1

DRUGS USED IN THE TREATMENT OF GASTROINTESTINAL DISEASES

OVERALL REGULATION AND FUNCTIONS OF GI TRACT ( FIGURE 62-1 ,p1068 )

DRUGS USED IN ACID PEPTIC DISEASE

• Antacids
• H2 histamine receptor antagonists
• Proton pump inhibitors
• Mucosal Protective agents ( sucralfate, Prostaglandin analogs, Bismuth compounds )

ANTACIDS (p1068)
• weak bases that react with gastric HCl acid to form salt and water
• act primarily by neutralizing intragastric HCl
• acid neutralizing capacity is dependent on rate of dissolution, water solubility, rate of reaction with
acid and rate of gastric emptying
• Neutralizing capacity lasts 2 hours in the presence of food

1. SODIUM BICARBONATE ( e.g. baking soda, Alka Seltzer )

• Reacts rapidly with HCl to produce CO2 ( causes belching and abdominal distention and NaCl
•Unreacted alkali is readily absorbed which can cause metabolic alkalosis ( milk – alkali
syndrome) when given in high doses
• AE: exacerbate fluid retention in patients with heart failure, hypertension and renal
insufficiency.
2. CALCIUM CARBONATE
• Less soluble and reacts slowly with HCl to form CO2 and CaCl2
• AE: belching , abdominal distention, metabolic alkalosis ( milk – alkali syndrome)
3. MAGNESIUM HYDROXIDE OR ALUMINUM HYDROXIDE
• Slowly reacts with HCl to form magnesium chloride or aluminum chloride and water.
• Metabolic alkalosis is uncommon because of the efficiency of the neutralization reaction
• AE: osmotic diarrhea ( Mg salts ) , constipation ( Al salts )
• Absorbed and excreted in the kidneys

*** All antacids may affect the absorption of tetracycline, fluoroquinolones, itraconazole and iron either by
binding the drug ( reducing its absorption ) or by increasing intragastric pH so the drug’s dissolution or
solubility is altered.

H2 HISTAMINE RECEPTOR ANTAGONISTS (p1069)

Cimetidine, Ranitidine, Famotidine and Nizatidine

Chemistry and Pharmacokinetics:

• All rapidly absorbed from the intestine.
• Undergo the first-pass hepatic metabolism
 Cimetidine, ranitidine, famotidine  50% bioavailability
 Nizatidine  little first pass metabolism
• Half-life = 1.1 – 4 hours
• Duration of action is dose dependent
• Cleared by : hepatic metabolism, glomerular filtration and renal tubular secretion
• Dose reduction among patients with renal and liver diseases and in the elderly there is a decline of
up to 50% in drug clearance as well as a significant reduction in volume of distribution
Pharmacodynamics:
• Competitively blocks H2 receptors on parietal cells and suppress basal and meal – stimulated acid
secretion ( Figure 62 – 2 p 1070 ) in a linear and dose dependent manner
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• Highly selective
• The volume of gastric secretion and the concentration of pepsin are also reduced.
• Reduce acid secretion stimulated by histamine, gastrin and cholinomimetic agents thru the
following mechanisms
o Histamine released from ECL either by vagal or gastrin stimulation
o Direct stimulation of the parietal cell by gastrin or acetylcholine
• Clinical comparison as to the potency, dose to achieve >50% acid inhibition for 10 hours ( Table
62-1, p 1069 )
• Especially effective by inhibiting nocturnal ( H) acid secretion and modest impact on meal
stimulated acid secretion ( G, A, H effects )
• Recommended prescription doses maintain greater than 50% acid inhibition for 10 hours
Clinical Uses
• GERD, PUD, Non ulcer Dyspepsia, prevention of bleeding from stress related gastritis

Adverse Effects
• Occur in less than 3% ( diarrhea, headache, fatigue, myalgia and constipation )
• Increase risk of Nosocomial pneumonia ( parenteral )
• Mental status changes ( confusion, hallucination, agitation ) if given thru IV in an elderly ICU
patient. More common in cimetidine
Cimetidine
• Inhibits binding of dihydrotestosterone to androgen receptors, inhibits metabolism of estradiol and
increases the PRL level
• May cause impotence, gynecomastia and galactorrhea. These are associated with long term use
and high doses.
• May cross the placenta
• Rarely cause blood dyscrasia, bradycardia and hypotension therefore it should be given over 30
minutes
Drug Interaction
• Interfere with drugs metabolized by hepatic cytochrome P450 enzymes.
• Ranitidine binds 4 – 10 times less than Cimetidine
• Negligible interaction occur with Nizatidine and Famotidine

PROTON PUMP INHIBITORS ( PPIS ) (p1071)

Omeprazole, Lanzoprazole, Rabeprazole, Pantoprazole, Esomeprazole

Structures
• All are substituted benzimidazoles that resemble H2 antagonists in structure
• Omeprazole – recemic mixture of R- and S- isomers
• Esomeprazole – S- isomer of omeprazole

Pharmacokinetics ( see Table 62 – 2 p 1072 )

• All are available in oral formulations. Esomeprazole and Pantoprazole are also available in
Intravenous preparations
• Administered as inactive prodrugs ( acid labile )
• Prepared as enteric coated capsules or tablets ( Lanzoprazole ), powder form or non enteric
coated ( Omeprazole )
• A lipophilic weak bases ( pKa 4 – 5 ) and after intestinal absorption diffuse readily across lipid
membranes into acidified compartments ( e.g. the parietal canaliculi )
• Bioavailabilty of all agents is decreased approximately 50% by food
• In fasting state, only 10% of proton pumps are actively secreting acid and susceptible to inhibition.
Should be administered approximately 1 hour before meal (usually breakfast )
• Drugs have short serum half life of about 1.5H. Acid inhibition lasts up to 24H. If intravenously
given, it must be during the first 24 – 48 hours of treatment to provide maximal inhibition, either
continuous or as repeated bolus injection. Full acid inhibiting potential may be achieved after 3 – 4
days
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• After stopping the drug, it takes 3 – 4 days for full acid secretion to return.
• Undergo rapid first –pass and systemic hepatic metabolism and have negligible renal clearance.
• Rabeprazole or immediate release omeprazole may have a slightly faster acid inhibition

Pharmacodynamics
• Acts only in the parietal cell
• Inhibits both fasting and meal-stimulated secretion. In standard doses, it inhibits 90-98% of 24H
acid secretion.
• The prodrug rapidly becomes protonated within the canaliculus and is concentrated more than
1000 fold by Handerson Hasselbalch trapping. Therefore, it rapidly undergoes a molecular
conversion to the active form, a reactive thiophilic sulfonamide cation, which forms a covalent
disulfide bond with the H+,K+ATPase, irreversibly inactivate the enzyme
• This inactivates the pump and prevents the transport of H into the stomach lumen.
• Most effective way to diminish acid secretion
• They inactivate acid pumps that are actively secreting.

Clinical Uses:
• GERD, PUD ( H pylori-associated ulcers, NSAID-associated ulcers, prevention of re bleeding from
peptic ulcers ), non ulcer dyspepsia, prevention of stress-related mucosal bleeding, gastrinoma
and other hypersecretory conditions

Adverse Effects
• Diarrhea, headache and abdominal pain
• No teratogenecity
• Minor reduction in oral cyanocobalamin absorption leading to subnormal B12 levels with prolonged
therapy
• Modest risk of hip fracture
• May reduce calcium absorption or inhibit osteoclast function
• May increase in gastric bacterial concentration
• Increased CAP and nosocomial pneumonia, Clostridium difficile infection
• Median serum gastrin level rise 1.5 – 2 fold because of alteration in the normal feedback inhibition.
Gastric carcinoid tumor developed in female rats

Drug Interaction
• All are metabolized by hepatic cytochrome P450
• Increase intragastric pH and may also decrease the bioavailability of drugs ( e.g. ketoconazole,
itraconazole, digoxin, atazanavir ) that require gastric acidity for absorption
• Omeprazole may inhibit the metabolism of warfarin, diazepam, and phenytoin
• Esomeprazole may also decrease metabolism of diazepam
• Lansoprazole may enhance clearance of theophylline

MUCOSAL PROTECTIVE AGENTS (p1075)

Sucralfate, Prostaglandin analogues, Bismuth Compounds

SUCRALFATE
Chemistry and Pharmacokinetics
• Is a salt of sucrose complexed to sulfated aluminum hydroxide.
• In water or acidic solution it forms a viscous , tenacious paste that binds selectively to ulcers or
erosions for up to 6 hours.
• Has limited solubility, breaking down into sucrose sulfate ( strongly negative charged ) and an
aluminum salt
• Less than 3% of intact drug and aluminum is absorbed, the remainder is excreted in the feces

Pharmacodynamics
• Negatively charged sucrose sulfate binds eletrostatically to positively charged tissue protein ( base
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of the ulcers or erosions ) forming a physical barrier

Clinical use
• Stress related bleeding

Adverse effects
• Devoid of systemic adverse effects
• Constipation (2%) is related to the aluminum salt
• Not be used for prolonged period in patients with renal insufficiency.

PROSTAGLANDINS ANALOG
Misoprostol

Chemistry and Pharmacokinetics

• synthetic prostaglandin E1 methyl analog
• After oral administration, it is rapidly absorbed and metabolized to a metabolically active free acid
• Serum HL less than 30 minutes, hence administered 3 – 4 times daily
• Excreted in the urine, Dose reduction not needed in patients with renal insufficiency

Pharmacodynamics
• Both acid inhibitory ( binds to PG receptor on parietal cells, reducing histamine-stimulated cAMP
production ) and mucosal protective properties ( stimulate mucus and bicarbonate secretion and
enhanced mucosal blood flow )
• Stimulation of intestinal electrolyte and fluid secretion, intestinal motility and uterine contractions

Clinical uses
• NSAID induced ulcers and its complications

Adverse effects
• Diarrhea and cramping abdominal pain ( 10 – 20% )

BISMUTH COMPOUNDS
Bismuth subsalicylate , Bismuth subcitrate potassium

Chemistry and Pharmacokinetics

• Available in combination with other drugs
• Undergoes rapid dissociation within the stomach, allowing absorption of salicylate.
• > 99% of bismuth appears in the stool

Pharmacodynamics
• Precise mechanism is unknown
• Bismuth coats ulcers and erosions, may also stimulate PG, mucus, and bicarbonate secretion
• Reduces stool frequency and liquidity in acute infectious diarrhea
• Direct antimicrobial effects and binds enterotoxins

Clinical uses
• Travellers diarrhea, dyspepsia and acute diarrhea

Adverse effects
• Turns the tongue and stool black and cause tinnitus
• Avoided in patients with renal insufficiency
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• Toxicity: ataxia, headaches, confusion, seizure )

DRUGS STIMULATING GASTROINTESTINAL MOTILITY

PHYSIOLOGY OF THE ENTERIC NERVOUS SYSTEM ( pp 1077 )

CHOLINOMIMETIC AGENTS ( p 1078 )

Betanechol , Neostigmine

BETANECHOL
• Agonists, that stimulate muscarinic M3 receptors on muscle cells and at myenteric plexus
synapses
• Use for treatment of GERD and gastroparesis

NEOSTIGMINE
• Can enhance gastric, small intestines and colonic emptying
• Use in acute large bowel distention ( acute colonic pseudo obstruction or Ogilvie’s syndrome )
• Cholinergic effects include excessive salivation, nausea, vomiting, diarrhea, and bradycardia

DOPAMINE ANTAGONISTS
Metoclopramide, Domperidone

METOCLOPRAMIDE & DOMPERIDONE

• Increase esophageal peristaltic amplitude, increase lower esophageal sphincter pressure, enhance
gastric emptying but have no effect on small intestines or colonic motility
• Block the D2 receptor in the CTZ of the medulla, thus potent anti nausea and antiemetic action

Clinical uses
• GERD, Impaired gastric emptying, nonulcer dyspepsia, prevention of vomiting, postpartum
lactation stimulation

Adverse Effects
• Most common adverse effect of metoclopramide is CNS
• Restlessness, drowsiness, insomnia, anxiety and agitation ( 10-20% especially the elderly )
• Extrapyramidal effects ( dystonia, akathisia, parkinsonian features ) in high doses or long term use
• Tardive dyskinesia sometimes irreversible, with prolonged use of metoclopramide
• Elevated prolactin levels ( both metoclopramide and domperidone ) can cause galactorrhea,
gynecomastia, impotence and menstrual disorders

MACROLIDES ( Erythromycin )
• Directly stimulate motilin receptor on GI smooth muscle and promote the onset of a migrating
motor complex

Clinical use
• Beneficial in patients with gastroparesis , however, tolerance rapidly develops
• Acute upper GI hemorrhage to promote emptying of blood before endoscopy
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LAXATIVES
BULK FORMING LAXATIVES
Polycarbophil, psyllium, methylcellulose

• Ingestible , hydrophilic colloids that absorb water, forming a bulk

• Emollient gels that distend the colon and promote peristalsis
• Natural plants ( psyllium, methylcellulose )
• Synthetics ( Polycarbophil )
• Adverse effects: bloating and flatus

STOOL SURFACTANT AGENTS ( SOFTENERS )

Docusate sodium, Glycerin, mineral oil

• Soften stool material, permitting water and lipids to penetrate

• Oral ( tablet or suspension ) or rectal preparation ( enema or suppository )

Clinical use
• To prevent and treat fecal impaction
• To minimize straining

Adverse effects
• Severe lipid pneumonitis
• Impair absorption of vitamins ( prolonged use )

OSMOTIC LAXATIVES
Magnesium hydroxide, Sorbitol, Lactulose, Magnesium citrate and sodium phosphate, PEG

NON ABSORBABLE SUGARS OR SALTS

Magnesium hydroxide
• Treatment of acute constipation and prevention of chronic constipation
• AE: hypermagnesemia ( prolonged use )

Sorbitol and lactulose

• Treatment and prevention of chronic constipation
• Metabolized by colonic bacteria

Magnesium citrate
• Purgative

Sodium Phosphate
• Purgative that is available in liquid and tablet formulation
• Precaution: patient should be well hydrated.
Adverse effects
• Hyperphosphatemia, hypocalcemia, hypernatremia, hypokalemia ( these may lead to cardiac
arrythmia or renal failure – nephrocalcinosis )
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BALANCED POLYETHYLENE GLYCOL

• Lavage solutions
Clinical use
• For complete colonic cleansing prior to a GI procedure
• Balanced isotonic solution
• Contain an inert, non absorbable, osmotically active sugar (PEG ) with sodium sulfate, sodium
chloride, sodium bicarbonate and potassium chloride
• No significant intravascular fluid and electrolytes shifts
• Does not produce significant cramps or flatus

STIMULANT LAXATIVES ( CATHARTICS )

Mechanism
• Direct stimulation of the enteric nervous system and colonic electrolyte and fluid secretion
• Dependence with long term use and destruction of the myenteric plexus, resulting into colonic
atony and dilation

ANTRAQUINONE DERIVATIVES
Aloe, Senna, Cascara

Pharmacokinetics
• Poorly absorbed and after hydrolysis in the colon, produce a bowel movement in 6 – 12 hours
when given orally and within 2 hours when given rectally

Adverse effect
• Melanosis coli

DIPHENYLMETHANE DERIVATIVES
Bisacodyl

Pharmacokinetics
• Tablet and suppository form
• Induces a bowel movement within 6 – 10 hours when given orally and 30 – 60 min when given
rectally
• Minimal systemic absorption and safe for acute and long term use

Clinical Uses:
• For acute and chronic constipation
• For colonic cleansing

CHLORIDE CHANNEL ACTIVATORS

Lubiproston

Chemistry and Pharmacokinetics

• Prostanoic acid derivative
• No loss of efficacy with long term use
• Has minimal systemic absorption
Pharmacodynamics:
• Acts by stimulating the type 2 Chloride channel ( ClC – 2 )
• Increases chloride rich fluid section into the intestines, which stimulates intestinal motility and
shortens intestinal transit time

Clinical uses
• For chronic constipation and IBS with predominant constipation
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Adverse effect
• Category C
• Delayed gastric emptying time

OPIOID RECEPTOR ANTAGONISTS

Methyl Natrexone Br, Alvimopan

• Selective antagonist of the peripheral mu ( µ ) opioid receptor without impacting analgesic effects
• Do not readily cross the BBB

Clinical use
• Methyl Natrexone Br - Opioid induced constipation
• Alvimopan – to shorten the period of postoperative ileus, restricted to hospitalized patients only
SEROTONIN 5-HT4 – RECEPTOR AGONISTS
Tegaserod, Cisapride, Prucalopride

Pharmacokinetics
• T – high affinity for 5HT 4 , no affinity to 5HT – 3 or Dopamine receptor
• C – partial 5HT 4 agonists, inhibits hERG K channels
• P - high affinity for 5HT 4 , no affinity for either hERG channels or 5 HT 1B

Clinical uses
• T - For chronic constipation and IBS with predominant constipation

ANTIDIARRHEAL AGENTS
OPIOID AGONISTS
Loperamide, Diphenoxylate

Loperamide
• Opioid agonists that dose not cross the BBB
• No analgesic properties or potential for addiction

Diphenoxylate
• Prescription opioid agonists
• No analgesic properties in standard doses
• Higher doses have CNS effects
• Prolonged use can lead to opioid dependence
• Anticholinergic property contribute to the antidiarrheal action

COLLOID BISMUTH COMPOUNDS

KAOLIN & PECTIN

Structure
Kaolin ( Attapulgite )
• Naturally occurring hydrated magnesium aluminum silicate

Pectin
• Indigestible carbohydrate derived from apples

Pharmacodynamics
• Both acts as absorbent of bacterial toxins and fluid thereby decreasing stool liquidity and number
• Should not be taken within 2 hours of other medications
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BILE SALT BINDING RESINS

Cholestyramine, Colestipol, Colesevelam

Clinical use
• Colonic secretory diarrhea

Adverse effect
• Bloating, flatulence, constipation, fecal impaction

OCTREOTIDE
Chemistry and Pharmacokinetics
• Synthetic octapeptide

Pharmacodynamic
• Inhibits secretion of gastrin, cholestyramine, glucagon, growth hormone, insulin, secretin,
pancreatic polypeptide, 5HT
• Reduces intestinal fluid secretion and pancreatic secretion
• Slows GI motility and inhibits gallbladder contraction
• Induces direct contraction of vascular smooth muscle
• Inhibits some anterior pituitary hormone

Clinical uses
• Inhibition of endocrine tumor,
• diarrhea due to vagotomy , dumping syndrome, short bowel syndrome or AIDS

Advese effect
• sludge or gallstone formation, hypoglycemia, hypothyroidism, bradycardia

DRUG USED IN THE TREATMENT OF IRRITABLE BOWEL SYNDROME

ANTISPASMODICS ( ANTICHOLINERGIC )
Dicyclomin, Hyoscyamine

Pharmacodynamic
• Inhibits muscarinic receptor in the enteric plexus and on smooth muscle

Adverse effects
• Low dose, minimal autonomic effects
• Higher dose, dry mouth, visual disturbance, urinary retention, constipation

SEROTONIN 5-HT3 RECEPTOR ANTAGONISTS ( ALOSETRON )

Pharmacodynamic
• Inhibition of afferent GI 5HT3 receptors - Inhibit unpleasant visceral afferent sensation, including
nausea, bloating, pain
• Inihibition of central receptors reduces the central response to visceral afferent stimulation
• Blockage of the receptor on the terminal of enteric cholinergic neurons inhibits colonic motility
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Chemistry and Pharmacokinetics
• Selective antagonists
• Rapidly absorbed from the GIT, bioavailability of 50 60%, plasma half life 1.5 hours,
• Undergoes extensive hepatic cytochrome p450 metabolism with renal excretion
• Binds with hgher affinity and dissociates more slowly from 5-HT3 receptors

Clinical use
• Severe IBS in whom diarrhea is predominant
• Reduction in number of bowel movements per day and improvement of stool consistency

Adverse effects
• Rare but serious GI toxicity, constipation with ischemic colitis

SEROTONIN 5-HT4 AGONISTS

Tegaserod for short term treatment of IBS in whom constipation is predominant

CHLORIDE CHANNEL ACTIVATOR

Lubiprostone is used for treatment of IBS in whom constipation is predominant

ANTI EMETIC AGENTS

SEROTONIN 5-HT3 ANTAGONISTS
Ondansetron, Dolasetron, Granisetron, Palonosetron

Pharmacodynamics
• Antiemetic properties are mediated in part through central 5HT3 receptor blockade in the vomiting
center and CTZ but mainly thru the blockade of peripheral 5HT3 receptors on extrinsic intestinal
vagal and spinal afferent nerves
• Action is restricted to emesis attributable to vagal stimulation and chemotherapy
• Do not inhibit dopamine or muscarinic receptors

Structure and Pharmacokinetics

• O, G, D – serum half life of 4 – 9 hours
• P – serum half life of 40 hours

• All undergo extensive hepatic metabolism and eliminated by renal and hepatic excretion
Clinical uses
• Chemotherapy induced nausea and vomiting, post operative and post radiation nausea and
vomiting

Adverse Effects
• Headache, dizziness, constipation
• Prolonged QT interval (*** Dolasetron )

CORTICOSTEROIDS
Dexamethasone , Methyprednisolone

Pharmacodynamics
Enhances the efficacy of 5HT 3 receptor antagonists

NEUROKININ RECEPTOR ANTAGONISTS

Aprepritant
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Pharmacodynamics
• Antiemetic properties that are mediated through central blockade in the area postrema

Pharmacokinetics
• Bioavailability is 65%, HL 12hours, metabolized primarily by the CYP3A4 pathway

Clinical uses
• Chemotherapy induced acute and delayed nausea and vomiting

Adverse Effects
• Headache, dizziness, diarrhea

PHENOTHIAZINES
Prochlorperazine, Promethazine, Thiethylperazine

Pharmacodynamics
• Antiemetic properties are mediated through inhibition of dopamine and muscarinic receptors

BUTYROPHENONES
Droperidol

Pharmacodynamics
• Antiemetic properties are mediated through central dopaminergic blockade
• Extremely sedating

Clinical uses
• Postoperative nausea and vomiting, for neuroleptanalgesia, for induction and maintainance of
general anesthesia

Adverse effects
• EPS and hypotension, prolonged QT interval

SUBSTITUTED BENZAMIDES
Metoclopramide, Trimethobenzamide

Trimethobenzamide also has weak antihistaminic activity.

H1 ANTI HISTAMINES & ANTICHOLINERGICS

Meclizine, Diphenhydramine, Dimehydrinate ( first generation antihistamine ), Hyoscine
Pharmacokinetics
• Hyoscine is a prototypic muscarinic receptor antagonists

Clinical uses
• Weak antiemetic if used alone, used in conjunction with other antiemesis (chemotherapy induced )
• Motion sickness

BENZODIAZEPINES
Lorazepam , Diazepam

Clinical uses
• Reduces anticipatory vomiting or vomiting caused by anxiety

CANNABINOIDS
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Dronabinol, Nabilone

Pharmacokinetics
• Completely absorbed after oral ingestion
• Metabolites are excreted slowly over days to weeks in the feces and urine

Adverse effect
• Euphoria, dysphoria, sedation, hallucination, dry mouth, increased appetite, tachycardia,
conjucntival injection and orthostatic hypotension

DRUGS USED TO TREAT INFLAMMATORY BOWEL DISEASE

AMINOSALICYLATES
Sulfasalzine, Olsalazine, Balsalazide, Mesalamine

AZO COMPOUNDS
Sulfasalzine, Olsalazine, Balsalazide

Structure
Sulfasalazine
• Prototype
• Conjugate of 5 aminosalicylic acid ( 5-ASA ) and sulfapyridine linked by a diazo bond (N=N)
Balsalazide
• Conjugate of 5 aminosalicylic acid ( 5-ASA ) and 4 amino benzoyl B alanine
Olsalazine
• Conjugate of TWO 5 aminosalicylic acid ( 5-ASA )

MESALAMINE COMPOUNDS
Pentasa, Asacol, Lialda, (Rowasa, Canasa)

Pentasa
• A mesalamine formulation that contains timed release microgranules that release 5-ASA
throughout the small intestine
Asacol
• Has 5-ASA coated in a pH sensitive resin that dissolves at pH7 ( the pH of distal ileum and
proximal colon )
• Delivered in high concentration by enema ( Rowasa ) or suppository ( Canasa )

Pharmacodynamics
• Azo structure markedly reduces absorption of the parent drug from the small intestines
• In the terminal ileum and colon resident bacteria cleave the azo bond by means of azoreductase
enzymes releasing the 5-ASA
• Mechanism of 5-ASA is uncertain, the primary action of salicylates and other NSAID’s is due to
blockade of PG synthesis by inhibition of cyclooxygenase pathways ( see Figure 62 – 8 , p 1088 ).
• Thought that 5-ASA modulates inflammatory mediators derived both cyclooxygenase and
lipooxygenase pathways. It interfere with the production of inflammatory cytokines. It inhibits
activity of nuclear factor-KB.Inhibits cellular function of NK cells, mucosal lymphcytes and
macrophages and it may scavenge reactive oxygen metabolites
 13

Clinical uses
• Induce and maintain ulcerative colitis

Adverse effects
• attributable to systemic effects of sulfapyridine. Slow acetylators of sulfa have more frequent and
mor severe adverse effects
• Dose dependent - nausea, loss of appetite, headache, malaise, diarrhea
• HPS to sulfapyridine
• Oligospermia, impairs folate absorption, interstitial nephritis

GLUCOCORTICOIDS
Prednisone , Prednisolone, Hydrocortisone, Budesonide

Pharmacokinetics
Budesonide
• Potent synthetic analog of prednisolone
• High affinity for glucocorticoid receptor but is subject to rapid first pass hepatic metabolism
• Release of the drug in the distal ileum and colon, where it is absorbed

Pharmacodynamics
• Reduce expression of inflammatory cell adhesion molecules
• Inhibit production of inflammatory cytokines
• Inhibit gene transcription of nitric oxide synthase,phospholipase A2 cyclooxygenase-2 and NF-kB

Clinical uses
• Moderate to severe IBD

PURINE ANALOGS
Azathioprine, 6 Mercaptopurine

Pharmacokinetics
• Purine antimetabolites with immunosuppressive properties
• Bioavailability – A ( 80% ) > M ( 50% )
• Serum half life of both is less than 2 hours, however the active thioguanines is concentrated in
cells resulting in prolonged half life

Pharmacodynamics
• After absorption azathioprine is rapidly converted by a nonenzymatic process to 6 MP. 6
mercaptopurine undergoes a complex biotransformation via xanthine oxidase and thiopurine
methyltransferase that produce inactive metabolites and anabolic pathways that produce active
thioguanine nucleotides

Clinical uses
• Induce and maintainance of remission of ulcerative colitis and Chron’s disease

Adverse effects
 14
• Nausea, vomiting, bone marrow depression and hepatic toxicity. Routine laboratory monitoring
is required on all patients
• Hypersensitivity
• Increased risk of lymphoma
• Teratogenicity is small

METHOTREXATE

Pharmacokinetics
• Orally ( 50 – 90% bioavailability ) , SQ and IM ( complete bioavailabity )

Pharmacodynamics
• Inhibition of dihydrofolate reductase

Clinical use
• Induce and maintain remission of Chron’s disease

Adverse effects
• Bone marrow depression, megaloblastic anemia, alopecia, mucositis, hepatic damage

ANTI TUMOR NECROSIS FACTOR THERAPY

Infliximab, Adalimumab, Certolizumab

Pharmacokinetics ( see Table 62 – 3 , p 1091 )

Clinical uses
• Acute and chronic treatment of patients with moderate to severe Chron’s disease who have had
inadequate response to conventional therapies
• Infliximab – acute and chronic treatment of moderate to severe ulcerative colitis

Adverse effects
• Infection due to suppression of the Th1 inflammatory response
• Acute or delayed infusion or injection reactions
• Delayed serum sickness like reaction
• Increase risk of lymphoma

ANTI INTEGRIN THERAPY

Natalizumab

• A humanized IgG4 monoclonal antibody targeted against the â4 subunit, which thereby blocks
several integrins on circulating inflammatory cells and thus prevents binding to the vascular
adhesion molecules and subsequent migration into surrounding tissues

PANCREATIC ENZYMES SUPPLEMENTS

Pancreatin , Pancrelipase

BILE ACID THERAPY FOR GALLSTONES

Urosidol ( Ursodeoxycholic acid )

DRUGS USED TO TREAT VARIACEAL HEMORRHAGE

Somatostatin & Octreotide, Vasopressin & Terlipressin