L11 Therapeutics for Diarrhea Flashcards
3 Clinical Types of Diarrhea?
- Acute Watery Diarrhea: hours to days (Includes Cholera)
- Acute Bloody Diarrhea (aka Dysentery):
- Persistent Diarrhea: Last 14 days or longer
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
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
Classification of Severe Acute Diarrhea?
- profuse watery diarrhea with signs of hypovolemia
- passage of ≥6 unformed stools per 24 hours
- severe abdominal pain
- need for hospitalization
Signs or symptoms concerning for inflammatory diarrhea?
- Bloody diarrhea
- Passage of many small volume stools w/ blood/ mucous
- Temp >38.5
Transmission/Primary Concerns of Cholera Infection?
- 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)
Pathogenesis of Cholera Infection?
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!!
Cholera Pathogenesis?
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
Where is there still an active cholera outbreak?
Yemen
General Approach to Therapy for Diarrhea?
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
Fluid Replication/Maintenance Goals?
- 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!
Importance of Zinc/Consequences of Deficiency?
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
Zinc’s Role in Cholera Management?
Inhibits cAMP production!!!!=> blocks cAMP activated K channels => Cl- dependent fluid secretion inhibited
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
- 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
Treatment for Severe Campylobacter?
Ciprofloxacin
Treatment for Pregnant woman with suspected Listeria Monocytogenes?
Ampicillin
Treatment for Cholera?
Single doses of either:
- Doxycycline 300mg
- Azithromycin 1g
- Ciprofloxacin 1g
Treatments for C. DIfficile Infection?
Metronidazole
Vancomycin
Fidaxomicin (Macrolide)
Prescribing Prevention of C. Diff infections?
Limiting use of ____________ and _____________
Use C Diff Targetting antibiotics (_____________, _____________, __________)
Limiting use of Quinolones and Cephalosporins
Use C Diff Targeting antibiotics (Metronidazole, Vancomycin/Fidaxomicin)
_________________________:
- 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
Metronidazole
_____________________:
- 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
Vancomyocin
____________________:
- Macrolide Antibiotic
- Bactericidal - targets bacterial RNA polymerase
- Inhibits C. Diff spore formation
- Minimal systemic absorption => high concentration in colon
- Narrow spectrum, long lasting effect
Fidaxomicin
Among patients with severe C. Diff infections, those treated with ________________ have a significantly lower risk of death than patients treated with ___________________
Among patients with severe C. Diff infections, those treated with Vancomycin have a significantly lower risk of death than patients treated with Metronidazole
Treatment of Recurrent C. Diff Infection?
Recurrence treated by tapering course of oral Vancomycin followed by pulse dosing
Fecal Microbiota Transplant used for resistant recurrent C. Diff
Role of Probiotics in Diarrheal Therapy?
______________: decreased duration of childhood infectious diarrhea
______________: decreased duration of C. Dif Infection
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
Classification of Chronic Diarrhea?
3 or more loose or water stools daily for 4 weeks or more!!
Causes of Chronic Diarrhea (Developing vs. Developed)
Anti-motility agents for treating diarrhea
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
Pharmacogenetics/MOA/Risks of Loperamide as an Anti-Motiligy Agent?
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!!!!!!!
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
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
What does Diphenocuylate (Anti-Motility Agent) usually contain to decrease abuse potential?
Atropine (Deadly Nightshade)
Adverse effects of all opioids?
Constipation
Abdominal cramps
Drowsiness
Dizziness
Paralytic Ileus
Drugs/MOA of Muscarinic Receptor Antagonists?
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
Drugs that can cause Diarrhea?
Cardiac: ____________,______________
Endocrine: __________,______________,________________
GI: ______________,_____________
Others: ____________,_____________,_____________
Cardiac: Digoxin, ACE Inhibitors
Endocrine: Sulhonyureas, Metformin, Levothyroxine
GI: Proton Pump Inhibitors (-Prazoles) , Laxatives
Others: NSAIDS, Orlistat, SSRIs
