10/6/2020

Pharmacotheraphy
Gastrointestinal Tract
Liza Yudistira Yusan,S.Farm.,M.Farm-Klin.,Apt.
Prodi Farmasi FK UHT Surabaya
Gasal-2020

OUTLINE

Dyspepsia
GERD
Peptic Ulcer Disease
H.pylori

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PENDAHULUAN
 GER ( refluks gastroesofageal ) adalah
fenomena yang dapat timbul sewaktu-waktu
pada populasi umum , terutama sehabis
makan dan kemudian kembali seperti normal
 refluks fisiologis.
 Dikatakan patologis (GERD) bila terjadi refluks
berulang dalam waktu lama sehingga menim
bulkan keluhan/kerusakan mukosa esofagus
 Terdapat peningkatan prevalensi GERD

GERD-Definition

A common medical disorder or “a condition that

occurs when the refluxed stomach contents lead
to troublesome symptoms and/or complication”.

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GERD

Often called reflux

It is the recurring backflow of acid from the
stomach into the esophagus
Symptom-based esophageal GERD
syndromes may exist with or without
esophageal injury and most commonly
present as heartburn, regurgitation, or
dysphagia

EPIDEMIOLOGY
Most common in patient older than age 40 years
Mortality is rare
Significant impact on quality of life
 About 44% of the US adult population have heartburn at
least once a month
14% of Americans have symptoms weekly
7% have symptoms daily
10-20% of adults in Western countries suffer from GERD
symptoms on weekly basis
The prevalence of GERD in Asian populations is
reported to be lower than that in the west

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GERD has a greater impact on quality

of life than other common diseases

Psychiatric patients
Esophagitis, untreated
Duodenal ulcer, untreated
Angina pectoris
Heart failure (mild)
Normal female
Normal male
Hypertension, untreated

60 70 80 90 100 110
PGWB Index score

Normal Function
Esophagus
Transports food from mouth to stomach
through peristaltic contractions

Lower esophageal sphincter (LES)

Relaxes, on swallowing, to allow food to enter
stomach and then contracts to prevent reflux

Normal to have some amount of reflux multiple

times each day (transient relaxation of LES –
not associated with swallowing)

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http://www.gerd.com/intro/noframe/grossovw.htm

Clinical Presentation of GERD

Typical / Esophageal Atypical/
 Common symptoms Supraesophageal
most common when • Chest pain
pH<4
 Heartburn • Laryngitis
 Belching and • Asthma
regurgitation • Sinusitis
 Hypersalivation
• Chronic cough
 May be episodic or
nocturnal • Aspiration pneumonia
 May be aggravated • Tooth decay
by meals and
reclining position

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PATHOGENESIS

3 lines of defense must be impaired for GERD to

develop
1. LES barrier impairment
Relaxation of LES
Low resting LES pressure
Increased gastric pressure
2. Decreased clearance of refluxed materials
from esophagus
3. Decreased esophageal mucosal resistance

CONTRIBUTING FACTORS
Decrease LES pressure Directly irritate the gastric
 Chocolate mucosa
 Alcohol  Tomato-based products
 Fatty meals  Coffee
 Coffee, cola, tea  Spicy foods
 Garlic  Citrus juices
 Onions
 Meds: NSAIDS, aspirin, iron,
 Smoking KCl, alendronate
Stimulate acid secretions
 Soda
 Beer
 Smoking

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CONTRIBUTING FACTORS
Drugs that decrease LES pressure
 Alpha-adrenergic agonists
 Anti-cholinergic agents (e.g. TCA’s, antihistamines)
 Beta-adrenergic agonists
 Calcium channel antagonists (nifedipine most reduction)
 Diazepam
 Dopamine
 Meperidine
 Nitrates/Other vasodilators
 Estrogens/progesterones (including oral contraceptives)
 Prostaglandins
 Theophylline

SYMPTOMS

 The main symptom of GERD in adults is

frequent heartburn, also called acid
indigestion
 Radiating substernal chest pain
 Most children under 12 years with GERD,
and some adults, have GERD without
heartburn. Instead, they may experience a
dry cough, asthma symptoms, or trouble
swallowing.
 Symptoms similar to MI

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CAUSES
Most likely to occur in conditions that force
abdominal contents superiorly
Loose lower esophageal sphincter (LES)
Eating or drinking to Excess
Extreme Obesity
Pregnancy
Running
Lying flat after eating
Hiatal hernia
Smoking

Pathophysiology of GERD
The pathophysiology of reflux disease is
multifactorial
 Gastroduodenal factors :
- Acid and pepsin
- Duodenal agents
- Gastric emptying
- Helicobacter pylori ?
 Gastroesophageal junction factors :
- Transient lower esophageal sphincter relaxation
- Hypotensive lower esophageal sphincters
- Hiatal hernia
 Esophageal factors :
- Esophageal clearance
 Genetic factors

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Pathophysiology of GERD
salivary HCO3
Impaired
mucosal oesophageal
defence clearance of acid
(lying flat, alcohol,
coffee)
Impaired LOS
(smoking, fat, alcohol) Hiatus hernia
– transient LOS
relaxations acid output
H+ (smoking, coffee)
– basal tone Pepsin
Bile and
pancreatic
enzymes intragastric pressure
(obesity, lying flat)

bile reflux gastric emptying (fat)

Pathophysiology

A. Abnormal lower esophageal sphincter

1. Functional (frequent transient LES relaxation) The most
common cause
2. Mechanical (hypotensive LES) of (GERD).
3. Foods (eg, coffee, alcohol), decrease the
4. Medications (eg, calcium channel blockers), pressure of the
LES.
5. Location .......... hiatal hernia

or
obesity
Pregnancy
B. Increase abdominal pressure increased gastric volume

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Summary of Pathogenesis of GERD

1. Impaired lower esophageal
sphincter-low pressures or
frequent transient lower
esophageal sphincter
relaxation
2. Hypersecretion of acid
3. Decreased acid clearance
resulting from impaired
peristalsis or abnormal saliva
production
4. Delayed gastric emptying or
duodenogastric reflux of bile
salts and pancreatic
enzymes.

Diagnostic Tests for GERD

 Laryngoscopy
 24-hour pH monitoring
 Endoscopy
 For mucosal injury and to assess other complication
(bleeding)
 Biopsies to identify Barrett’s esophagus,
adenocarcinoma, eosinophilic esophagitis.
 Noninflammatory GERD and major motor disorders
may be missed by endoscopy
 Absence of erosions does not definitively show
symptoms are GERD related.

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Los Angeles classification

system for esophagitis
Grade A Grade B
One or more mucosal One or more mucosal
breaks, no longer than breaks, more than 5
5 mm, that do not mm long, that do not
extend between the extend between the
tops of two mucosal tops of two mucosal
folds folds

Grade C Grade D
One or more mucosal One or more mucosal
breaks, that are breaks, that involve at
continuous between the least 75% of
tops of two or more the oesophageal
mucosal folds, but which circumference
involve less than 75% of
the circumference

Savary-Miller classification
of esophagitis
Grade I
 One or several erosions in one mucosal fold

Grade II
 Several erosions in several mucosal folds,
the erosions can merge

Grade III
 Erosions surrounding the oesophageal circumference

Grade IV
 Ulcer(s), strictures, shortening of the oesophagus

Grade V
 Barrett’s epithelium

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Management
Theraphy
of GERD

Treatment Goals for GERD

Eliminate symptoms
Decrease the frequency or recurrence and
duration of GER
Promote healing of the injured mucosa
esophagitis
Manage or prevent development of
complications

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Management of GERD

Cont...

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Initial Management of Heartburn

A. Antacids and lifestyle changes

B. H2-receptor antagonists
C. Standard Proton pump inhibitor therapy
D. High-dose Proton pump inhibitor therapy
• Continuous?
• On-Demand?
E. Endoscopy and/or pH testing followed by
therapy based on results

Mechanisms of Action
of GERD Pharmacotherapy
HCI Antacids neutralize
secreted HCl

PPIs block acid at

H+ K+ its source in the
proton pump

H2RAs block the

histamine receptor,
interfering with one
of the stimulation
Gastrin pathways

ACh Histamine
ACh=acetylcholine

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Reasons for PPI “Failure”

Patient non-compliance
Persistent esophageal acid exposure
Hypersecretory state
Large hiatal hernia
Nocturnal acid breakthrough
Acid-sensitive esophagus
Non-acid reflux
Wrong diagnosis
Functional heartburn (NOT GERD!!)

Complications

Erosive esophagitis
Esophageal Stricture
Barrett’s esophagus
Esophageal adenocarcinoma

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Complications
Erosive esophagitis
Responsible for 40-60% of GERD
symptoms
Severity of symptoms often fail to match
severity of erosive esophagitis

Complications

Esophageal stricture
Result of healing of
erosive esophagitis
May need dilation

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Complications
8-15%
Barrett’s Esophagus
Intestinal metaplasia of
the esophagus
Associated with the
development of
adenocarcinoma
Many patients with
Barrett’s are
asymptomatic

Nonpharmacologic Theraphy

Life style modification

If you smoke, stop.
Avoid foods and beverages that worsen
symptoms.
Lose weight if needed.
Eat small, frequent meals.
Wear loose-fitting clothes.
Avoid lying down for 3 hours after a meal.
Raise the head of your bed 6 to 8 inches by
securing wood blocks under the bedposts. Just
using extra pillows will not help.

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Treatment

Medications-
 Antacids
 Foaming agents
 H2 blockers
 Proton pump inhibitors
 Prokinetics

Pharmacotherapy

Reduce acidity
H2 Antagonists
Over the counter
Pepcid & Zantac
Proton Pump Inhibitors (PPI)
Prescription only
Prilosec, Prevacid, & Nexium

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Therapy

Therapy is directed at:

Increasing LES pressure
Enhancing esophageal acid clearance
Improving gastric emptying
Protecting esophageal mucosa
Decreasing acidity of reflux
Decreasing gastric volume available to be
refluxed

Treatment
Three phases in treatment
 Phase I: Lifestyle changes – 2 weeks
Lifestyle modifications
Patient-directed therapy with OTC medications
 Phase II: Pharmacologic intervention
Standard/high-dose antisecretory therapy
 Phase III: Surgical intervention
Patients who fail pharmacologic treatment or
have severe complications of GERD
LES positioned within the abdomen where it is
under positive pressure

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Treatment Selection

Mild intermittent heartburn (Phase I)

Treat with lifestyle changes plus antacids
AND/OR low dose OTC H2-receptor antagonists
(H2RA’s) as needed

Symptomatic relief of mild to moderate GERD

(Phase II)
Treat with lifestyle changes plus standard doses
of H2RA’s for 6-12 weeks OR proton pump
inhibitors (PPI’s) for 4-8 weeks

Treatment Selection

Healing of erosive esophagitis or treatment of

moderate to severe GERD (Phase II)
Lifestyle modifications plus PPI’s for 8-16 weeks
OR high dose H2RA’s for 8-12 weeks
PPI’s preferred as initial choice due to more
rapid symptom relief and higher rate of healing
May also add a prokinetic/promotility agent

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Treatment Considerations

Prokinetic agents are an alternative to H2RA’s

Efficacy similar to prescription dose H2RA’s
Used as a single agent only in mild to moderate,
nonerosive GERD
May be more expensive and use is limited by
side effects

Treatment Considerations
Maintenance therapy may be needed
 Large % of patients experience recurrence
within 6-12 months after D’C of therapy
 Goal is to control symptoms and prevent
complications
 May use antacids, PPIs or H2RAs
 In patients with more severe symptoms,
PPI most effective

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Esophageal mucosal
resistance:
Esophageal Alginic acid, Sucralfate
clearance:
Cisapride
LES pressure:
Gastric emptying: Metoclopramide
Metoclopramide Cisapride
Cisapride

Gastric acid:
Antacids
H2RAs
PPIs

http://www.gerd.com/intro/noframe/grossovw.htm

Drug Therapy - Antacids

Antacids with or without alginic acid

Antacids increase LES pressure and do not
promote esophageal healing
Neutralize gastric acid, causing alkalinization
Alginic acid (in Gaviscon) forms a highly viscous
solution that floats on top of the gastric contents
Dose as needed – typical action – 1-3 hours
Not best choice for nocturnal symptoms because
pH suppression cannot be maintained

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Drug Therapy - Antacids

Products: Magnesium salts, aluminum salts,

calcium carbonate, and sodium bicarbonate
Dosing: Initially 40-80 mEq prn (no more than
500-600 mEq per 24 hours)
Maalox/Mylanta 30 ml prn or PC & HS
Maalox TC/Mylanta II 15 ml prn or PC & HS
Gaviscon 2 tabs PC & HS
Tums 0.5-1 gm prn

Drug Therapy – H2RA’s

H2RA’s
Mainstay of treatment for mild to moderate GERD
H2RA’s equally efficacious
Select based on pharmacokinetics, safety profile
and cost
Timing
Give in divided doses for constant gastric acid
suppression
May give at night if only nocturnal symptoms
Give before an activity that may result in reflux
symptoms

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Drug Therapy – H2RA’s

Cimetidine Famotidine Nizatidine Ranitidine

Low dose 200 mg 10 mg 75 mg 75 mg

(qd to
bid)
Standard 400 mg 20 mg 150 mg 150 mg
dose
(bid)
High 400 mg 40 mg bid 150 mg 150 mg
dose qid or 800 qid qid
mg bid

Drug Therapy – H2RA’s

Response to H2RA’s dependent upon:

1) Severity of disease

2) Duration of therapy

3) Dosage regimen used

Tolerance to effect develops

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Drug Therapy - PPI’s

Proton Pump Inhibitors
Used to treat moderate to severe GERD
More effective and faster healing than H2RA’s
May be used to treat esophagitis refractory
to H2RA’s
All agents effective - choose based on cost
Prilosec released OTC 2003
Use for heartburn that occurs ≥ 2 days/week
Label - Don’t use for more than 14 days

Drug Therapy - PPI’s

Standard dosing
Esomeprazole 20 mg qd
May 2006: FDA approved Nexium for
adolescents 12-17 years for the short-term (up
to 8 weeks) treatment of GERD
Lansoprazole 15-30 mg qd
Omeprazole 20 mg qd
Pantoprazole 40 mg qd
Rabeprazole 20 mg qd
Timing
Best is 30 minutes prior to breakfast

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Drug Therapy - PPI’s

May give higher doses bid for
Patients with a partial response to standard
therapy
Patients with breakthrough symptoms
Patients with severe esophageal dysmotility
Patients with Barrett’s esophagus
Always give second dose 30 minutes prior to
evening meal

Drug Therapy - Prokinetics

Prokinetic Agents -- MOA

 Enhances motility of smooth muscle from

esophagus through the proximal small
bowel

 Accelerates gastric emptying and transit

of intestinal contents from duodenum to
ileocecal valve

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Drug Therapy - Prokinetics

Prokinetic Agents

Results of therapy

Improved gastric emptying

Enhanced tone of the lower esophageal
sphincter
Stimulated esophageal peristalsis
(cisapride only)

Prokinetic Agents - Products

Metoclopramide
 Dopamine antagonist
 Only use if motility dysfunction documented
 Administer at least 30 minutes prior to meals
 Dose - 10 to 15 mg AC and HS
 Adverse Effects – limit use
diarrhea
CNS - drowsiness, restlessness, depression
extrapyramidal reactions – dystonia, motor
restlessness, etc.
breast tenderness

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Prokinetic Agents - Products

Cisapride
 Was removed from the market July 14, 2000
due to adverse cardiovascular effects (i.e.
ventricular arrhythmias)
 Available only through an investigational
limited access program for patients who
have failed all other treatment options

Drug Therapy –
Mucosal Protectants

Sucralfate
Very limited value in treatment of GERD
Comparisons
Similar healing rate to H2RA in treatment of
mild esophagitis
Less effective than H2RAs in refractory
esophagitis
Only use in mildest form of GERD

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Special Populations

Infants can experience a form of GERD

Postmeal regurgitation or small volume vomiting
Occurs due to a poorly functioning sphincter
Treatment
Supportive therapy
Diet adjustments – smaller, more frequent
feedings; thickened feedings
Postural management
H2RA’s have been used (e.g. ranitidine 2
mg/kg) and antacids

Special Populations

Pregnancy
 Common, due to decreased LES pressure and
increased abdominal pressure
 Nearly half of all pregnant women experience
 Antacids other than sodium bicarbonate
generally considered safe, but avoid chronic
high doses

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GERD in the Elderly

In the US, 20% report acid reflux

Worldwide, 3X prevalence in > 70 yo of patients
younger than 39 yo
More likely to develop severe disease
More likely to be poorly diagnosed or
underdiagnosed
Due to atypical symptoms
Always look for medication causes

GERD in the elderly

Symptoms
Dysphagia
Vomiting
Weight loss
Anemia
Anorexia
Typical symptoms are less frequent

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GERD in the Elderly

Diagnosis should always include endoscopy

Prokinetic agents should be avoided
PPI’s are medications of choice for acute episodes
and prevention of recurrence due to efficacy,
safety, and tolerability
Step down approach is preferred – more
clinically effective and more cost effective

PPIs in the Elderly

Decreased clearance with omeprazole,

lansoprazole, rabeprazole
Little effect on clearance with pantoprazole
Dosage adjustments not necessary
Pantoprazole – lower affinity for CYP450

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Counseling Questions

Before recommending a therapy, ask:

Duration and frequency of symptoms
Quality and timing of symptoms
Use of alcohol and tobacco
Dietary choices
Medications already tried to treat symptoms
Other disease states present and
medications being used

Cont...

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Evaluation of Therapheutic
Outcomes

 Successful outcomes are generally measured in

terms of three separate end points: (Long-term
benefits)
Relieving symptoms
Healing the injured mucosa
Preventing complication
 The short-term goal of theraphy is to relieve
symptoms heartburn and regurgitation
 Patient should be educated
 Patient should also be instructed to avoid or
limit foods that aggravate GERD symptoms
 Monitoring symptoms and the risk of complication

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THANK YOU

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