Aminosalycials

Question 1

what are aminosalicylates?

Answer 1

Drugs for Inflammatory Bowel Disease (Ulcerative Colitis)

and mild-to-moderate Crohn’s disease

Question 2

aminosalycialates that act locally in the gut have what kind of side effects?

Answer 2

few systemic side effects

Question 3

where is the desired location of work for aminosalicylates?

Answer 3

tomically not systemically in areas of dieases GI mucosa

Question 4

what are the prodrugs of 5-aminosalicylic acids?

Answer 4

–Olsalazine(dipentum)
–(Ipsalazine)
–Balsalazide(colazide)
–Sulfasalazine

Question 5

what is the role of the colon?

Answer 5

Highly efficient part of lower GI tract–reabsorbs water from waste material
–stores solid waste
–eliminates faecal waste

Question 6

why do we have colon-targeted drug delivery?

Answer 6

–avoid absorption and degradation of drugs in upper GI tract

Question 7

how do prodrugs work to target colon drug delivery?

Answer 7

–avoid absorption and degradation of drugs in upper GI tract

Question 8

what are some of the gross features of UC?

Answer 8

• Oedematous, reddened, friable surface; often visible ulceration
• Isolated islands of regenerating mucosa from pseudopolyps
• Continuous distribution from rectum towards proximal colon

Question 9

what are some of the microscopic features of UC?

Answer 9

• Diffuse inflammatory infiltrate
• Frequent microscopic ulcerations into lamina propria and submucosa, but not extending into deeper layers
• Risk of epithelial dysplasia and adenocarcinoma after many years of disease

Question 10

what is sulfasalazine?

Answer 10

5-ASA linked to sulfapyridine by an azobond

- for UC developed originally for rheumatoid arthritis

Question 11

what are some of the features of sulfasalazine?

Answer 11

–highly polar, poorly absorbed, ~80% of dose reaches colon
–given individually, either 5-ASA or sulfapyridineis absorbed in the upper GI tract
–the azolinkage prevents absorption in the stomach and small intestine
–individual components are not liberated for absorption until colonic bacteria cleave the bond–5-ASA is now regarded as the therapeutic moiety, with little, if any, contribution by sulfapyridine
–sulfapyridineposes toxic, adverse effects

Question 12

what are some of the problems associated with sulfasalazine?

Answer 12

Sulfasalazine can cause sulfonamide toxicity

•Hypersensitivity reactions independent of sulfapyridine levels

Question 13

why do 50% of Caucasians have altered hepatic phase 2 metabolism of sulfasalazine?

Answer 13

due to missing isoform of N-acetylation enzyme NAT-1/2

Question 14

what is the effect of altered phase metabolism of sulfasalazine?

Answer 14

• ‘slow acetylation’
• decreased sulfapyridine clearance
• elevated sulfapyridine serum levels

Question 15

what is aminosalicylates MOA?

Answer 15

• anti-inflam
• immunosupressive
• antioxidant

Question 16

how does it produce its anti-inflam response?

Answer 16

•Inhibits enzymatic activity of cyclooxygenase, lipoxygenase and platelet activating factor
•Reductions in levels of products of arachidonic acid metabolism
–reduces levels of pro-inflammatory mediators

Question 17

how does it produce its immunosupressive activity?

Answer 17

Promotes release of adenosine–impairs leukocyte function and activation
•Reduces levels / efficacy of pro-inflammatory mediators
•Interferes with IL-1, IL-2, TNF-alpha synthesis
•Inhibition of transcription factor nuclear factor NF-kB
•Depresses antibody synthesis–limits antibody-mediated disease process

Question 18

how does it produce its antioxidative effect?

Answer 18

Chronic gastrointestinal inflammation is associated with enhanced levels of reactive oxygen species derived from leucocyticin filtrates in the mucosa
–oxidising effects lead to tissue injury

Question 19

5 ASA has powerful antioxidant effects- what does it reduce?

Answer 19

–reduces peroxynitriteanions (ONOO-)
hyperchlorousacid (HOCl)
superoxide anions (O2.-)
hydroxyl radicals (HO.)

Question 20

where does metabolism take place?

Answer 20

Primary metabolism is in gut wall or liver, leading to N-acetylation
Typically, ~40-50% of dose excreted in faeces

Question 21

how is urine and faeces excreted?

Answer 21

primary excreted material is N-Ac-5-ASA5-ASA and N-Ac-5-ASA have been detected at low conc. in fetalplasma and breast milk

Question 22

why is colon drug delivery better?

Answer 22

–less hostile environment
–less diversity
–less intensity of action
–longer retention time

Question 23

how do we colon- target drug delivery?

Answer 23

covalent linkage of a drug with a carrier
approaches to delivery the intact drug into the colon:
–coating with pH sensitive / biodegradable polymers
–coating with microparticles
–embedding in pH sensitive / biosensitivematrices–time
-release systems
–redox-sensitive polymers
–bioadhesivesystems
–osmotic controlled drug delivery

Question 24

what kind of formulation is pentasa?

Answer 24

contains timed-release ethylcellulose-coated microgranules that release 5-ASA throughout the small intestine

Question 25

what kind of formulation is asacol?

Answer 25

is a formulation coated with a pH-sensitive resin (EudragitS/L) that dissolves at the pH of the distal ileum and proximal colon (pH 7)

Question 26

what kind of formulation is Lialda/Mezavant?

Answer 26

a pH-dependent resin (EudragitS) encasing a amultimatrixcore (hydrophilic and lipophilic). When the pH-sensitive resin dissolves, it allows water to penetrate, resulting in a slow release of mesalaminethroughout the colon

Question 27

when can 5ASA be delivered in high concentrations?

Answer 27

5-ASA may also be delivered in high concentrations by means of enema (Rowasa) or suppository formulations (Canasa)

Question 28

what is a prodrug?

Answer 28

• A prodrugis a pharmacologically inactive form of a parent drug
• The parent drug is chemically modified to produce the prodrug(enzymicor non-enzymic)
• The prodrug breaks down in the body by a defined pathway to release the parent drug

Question 29

what are the two types of prodrugs?

Answer 29

1- carrier-linked prodrug

2- bio-precursor prodrug

Question 30

what is a carrier-linked prodrug?

Answer 30

–a compound that contains an active drug linked to a carrier group that is removed enzymatically

Question 31

what are examples of carrier-linked prodrugs?

Answer 31

• bipartate-comprised of a carrier attached to the drug
• tripartate-the carrier is connected viaa linker that is connected to the drug
• mutual -two, usually synergistic, drugs attached to each other

Question 32

what is a bio-precursor prodrug?

Answer 32

–a compound metabolised by molecular modification into a new compound, which is a drug or is metabolised further to a drug
–not just simple cleavage of a group from the prodrug

Question 33

how do you reduce azo compounds?

Answer 33

Azoreductases
–NADPH dependent multicomponent hepatic microsomal reductasesystem
–bacterial reductasesin anaerobic intestinal environment reduce azocompounds [using flavinmononucleotide(FMN)/ reduced nicotinamideadenine dinucleotide phosphate (NADPH)]

Question 34

what is dersalazine?

Answer 34

• Provides an alternative approach that is mutual prodrug
• Combines a potent platelet activating factor (PAF) antagonist (UR-12746) with 5-ASA
• Increased production of PAF correlated with local injury and inflammation in ulcerative colitis

Question 35

what effect does dersalazine have?

Answer 35

nti-inflammatory effects in ulcerative colitis patients in phase II trials
Increasing evidence that Th17 cells have an important role in the pathogenesis of inflammatory bowel disease