAIDS
-Al+3 containing antacids
-Alosetron (Lotronex) - used in diarrhea-predominant IBS
-Opiates (e.g. loperamide)

Question 4

Why do anticholinergics cause constipation?

Answer 4

Blockage of ACh receptors
-ACh stimulates gut motility

Question 5

Why do TCAs and Antihistamines (1st) cause constipation?

Answer 5

due to their anticholinergic effect
-dry mouth, slow gut, …

Question 6

Why do NSAIDs cause constipation?

Answer 6

-prostaglandins cause smooth muscle contraction

-NSAIDs block prostaglandin production

Question 7

How do Bulk-forming agents work as a Laxative?

Answer 7

-absorbing water
-swells and distends -> distends the wall -> stimulation of peristalsis

-Methylcellulose
-Polycarbophil
-Psyllium (natural fiber -> prebiotic)

Question 8

Which bulk-forming agent may cause bloating and gas?

Answer 8

Psyllium (Metamucil, a fiber)

Question 9

How do Lubricating agents work as Laxatives?

Answer 9

reduces water absorption, prevents fecal impaction, keeps the feces wet
-often used for kids (suppository)

-Glycerin
-Mineral oil (oral)
-Magnesium hydroxide and mineral oil

Question 10

Where are Stool softeners used?

Answer 10

-hospital-setting
-preventing strain of the rectum
-hydrates the stool as a surfactant by reducing the barrier between water and the stool

-Docusate sodium

Question 11

Saline (Lactulose, sorbitol, PEG)

Answer 11

hydration of the stool by osmotic pressure
-colonoscopy

-magnesium hydroxide
-PEG (Golytely, Nulytely) -> salts added to compensate for salt loss when water is absorbed and excreted with feces
-Miralax

Question 12

Stimulants

Answer 12

-triggering peristalsis
-stimulates nitric oxide synthase (NOS) and release of platelet active factor -> secretion and motility

-Bisacodyl
-Sodium bicarbonate and potassium bitartrate
-Sennosides
-Castor oil
-Senna

Question 13

Signs of abuse from laxatives

Answer 13

-loss of fluids/electrolytes
-steatorrhea (fat in stool)
-hypoalbuminemia
-osteomalacia (bone softening)

Question 14

How does Lubiprostone work?

Answer 14

-PGE2 agonist (prostaglandin) -> EP4 receptor
-Chloride channel activator

-works locally, not absorbed
-stimulates Cl(-) channel efflux (G2 coupled)
-Na+ will follow through the paracellular pathway
-water will follow

Question 15

Indication of Lubiprostone

Answer 15

-for chronic idiopathic constipation
-IBS-C and opioid-induced constipation

Question 16

MOA of Linaclotide (Linzess) and Plecanatide

Answer 16

-MOA similar to cholera toxin for IBS-C
1. Guanylate cyclase C activation -> increase in GMP 2. secretion of Cl(-) and HCO3(-)
3. Na+ follows passively the negative ion gradient
4. H20 follows the osmotic gradient

cGMP reduces visceral pain
-> increases of 1–2 bowel movements per week

Question 17

How is Linaclotide different from other laxatives?

Answer 17

no dependence

Question 18

How does Tegaserod work

Answer 18

5-HT4 agonist (serotonin)

-stimulates peristaltic reflex on 5HT4
receptors on the enteric nervous system

-proximal contraction and distal relaxation

-for IBS-C

Question 19

Which drugs antagonize peripheral opioid
agonist effects?

Postop ileus

Answer 19

-Methylnaltrexone Br
-Alvimopan

-work systemically but do not cross the BBB! (the other laxatives work locally)
-reverse postop opioid-induced constipation (paralyzation of the gut)

Question 20

How do opioids cause constipation?

Answer 20

-enhance moisture reabsorption
-reduce motility
-increase sphincter tone (it doesn’t relax)
-prolong postop ileus (paralyzed colon - no contraction) -> opioids bind to mu receptors

(Loperamide (Imodium), an opioid is used to treat diarrhea by its constipating effect, but doesn’t cross BBB)

Question 21

What is the non-pharmacological approach to increasing bowel movement?

Answer 21

-dietary fiber
-30g/day

-soluble: gel-forming (pectin, psyllium inulin) - may cause bloating

-insoluble: bulk-forming (methylcellulose, cellulose, lignin, synthetic fiber) -> doesn’t feed bacteria

Question 22

Benefits of fibers

Answer 22

-Improves regularity (bulk and hydration)
- Increases transit time (and nutrient absorption; why?)
- Improves blood glucose profile -> slows down glucose absorption into the bloodstream
- Reduces blood cholesterol -> absorbs cholesterol -> feces
- Nurtures “good bacteria” (why?)
- Improves barrier function (butyric acid feeds gut epithelia)
- Healthy weight and longevity

Question 23

Definition of diarrhea

Answer 23

more than 3 Bowel movements/week

-hypersecretion (ions/paracellular fluid draw)
-osmotic imbalance (ions, protein, AAs exudation)
-Accelerated motility

Question 24

How do PPIs cause diarrhea?

Answer 24

-increased risk for C. diff with long-term use
-> diarrhea

Question 25

Treatment for diarrhea

Answer 25

-Loperamide
(peripheral acting opioid agonists (mu receptor)
increases transit time

• Eluxadoline (Viberzi)
  (peripheral mu/kappa opiate agonist, delta opiate antagonist): approved for IBS-D

Question 26

What is the consequence of an overdose of Loperamide and which patients to avoid using it?

Answer 26

may cause constipation and paralytic ileus (gut paralyzation)

Caution in IBD patients (bc of long-term use): toxic megacolon

Question 27

Which anti-diarrheal drug is an opioid?

Answer 27

Diphenoxylate and Difenoxin -> crosses the BBB
-formulated with atropine to prevent abuse

-atropine is an anticholinergic: photophobia, dry mouth, loss of accommodation of the eye reflex -> unpleasant effects to prevent abuse

-long-term use in IBD may cause megacolon

Question 28

How is the emesis reflex regulated?

Answer 28

-sensory stimuli (smell, eyes, sound, sensation) -> stimulates prefrontal cortex -> central pattern generator in the brain stem

-central pattern generator in the brain: triggering a sequence of events from the bottom (stomach) to the top pharynx

-stomach contraction, opening of lower esophagus sphincter then upper esophagus sphincter, closure of the airway

Question 29

Different factors stimulating the vomiting center?

Answer 29

-sensory stimuli (smell, eyes, sound, sensation)

-vagal afferent nerves from the stomach and heart: via mechanoreceptors, chemoreceptors, 5-HT receptors -> radiation, cytotoxic drugs (chemo), emetine, bacteria, virus

-vestibular system in the ear: may be stimulated by aminoglycosides (histamine and M-receptors)

-chemoreceptor trigger zone: doesn’t have BBB so it can sense toxic molecules in the blood an activate the vomiting center
-> chemoreceptors, D-receptors, 5-HT receptors

-vomiting center itself: has H1 receptors, M-receptors, 5-HT 3 receptors

Question 30

How do 5-HT3 antagonists work?

Answer 30

-“setrons” Ondansetron, Granisetron, Dolasetron
-reduces the activity of vagal afferents that go to the brain (by blocking 5-HT3 receptors in the brain???)

-it may also reduce motility by binding to 5-HT3 receptors -> Constipation (Alosteron used for IBS-D)

-CAUTION: prolong QT interval

Question 31

What may be co-administered to counter severe nausea-inducing chemotherapy?

Answer 31

-dexamethasone
-Corticosteroids
-NK-1 antagonists

Question 32

What is the role of steroids in nausea therapy?

Answer 32

adjuvant, in combination with “setrons” and NK1 antagonists

fe: Dexamethasone, methylprednisolone

Question 33

MOA of NK1 antagonists

Answer 33

-block NK1 receptors in the chemoreceptor trigger zone (CTZ) and vomiting center

Question 34

Why is NK1 so effective and what type of cancer regimen is it used?

Answer 34

-because it directly acts on the vomiting center

remember that nausea-causing signals are sent from different sources to the center -> NK1 antagonists are more effective by blocking the center, and don’t rely on blocking every single nausea-causing pathway

-it has a long halflife
it is used for the second wave of cancer treatment which is slowly and longer-lasting

-combined with 5-HT setrons and dex (steroids) covering the first wave of nausea -> short-halflife

Question 35

Examples of NK1 antagonists

Answer 35

-Aprepitant
-Netupitant
-Ranolapitant

Question 36

D2 antagonists

Answer 36

-Antagonize D2, also anticholinergic and anti-histaminergic activity
-for motion sickness and chemotherapy-induced nausea
-low to moderate nausea

-antiemetic + sedative

-Prochlorperazine, promethazine and droperidol

Question 37

CB1 antagonists

Answer 37

-present in the CTZ and vomiting center
-for AIDS-induced loss of appetite/weight loss and chemotherapy-induced nausea
-has a euphoric and dysphoric effect -> counteracted when given with antipsychotic

-eg
Dronabinol (synthetic delta9-THC, tetrahydro-cannabinol)
Nabilone (THC analog)

Question 38

Where are D2 and CB1 receptors in the brain?

Answer 38

-D2: vomiting center
-chemoreceptor trigger zone (CTZ) + vomiting center

Question 39

H1 antagonists

Answer 39

-used for motion sickness -> blocking H1 and M1 in the vestibulocerebellar pathway (balance)
-used for pregnancy-related nausea
-sedative + anticholinergic side effects (dizziness, dry mouth, constipation), hypotension (block alpha1-receptor)

-Diphenhydramine
-Dimenhydrinate
-Cyclizine
-Meclizine

Question 40

Scopolamine

Answer 40

-transdermal (most effective, others are oral)
-for prevention of motion sickness, apply before traveling

-side effects: dry eyes, dry mouth, photosensitivity