GIT Pharmacology

Akoko Sokiprim
Introduction
• PUD
• Definition
• Lesion of the GIT especially the stomach and
duodenum. It causes damage to the mucosa due
• Increased acid production by the parietal cells
• Pepsin secretion by the chief cells
• Causes
• H.Pylori Infections
• Stress in Chronic disease patients
• NSAIDs
Introduction-2
• Laxatives
• AntiDiarrhoeal
• Emetic and Antiemetic
•Drugs used in Peptic
Ulcer Disease
Classification
(These descriptions are intended as a supplement to the more complete
discussions in the text.)
• Gastric acid secretion
• PPI
• H2Receptor blockers
• Antimuscarinic
• Prostaglandin analogue
• Ulcer Protective
• Acid Neutralizing agents
• Non systemic
• Systemic
• Anti H.Pylori Agents
1. PPI
Proton Pump Inhibitor (PPI)
• Examples:
• Omeprazole, Pantoprazole, esomeprazole, lansoprazole, Rabeprazole
• Omeprazole- Prototype drug, Pantoprazole - has minimal drug interactions, while esomeprazole,
lansoprazole and Rabeprazole are available in parenteral formulations

• MOA:
• converted to sulfenamide or sulfenic acid that blocks gastric acid secretion
• They inhibit the proton pump irreversibly
• Inhibits H+/K+ ATPase (non competitive inhibitors)
• PK:
• Increased duration of action
• Although they have a short half live
• Given in enterocoated tabs
• Diffuse to blood then to the parietal cells. In acid pH they are converted to
sulphonamide the active forms of the drug
• Food increases acid secretion thus the active forms of the drug will be in high
concentration
• Given 30mins before food
• Highly bound to plasma protein
PPI-2
• Uses
• PUD
• ZES
• GERD(DOC)
• To decrease risk for aspiration pneumonia
• Eradication regimen for H. Pylori
• SE
• Mild CNS and GI effects, decreases bioavailability of some weak
acids
• Vitamin B 12 Absorption due to inhibition of parietal cell secretion
• Gastric tumors via increase production of gastrin via negative
feedback on gastric acid and intrinsic factors inhibition
• Hyperprolactinaemia via inhibition of P450 , inhibiting the
metabolism of oestrogen
• Gynaecomastia , erectile dysfunction galactorrhea, menstral
dsiturbances
H2 Receptor Antagonist
• Examples:
• Cimetidine- Prodrug, Ranitidine- Longer acting, more potent, Rare Side
effect doesnt cross BBB, Farmotidine- High bioavailability and no anti
adrenegic action, Nizatidine-High bioavailability
• MOA:
• Less potent than PPI
• Acts chiefly on the H2 receptors on the parietal cells reversibly
and indirectly decreases proton pump activity
• Antagonises HCL secretion caused by vagally or gastrin
mediated release of histamine from enterochromaffin like
cells(GI Mast cells)
• PK:
• Increased duration of action
H2 Receptor Antagonist

• Uses
• PUD
• GERD
• ZES
• Preoperative use to prevent aspiration Pneumonia
• inhibit noctunal acid production

• SE
• GI distress, dizziness, somnolence
• Cimetidine is a major inhibitor of P450 leading to decrease
androgens
• Gynaecomastia ,decreased libido
Antimuscarinic Agents

• Examples:
• Pirenzipine, Telenzipine
• MOA:
• Selective for M1 receptors
• Decreased efficacy
• PK:
• Increased duration of action
Antimuscarinic Agents

• Uses
• PUD
• SE
• Rarely used due to atropine like side
effects
Prostaglandin Analogue

• Examples:
• Misoprostol (PG E1 analogue)
• MOA:
• They inhibit the gastric acid secretion
• increases the secretion of mucus
• increases bicarbonate secretion
• Increases mucosal blood flow
• They have a cytoprotective effect
• proton pump irreversibly
• PK:
• Increased duration of action
Prostaglandin Analogue-2

• Uses
• PUD
• selective use in NSAIDs induced GI ulcers
• SE
• Uterine contraction
• Abortions
• Indigestion
• CI
• Pregnancy
Ulcer Protective Agents
• Examples:
• Sulcrafate

• MOA:
• in Acidic pH in the stomach it polymerises to form a sticky polymer
that adheres to the ulcer base to protect it
• It prescipitate proteins at the site of the ulcer to wall of the ulcers
from futher damage
• Increases Prostaglandin release
• Increases mucus secretion
• Increase epidermal growth factors
• increase bicarbonate secretion
• PK:
• Taken 1hour before meal
Ulcer Protective Agents-2
• Uses
• PUD
• GERD
• Oesophagitis
• Increases healing and reduces ulcer recurrence
• SE
• Back pain.
• Constipation.
• Diarrhea.
• Dizziness.
• Drowsiness.
• Dry mouth.
• Gas (flatulence)
• Headache
• CI
Not taken with PPI, H2 receptor blocker and antacids should not be used together
cause they need acidic pH to work
Ulcer Protective Agents-3
• Examples:
• Bismuth subsalicylate and Bismuth subcitrate
• MOA:
• Not clear
• Binds selectively to the ulcer, coating and protecting it from acid
and pepsin
• PK:
• Taken 1hour before meal
• Uses:
• PUD
• combines with metronidazole and tetracycline in eradication of H.
pylori
• SE:
• Black Tongue and stool
Acid Neutralizing Agents

• There are 2 types

• Systemic
• Mg(OH)2
• Al salts
• Mrg salts
• CaCO3
• Non Systemic
• NaHCO3
• Na Citrate
Antacid

• What is an ideal antacid

• It should be Insoluble and not absorbed
• Should be Quick with prolonged action
• Inexpensive
• The buffer range should be between pH1-6
• Must not distort acid base balance of the body
• It should not liberate carbondioxide
• Less drug interaction
Acid Neutralizing Agents-2

• Systemic
• Mg(OH)2, Al salts, Mg salts, CaCO3
• MOA:
• Reacts with acid in the stomach to produce salts
• To prevent alkalosis they neutralise HCO3 which is not
absorbed
• SE
• Hypercalcemia- Caco3; Constipation- Al salt; Diarrhoea-
Mg Salt
• CI: Drug interaction (Decrease absorption) of
tetracycline, iron and ketoconazole
Acid Neutralizing Agents-3

• Non Systemic
• NaHCO3;Na Citrate
• MOA:
• PK
• Short acting with high water solubility (rapid
absorption) thereby releasing CO2
• SE:
• Rebound Acidity
• Metabolic acidosis
• CI
• Hypertensives and congestive heart failure
Antacid and drug absorption

• Increase oral absorption of weak bases(

eg quinidine)
• Decrease Oral absorption of weak acid
(eg warfarin)
• Decrease oral absorption of tetracycline
(via chelation)
Summary on Antacids
Antacid Alkalosis Acid Rebound Diarrhoea Constipation Other Toxicity
Al(OH)3 - - - ++ decrease
phosphate,
osteodystrophy
and dementia
CaCO3 + ++ - ++ Hypercalcemia
Mg(OH)2 - ++ ++ - Increase
magnesium,
respiratory
collapse
NaHCO3 ++ ++ - - Gas
Anti H. Pylori Agents

• Examples:
• Triple Regimen
• Omeprazole, Amoxicillin and clarythromycin
• Quadriple Regimen
• Colloidal Bismuth sulphate, metronidazole, Omeprazole,
Tetracycline

• How does H. Pylori cause PUD

• Not clear, however may be due to the ammonia produced
by the bacteria
• Treatment is usually for 1-2 weeks
• PPI are given afterwards for 6weeks
Mechanism of Action Penicilline and
Tetracycline
MOA Antimicrobial Agent
Inhibitors of bacterial cell wall Penicillin, cephalosporins,
synthesis Imepenem/Meropenem,
Aztreonem, Vancomycin

Inhibitors of bacterial Protein Aminoglycoside, chloramphenicol,

Synthesis macrolides, tetracyclines,
stroptogramins, linezolid
Protein Synthesis Inhibitor
Event Antibiotic and Binging Site MOA
Amino Acid Incorporation Tetracycline (30s) Block attachment of Amino Acyl
tRNA to acceptor
Antibiotic Resistance mechanism
Antimicrobial Agent
Penicillin and Cephalosporin
Macrolides(Erythromycin, clarithromycin and
clindamycin)
Tetracyclines
Primary Mechanism of Resistance
 Production of β–lactamase, which cleaves β–
lactam ring structure
 Change in penicillin binding protein
 Change in the Porin structure by an Efflux pump
 Formation of methotransferase that alters binding
site on the 50s ribosomal subunits
 Esterases that inhibits the drugs
 Non selective pump called glycoprotein that
allows cell to pump out tetracycline
Clarithromycin

• Clarithromycin, a 14-membered ring macrolide antibiotic, is a derivative of

erythromycin, with a similar spectrum of activity and clinical application.
However, clarithromycin is more acid-resistant, has more consistent
absorption, and has a longer elimination half-time compared with
erythromycin.
• Results of studies showing approximately 90% H pylori eradication with triple-
therapy regimens using clarithromycin have led to widespread use of this
antibiotic. However, the increasing prevalence of clarithromycin-resistant H
pylori strains must be kept in mind before using this antimicrobial agent.
• Unlike the situation with metronidazole, there is no evidence that increasing
the dosage of drug will overcome the problem of bacterial resistance.
 Drug of Choice and Common Side effects of
Protein
S/No Drug
synthesis inhibitors
Uses SE
1 Macrolides Erythromycin- gram positive cocci
Azithromycin- mycobacterium
Avium, *COVID-19
Clarythromycin- mycobacterium
Avium, H.Pylori
2 Tetracyclines • H.pylori, vibro, chlamydia
• Doxycycline- Prostitis
• Minocycline- Acne
• Demeclocycline- SIADH
They stimulate motilin receptor
and cause GI distress, reversible
deafness at high doses,
Erythromycin- cholestasis
Jaundice
Tooth enamel dysplasia, possible
decrease in bone growth in
children
Phototoxicity-> demeclocycline,
doxycycline
GI distress, vestibular
dysfunction->minocycline
CI- Pregnancy
Nitroimidazole(Metronidazole)
• H pylori is generally highly sensitive to metronidazole, which is actively secreted
into gastric juice and saliva, with activity independent of pH. Metronidazole is a
prodrug that must undergo activation by bacterial nitroreductases. There are a
number of H pylori enzymes with the potential to reduce metronidazole, and it is
possible that increased drug dosage and resulting very high concentrations in the
stomach allow sufficient drug to become activated to kill the organism.
Metronidazole causes loss of the helical structure of bacterial DNA, strand
breakage, and thus, impairment of bacterial function.
• It acts by producing free radicals; decreases glucose uptake and decreases
microtubular structure.
• Used for antiprotozoal infections; Eradication of H.Pylori
• Side Effects include: Stomatitis, metallic taste in mouth, cystitis, nausea,
diarrhoea, Disulfiram like reaction, reversible peripheral neuropathy
Recent Advances
• It has also been reported that probiotics may exert a favorable effect
on H pylori gastritis and significantly reduce the incidence of side
effects related to antimicrobial therapy.
• Moreover, the efficacy of a standard PPI-based triple-therapy
regimen was significantly increased by adding bovine lactoferrin in an
open, randomized, single-center study,whereas human recombinant
lactoferrin was ineffective in the treatment of human H pylori
infection.
•LAXATIVES
Laxatives

• MgSO4- Water retaining leading to increase in

intraluminal pressure
• BIsacodyl- Direct intestinal wall stmulant
• Methyl cellulose- Collects water and swells leading
to increase bulk
• Docusate- Detergent- Stool Softner
• Mineral Oil- Lubricant
• Lactulose- Hyperosmotic(also indicated for
systemic encephalopathy)
•AntiDiarrhoeal
Antidiarrhoeal

• Examples:
• Loperamide and diphenoxylate
• Adsorbants: Kaolin , Pectin
• ORS
• uses the sodium-glucose cotransport mechanism to passively
absorb water across the intestinal mucosa.
• Zinc Sulphate
• zinc restores mucosal barrier integrity and enterocyte brush-
border enzyme activity, it promotes the production of
antibodies and circulating lymphocytes against intestinal
pathogens, and has a direct effect on ion channels, acting as a
potassium channel blocker of adenosine 3-5-cyclic
monophosphate-mediated chlorine secretion
• shortens the average duration of diarrhoea by around 16
hours but it probably increases the risk of vomiting
•AntiEmetic
Picture showing pathophysiology of vomiting
d Stimulation of D2 leads to emesis
Labyrinthine Chemorece D2
wh while 5HT is blocked by o
vestibular ptor trigger Receptor ondasetron
system zone(CTZ)
area 5HT3
postrema receptor

Blocked by anticholinergic

and antihistamines

Pain
receptor Vomiting GI Tract 5HT2
especially Centre
Blocked by ondasetron
GU Tract

Effect:
Blocked by morphine Projectile
vomiting
Classification of Antiemetic
• 5HT3 Antagonist: Ondasetron, Granisetron
• Blocks vagal afferent from the gut
• Blocks impulses to CTZ
• Antidote to cisplantin Nausea and vomitting
• Palonostron: Loner half life
• Ramosetron used in IBS
• SE: Headache
• CI: Motion sickness
• H1 Antagonists: Diphenhydramine, meclizine,
cyclizine, promethazine
• Central antichorlinergic action and cause sedation
• SE: Dry mouth, drowsiness
Classification of Antiemetic-2
• DA Antagonist: Prochlorperazine, metoclopramide
• Very potent with antihistamine and andtichorlinergic actions
• Prochlorperazine has dystonia and tremors as a side effect
• D1 receptors are found in the lower oesophageal sphinters
• Not effective in motion sickness
• Muscarinic receptor antagonist(M1): scopolamine-
DOC for motion sickness
• blocks M1 receptors on the vestibular apparatus and
vomiting centre
• SE; atropine like side effects
Classification of Antiemetic-3
• Cannabinoids(CB1 receptor) agonist: Dronabinol
and Nabilone
• Acts on the CB1 receptors on CTZ
• Reserved drug as last option when other drugs fail
• SE: Sedation, Hallucinations
• NK1 receptor antagonist: Aprepitant, Fosoprepitant
• Blocks receptors to substance P on CTZ
• Blocks slow pain transmission
• Used to prevent delayed emesis; dull and
visceral pain; also to increase efficacy of other
antiemetic
• SE: Flatulence and diarrhea
Classification of Antiemetic-4
• Prokinetic Agents:
• Acts by promoting gastric emptying
• centrally acts on D2 reeptor on CTZ and also acts on
5HT3 receptors
• Peripherally acts on the GIT by 5HT4 agonism and 5HT3
antagonism to increase ACh secretions which increase
tone of lower oesophageal sphincter; relaxation of
pylorus; increased peristalsis
• Examples: Metoclopramide
• Uses; Antiemetic; GERD; Gastroparesis, irritable Hiccups
• CI: increase absorption of diazepam and descreases
digoxin
• SE: EPS and drug induced parkinsonism
Classification of Antiemetic-5
• Adjuvants:
• Glucocorticoids
• Acts as antiinflammatory with
metabolic disturbances
• Benzodiazepines
• They are sedative and it is an anti anxiety
drug
• Uses : Psychogenic vomiting; anticipatory
vomiting
•THE
END