PHARM; Lecture 19, 20 and 21 - Anti-emetic, IBD, Tx gastric and duodenal ulcers Flashcards Preview

Y2 LCRS 1 - Pharm, Endo, Reproduction > PHARM; Lecture 19, 20 and 21 - Anti-emetic, IBD, Tx gastric and duodenal ulcers > Flashcards

Flashcards in PHARM; Lecture 19, 20 and 21 - Anti-emetic, IBD, Tx gastric and duodenal ulcers Deck (85)
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What are the 2 major forms of IBD?

UC and Crohn's disease -> distinction incomplete in 10% of patients; 300,000 people in UK


Who does IBD affect?

Children, adolescents and adults


What are the risk factors for IBD?

Genetic = white european origin most susceptible; environmental factors = smoking (CD esp), diet, obesity and gut microbiome. NB: obesity is RF in CD but not UC


What is IBD?

Defective interaction between mucosal immune system and gut flora -> 10x more bacteria than host cells


What is the difference between CD and UC - type of AI disease, gut layers affected, regions of gut affected, inflamed area characteristics, abcesses/fissues/fistulas, surgery use?

NB: because inflammation is patchy in CD, surgery isn't curative as it is difficult to extract each site in the GIT and it often reoccurs (unlike UC which doesn't)


What is a fistula?

Abnormal/surgically made passage between hollow tubular organ and body surface/between 2 hollow tubes/organs


What are the clinical features of IBD?


What are the types of treatments used for IBD?


What are the general ideas about aminosalicylates for UC/CD?

UC = first in line for inducing/maintaining remission; CD = unsure effectiveness in active disease, may help to maintain surgically induced remission


What are some examples of aminosalicylates?

Mesalazine(!! and also called 5-ASA) and Olsalazine (more complex molecule) and are anti-inflammatory


What is the mechanism of anti-inflammatory action?

Inhibition of IL-1, TNF-a, Platelet activating factor; decreased Ab secretion and cell migration; non-specific cytokine inhibition; localised inhib of IR


What are the targets of aminosalicylates?

Target Th1 mechanisms (TNFa) but works better with UC (governed by Th2)


What are the pharmacokinetics of 5-ASA?

NO metabolism needed -> absorbed by small bowel and colon (olsalazine needs to be activated by colonic flora - so only absorbed in colon); 5-ASA is safe and good at maintaining remission


What is the relative efficacy between steroids, 5-ASA and olsalazine in IBD?

Olsalazine needs to be activated by colonic bacteria, so is absorbed there and only acts in colon; 5-ASA (topical) is more effective at inducing remission than topical steroids BUT combined topical 5-ASA and oral steroids are better at inducing remission than oral 5-ASA


What are the uses of glucocorticoids in UC?

In decline, can be used topically (enema) or iv if v. severe; BUT ASA is superior (evidence suggests)


What are the uses of glucocorticoids in CD?

Drug of choice to induce remission; likely to get side effects if continued use to maintain remission


What are glucocorticoids?

Prednisolone, fluticasone, budesonide -> powerful anti-inflammatory and immunosuppressive drugs -> activate GR which act as +/-ve transcription factors


How can you minimise the side effects of glucocorticoids?

Topical admin (fluid/foam enemas/suppositories); low dose in combination with other drug; use oral/topically admin drug with high hepatic first pass met (budesonide = less side effects than prednisolone) to minimise GC in systemic circulation


What are the different immunosuppressive agents used in IBD?

Azathioprine and 6-mercaptopurine (not in CD, some success in UC); methotrexate (some IBD); cyclosporin (in severe UC only)


What is azathioprine?

Immunosuppressive; maintain remission in CD with slow onset = 3-4 months treatment for clinical benefit; steroid-sparing, superior to placebo and budesonide


What is the pharmacokinetics of azathiprine and what is the mechanism of immunosuppression?

Activated by gut flora to 6-mecaptopurine -> purine antagonist, interfering with DNA synthesis and cell replication


What are the unwanted effects of azathioprine?

Nearly 10% of patients have to stop treatment -> associated with pancreatitis, bone marrow suppression, hepatotoxicity, increased risk of lymphoma and skin cancer


What are the main routes of metabolism of azathioprine?

  • 3 -> 6-TGN produces beneficial active metabolites which can also cause myelosuppression;
  • 6-MMP causes non-beneficial metabolites which are hepatotoxic;
  • main metabolic route is the Xanthine oxidase pathway as metabolites are inert so won't cause problems ->
  • but if allopurinol (gout) taken inhibition of XO occurs, shunting AZA to other pathways


What is methotrexate?

Demonstrable effect in CD; folate antagonist reducing thymidine (and other purines) synthesis; not widely used in monotherapy (significant unwanted effects)


What are the 3 different ways to manipulate the microbiome to treat IBD?

Nutrition based therapies (No evidence in CD, evidence for probiotics in induction and maintenanc of remission UC), faecal microbiota replacement therapies (no evidence) and antibiotic treatment (rifaximin)


How does rifaximin (Ab treatment) help treat IBD?

Interferes with bacterial transcription by binding to RNA polymerase; induces and sustains remission in moderate CD, may be beneficial in UC and microbiome modulator; also shown to reduce amount of mRNA coding for inflammatory mediators in UC


What are the different biological therapies available for IBD?

Anti TNF-a Ab = infliximab (IV - can bind to soluble, cell membrane and bound TNF-a) and Adalimumab (SC); used in CD (some evidence in UC), with potentially curative (60% respond within 6wks) abilities even in some patients with refractory diseases and fistulae


What is the mechanism of action of anti-TNF-a Ab?

  • Anti-TNF-a reduces activation of TNF-a receptors in gut and get general downregulation of other cytokines as well;
  • reduces infiltration/activation of leukocytes;
  • binds to membrane associated TNF-a, inducing cytolysis of cells expressing TNF-a and promotes apoptosis of activated T-cells


What is the pharmacokinetics of ATNFa Ab?

Infliximab given IV, v. long half life (9.5d), with benefits lasting for 30wks after single infusion; relapse after 8-12wks, so repeat infusion every 8 wks


What are the problems that can occur (not side effects) with ATNFa Ab?

Emerging evidence that up to 50% responders lose response within 3y due to production of anti-drug Ab and increased drug clearance

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