Pharmacology Learning Outcomes

By
 After the end of this lecture YOU will be able to
Dr. Muneeb  Describe Inflammatory Bowel Disease (IBD)
 Differentiate between ulcerative colitis and Crohn’s disease
 Identify drugs to treat IBD
 Describe mechanisms of action of drugs used for management of IBD

Drugs acting on GIT  Recognize Side Effects (SE) of drugs used to treat IBD

IBS, bile flow and

Cholelithiasis
Dr. Syed Muneeb Anjum (Ph.D.)
IPS, UVAS University of Veterinary and
Animal Sciences 1 2

Inflammatory Bowel disease (IBD) Inflammatory Bowel disease (IBD)

 Inflammatory Bowel Disease (IBD)  Ulcerative colitis (UC)
 An idiopathic disease with strong immune component triggered  It involves only the colon starting from the anal canal. The disease may remain restricted to the rectum or extend
by various factors proximally in a contiguous manner to variable extent up to caecum.
 A chronic relapsing inflammatory disease of the ileum, colon, or  The lesions are mucosal and may be diffuse or confluent
both that may be associated with systemic manifestations.  Crohn's disease (CrD)
 Characterised by bouts of diarrhoea, constipation or abdominal  In CrD lesions are patchy and transmural
pain  May involve any part of the GIT from mouth to the anus.
 Aetiology  Majority of patients have ileocaecal disease up to ascending colon
 The etiology and pathogenesis of these disorders remain  In some cases it may be restricted to the small intestine
unknown but psychological factors may play a part  The lesions are transmural, complications like perforation,
abscess, fistula, strictures, etc. can occur.
 Treatment
 CrD is less responsive to medical therapy than is UC
 Symptomatic treatment with a high-residue diet plus loperamide
or laxative if needed
 Drugs used in IBD are chosen on the basis of disease severity,
responsiveness, and drug toxicity

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 Inflammatory Bowel disease (IBD)
 Types of Crohn’s disease
 There are six variations of Crohn’s disease, all based on location. They are:
 Gastroduodenal Crohn’s disease
 mainly affects your stomach and the duodenum, which is the first part of your small intestine. About 5 % of people with Crohn’s
disease have this type.
 Jejunoileitis
 occurs in the second portion of your intestine, called the jejunum. Like gastroduodenal Crohn’s, this variation is less common.
 Ileitis
 Inflammation in the last part of the small intestine, or ileum. About 30 % of people with Crohn’s disease are affected at this location.
 Ileocolitis
 Affects the ileum and the colon and is the most common variation of Crohn’s. Approximately 50 % of people with Crohn’s disease have
this variation.
 Crohn’s colitis
 Found in about 20 % of people with Crohn’s disease. It affects the colon only. Both ulcerative colitis and Crohn’s colitis impact the
colon only, but Crohn’s colitis can affect deeper layers of the intestinal lining.
 Perianal disease
 Affects about 30 % of people with Crohn’s. This variation often involves fistulas, or abnormal connections between tissues, deep tissue
infections, as well as sores and ulcers on the outer skin around the anus.

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Inflammatory Bowel disease (IBD)

 Drug used in treatment of IBD
 Aminosalisylates (Azo compounds)
 5-Amino salicylic acid (5-ASA)
compounds
 Sulfasalazine, Balsalazide, Olsalazine
 Corticosteroids
 Immuno-suppressants
 TNF- α inhibitors
 Treatment of IBD
 Corticosteroids
 Acute attacks
 Not used for long term
 Aminosalicylates
 Maintenance of remission in both
ulcerative colitis and Crohn’s disease
 Less effective in CrD

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 Drug used in treatment of IBD Drug used in treatment of IBD
 Azo compounds  Sulfasalazine (SALAZOPYRIN) Indications Drug Interactions Adverse Effects

 They contain 5-ASA bound by an azo (N=N) bond to an inert compound or to another 5-ASA molecule.  Consists of the sulphonamide sulfapyridine linked to 5-aminosalicylic ! Sulfasalazine
• Nausea
 In sulfasalazine, 5-ASA is bound to sulfapyridine acid (5-ASA) • Vomitting
 In balsalazide, 5-ASA is bound to 4-aminobenzoyl-β-alanine (inert  safer than sulfapyridine)  Reduces number of stools, abdominal cramps and fever during active • Headache
disease state • Malaise
 In olsalazine, two 5-ASA molecules are bound together • Oligospermia
 Mechanism of Actions  Less effective than corticosteroids • Male infertility
 Beneficial actions are not due to sulfapyridine (antibacterial action) • Folic acid malabsorption
 The azo structure markedly reduces absorption of the parent drug from the small intestine
 Terminal ilium and colon  Azoreductase enzyme by resident microbes  cleavage of AZO bond  Dose:
 High concentrations of active drug are made available in the terminal ileum or colon  3-4 g/day  lessens the disease severity in many patients of UC 
 Release of the active 5-ASA  inhibits COX and LOX  minor effects relapse common after stopping drug treatment
Disease modifying effects in
 Inhibition of cytokine, PAF, TNF-alpha and nuclear transcription factor beta (NFkB)  major effects  Maintenance therapy with 1.5-2 g/day  postpones relapse in many,
rheumatoid arthritis
 Migration of inflammatory cells into bowel wall is interfered and mucosal secretion is reduced  symptomatic relief but not all cases.
 The primary value of sulfasalazine is in maintaining remission in UC,
while corticosteroids are reserved to treat acute exacerbations
 The current treatment guidelines do not recommend use of 5-ASA
compounds in CrD What are other
 Side effects uses of
sulfapyridine?
 Sulfapyridine linked (Sulfonamindes)
9  see box 10

Drug used in treatment of IBD Drug used in treatment of IBD

 Mesalamine or Mesalazine (ASACOL, MESACOL) Indications Drug Interactions Adverse Effects
 Corticosteroids
 Contain 5-ASA itself ! Sulfasalazine  Glucocorticoids  drugs of choice for moderately severe exacerbations
Hepatic impairment • Nausea
 Unable to reach colon due to absorption in intestine Renal impairment • Vomitting  Patients who do not respond to 5-ASA compounds
 Coated forms (pH sensitive acrylic polymer) Glucocorticoids  inc. • Headache  Prednisolone (40-60 mg/ day) or equivalent dose of another glucocorticoid
gastric toxicity • Abdominal pain
 Dose: Sulfonylureas  Inc. • Fever
 Highly effective in controlling symptoms as well as in inducing remission in both UC and CrD
 2.4 g / day  >50% drug available at site of action hypoglycaemic actions • Itching  Onset of action
• Lukopenia
 > 50% patients of UC show improvement  Symptomatic relief  within 3- 7 days
 Use:  Remission is induced in 2-3 weeks
 Prevention of relapse of UC  Proctitis and distal ulcerative colitis
 Metabolism  Hydrocortisone enema, or foam (ENTOFOAM 10%) can be used for topical treatment
 < 50 % absorbed systemically  Less effective than oral treatment
 Acetylated in liver and excreted in urine  Duration of treatment
 5-ASA enema  Generally used for short term; tapered over 8- 12 weeks and discontinued after remission is induced
 Because of the high dosage requirement even short term therapy with glucocorticoids is mostly attended
 Another mode of delivery of 5-ASA to colon is to administer it by a retention enema
by significant side effects, which should be managed symptomatically.
 4 g enema once or twice daily is effective in distal ulcerative colitis and proctitis or refractory cases.
 Neither effective nor suitable for maintaining remission either in UC or CrD.
 Not useful for maintenance of remission.

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 Drug used in treatment of IBD Drug used in treatment of IBD
 Immunosuppressants  TNFa inhibitors
 Indicated in patients with resistive IBD conditions  lnfliximab
 They also serve to avoid long-term steroid therapy which carries hazards
 It is chimeric anti-TNF-α antibody
 About 60% patients with CrD and substantial number of UC patients require immunosuppressive therapy.  Indicated in severe active CrD, fistulating CrD and severe UC which has not improved with i.v. conicosteroids and
 Risks of chronic immunosuppression must be weighed in each patient before instituting therapy immunosuppressants, or when the latter are inappropriate.
 Not suitable for acute flareups of the disease, but have good remission maintaining and steroid-sparing property  Administration
 Azathioprine  Infused i.v. every 2- 8 weeks, it decreases acute flare-ups and helps in fistula closure.
 A purine antimetabolite, the most effective and most commonly used immunosuppressant in IBD.  Response occurs in 2-4 weeks.
 6-Mercaptopurine (into which azathioprine is converted in the body) can be used in its place.  Therapy is continued till response is maintained.
 Indications and limitations of use  Adverse effects
 Steroid-dependent, steroid-resistant and relatively severe cases of IBD, as well as for those who experience frequent flareups.  lnfliximab produces substantial toxicity,
 Lower SE potential than that of prolonged steroid therapy.  Acute reactions
 Some patients experience higher bone marrow toxicity of azathioprine and 6-MP due to genetic abnormality of one of its metabolizing  Formation of antibodies
enzymes (thyopurine methyltransferase )TPMT  Poor resistance to infections.
 Such patients cannot be treated with these drugs.  Only a reserve drug for selected patients with refractory disease
 Methotrexate  Adalimumab
 2nd line drug in IBD, faster action than Azathioprine  Adlimumab and some other TNF-α inhibitors arc also being used in severe and refractory IBD.
 been shown to suppress TNF-aplha expression in macrophages and monocytes
 Role only in severe CrD and in patients not responsive to or not tolerating azathioprine 13 14

Drug for Cholelithiasis Drug for Cholelithiasis

 Cholelithiasis  Characteristics of biliary colic include the following:
 Cholelithiasis involves the presence of gallstones which are compact masses that forms in the biliary tract, usually in  Sporadic and unpredictable episodes
the gallbladder  Pain that is localized to the epigastrium or right upper quadrant, sometimes radiating to the right scapular tip
 Pain that begins post-prandially, is often described as intense and dull, typically lasts 1-5 hours, increases steadily over 10-
 Choledocholithiasis 20 minutes, and then gradually diminishes
 The presence of one or more gallstones in the common bile duct (CBD)  Pain that is constant; not relieved by emesis, antacids, defecation, flatus, or positional changes; and sometimes
 Cholesterol Cholelithiasis accompanied by diaphoresis, nausea, and vomiting
 The formation of gallstones with high cholesterol content  Nonspecific symptoms (eg, indigestion, dyspepsia, belching, or bloating)

 Signs and symptoms  Stone formation

 Gallstone disease may be thought of as having the following four stages:  Cholesterol remains in dissolved form usually with the help of bile salts
 Lithogenic state  e.g. Cholic acid and chenodexoycholic acid in conjugation with glycine and taurine
 Conditions favour gallstone formation  High cholesterol : Bile salts ratio  favours crystallization of cholesterol in bile which serves as nidi for stone formation
 Asymptomatic gallstones  Management
 Symptomatic gallstones,  Laparoscopic cholecystectomy is the treatment of choice for gallstones
 Characterized by episodes of biliary colic (cramp)
 Medical therapy is an option in patients with small cholesterol (CH) stones who are unwilling or unfit for surgery
 Complicated cholelithiasis
 Orally active drugs that dissolve non-calcified ‘radiolucent’ cholesterol gallstones
 Symptoms and complications result from effects occurring within the gallbladder or from stones that escape the  Chenodeoxycholic acid (Chenodiol) and Ursodeoxycholic acid (Ursodiol) decrease Cholestrol content of bile, enabling
gallbladder to lodge in the CBD. 15 solubilisation of CH from the stone surface 16
 Drug for Cholelithiasis Drug for Cholelithiasis
 Chenodeoxycholic acid (Chenodiol)  Management of Biliary colic
 Not used now, because it is less effective, frequently causes diarrhoea, can raise plasma LDL-CH and  Biliary colic, the pain produced by the passage of gallstones through the bile duct, can be very intense, and
carries risk of liver damage immediate relief may be required.
 Ursodeoxycholic acid (Ursodiol) (URSOFALK, URSOGAL)  Morphine
 Hydroxy epimer of chenodiol  more effective and can be given at lower doses.  Relieves the pain effectively, but it may have an undesirable local effect because it constricts the sphincter of Oddi
 Administered orally, ursodiol is well absorbed, gets conjugated in liver with glycine and taurine, and is excreted in bile. and raises the pressure in the bile duct. Buprenorphine may be preferable. Pethidine has similar actions,
 Largely undergoes enterohepatic circulation and has a long plasma t½ of - 4 days. although it relaxes other smooth muscle, for example that of the ureter.
 Promptly reduces CH secretion into bile and promotes solubilization of biliary CH by liquid crystal formation.  Atropine
 Ursodiol also inhibits intestinal CH absorption. Plasma LDL-CH level is not raised.  commonly employed to relieve biliary spasm because it has antispasmodic action and may be used in conjunction
 Can achieve complete dissolution of biliary CH stones in upto 50% cases when given for 6- 24 months. with morphine.
 More likely to succeed in patients who have a functioning gallbladder with multiple small floating gall stones
 Glyceryl trinitrate
 Dose
 Produces a marked fall of intra biliary pressure and may be used to relieve biliary spasm
 450- 600 mg daily in 2- 3 divided doses after meals
 Side effects
 Less common, Gastric ulcer due to decrease gastric mucosal resistance

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