L11 Therapeutics for Diarrhea

Question 1

3 Clinical Types of Diarrhea?

Answer 1

• Acute Watery Diarrhea: hours to days (Includes Cholera)
• Acute Bloody Diarrhea (aka Dysentery):
• Persistent Diarrhea: Last 14 days or longer

Question 2

4 Major Classifications of Diarrhea?

___________________: Excess water pulled into GI tract due to excessive solutes => diarrhea

___________________: Water and other nutrients cannot pass the intestinal wall as normal

___________________: Contents move through the intestines too quickly for normal absorption

____________________: Epithelial cells in intestines actively secrete more water than they absorb due to pathogenesis => large volumes of fluid diarrhea => rapid dehydration

Answer 2

Osmotic Diarrhea (Lactose Intolerance): Excess water pulled into GI tract due to excessive solutes => diarrhea

Inflammatory/Infectious/Infiltrative Diarrhea (Crohn’s): Water and other nutrients cannot pass the intestinal wall as normal

Abnormal Gi Motility: Contents move through the intestines too quickly for normal absorption

Secretory Diarrhea (Cholera): Epithelial cells in intestines actively secrete more water than they absorb due to pathogenesis => large volumes of fluid diarrhea => rapid dehydration

Question 3

Classification of Severe Acute Diarrhea?

Answer 3

• profuse watery diarrhea with signs of hypovolemia
• passage of ≥6 unformed stools per 24 hours
• severe abdominal pain
• need for hospitalization

Question 4

Signs or symptoms concerning for inflammatory diarrhea?

Answer 4

• Bloody diarrhea
• Passage of many small volume stools w/ blood/ mucous
• Temp >38.5

Question 5

Transmission/Primary Concerns of Cholera Infection?

Answer 5

• Caused by toxin-producing strain of vibrio cholera
• Transmitted through water
• Acute secretory diarrhea/vomitting=> profound fluid/electrolye loss => HYPOVOLEMIC shock (25-50% of severe cases die)

Question 6

Pathogenesis of Cholera Infection?

Answer 6

Active Transport Disease: Toxin behaves like a hormone that binds intestinal epithelial cells causing them to release excessive amounts of water/electrolytes=> HYPOVOLEMIC shock (25-50% of severe cases die)

Does NOT damage the intestinal mucosa!!

Question 7

Cholera Pathogenesis?

Answer 7

Cholera produces toxin that binds to CFTR receptor on wall of small intestine => Toxin upregulates cAMP => causes CFTR receptor to remain open => Cl- ions leave the epithelial cell=> Na+ attracted by negative Cl- ions=> w/ more ions in lumen water leaves as well => increased water in small intestines leading to vomitting/diarrhea

Question 8

Where is there still an active cholera outbreak?

Answer 8

Yemen

Question 9

General Approach to Therapy for Diarrhea?

Answer 9

REPLATION is VERY important
Solutions of water, salt, and sugar
Oral preferred however Adults w/ severe hypovolemia should receive IV fluids first, then oral rehydration

Question 10

Fluid Replication/Maintenance Goals?

Answer 10

• Replace 50% in the first 4 hours, 50% in next 20 hours
• Choice of fluid replacement depends on type of fluid/electrolyte loss:
  Usually Crystoloid (guided by Urea and Electrolyte result!!)
• 25-30mls/kg/day fluid needed for maintenance
• More fluids are needed for Fever/Further fluid loss!

Question 11

Importance of Zinc/Consequences of Deficiency?

Answer 11

Zinc is vital for protein synthesis, cell growth, and intestinal transport of water/electrolytes

Zn deficiency associated w/ increased risk of GI infections

WHO recommends Zinc supplementation for children with diarrhoea in developing countries

• Reduces severity and dirration of diarrhea
• Reduces likelihood of subsequent infections

Question 12

Zinc’s Role in Cholera Management?

Answer 12

Inhibits cAMP production!!!!=> blocks cAMP activated K channels => Cl- dependent fluid secretion inhibited

Question 12

Use of Antibiotics for treating diarrheal Infections?

• Most are _________ infections while _______ diarrhea often resolves quickly
• DO NOT USE ABX in suspected ________________ infection: Releases Shiga toxin => hemolytic-uremic syndrome (HUS)

_________________ preferred therapy when ABX indicated in cases of:

• SEVERE Diarrhea + fever
• Immunocompromised/Elderly
• Invasive (Bloody) Diarrhea
• Public Health Concern

Answer 12

• Most are VIRAL and Bacterial diarrhea usually resolves quickly
• DO NOT USE in suspected Enterohemorrhagic E. Coli (EHEC): Releases Shiga toxin => hemolytic-uremic syndrome (HUS)

Fluoroquinolones (Ciprofloxacin) preferred therapy when ABX indicated in cases of:

• SEVERE Diarrhea + fever
• Immunocompromised/Elderly
• Invasive (Bloody) Diarrhea
• Public Health Concern

Question 13

Treatment for Severe Campylobacter?

Answer 13

Ciprofloxacin

Question 14

Treatment for Pregnant woman with suspected Listeria Monocytogenes?

Answer 14

Ampicillin

Question 15

Treatment for Cholera?

Answer 15

Single doses of either:

• Doxycycline 300mg
• Azithromycin 1g
• Ciprofloxacin 1g

Question 16

Treatments for C. DIfficile Infection?

Answer 16

Metronidazole

Vancomycin

Fidaxomicin (Macrolide)

Question 17

Prescribing Prevention of C. Diff infections?

Limiting use of ____________ and _____________

Use C Diff Targetting antibiotics (_____________, _____________, __________)

Answer 17

Limiting use of Quinolones and Cephalosporins

Use C Diff Targeting antibiotics (Metronidazole, Vancomycin/Fidaxomicin)

Question 18

_________________________:

• Inhibits nucleic acid synthesis by stopping bacterial DNA from replicating
• High systemic absorption => reduced effectiveness in moderate/severe C Diff. Infection
• Broad spectrum => reduction of microbiome diversity

Answer 18

Metronidazole

Question 19

_____________________:

• Inhibits cell wall synthesis in Gram-Positive bacteria
• Minimal systemic absorption => high concentration in colon increasing effectiveness at treating C. Diff
• Broad spectrum => reduction of microbiome diversity

Answer 19

Vancomyocin

Question 20

____________________:

• Macrolide Antibiotic
• Bactericidal - targets bacterial RNA polymerase
• Inhibits C. Diff spore formation
• Minimal systemic absorption => high concentration in colon
• Narrow spectrum, long lasting effect

Answer 20

Fidaxomicin

Question 21

Among patients with severe C. Diff infections, those treated with ________________ have a significantly lower risk of death than patients treated with ___________________

Answer 21

Among patients with severe C. Diff infections, those treated with Vancomycin have a significantly lower risk of death than patients treated with Metronidazole

Question 22

Treatment of Recurrent C. Diff Infection?

Answer 22

Recurrence treated by tapering course of oral Vancomycin followed by pulse dosing

Fecal Microbiota Transplant used for resistant recurrent C. Diff

Question 23

Role of Probiotics in Diarrheal Therapy?

______________: decreased duration of childhood infectious diarrhea

______________: decreased duration of C. Dif Infection

Answer 23

Assist in maintaining/recolonizing intesine w/ non pathogenic flora
Can prevent antibiotic-associated diarrhea

Lactobacillus: decreased duration of childhood infectious diarrhea

Saccharomyces boulardii: decreased duration of C. Dif Infection

Question 24

Classification of Chronic Diarrhea?

Answer 24

3 or more loose or water stools daily for 4 weeks or more!!

Question 25

Causes of Chronic Diarrhea (Developing vs. Developed)

Answer 25

Question 26

Anti-motility agents for treating diarrhea

Answer 26

**Opioid Agents (Loperamide)**: Act on GIT leading to decreased intestinal peristalsis and secretion of water/electrolyes=> Increases time material stays in intestine allowing water absorption **Muscarinic Receptor Antagonists (Hyoscine, Atroprine)**: GI antispasmodics/anticholinergics that inhibit acetylcholine action => Decrease motility *Rarely used due to actions on other systems outside the GIT*

Question 27

Pharmacogenetics/MOA/Risks of Loperamide as an Anti-Motiligy Agent?

Answer 27

_Pharmacogenetics (Opiod Family):_ * Does not cross BBB at low doses * Relatively selective for GIT * No analgesic effect due to poor absorption _MOA (Anti-Motility):_ Acts on Mu & delta receptors on myenteric receptor of gut=>Decreases circular/longitudinal muscle activity in small intestine=>Slows gut transit time => increased fecal water absorption and reduces the frequency of abdominal cramps _Risks:_ * Undergoes significant **Enterohepatic cycling** (limited systemic absorption) =>Persists in body bc repeatedly circulated from the intestine to liver * Prolonged use can promote **ILEUS** (No active peristalsis) * **NOT to be used in children under 4!!!!!!!**

Question 28

**5 Important Facts about Loperaminde?** ① It shortens the duration of ________________ ② Not recommended in ____________________as the decreased gut transit time can prolong the contact of contaminant with the damaged mucosa making things worse ③ Should not be used in _______________ ④ Also has __________________ activity ⑤ More potent than ___________ as an antidiarrhoeal agent

Answer 28

**5 Important Facts about Loperaminde?** ① It shortens the duration of **travellers’ diarrhea** ② Not recommended in **dysentery (fever bloody diarrhoea)** as the decreased gut transit time can prolong the contact of contaminant with the damaged mucosa making things worse ③ Should not be used in **young children (<4)** ④ Also has **anti-muscarinic** activity ⑤ More potent than **morphine** as an antidiarrhoeal agent

Question 29

What does **Diphenocuylate** (Anti-Motility Agent) usually contain to decrease abuse potential?

Answer 29

Atropine (Deadly Nightshade)

Question 30

Adverse effects of all opioids?

Answer 30

Constipation Abdominal cramps Drowsiness Dizziness Paralytic Ileus

Question 31

Drugs/MOA of Muscarinic Receptor Antagonists?

Answer 31

**Hyoscine, Atropine, Propantheline, Dicycloverine** M3 receptors (predominantly expressed in smooth muscle) activation leads to the contraction of visceral smooth muscle. Activation of receptors is prevented by parasympatholytic drugs => inhibition of GI motility _Rarely used– systemic affects_

Question 32

Drugs that can cause Diarrhea? Cardiac: ____________,______________ Endocrine: __________,______________,________________ GI: ______________,_____________ Others: ____________,_____________,_____________

Answer 32

Cardiac: **Digoxin, ACE Inhibitors** Endocrine: **Sulhonyureas, Metformin, Levothyroxine** GI: **Proton Pump Inhibitors (-Prazoles) , Laxatives** Others: **NSAIDS, Orlistat, SSRIs**