Therapeutics GI Disordes by Pawlos Asfaw For 3rd Year Regular BPharm

THERAPEUTICS I
GASTROINTESTINAL DISORDERS
Pawlos Asfaw, BPharm, MSc

School of Pharmacy, Haramaya University, 2022
GASTROESOPHAGEAL
REFLUX DISEASE
(GERD)
4/21/2022 GID Therapeutics by Pawlos AT 2

OUTLINE
Introduction
Epidemiology
Etiology
Pathophysiology
Clinical presentation & Dx
Treatment
Outcome evaluation
INTRODUCTION
The Lower Esophageal Sphincter (LES)

Introduction
The Lower Esophageal Sphincter (LES)
»A specialized thickening of the smooth muscle
»Lining the distal esophagus
»Has elevated basal resting pressure
»Tonic, in contracted state, preventing reflux
»Transient relaxations on swallowing
• To permit passage of food into the stomach

Introduction
GERD grows as refluxed stomach contents incur
»Troublesome symptoms
• Heartburn…
»Complications
• Esophagitis
• Esophageal strictures
• Barrett’s esophagus
• Esophageal adenocarcinoma
EPIDEMIOLOGY
Prevalence of GERD
»Global: 8% - 33% (Katz PO et al. 2012)
»In GBD region nations: 4.4% - 14% (GBD 2017)
»In Africa: 7.6% in Nigeria (Sylvester et al. 2020)
Mortality of GERD
»2/106 annual death in Finland (Rantanen et al 1999)
Cost: >$12 billion DMC in the US (Chan HP 2020)
»DMC from all digestive
4/21/2022 GID Therapeutics tract
by Pawlos ATcancers: $8.4 billion7
ETIOLOGY
Risk factors for GERD & it’s complications
»Age >40 years
»FHx, smoking, alcohol, foods, medications
»Airway disease, reflux chest pain syndrome, obesity
»In females: pregnancy & nonerosive reflux disease
»In men: erosive esophagitis
• BE & esophageal adenocarcinoma
»Chronic GERD → esophageal adenocarcinoma
PATHOPHYSIOLOGY
The key factor in the development of GERD
»The abnormal reflux of gastric contents
• From the stomach
• Into the esophagus, Oral cavity/Larynx, Lung
Defective natural defense mechanisms
Damaging refluxates
»HCl, pepsin, bile acids, pancreatic enzymes
Pathophysiology
Defective natural defense mechanisms
»Decreased LES pressure
»Abnormal esophageal anatomy
»Improper esophageal gastric fluid clearance
»Reduced mucosal resistance to acid
»Delayed or ineffective gastric emptying
»Inadequate production of endothelial GFs
»Reduced salivary buffering of acid
Pathophysiology
Decreased LES pressure
»Spontaneous transient LES relaxations
• Not associated with swallowing
• >½ of reflux episodes in patients with GERD
• Unknown exact mechanism but occurs during
• Esoph distension, vomiting, belching, retching
• Important role in symptom-based GERD
• Trivial in erosive esophagitis
Pathophysiology
»Spontaneous transient LES relaxations
• Predictors of GERD in this case
• The degree of sphincter relaxation
• Efficacy of esophageal clearance
• Patient position → in recumbent position
• Gastric volume
• Intragastric pressure
Pathophysiology
»Transient rise in intra-abdominal pressure
• Stress reflux
• Strain, bending over, coughing, eating, Valsalva
»Atonic LES
• Permitting free reflux
• As in patients with scleroderma
»Other factors: pregnancy, foods, medications
Pathophysiology
GER pathophysiology is a complex cyclic process
Hard to tell w/c arises 1st: reduced LESP vs GER
Reduced LESP is not always associated with GER
Reduced LESP & GER may not result in GERD
»The other defense mechanisms must be evoked
Understanding the factors for GERD
»Provides insight into the treatment modalities
CLINICAL PRESENTATION & Dx
GERD can be described as per
1. Symptom-Based GERD syndrome
»Typical symptoms
»Heartburn (hallmark)
»Regurgitation/belching
»Reflux chest pain
»Alarm symptoms:
»Dysphagia, Odynophagia, Bleeding, Wt loss
GERD can be described as per
2. Tissue Injury-Based GERD syndrome
»Esophagitis
»Strictures
»Barrett’s esophagus
»Esophageal adenocarcinoma

Extraesophageal GERD Syndromes
»Chronic cough
»Laryngitis
»Wheezing
»Asthma: ∼50% with asthma have GERD

Diagnosis
»Clinical history → in patients with typical symptoms
»Endoscopy: for mucosal injury & complications
»Ambulatory reflux monitoring
»Manometry/HREPT
»Empiric PPI diagnostic test
»Barium radiography

TREATMENT
GOT
»Alleviate or eliminate the patient’s symptoms
»Decrease the frequency and duration of GER
»Promote healing of the injured mucosa
»Prevent complications

Treatment
Therapy is directed at
»Decreasing the acidity of the refluxate
»Decreasing the gastric volume to be refluxed
»Improving gastric emptying
»Increasing LES pressure
»Enhancing esophageal acid clearance
»Protecting the esophageal mucosa

Treatment
GERD treatment → as per disease severity
»Includes
• LSM & patient-directed H2RAs &/or PPIs
• Prescription strength acid suppression therapy
• Surgery
• Endoscopic therapies

Treatment
The initial treatment modality
»Patient condition
• Frequency of symptoms
• Degree of esophagitis
• Presence of complications
»Clinicians should determine the best approach
• To aggressively control symptoms
• To prevent relapses & complications
Treatment
The initial therapeutic modality
»A step-down approach
• Starting with a PPI
• Most often advocated
»Once esophageal healing or symptoms improved
• Step down to the lowest effective dose of PPI
• Switch to an H2RA

Evidence-Based Treatment Recommendations: GERD in Adults



Therapeutic Approach: GERD in Adults



Oral PPI Therapy: Pediatric Patients

OUTCOME EVALUATION
Successful outcomes → Separate end points:
»Relieving symptoms
»Healing the injured mucosa
»Preventing complications

Outcome Evaluation
Symptoms relieve, do not impair patient’s QOL
Educate patients on specific applicable LSMs
Patient medication profiles review
»Medications that may aggravate GERD
»DDIs should also be assessed & managed
Patients should be monitored for ADRs

Outcome Evaluation
Monitor the frequency & severity of symptoms
Counsel patients on alarming symptoms
»Suggest the presence of complications
»Need immediate medical attention, like dysphagia
Monitor patients for extraesophageal symptoms
»Laryngitis asthma or chest pain
»Require further diagnostic evaluation
Outcome Evaluation
Long-term maintenance treatment → Strictures
»As strictures often recur if esophagitis is not treated
Asses adherence to regimen to heal the mucosa
Educate patients on relapse & long-term therapy
»To prevent recurrence or complications
Treatment failure despite high doses H2RAs/PPI
Monitor patients: pain, dysphagia, odynophagia
Drug Monitoring

PEPTIC ULCED DISEASE
(PUD)

OUTLINE
Introduction
Epidemiology
Etiology
Pathophysiology
Treatment
Outcome evaluation
INTRODUCTION
Gastric-acid
»Critical factor of upper GIT complications including
• Gastritis
• Erosions
• Peptic ulcer

Introduction
PUD differs from gastritis & erosions in that
»Full-thickness loss of gastric mucosa
»Large ulcers ≥5 mm
• Extend deeper into the muscularis mucosa

Introduction
The three common forms of peptic ulcers:
»H. pylori–positive
»NSAID–induced
»Stress-related mucosal damage

Introduction
H. pylori–positive & NSAID-induced ulcers
»Chronic peptic ulcers
»Often in stomach/duodenum of ambulatory patient
»Characterized by frequent ulcer recurrence
»Differ in etiology, clinical presentation, recurrence
SRMD occurs in
»Primarily in the stomach
»Critically ill patients
Introduction
Comparison of Common Forms of Peptic Ulcer

Introduction
Commonest sites of gastric & duodenal ulcers

EPIDEMIOLOGY
PUD remains a common GID, resulting in
»Impaired QOL, Work loss, High-cost medical care
Annual PUD incidence: 0.1% - 0.3%
Lifetime PUD prevalence: 5% to 10%
In the US
»Declined PUD prevalence & incidence
»Declined mortality, admission, ambulatory visits
»Increased ED visits
4/21/2022
for GI hemorrhage due to PUD
GID Therapeutics by Pawlos AT 45
Epidemiology
Mortality is higher in
Males, ≥65 years, gastric ulcer
H. pylori prevalence:
»Declined in the developed than developing nations
»In the US
• In the general population: 30% - 40%
• In those >60 years of age: 50% - 60%
4/21/2022
• In children (<12 years): 10%-15%
Epidemiology
NSAIDs ulcer
»In chronic users: up to 15% to 40%
»In short-term users: Up to 80% (upon endoscopy)
»Gastric ulcers are most common
• Occur primarily in the antrum
• Concern → Ulcer-related upper GI complications
• Bleeding, strictures, and perforations

Epidemiology
NSAIDs ulcer
»2% - 4% of the patients will bleed or perforate
»In the US
• ≥100,000 hospitalizations/year
• 7,000 - 10,000 deaths/year
»Ulcer-related complications & death in regular users
• 3 to 10x higher than nonusers

ETIOLOGY
Potential Causes of Peptic Ulcer

Etiology
Commonest RFs for PUD: H. pylori & NSAID
ZES with hypersecretion of acid can be involved
Mucosal disruption & healing allow acid/pepsin
to reach the gastric epithelium
Benign gastric ulcers, erosions, & gastritis
»Most common in the antrum & lesser curvature
Most duodenal ulcers arise in the duodenal bulb
Etiology
H. pylori
»Spiral, microaerophilic, flagellated G/-ve bacteria
»Has urease, catalase, & oxidase activity
• Urease vs. acidity of the stomach
• Catalase vs. reactive oxidation by phagocytes
• Flagella vs. gastric mucosa
»Transmission: gastro–oral or fecal–oral
• RFs: close contact, poverty, country of origin
Etiology
H. pylori
»Can cause acute/chronic gastritis in infected ones
»Associated with multiple GI complications
• PUD, MALT lymphoma, gastric cancer
»10% to 20% will develop PUD during their lifetime
»About 1% will develop gastric cancer
»3-7x increase in the risk of GI bleeding & PUD
»No specific link with dyspepsia or GERD
Etiology
H. pylori → PUD, MALT lymphoma, gastric ca

Etiology
NSAIDs
»Chronic use: U-GIT injury, PUD, Gastritis, erosion
»In minutes: Superficial mucosal damage/petechiae
• Progress to erosions with continued use
• Typically heal within a few days
• Rarely cause ulcers or acute upper GI bleeding
»NSAID-induced ulcers are usually gastric
»The enteropathy is linked with lower GI bleeding
Etiology
RFs → NSAID-Induced Ulcers & Complications

Etiology
Selected NSAIDs & COX-2 Inhibitors

PATHOPHYSIOLOGY
The balance b/n aggressive & protective factors defines
the pathophysiology of gastric & duodenal ulcers
Aggressive factors Protective factors

»Gastric Acid Vs »Mucosal defense
»Pepsin »Mucosal repair
Alterations in mucosal defense induced by H. pylori or

NSAIDs
4/21/2022
are central cofactors in peptic ulcers formation
Pathophysiology
The aggressive factors
»Gastric acid
• Independent factor → mucosal disruption
• Secreted by the parietal cells
• Have receptors for histamine, gastrin, & Ach
• Increased in patients with duodenal ulcers
• Normal/decreased in patients with gastric ulcer
4/21/2022
• Higher BAO:MAO ratio → ZES
Pathophysiology
The aggressive factors
»Pepsin
• Key cofactor in proteolysis in ulcer formation
• Pepsinogen is the inactive precursor of pepsin
• Secreted by the chief cells in the gastric fundus
• Activated at acid pH (optimal pH of 1.8-3.5)
• Reversibly inactivated at pH 4
4/21/2022
• Irreversibly destroyed at pH 7
Pathophysiology
The protective factors
»Mucosal defense
»Protect the gastroduodenal mucosa
»From noxious endogenous/exogenous entities
»Mechanisms
»Mucus & bicarbonate secretion
»Intrinsic epithelial cell defense
4/21/2022
»Mucosal blood flow
Pathophysiology
»Mucosal defense
»The mucus–bicarbonate barrier
»Viscous & near-neutral pH
»Protect the stomach from the acidic contents
»Endogenous PGs
»Facilitates mucosal integrity & repair
4/21/2022
»Prevent deep mucosal injury
Pathophysiology
»Mucosal defense
• Adaptive cytoprotection
• Short-term adaptation of mucosal cells
• To mild topical irritants
• Characterized by
• Gastric hyperemia
4/21/2022
• Increased PG synthesis
Pathophysiology
»Mucosal repair
»After injury
»Related to epithelial cell
»Restitution
»Growth
»Regeneration

Pathophysiology
H. pylori
»Resides
• B/n the gastric mucus layer & surface epithelium
• In any site where gastric-type epithelium is found
»Its spiral shape & flagellum permits it to move
• From the stomach lumen, where the pH is acidic
• To the mucus layer, where the local pH is neutral

Pathophysiology
H. pylori
»Produces large amounts of urease
• Hydrolyzes urea in gastric juice to NH3 & C2O
»The local buffering effect of NH3
• Creates a neutral microenvironment
• Protect H. pylori from the gastric acid lethality

Pathophysiology
H. pylori
»Produces acid-inhibitory proteins
• Allow it to adapt to the low-pH of the stomach
»Binds to gastric-type epithelium using pedestals
• Avoids shed off by cell turnover/mucus secretion
»Colonizes antrum & corpus → Gastric ulcer & ca
»Colonization in the duodenum → Duodenal ulcer

Pathophysiology
H. pylori
»Causes gastric mucosal injury using its
• Enzymes
• Lipases & proteases → degrade gastric mucus
• Urase → NH3 → toxic to gastric epithelium
• Adherence
• Enhances the uptake of toxins
• Virulence factors
Pathophysiology
H. pylori
»Induces gastric inflammation
• Directly by cell mediated immune mechanisms
• Indirectly by activated neutrophils/macrophages
»Diverse clinical outcomes related to variations in
• Bacterial pathogenicity → CagA & VacA
• Host susceptibility → Polymorphism

Pathophysiology
NSAIDs
»Damage gastric mucosa by local & systemic effect
»Systemic mechanism
• Inhibition COX-1 → protective PGs synthesis
• Limits mucosal defensiveness against injury
• Plays major role in gastric ulcer development
• Nonselective → high propensity to gastric ulcers

Pathophysiology
NSAIDs
»Local effect
»Acidic NSAIDs
»Have topical irritant properties
»Decrease hydrophobicity of the mucous layer
»Aspirin is the most damaging

Pathophysiology
NSAIDs
»Bypass strategies
»NSAID prodrugs
»Enteric-coated tablets
»Salicylate derivatives
»Parenteral or rectal preparations
»Associated with less acute gastric mucosal injury
»Can cause ulcers & complications systemically
Pathophysiology
Complications
»Life-threatening complications of chronic PUD
»Upper GI bleeding
»Perforation
»Obstruction

Pathophysiology
Complications
»Upper GI bleeding
»Bleeding peptic ulcers are commonest causes
»NSAID use is the major RF
»Mortality is highest in patients with
»Uncontrolled bleeding
»Rebleeding event

Pathophysiology
Complications
»Gastric perforation
»Depending on the ulcer location
»Into peritoneal cavity → 2nd most complication
»Ulcer may penetrate into an adjacent structure
»Decreased incidence with the availability of PPIs
»The mortality and morbidity remain high

Pathophysiology
Complications
»Gastric perforation
»Pain
»Usually sudden, sharp, and severe
»Beginning first in the epigastrium
»Quickly spreading over the entire abdomen
»Most have ulcer symptoms prior to perforation
»Elderly with NSAID ulcer may be asymptomatic
Pathophysiology
Complications
»Gastric outlet obstruction
»Narrowed duodenum
»Due to chronic inflammation & ulcer scaring
»Rare complication
»Patients often present with
»Severe vomiting
»Hematemesis
Variable clinical presentation of PUD as per
»The severity of epigastric pain
»The presence of complications
Pain related to duodenal ulcer
»Often occurs 1 to 3 hours after meals
»Usually relieved by food
Food may precipitate gastric ulcer pain


Symptoms are nonspecific & of limited Dx value
The diagnosis of PUD: visualizing ulcer crater
Endoscopy: the diagnostic procedure of choice
»Provides a more accurate diagnosis
»Permits direct visualization of the ulcer
»Allow implementation of therapeutic maneuvers
• Injection of epinephrine or hemostatic clips
TREATMENT
GOT
»General
• Relieve ulcer symptoms
• Heal the ulcer
• Prevent recurrence
• Reduce ulcer-related complications

TREATMENT
GOT
»In H. pylori/+ve ulcer
• Eradicate H. pylori
• Heal the ulcer
• Cure the disease

Treatment
The treatment of PUD varies as per
»The etiology of the ulcer
• H. pylori-positive ulcer
• NSAID-induced ulcer
»Whether the ulcer is initial or recurrent
»The presence of complications

Clinical evaluation & management of patients with ulcer-like symptoms
Treatment
LSMs
»Stress reduction & smoking cessation
»Avoid spicy foods, caffeine, alcohol
Surgery
»Elective surgery is rarely performed today
• Medical management is highly effective
»Emergent surgery in patients with complications
4/21/2022
• Bleeding, perforation, obstruction
Treatment
H. pylori-Positive Ulcers
»Ideal regimen:
• Highly-effective
• Free of significant side effects
• Easy to adhere to
• Cost-effective
»Existing treatments lack one or more of these areas

Treatment
»The initial regimen → highest odds of eradication
»Selection of an appropriate first-line regimen is key
»No available regimen offers 100% eradication
»1st-line drug regimen:
PPI + Multiple ABX ± Bismuth

Treatment
»Antimicrobials
• Well-studied ABX used in various combinations
• Clarithromycin
• Amoxicillin
• Metronidazole
• Tetracycline

Treatment
»Antimicrobials
• Monotherapy not recommended
• PPI + amoxicillin/clarithromycin: Not as 1st-line
• Substitutions to avoid
• Ampicillin for amoxicillin
• Doxycycline for tetracycline
• Azithromycin/erythromycin for clarithromycin
Treatment
»Antisecretory drugs: PPIs & H2RA
• Hastens ulcer healing
• Relieves pain in patients with an active ulcer
• Enhances antibiotic activity through
• Increasing intragastric pH
• Decreasing intragastric volume
• Enhancing the topical antibiotic concentration
Treatment
»PPIs
• Integral part of the first-line drug regimens
• Preferred antisecretory agents with class effect
• Yield a higher H. pylori eradication than H2RAs
• Should not be substituted with a H2RA
• Pretreatment does not influence the eradication

Treatment
»Bismuth salts
• Have a topical antimicrobial effect
• Do not inhibit or neutralize acid
• Used with caution in older patients & in RF
• Caution in patients with concurrent salicylates
• Black color stool & tongue with liquid forms
• Long-term use is not recommended → toxicity
Eradication of H. pylori infection

1st-Line Regimens used to eradicate H. pylori infection

Treatment
»PPI–Based Triple therapy
• Preferred initial TOC for eradicating H. pylori
• No longer 1st-line in North America
• Due to high clarithromycin resistance
• Remains an option in regions where
• Clarithromycin resistance is <15%
4/21/2022
• No documented prior macrolide exposure
Treatment
• Clarithromycin + amoxicillin or metronidazole
• More effective than the
• Amoxicillin–metronidazole regimen
• Metronidazole can be switched for amoxicillin
• In penicillin-allergic patients
4/21/2022
• Unless alcohol is consumed
Treatment
• Increased ABX dose doesn’t improve eradication
• The recommended treatment duration is 14 days
• Shorter treatment durations
• Increased resistance
• Lower overall eradication rates

Treatment
»Bismuth-Based Quadruple Therapy
1. PPI or H2RA
2. Bismuth salicylate
3. Metronidazole
4. Tetracycline

Treatment
• A recommended 1st-line option
• Particularly for penicillin-allergic patients
• Mean eradication rate after 10-day Tx was 91%
• Higher than PPI-based triple therapy
• Superior to 7-day clarithromycin triple therapy

Treatment
• Eradication rates are similar for d/t bismuth salts
• Take with meals & HS → all drugs except the PPI
• Demerits
• QID dosing, potential for nonadherence
• Frequent minor S/Es

Treatment
»Non-Bismuth Quadruple Therapy
1. PPI
2. Amoxicillin
3. Clarithromycin
4. Metronidazole

Treatment
»Non-Bismuth Quadruple Therapy
• Also called concomitant therapy
• Taken together
• At standard doses
• For 10 to 14 days
• Less clarithromycin resistance than triple therapy
4/21/2022
• 1 st-line alternative to the triple therapy
Treatment
»Sequential Therapy
• The ABXs are administered in a sequence
• PPI + amoxicillin for 5 days, then
• PPI, clarithromycin, & mtz for the next 5 days
• To initially treat with ABX rarely incur resistance
• To reduce bacterial load & resistant organisms
4/21/2022
• The 2 nd sequence → kill any remaining organisms
Treatment
»Sequential Therapy
• Superior eradication rates than the triple therapy
• The interim ABX change → Nonadherence
• Tinidazole can be substituted for metronidazole

Treatment
»Hybrid therapy
• Joint strategy: sequential & concomitant therapy
• Initial 7 days dual therapy (PPI + amoxicillin)
• Followed by 7 days of quadruple therapy
• PPI, amoxicillin, clarithromycin, & mtz
• Less clarithromycin resistance than triple therapy
4/21/2022
• 1 st-line alternative to the triple therapy
Treatment
»Levofloxacin-Based Therapy
• Triple therapy with amoxicillin & PPI
• 7-day therapy
• Similar to clarithromycin-based 7-day TT
• 10 to 14 days therapy
• Superior to clarithromycin-based 7-day TT

Treatment
• Modified sequential therapy
• Initial 5-7 days of amoxicillin + PPI
• Followed by 5 to 7 days of levofloxacin
• Higher eradication rates than pooled
• Clarithromycin-based triple & sequential Tx

Treatment
• Quadruple therapy
• Levofloxacin, nitazoxanide, doxycycline, & PPI
• Not currently recommended
• Cost
• Lack of data

Treatment
• Concerns
• Resistance
• A/Es:
• Tendonitis
• Hepatotoxicity…

Treatment
»Probiotics
• Lactobacillus, Bifidobacterium
• Limit H. pylori colonization
• As a supplement to antibiotic therapy
• Increases eradication rates
• May reduce the A/Es of the ABX
4/21/2022
• Low-cost alternatives
Treatment
»Salvage or 2nd-line therapy → Treatment Failure
• Use ABX not used initially or recently
• Use an extended treatment up to 10 to 14 days
• Empiric treatment decisions are necessary
• Region-specific or individual ABX resistance test
• Culture/DST or molecular resistance data

Treatment
• For patients failing clarithromycin triple therapy
• Bismuth quadruple therapy for 14 days or
• Levofloxacin triple regimen for 14 days
• For patients failing 1st-line sequential therapy
• PPI, bismuth, TTC, & levofloxacin for 10 days

Treatment
• High-dose dual therapy
• PPI + amoxicillin TID-QID for 14 days
• Other salvage regimens: rifabutin & furazolidone
• Penicillin skin testing is recommended
• As amoxicillin is key with low resistance
4/21/2022
• Many patients are not truly penicillin-allergic
Treatment
»Predictors of Successful H. pylori Eradication
»Antimicrobial resistance
• The most important & consistent predictor
»Duration of therapy
»Medication adherence
»Pharmacogenomic factors

Treatment
»Global resistance rates of H. pylori strains for
• Clarithromycin: 30.8%
• Metronidazole: 30.5%
• Levofloxacin: 14.2%
• Amoxicillin: 2%
• Tetracycline: 0%

Treatment
»Predictors of Successful H. pylori Eradication
»Medication adherence decreases with
• Multiple medications
• Increased frequency of administration
• Intolerable adverse effects
• Costly drug regimens

Treatment
NSAID-induced ulcers
»Confirmed active ulcer → Interrupt NSAID therapy
»Most uncomplicated ulcers heal with 8-week Tx of
• H2RA,
• PPI, or
• Sucralfate
»PPIs are preferred due to rapid relief & healing

Treatment
»Continued NSAID despite ulceration
• PPI (DOC) or misoprostol
»Considerations:
• NSAID dose reduction
• Switching acetaminophen or non-ASA salicylate
• Using a selective COX-2 inhibitor
»H. pylori/+ve → eradication regimen containing PPI
Treatment
»Preventive measures in chronic NSAID therapy
• Co-therapy with a PPI, H2RA, or misoprostol
• COX-2 selective NSAID alone
• COX-2 selective NSAID + gastroprotective agent
• COX-2 selective NSAID + PPI
• Greatest protection vs. upper GI complication

Treatment
• May not eliminate ulcers and complications for
patients at the “highest risk”
• Nonselective NSAID + H2RA
• Effective at preventing duodenal ulcers
• Ineffective at preventing gastric ulcers

Treatment
• Selection of a gastroprotective strategy
• GI benefits vs. CV risks
• Strategies vs. local A/Es of nonselective NSAIDs
• Prodrug, slow-release, enteric-coated products
• Ineffective at averting ulcers or complications

Prevention of PUD in Chronic NSAID Therapy

Treatment
»Misoprostol
• A synthetic analog of PGE1
• Improves mucosal blood flow
• Stimulates gastric mucous & bicarbonate secretion
• High dose (>600 mg/day) > 80% risk reduction
• Limits perforation, obstruction, and bleeding
• Dose limiting A/Es: nausea, diarrhea, & cramp
Treatment
Refractory Ulcers
»Ulcers after 8-12 weeks standard anti-secretory Tx
»Persistent H. pylori infection or use of NSAIDs
»Additional contributing factors:
• Poor patient compliance
• Cigarette smoking
• Gastric acid hypersecretion
• Tolerance to the effects of an H2RA
Treatment
Refractory Ulcers
»Upper endoscopy: nonhealing ulcer or malignancy
»Reassess H. pylori status → ≥2 diagnostic methods
»H. pylori–positive patients → Eradication therapy
»Fasting plasma gastrin levels if ZES is suspected
»Despite a complete standard PPI course
• Retreated with double-dose of PPI
• Consider a different PPI
Recommended Dosing of Drugs Used to Treat Ulcers

OUTCOME EVALUATION
The long-term benefits of treatment are difficult
to assess (dearth of data on GERD)
Successful outcomes → End points:
»Relieving symptoms
»Healing the injured mucosa
»Preventing complications

Outcome Evaluation
Drug Monitoring

LIVER CIRRHOSIS

OUTLINE
Introduction
Epidemiology
Etiology
Pathophysiology
Treatment
Outcome evaluation
INTRODUCTION
The Liver
»The largest viscera
»Has four lobes

Introduction
The Liver
»Lobes are made of thousands of hexagonal lobules
• At the center of each lobule is the central vein
• At the periphery of each lobule are regions of
• The portal triad, lymphatics, nerves
• Made up of numerous hepatocytes
• Line up in radiating rows
• B/n each rows are sinusoids
4/21/2022 GID Therapeutics by Pawlos AT
The hepatic lobule
136
Introduction
The Liver
»Receives blood from two sources:
1. The hepatic artery:
• 25% of the blood delivered to the liver
• Oxygenated blood
• From the systemic circulation
• Via abdominal aorta

Introduction
The Liver
»Receives blood from two sources:
2. The portal vein:
• 75% of the blood delivered to the liver
• Nutrient-rich deoxygenated venous blood
• From the splanchnic bed
• At a rate of 1 to 1.5 L/min
• Has a normal pressure of 5 to 10 mm Hg
4/21/2022
The portal venous system
Introduction
The Liver
»Arriving systemic & venous blood
• Travels via the sinusoids
• Drain via the space of Disse
• Exchange macromolecules with the hepatocytes
»Filtered sinusoidal blood empties into
• Central veins → Larger veins → Inferior vena cava

Introduction
The Liver
»Sinusoidal cells
• The predominant non-parenchymal cells
• About 35% & 17% of the liver cells & volume
• Endothelial cells: 44%
• Kupffer cells: 33%
• Stellate cells: 10 - 25%
• NK cells: 5%
Introduction
The Liver
»Sinusoidal endothelial cells
• Form the sinusoidal wall (endothelium)
• The sieve plates
• Group of open fenestrae (150-175 nm)
• Way of fluid, solutes & particles exchange
• B/n the space of Disse & sinusoidal blood

Introduction
The Liver
»Kupffer cells
• Tissue macrophages with phagosomes/lysosomes
• Anchored to the periportal zone of the lobule
• Move along sinusoids & scavenge foreign maters
»NK cells
• “Pit cells” → Liver specific natural killer cells
• Have the capacity to kill arriving ca cells
Introduction
The Liver
»Stellate cells
• Quiescent vitamin A storing cells
• Found w/n the space of Disse/perisinusoidal space
• B/n hepatocytes & sinusoid
• Containing the blood plasma
• Contain lipid droplets rich in vitamin A
• Synthesize & secrete various ECM proteins
Introduction
The Liver
»Hepatocytes → Parenchymal cells
• The basic structural unit of the liver
• 60% of the total liver cell number
• 80% of the total liver mass
• Set radially w/n lobules → Form cellular plates
• Surround the sinusoids
• Have microvilli extending into the space of Disse
Introduction
The Liver
»Hepatocytes → The workhorse of the liver
• Produce & excrete bile
• Excrete bilirubin, cholesterol, hormones, drugs
• Metabolize fat, proteins, & carbohydrates
• Detoxify & purify the blood
• Synthesize proteins: albumin, clotting factors
• Stores glycogen, vitamins & minerals
Introduction
Cirrhosis
»A late-stage of progressive hepatic fibrosis
»Damage to normal liver tissue
• Development of fibrous scar tissue
• Distortion of the architecture of the liver
• Loss of viable hepatocytes
• Progressive deterioration of liver function
»Leads to various dreadful complications & death
EPIDEMIOLOGY
Cirrhosis in the US
»The 12th leading cause of death
»AVB & SBP are among the acute fatal complications
»Ascites & HE are in the major causes of morbidity
»About 50% of patients develop ascites w/n 10-year
»Nearly half of patients with ascites die w/n 2 years

ETIOLOGY

PATHOPHYSIOLOGY
Chronic Liver Injury → Fibrosis → Cirrhosis
»The stellate cells undergo an “activation” process
• Lose vitamin A
• Become highly proliferative
• Synthesize fibrotic tissue → mount up in the SOD
»Hepatic-sinusoidal endothelial cells
• Lose their fenestrae → Become less permeable
• Imped macromolecules-hepatocytes interaction
Pathophysiology
Cirrhosis
»Diffuse nodular regeneration
»Dense fibrous septa
»Distort the basic architecture of the liver
»Disrupt hepatic blood flow
»Destruction of hepatocytes
»Deterioration of liver function
»Hepatic failure & death
Pathophysiology
Cirrhosis → Complications
»Portal hypertension
»Ascites
»Varices & variceal bleeding
»Hepatic Encephalopathy
»Spontaneous Bacterial Peritonitis
»Coagulopathy
»HRS, HPS, endocrine dysfunction, HCC
Pathophysiology
Portal hypertension
»Intrahepatic (sinusoidal) damage
»Increased resistance to hepatic blood flow
»Elevated portal vein pressure
• Exceeding 10-12 mmHg
»Incurs other perilous complications
• Ascites, VB, HE, HRS

Pathophysiology
Ascites
»Decompensated cirrhosis
»Fluid growth
»Peritoneal cavity
»Dire prognosis

Pathophysiology
Ascites
»Portal hypertension
»Splanchnic vasodilation
»Contracted effective intravascular volume
»Renal hypoperfusion → RAAS, ADH, SNS activation
»Salt & fluid retention → Plasma volume expansion
»Fluid extravasation into the peritoneal cavity

Pathophysiology
Ascites

Pathophysiology
Ascites
»Obstructions of hepatic sinusoids & LNs
• Fluid seeping into the peritoneal cavity
»Declined albumin production
• Hypoalbuminemia
• Elevated hydrostatic pressure
• Increased capillary permeability
• Fluid extravasation into the peritoneal cavity
Pathophysiology
Varices
»Weak collateral/superficial vessels
»Develop in the esophagus, stomach, & rectum
»As a result of portal hypertension
»To compensate for the increased blood volume
»Divert blood back to the systemic circulation
• Loss of 1st-pass effect
»Can rupture & bleed upon any additional pressure
Pathophysiology
Hepatic Encephalopathy
»A spectrum of neuropsychiatric abnormalities
»Due to accumulation of neurotoxic by-products
• Mainly gut-driven nitrogenous by-products
»Portosystemic shunting → Bypassing the liver
»Disrupted hepatocytes → Reduced NH3 conversion
»Accumulation of ammonia → Neurotoxicity
»NH3 is just one of the neurotoxic by-products
Pathophysiology
»Factors associated with acute HE
• Infections
• Variceal hemorrhage
• Renal insufficiency
• Electrolyte abnormalities
• Increased dietary protein

Pathophysiology
Spontaneous Bacterial Peritonitis
»Acute bacterial infection of peritoneal/ascitic fluid
• No intra-abdominal infection or perforation
»Possible means of contamination
• Translocation of intestinal flora via mesenteric LN
• Hematogenous spread into the peritoneal cavity
»Up to 30% of patients with ascites develop SBP
»Low protein ascites (<1 g/dL) → increased SBP rate
Pathophysiology
»Bacterial pathogens
• Enteric gram-negative aerobes → Commonest
• E. coli
• K. pneumoniae
• Gram-positive pathogen
• S. pneumoniae
• Rarely polymicrobial
Pathophysiology
Hepatorenal Syndrome
»Declined renal function in the setting of cirrhosis
»Decreased renal perfusion due to
• Renal artery vasoconstriction by the SNS
• Decreased MAP mediated by NO
»Overwhelmed renal compensatory mechanisms
• RAAS activation
• PGE2 & prostacyclin production
Pathophysiology
Hepatorenal Syndrome
»Type 1 HRS is characterized AKI
• In the presence of decompensated cirrhosis
• Not reversible with volume repletion
»Untreated it is rapidly fatal: 50% rate at 14 days
»Type 2 HRS
• Has similar pathophysiology to type 1 HRS
• Featured by a less acute decline in renal function
Symptoms
»Largely asymptomatic until decompensation
»Nonspecific Sxs:
• Fatigue
• Poor appetite
• Weight loss
»Complication Sxs:
• Body swelling, hematemesis, melena…
Signs
»Liver & spleen may be enlarged
»Icteric sclera
»Parotid gland enlargement
»Palmar erythema, spider angiomas, caput medusae
»Pubic & axillar hair loss
»Ascites & edema
»Sleep disturbance, b/r or mental status changes
Investigations
»Abdominal Ultrasound
»CBC: thrombocytopenia
»Elevated liver transaminases
»Increased bilirubin
»Elevated PT
»Hypoalbuminemia
»Upper GI endoscopy, SCr, Urea, serum electrolytes
Diagnosis
»The diagnosis is made based on combination of
• Clinical findings (Hx & PE): sign & symptoms
• Hypoalbuminemia
• Elevated INR/PT
• Thrombocytopenia
Regenerative nodules
• Ultrasound findings
enclosed by
4/21/2022 dense fibrotic materials!!!
Disease severity → Child–Pugh score

Need for transplantation → MELD score
»Ranges from 6 – 40
»A score ≥17:
• Candidate for LT
• Derive significant survival benefit
»A score of 40: have 3 month survival; 0% w/o LT

TREATMENT
GOT
»Reduce complication rates
»Treat the complications
»Decrease hospitalization

Treatment
Non-pharmacologic
»Salt restriction (< 2 g/day)
»Monitor weight regularly
»Bed rest
»Low protein diet
»Endoscopic sclerotherapy &/or banding

Treatment
Portal hypertension & varices
»Nonselective β-blockers are first-line treatments
• Reduce bleeding & mortality in known varices
»β1 blockade: reduces CO & splanchnic BF
»β2 blockade: deters β2-mediated visceral vasodilation
»Start low go slow dosing
»Propranolol 10 to 20 mg QD or BID

Treatment
Variceal bleeding
»Endoscopic band ligation: primary treatment tool
»Octreotide: preferred vasoactive agent
• Initial 50 mcg IV bolus
• Followed by 50 mcg/h continuous IV infusion
• From 2 to 5 days after acute variceal bleeding
• May d/c: patient is free of bleeding for ≥ 24 h

Treatment
Variceal bleeding
»Ceftriaxone 1g IV QD is recommended
• To prevent SBP & other infections
»Erythromycin 250 mg IV stat
• Prior to endoscopy
• To accelerate gastric emptying of clots
• To improve visibility during the procedure
»β-blocker & chronic EVL is TOC for 20 prophylaxis
Treatment
Ascites
»Spironolactone
• Starting dose 100 mg/day as QD or BID
• Titration:
• If no responses
• Every 3 to 7 days
• In 100 mg steps
• Maximum dose: 400mg/day
Treatment
Ascites
»Furosemide
• Add-on: BWt. reduction <2 kg in one week
• Alternative: Hyperkalemia or Renal impairment
• Starting dose: 20mg BID
• Increments by 40mg/day
• Maximum dose: 160 mg/day (80mg BID)

Treatment
»Prophylactic ABX is recommended during acute VB
• Reduces in-hospital infections & mortality
• Initiate with a 3rd-generation cephalosporin
»Empiric ABX:
• Initiate with IV 3rd-generation cephalosporin
• Cefotaxime 2g TID
• Ceftriaxone 1g QD
Treatment
»SBP is the primary cause of HRS
»Albumin therapy
• To reduce the risk of RF
• 1.5 g/kg initially
• Followed by 1 g/kg on day 3 of SBP therapy

Treatment
»Long-term Prophylaxis → Decreases mortality
• Recommended in a select group of patients
• Hx of SBP & LPA (<1.5 g/dL) + one of
• SCr ≥1.5 mg/dL,
• BUN ≥25 mg/dL,
• Serum sodium ≤130 mEq/L,
• Child–Pugh score ≥9 with bilirubin ≥3 mg/dL
Treatment
»Long-term Prophylaxis → Decreases mortality
• Recommended oral regimens include
• TMP-SMX DS tablet daily
• Ciprofloxacin 750 mg daily

Treatment
Spontaneous Bacterial Peritonitis: STG 2020
»1st-line: Ceftriaxone 1g IV BID for 7-10 days
»Option: Ciprofloxacin 200mg IV BID for 7-10 days
»Prophylaxis
• Advanced cirrhosis & ascitic protein <1.5 g/dl
• In GI bleeding & severe liver disease
• Patients who recover from an episode of SBP
• 1st-line: Norfloxacin 400mg PO QD indefinite
Treatment
»Lactulose
• The base of drug therapy to prevent/treat HE
• Nondigestible synthetic disaccharide laxative
• Activated in the gut, draws water, & defecation
• Lowers colonic pH: converts NH3 to NH4+
• Usually initiated at 15-30 mL BID-TID
4/21/2022
• Titrated to goal 2-4 soft bowel movements daily
Treatment
»Antibiotics
• To decreases urease-producing gut bacteria
• Rifaximin: 550 mg BID or 400 mg TID
• Effective & well tolerated
• Metronidazole & neomycin: not recommended
• A/Es: peripheral neuropathy, nephrotoxicity
»Flumazenil vs. false NTs in HE, used in research
OUTCOME EVALUATION
Review the drug regimen at each visit to assess
»Adherence
»Effectiveness
»Adverse events
»Need for drug titration

Outcome Evaluation
Determine adherence to lifestyle changes
»Cessation of ethanol intake
»Avoidance of OTC medications
»Dietary supplements
Assess dietary sodium intake: patient food recall
Measure dietary sodium adherence
»Using spot urine sodium-to-potassium ratio
»To assess appropriate
4/21/2022 sodium
GID Therapeutics by Pawlos AT excretion 196
Outcome Evaluation
Measure HR to assess success of β-blocker Tx
»Reduction of 25% from baseline or to 55-60 bpm
Ask the patient regarding A/Es of β-blockers
»Symptoms of orthostatic hypotension
• Lightheadedness
• Dizziness
• Fainting

Outcome Evaluation
Effectiveness of diuretic therapy in ascitic/edema
»Ask the patient regarding abdominal
• Girth, fullness, tenderness, & pain
»Weigh the patient at each visit
»Ask the patient to keep a weight diary
»Assess for peripheral edema at each visit

Outcome Evaluation
CBC & PT/INR to assess for
»Anemia, thrombocytopenia, coagulopathy
Ask the patient about bleeding
»Bruising, hematemesis, hematochezia, melena
Review biopsy reports and laboratory data
AST/ALT/NH3 not link well with progression
Raised coagulation times marker synthetic loss
Outcome Evaluation
Evaluate for signs & symptoms of HE
»Mental status changes may be subtle
»Ask caregivers about confusion or personality alter
In patients taking lactulose therapy
»Titrate the dose till 2-4 soft bowel movements daily
In HRS:
»Small changes in SCr/BUN may mean significant RI
Drug Monitoring Guidelines

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THERAPEUTICS I

Pawlos Asfaw, BPharm, MSc

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Aggressive factors Protective factors

Alterations in mucosal defense induced by H. pylori or

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PPI + Multiple ABX ± Bismuth

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