PHARM; Lecture 19, 20 and 21 - Anti-emetic, IBD, Tx gastric and duodenal ulcers Flashcards
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
What are the adverse effects of ATNFa Ab?
All consequences of knocking out key cytokines in inflammatory cascade -> 4-5x increase in TB/other infection incidence; risk of reactivating dormant TB, increased risk of septicaemia, worsening HF, increased risk of demyelinating disease, increased risk of malignancy, can be immunogenic (AZA reducing risk but raising TB/malignancy risk)
When is infliximab used?
Early use is better, combined with AZA therapy may be more effective than Ab alone
Metabolised and inactivated locally
Interferes with purine biosynthesis
What is nausea?
Subjective unpleasant sensation in throat and stomach, often precedes vomiting
What is vomiting?
Forceful propulsion of stomach contents out of the mouth
What often precedes nausea/vomiting?
Salivation, sweating and increased heart rate
What is the sequence of events in N/V?
What are the consequences of acute/chronic nausea and severe vomitng?
What are the pathways of N/V?
- Vestibular system important in motion sickness in children;
- lots of CNS inputs;
- mechano/chemoreceptors in stomach also capable feeding back to vomiting centre;
- CTZ sit in brain with very porous BBB which can act as early warning system to protect brain from toxin damage, stimulating vomiting centre and CTZ and cause vomiting before it crosses BBB
What are the targets of anti-emetic drugs in the vomiting pathway?
What is the mode of action of promethiazine?
- Phenothiazine derivative;
- competitive antagonist at histaminergic (type H1),
- cholinergic (muscarinic, M) and
- dopaminergic (type D2) receptors.
- Order of potency of antagonistic activity: H1> M > D2 receptors
- Acts centrally (vestibular nucleus, CTZ, vomiting centre) to block activation of vomiting centre.
What is promethiazine used for?
MOST useful prophylactically
What are the pharmacokinetic considerations of promethiazine?
Administer orally Onset of action 1-2 hours Maximum effect circa 4 hours Duration of action 24 hours
What are the side effects of promethiazine?
Dizziness Tinnitus Fatigue Sedation (‘do not drive or operate machinery’) Excitation in excess Antimuscarinc side-effects
What is the mode of action of D2 receptor antagonists - Metoclopramide and domperidone?
Order of antagonistic potency: D2 >> H1 >>> Muscarinic receptors Acts centrally, especially at CTZ Prokinetic effects in the gastrointestinal tract - increases smooth muscle motility (from oesophagus to small intestine - accelerated gastric emptying - accelerates transit of intestinal contents (from duodenum to ileo-coecal valve). Basically empties stomach contents
Where do D2 receptor antagonists act on?
Isn’t going to have much effect on stimulus not coming from CTZ
What are the uses of metoclopramide and domperidone?
What are the pharmacokinetic considerations of D2 receptor antagonists?
What are the side effects of D2 receptor antagonists?
Due to CNS blockade of D2 the motor disturbances, fatigue etc occurs
What is hyoscine’s MOA?
- Order of antagonistic potency: Muscarinic >>>D2 = H1 receptors
- Acts centrally, especially in the vestibular nuclei and CTZ to block activation of vomiting center.
What is the use of hyoscine?
Muscarinic receptor antagonist; Prevention of motion sickness; has little effects once nausea/emesis is established; pre-op; MOST useful prophylactically
What are the pharmacokinetic considerations of hyoscine?
Can be admin orally with peak effect 1-2h, IV/transdermally as well
What are the side effects of hyoscine?
Typical anti-muscarinic -> drowsiness, dry mouth, cyclopegia, mydriasis
What is the mode of action of ondansetron and how does it act as an anti-emetic?
- Serotonin (5-HT3) receptor antagonists.
- MOA: acts to block transmission in visceral afferents and CTZ;
- main use in preventing anticancer drug-induced vomiting, especially cisplatin radiotherapy-induced sickness post-operative nausea and vomiting
What are the pharmacokinetic considerations and unwanted effects of ondansetron?
Admin orally, well absorbed and excreted in urine. Side effects: headache, sensation of flushing and warmth, increased large bowel transit time (constipation)
What occurs when ondansetron is given with corticosteroids?
5-HT3 receptor antagonists may be used for low emetogenic chemotherapy. Corticosteroids, such as dexamethasone, may be used in combination with 5-HT3 receptor antagonists for high or moderately high emetogenic chemotherapy. Improved efficacy of combined therapy may be due to anti-inflammatory properties of corticosteroids.
How are cannabinoids used as anti-emetics?
What are the main kinds of drugs used as anti-emetics?
Cannabinoids, 5-HT3 receptor antagonists (serotonin), D2 receptor antagonists, muscarinic receptor antagonists, promethiazine (phenothiazine derivative)
What is peptic ulcer disease?
Area of damage to the inner lining of the stomach or upper part of duodenum -> ulcers caused by imbalance of factors that protect/damage the GI barrier
How can you differentiate between gastric and duodenal ulcers?
Gastric = pain at meal times; duodenal = pain relieved by a meal as pyloric sphincter closes + pain 2-3h after a meal; occurrence 4 duodenal : 1 gastric
What are the protective factors of the GI tract to maintain integrity of mucosal barrier?
In the mucosal membrane there are bicarbonate ions trapped generating pH of 6-7 at mucosal surface, locally produces prostaglandins stimulate bicarb and mucous production and inhibit gastric acid secretion
What are the factors that can damage the mucosal barrier?
Other factors are needed to convert food into chyme can damage mucosal barrier -> acid secretion from parietal cells of the oxynitic glands in gastric mucosa and pepsiongens from chief cells which can erode the mucous layer
What is the pathogenesis of factors which may cause damage to mucosal GI barrier?
Increased acid and/or decreased bicarbonate production Decreased thickness of mucosal layer Increase in pepsin type I Decreased mucosal blood flow Infections with Helicobacter pylori; may also play role in pathogenesis of gastric cancer
What are the risk factors and prevalence of peptic ulcers?
RF: genetic predisposition, stress, diet, alcohol, smoking; prevalence: 1:10 in developed countries
What are the aim of treatments for peptic ulcers?
Eliminate cause of mucosal damage (difficult to ascertain); promote ulcer healing
What are the drugs and their targets for peptic ulcers?
What is the target of antibiotics in peptic ulcers?
Eliminate H pylori -> infects 50-80% of popn worldwide chronically and 10-20% develop peptic ulcer disease/neoplasia -> 90% eradication within 7-14d is current therapy aims
How do you test for H. pylori?
Ask subject to swallow urate mixture with unique C isotope; bacteria has unique enzyme which breaks down urate and CO2 which then is formed using C isotope; breath test performed 20-30min later and if contaminated with isotope then high conc of H pylori in patient
What are the risk factors and methods of transmission for H pylori?
Unknown risk factors and uncertain MoT -> socioeconomic conditions, contact with animals/contaminated faeces
What is triple therapy for peptic ulcers?
Antibiotics. A single antibiotic is not sufficiently effective - partly due to development of resistance Drugs which reduce gastric acid secretion Drugs which promote healing
How is gastric acid secretion controlled?
- PSNS acts on the H cells in the stomach, stimmulating histamine production, which stimulates the parietal cels to produce more acid
- When a.a. released, G cells in antrum of stomach release gastrin which then triggers release of more histamine from H cells to more acid production by parietal cells
- Secretin and GIP act on fundus of stomach to inhibit formation of gastric acid
- D cells are found in lining of stomach whihc release somatostatin when stimulated by PSNS
What are the drugs that can inhibit gastric acid secretion?
Proton pump inhibitors, H2 (histamine) receptor antagonists, anti-muscarinics
What is omeprazole and its MOA?
What are the uses, pharmacokinetics and unwanted effects of proton pump inhibitors?
What are H2 receptor antagonists - MOA, pharmacokinetics, unwanted effects?
- Main method of acid production is via H2 but there are other methods of producing gastric acid, so isn’t very effecting at healing ulcers;
- Ranitidine is much longer acting c.f. cimetidine
What are the uses of anti-muscarinic agents?
Not used as anti-ulcer drugs alone; more effective in combination therapies
What are cytoprotective drugs?
Enhance mucosal protection mechanisms and/or build a physical barrier over the ulcer -> sucralfate, bismuth chelate and misoprostol
Where do the drugs target at the cellular level for treatment of peptic ulcers?
What is sucralfate, MOA and side effects? (NB: little bit about bismuth chelate too)
BC acts like sucralfate and is used in triple therapy (in cases of resistance to drugs)
What is misoprostol, MOA, admin and side effects?
What are antacids, MOA and admin method?
x
Give some examples of triple combination therapy?
–Example 1 Metronidazole (active against anaerobic bacteria and protozoa) or amoxycillin (broad spectrum antibiotic), depending on pattern of local resistance Clarithromycin - antibiotics with a macrolide structure; inhibits translocation of bacterial tRNA) Proton pump inhibitor (PPI) improves antibiotic efficiency possibly by increasing gastric pH which improves stability and absorption –Example 2 H2 receptor antagonist Clarithromycin Bismuth
What are the problems associated with triple combination therapy?
Compliance, resistance to Ab (superseded by vaccination), adverse response to alcohol (metronidazole interferes with alcohol metabolism)
What is GORD and how would you treat it?
