GIT PHARMACOLOGY

PHA 302
Pharm (Mrs) Ajayi
 Peptic Ulcer Disease
Peptic Ulcer Disease
Imbalance between defenses and aggressive factors

Defensive factors:
1. Mucus: continually secreted, protective effect
2. Bicarbonate: secreted from endothelial cells
3. Blood flow: good blood flow maintains mucosal
integrity
4. Prostaglandins: stimulate secretion of bicarbonate
and mucus, promote blood flow, suppress secretion
of gastric acid
 Peptic Ulcer Disease”Cont
Aggressive factors:
1. Helicobacter pylori: gram negative bacteria, live in stomach
and duodenum, may breakdown mucus layer =>
inflammatory response to presence of the bacteria also
produces urease  forms CO2 and ammonia which are toxic
to mucosa
2. Gastric Acid: needs to be present for ulcer to form =>
activates pepsin and injures mucosa
3. Decreased blood flow: causes decrease in mucus production
and bicarbonate synthesis, promote gastric acid secretion
4. NSAIDS: inhibit the production of prostaglandins
5. Smoking: nicotine stimulates gastric acid production
 Classes of Agents

1. Proton Pump Inhibitors

2. Histamine H2-Receptor Antagonists
3. Prostaglandin Analogs
4. Cytoprotectants
5. Antacids
 Protein pump inhibitors
1. Most potent suppressors of acid secretion
2. 24-48 hr effects on acid suppression
Irreversible inhibitor of proton pump; blocks 98% of

• acid secretion in all forms of ulcer and

• hypersecretory Zollinger-Ellison syndrome.
The drug is given in gelatin coated capsule to
resist
• breakdown in stomach acid. It reaches the
intestine,
• well absorbed, enters blood stream,reaches the
• parietal cell.
 PPIs
• Irreversibly inhibit H+/K+ATPase function to:
– Block gastric acid secretion
– Decrease pepsin concentration
– Increase gastric pH
• Secretion of acid only resumes when new
proton pumps are deployed
• Steady-state inhibition (affecting 70% of pumps)
may take 2-5 days
 PPIs
• Activated only when pH decreases below 4
– Occurs only in parietal cell
– Achieved only when parietal cell activation
occurs (after meals)
– Most effective after a prolonged fast when
large amounts of active proton pumps are
present (i.e. breakfast)
 Examples of PPI
• Esomeprazole (Nexium)
• Lansoprazole (Laproton. Lapraz)
• Omeprazole (Protop, Pumpitor, OGB)
• Pantoprazole (Pantozol) (iv)
• Rabeprazole (Pariet)
 PPI Metabolism
• Rapidly absorbed and Highly protein bound
• Extensively metabolized in the liver by the
P450 system (CYP2C19 and CYP3A4)
• Sulfated metabolites are excreted in the urine
or feces
• Hepatic disease reduces the clearance of
lansoprazole  reduce dose
 Side effects
• Headache
• Diarrhea
• Abdominal pain
• Constipation
 Drug-Drug Interactions
• Ketoconazole and Digoxin absorption is
decreased due to reduced acidity.
• Omeprazole may inhibit diazepam and
phenytoin metabolism
Histamine H2 Receptor Anatagonist
• Reversibly compete with histamine for binding to H2 receptors
on the basolateral membrane of parietal cells
• Less potent than PPIs but still suppress acid by 70% over 24
hrs
• H2 receptor blockers:
• Cimetidine (OGB, iv)
• First H2-blocker available Inhibits P450
Drug interaction
• Ranitidine (OGB, iv)
• Does not inhibit P450  fewer side effects
• Famotidine ((Famocid, Gaster:iv®)
 Pharmacokinetics
• Rapidly absorbed after oral administration
• Serum concentrations peak in 1-3 hr
• Therapeutic levels maintained up to 12 hrs
• Small percentage is protein bound
• 10% to 35 % metabolized by the liver
• Drugs and metabolites primarily excreted by
kidneys (**reduce doses in renal disease)
 Pharmacokinetics
1. inhibit 90% acid secretion in basal state as
well as food-induced and nocturnal acid
production.
2. they are helpful in healing gastric and
duodenal ulcers and prevent their
recurrence. Have benefits in preventing
increased gastric acid secretion in Zollinger-
Ellison syndrome.

3. Cimetidine Has several side effects, not a

choice now - Under Prescription.
 Common H2RA Side Effects
• All less than 3%
– Diarrhea
– Headache
– Drowsiness
– Fatigue
– Muscular pain
– Constipation
• Much less common
– Confusion, delirium in the elderly
– Associated with thrombocytopenia
– Cimetidine anti-androgen effects
 Drug-Drug Interactions
1. Inhibits CyP450: Inhibits the
metabolism of various drugs that
are concomitantly taken: phenytoin,
warfarin, theophylinne, BZD.

2. These adverse effects are relatively

least with ranitidine and famotidine
 Prostaglandin Analogs
• Prostaglandin Analogs: Misoprostol
• Protective Effects of ProstaglandinsPGE2 and PGI2 synthesized
by gastric mucosa
• Acid-reducing effects
– Bind to EP3 receptors on parietal cellsDecrease acid
production
• Cytoprotective effects
– Stimulation of mucin and bicarbonate
– Increase mucosal blood flow
• Contrast with NSAIDS which diminish prostaglandin formation
by inhibition of cycloxygenase and lead to
ulcer formation
 Misoprostol: Cytotec
• Synthetic analog of PGE1
– Enhanced potency
– Increased oral bioavailability
• Inhibit basal acid secretion (85-95%)
• Inhibit stimulated acid secretion (75-85%)
 Pharmacokinetics
• Rapidly absorbed
• Rapidly de-esterfied to misoprostol acid--the
active metabolite
• Therapeutic effect peaks at 60-90 minutes
• Lasts 3 hours (qid dose required)
 Side Effects
• Diarrhea ± abdominal cramps as high as 30%
• Begins within 2 weeks and often resolves
spontaneously in 1 week
• Can exacerbate inflammatory bowel disease
• Contraindicated during pregnancy
 Sucralfate
• Aluminium Sulfated polysaccharide, Acid
activated
• Administered on an empty stomach 1 hr
before meals
• Stimulates local prostaglandin synthesis,
adsorbs pepsin
• AH2 & antacids  reduce bioavailability
• Not absorbed  essentially free of side effects
 Common Side Effects
• Constipation (2%)
• Aluminium  hyphosphatemia: Avoid in renal
failure
• May impair absorption of other drugs :
tetrasiklin, warfarin, digoxin, phyentoin  2 hr
interval
 Antacids
• Sodium bicarbonate (NaHCO3)
• Calcium Carbonate or CaCO3
• Mg2+ hydroxides or Mg(OH)2
• Al3+ hydroxide or Al(OH)3
 Antacids
• Given orally 1-3 hrs after meals and bedtime
• Mg2+ based preparations increase motility 
Diarrhea
• Al3+ based preparations relax smooth muscle 
Constipation
• Ca2+ based preparations release CO2 
Belching, nausea, distension, and flatulence.
 Common Side Effects
• Aluminum toxicity with renal disease 
Osteoporosis, encephalopathy, Osteomalacia
• Hypercalcemia
– Phosphate retention
– Calcium precipitation in the kidney
• Impair absorption of some drugsTake 2 hrs
before or after other drugs : INH, tetrasiklin
 Antibiotic ulcer therapy
Antibiotic ulcer therapy:
Combinations must be used:
1. Bismuth (Scantoma, Stobiol®) – disrupts cell wall of H. pylori
2. Clarithromycin – inhibits protein synthesis
3. Amoxicillin – disrupts cell wall
4. Tetracyclin – inhibits protein synthesis
5. Metronidazole – used often due to bacterial resistance to
amoxicillin and tetracyclin, or due to intolerance by the
patient

Standard treatment regimen for peptic ulcer:

Omeprazole + amoxicillin + metronidazole
 LAXATIVES
• Constipation
• Abnormally infrequent and difficult passage of
faeces through the lower GI tract
• Symptom, not a disease
• Disorder of movement through the colon
and/or rectum
• Can be caused by a variety of diseases
(hemorrhoid, multipara) , drugs (opium,
aluminium antacids)
 Laxatives :
• Bulk forming
• Emollient
• Hyperosmotic
• Saline
• Stimulant
 Laxatives:
Mechanism of Action

Bulk forming
High fiber
Absorbs water to increase bulk
Distends bowel to initiate reflex bowel activity
Examples:
psyllium (Mulax)
Methylcellulose, polycarbophil
Agar-agar
 Laxatives:
Mechanism of Action

Emollient
• Stool softeners and lubricants
• Promote more water and fat in the stools
• Lubricate the fecal material and intestinal
walls
• Examples:
– Stool softeners: docusate sodium
– Lubricants: mineral oil
 Laxatives:
Mechanism of Action

Hyperosmotic
• Increase fecal water content
• Result: bowel distention, increased peristalsis,
and evacuation
• Examples:
– polyethylene glycol
– sorbitol
– glycerin
– lactulose
 Laxatives:
Mechanism of Action

Saline
• Increase osmotic pressure within the intestinal tract,
causing more water to enter the intestines
• Result: bowel distention, increased peristalsis, and
evacuation
• Saline laxative examples:
– magnesium sulfate (Epsom salts, garam Inggris)
– magnesium hydroxide
– magnesium citrate
– sodium phosphate
 Laxatives:
Mechanism of Action

Stimulant
• Increases peristalsis via intestinal nerve
stimulation
• Examples:
– castor oil
– senna
– cascara
– bisacodyl
 Laxatives: Side Effects
• Bulk forming :Impaction, Fluid overload
• Emollient : Skin rashes, Decreased absorption of
vitamins (ADEK  parafin )
• Hyperosmotic : Abdominal bloating, Rectal
irritation
• Saline :Magnesium toxicity (with renal
insufficiency), Cramping, Diarrhea, Increased
thirst
• Stimulant : Nutrient malabsorption, Skin
rashes, Gastric irritation, Rectal irritation
 Antidiarrheals
Causes of Diarrhea
Chronic Diarrhea
Tumors
Diabetes
Addison’s disease
Hyperthyroidism
Acute Diarrhea Irritable bowel syndrome
Bacterial
Viral
Drug induced
Nutritional
Protozoal
 Antidiarrheals
Antidiarrheals
– Drugs that decrease peristalsis, thereby
allowing fluid absorption from the intestinal
contents
– Examples:
• Anticholinergics
• Protectants/adsorbents
• Opiate-related agents
• Probiotics
• Metronidazole
 Antidiarrheals
– Anticholinergics are used to treat tenemus and
vomiting
– Examples:
• Atropine
• Aminopentamide
• Isopropamide
• Propantheline
• Methscopolamine
– Side effects include dry mucous membranes, urine
retention, tachycardia, and constipation
 Antidiarrheals

– Protectants/adsorbents coat inflamed intestinal mucosa

with a protective layer (protectants) or bind bacteria
and/or digestive enzymes and/or toxins to protect
intestinal mucosa from damaging effects (adsorbents)
– Examples:
• Bismuth subsalicylate (bismuth + aspirin-like product)
• Kaolin/pectin
• Activated charcoal
– Side effects include constipation
 Antidiarrheals

• Opiate-related agents control diarrhea by

decreasing both intestinal secretions and the flow
of feces and increasing segmental contractions
– Examples:
• Diphenoxylate
• Loperamide
• Paregoric
– Side effects include CNS depression, ileus, urine
retention, bloat, and constipation
 Antidiarrheals
• Probiotics seed the GI tract with beneficial
bacteria; use is based on the theory that some
forms of diarrhea are caused by disruption of
the normal bacterial flora of the GI tract
– Must be refrigerated to maintain the viability
of the bacteria
– Examples:
• Plain yogurt with active cultures
• Variety of trade-name products
 Antidiarrheals
– A theory regarding the development of
diarrhea is that anaerobic bacteria may
increase due to disruption of normal GI
flora
– One way to treat this is to use an antibiotic
effective against anaerobic bacteria
– Metronidazole is an example of an
antibiotic used to treat diarrhea
 Antiemetic drugs
• Antiemetic drugs are types of chemicals that help
ease symptoms of nausea or vomiting. Antiemetic
drugs may also be used to treat nausea and
vomiting caused by other medications, frequent
motion sickness, infections, or stomach flu.
• Antiemetic drugs help to block specific
neurotransmitters in the body. These
neurotransmitters trigger impulses such as nausea
and vomiting, so blocking the impulses will help
shut them down.
 The main classes of antiemetics
• The main classes of antiemetics are:
• Dopamine antagonists (eg, metoclopramide,
haloperidol, domperidone, levomepromazine, other
antipsychotics)
• Antihistamines (eg, cyclizine, promethazine)
• Serotonin (5HT3) antagonists (eg, ondansetron,
tropisetron, granisetron)
• Other agents (eg, anticholinergics, steroids,
neurokinin-1 antagonists, benzodiazepines for
anticipatory nausea).
 Antiemetics during motion sickness
• These medications desensitize the inner ear to the
motion of the head. The inner ear plays a significant
role in a person's balance, which can be affected by
sitting in a moving car or being on a boat.
• Antiemetics for motion sickness include:
• dimenhydrinate (Dramamine, Gravol)
• diphenhydramine (Benadryl)
• meclizine (Bonine)
• promethazine (Phenergan)
 Antiemetics during pregnancy
• Antiemetics during pregnancy
• Pregnant women with morning sickness may
use antiemetic drugs to reduce their symptoms.
• Some antiemetics for morning sickness include:
• dimenhydrinate (Dramamine)
• prochlorperazine (Compazine)
• promethazine (Pentazine)
• vitamin B-6