Pharmacotherapy of Inflammatory Bowel Disease Flashcards
What is Inflammatory Bowel Disease?
Inflammatory bowel disease is a spectrum of remitting and relapsing chronic, inflammatory intestinal conditions
What are the two types of IBD?
CRohn’s and UC
What is Crohn’s?
TRansmural inflammation of any part of the GIT but most commonly in the area adjacent to the ileocecal valve
What is UC?
Characterized by confluent mucosal inflammation of the colon, the anal verge and extending for a variable extend
What are the different types of UC based on their location?
Proctitis
Left-sided colitis
Pancolitis
What do the extra-intestinal manifestations of Crohn involve?
Joints
Skin
Eyes
What are the objectives of the treatment?
Scute treatment of illness
Induction and maintenance of clinical remission and improvement of quality of life
Cellular level: induction of mucosal healing
Reduced risk of surgical complication
Reduced rates of hospitalization
What are possible surgical complications regarding IBD?
Fistula, colorectal cancer, Intestinal obstruction
Which drugs are used for induction of remission?
Sulfasalazine, Mesalamine
Steroids (glucocorticoids)
In the case of steroid refractory (steroid resistance) which drugs are given?
Azathioprine or 6-Mercapto-purine
Methotrexate
anti-TNFα
What is the maintenance of remission medications?
Azathioprine or 6-Mercapto-purine
Methotrexate with anti-TNFα
In which kind of IBD cases is Methotrexate given as maintenance of remission?
Crohn’s
What are other biological therapies?
Anti-integrins
Anti-IL-12/23 (Ustekinumab)
Inhibitors of new targets (Jak kinase and S1 receptors)
What are the examples of 5-aminosalicylates?
Mesalamine
Sulfasalazine
Olsalazine
Balsalazide
Which kind of steroids are used as treatment of IBD?
Glucocorticoids
What are the examples of disease-modifying agents?
Methotrexate
Azathioprine/6 - Mercatopurine
What are other treatment options for IBD?
Fecal microbiota transfer
Probiotics
Balance of nutrition
Surgery followed by medication
What are the cellular and molecular aspects of IBD?
Interaction of bacteria and immune cells in the intestine
APCs activate T lymphocyte helper cells through the HLA2-TCR bond
Pro-inflammatory TH1 lymphocytes activate macrophages (which cause inflammation, modification, and proliferation)
Recruitment of monocytes to the inflammatory patches
What causes the destruction of the barrier of epithelia to allow for bacterial components to enter the intestinal lamina propria?
Dysbiosis - dysbacteriosis –> disruption of the microbiota
What is the other name of Mesalamine?
Mesalazine
Which 5-ASA drug has antibiotic activity?
Sulfasalazine
What are 5-ASA the first line treatment for?
Mild to moderate ulcerative colitis
How can 5-ASA be used?
With or without glucocorticoids
Where are the anti-inflammatory effects of 5-ASA targetted?
Targetted topically to the mucosa, with limited effects on deeper inflammation –> more used in UC
What is the MOA of 5-ASA?
Not identified clearly:
1. Inhibition of the production of IL-1 and TNF-a
2. Inhibition of the production of cyclooxygenase-lipoxygenase pathway,
3. Scavenging of free radicals and oxidants
4. Activation of PPAR-γ or inhibition of NF-kB
What is NF-kB?
A transcription factor pivotal to the production of inflammatory mediators
What is the cyclooxygenase-lipoxygenase pathway function?
What is their effect?
To convert arachidonic acid into:
ROS
PGE2
IL-6
IL-1
TNF-a
These increase inflammation
Why do physicians give 5-ASAs even though they are not specific inhibitors?
They have results and they also have few side effects
What are the PK of 5-ASAs?
Well absorbed
Clinical effect usually occurs 1 week to 3 months
Mild states of IBD
What is the PK of Mesalamine?
Directly active
Large part eliminated in the stool
Catabolysed by acetylation and hydroxylation in the liver and eliminated in the urine
What are the PK of Sulfasalazine?
Sulfasalazine is broken down by bacteria in the intestine to sulfapyridine and 5-ASA
What are the PK of Olsalazine?
Bacterial flora breaks it into two 5-ASAs
WHat are the PK of Balsalazide?
Broken by the colon bacteria
What is the site of action for Mesalamine?
Mesalamine has a delayed release or pH-dependent release –> only broken down when it reaches the colon
Sites of action: duodenum, ileum, jejunum and colon
What is the site of action of Sulfasalazine, Balsalazide, Olsalazine?
Colon
What are the side effects of Mesalazine?
Generally well tolerated:
1. Headache, dyspepsia, skin rash, flatulence, hepatitis
2. Nephrotoxicity (rare but serious)
3. Association with interstitial nephritis
What are the side effects of Sulfasalazine?
- Headache, nausea, and fatigue
- Alergic reaction (rash, fever, hepatitis, pneumonitis, hemolytic anemia and bone marrow suppression)
- Reversible oligospermia
- Inhibitions of intestinal folate absorption
What % of patients on Sulfasalazine present with side effects?
10 to 45%
What causes the allergic reaction in Sulfasalazine?
Sulfa molecule
What are the side effects of Olsalazine and Balsalazide?
Diarrhea (10 to 20% of patients)
What are glucocorticoids first-line therapy for?
Severe UC
What are the PK of glucocorticoids?
Good absorption / excellent bioavailability
Oral, IV, rectal
How can glucocorticoids be given orally/rectally?
Suppositories or enema
What are examples of glucocorticoids?
Budesonide
Prednisolone
Methylprednisolone
Hydrocortisone
What are glucocorticoids useful for?
Induction of remission for both UC/CD
NOT during maintenance of remission
What are the 3 categories of glucocorticoid patients?
Glucocorticoid-responsive patients
Glucocorticoid-dependent patients
Glucocorticoid-unresponsive patients
What are glucocorticoid-responsive patients?
Patients that improve and remain in remission as the steroids are tapered and then discontinued
What are glucocorticoid - dependent patients?
Patients that respond to glucocorticoids but then there is a relapse of symptoms if tapered opr discontinued
What are glucocorticoid-unresponsive patients?
Patients who do not improve even with prolonged high-dose steroids
What is the MOA of steroids?
The steroid present is blood bond to CBG, binds in free form
The main receptor is an intracellular steroid receptor that is associated with heat steroid protein HSP90
Receptor complex H-receptor is formed and HSP90 is released
The H/R complex enters the nucleus as a dimer, binds to Glucocorticoid-response-elements on the gene, and regulates transcription factor
Protein expression/ modualtion decreases
What is the MOA of glucocorticoids?
They are strong anti-inflammatory
- Inhibit expression of Phospholipase A2 and formation of prostaglandin, and leukotrienes
- Inhibit the expression of cyclooxygenases and thus formation of prostaglandins and leukotrienes
- Inhibit the activation of transcription factor NFkB and the synthesis of pro-inflammatory cytokine through activation of macrophages and IL-10
What are the examples of proinflammatory cytokines?
TNF-a
IL-1b
integrins
IL-12
IL-23
What are the side effects of glucococrticoids?
Fluid retention
Alteration in glucose tolerance
High BP
Behaviour and mood changes
Increased appetite and weight gain
Increased blood neutrophils
What are examples of chemical immunomodulators?
Azathioprine
6 Mercaptopurine
Mathetrexate
What are the different kinds of immunomodulators -immunosuppressants?
Chemicals
Biologics
What are examples of the biologic immunomodulators?
Antibodies
Anti-TNFa
Integrins
What is the prodrug that gets converted into 6 - mercaptopurine, and where does that conversion happen?
Azathioprine
Conversion occurs in the gut or the liver
What is the function of Azathioprine/6-mercaptopurine?
Reduces inflammation
Which drug category does Azathioprine/6-mercaptopurine replace?
Glucocorticoids
In which cases of IBD is Azathioprine/6-mercaptopurine used in?
Moderate to severe cases,
Used to treat patients with severe IBD or those who are steroid-resistant or steroid-dependent
What does 6-MP break into? What are they?
Thiouric acid and 6-methyl MP
They are inactive metabolites
Which enzyme converts 6-MP into thiouric acid?
Xanthine oxidase
WHich enzyme converts 6-MP into 6-methyl MP?
Thiopurine methyltransferase
What happens to 6-MP with the help of HPGRT?
It gets converted into 6-thioguanine nucleotide (6-TGNs)
What is the effect of 6-TGNs?
DNA incorporation which causes clinical efficacy and bone marrow suppression
What are the effects of Azathioprine/6-mercaptopurine?
- Impair purine biosynthesis
- Inhibition of DNA replication and RNA transcription
- Limit lymphocytes proliferation and increase apoptosis
- Inhibit inflammation
What is the plasma half life of 6-MP?
Short: 1 to 2 hours
What are the drug interactions of Azathioprine/6-mercaptopurine?
Metabolism with differences in TPMT activities (low or high activity)
90% of US population have normal metabolism (lower)
10% of the population has high TPMT activity
What is a rare phenomenon regarding the TPMT activity?
Absence of TPMT activity
What is the importance of checking and categorizing TPMT metabolizing patients?
Adjustment of the dose required
What causes increased toxicity of Azathioprine/6-mercaptopurine?
Combination with Alluprinol, an inhibitor of Xanthine oxidase
What are the adverse effects of Azathioprine/6-mercaptopurine?
Pancreatitis
A major dose-related side effect is bone marrow suppression
Common: vomiting and nausea
Less common: fever, rash and arthalgia
Severe but rare: hepatitis
What is methotrexate?
A drug that is used in chemotherapy and immunosuppressant in autoimmune disease and RA
When is methotrexate used in IBD?
In patients resistant to glucocorticoids
What is the MOA of methotrexate?
Folic acid analogue that inhibits DHFR and blocks DNA synthesis –> cell death
Fewer lymphocytes
What is the difference between chimeric and humanised antibodies?
Chimeric = variable regions are from mouse origin
Humanized = hypervariable regions are from mouse origin (sections from the mouse are a lot smaller in this antibody)
What is the transitions from mouse to human antibody?
Mouse
Chimeric
Humanised
Human
What is Infliximab?
Chimeral human-mouse IgG
What is Adalimumab?
Human IgG
What is Etanercept?
Fusion protein: receptor for TNFa
What is Certolizumab?
PEG (humanized Fab; increase serum half-life)
Which anti-TNFa therapies are used for IBD?
Infliximab
Adalimumab
Cetrolizumab
When are anti-TNFa treatments given?
Moderate to severe Crohn’s
Glucocorticoid unresponsive patients
When is Infliximab more efficient?
When used with methotrexate or azathioprine, it is rarely used as monotherapy
What is the exception case of giving Infliximab on its own?
In elderly patients or when Aza cannot be administered
How is Infliximab eliminated?
Through the reticular endoplasmic system which causes loss of response
How is Adalimumab given?
Monotherapy or co-treatment with methotrexate
How is Certolizumab given?
Monotherapy or co-treatment
What are the PK for anti-TNFa?
IV administration for Infliximab
Subcutaneous for all the others
What are integrins?
They are membrane glycoproteins that bind components of the extracellular matrix
What are the examples of components of extracellular matrix that integrin bind?
Collagen
Laminin
Vitronectin
Fibronectin
ICAM
VCAM
Fibrinogen
What do integrins recognise?
The RGD (Arg Gly Asp) sequence present in these ligands
What does the binmding of the integrins to their ligands depend on??
Extracellular divalent cations (Ca2+ or Mg2+)
When are integrins used?
In moderate to severe cases (non-responsive to anti-TNFa and immunosuppressants)
What are the PK of integrins?
IV administration
What is the MOA of integrins?
It blocks lymphocytes recruitment
What are the examples of integrins?
Vedolizumabb
Natalizumab
What is the MOA of Vedolizumab?
Inhibits α4β7 interaction with MAdCAM-1
What is the MOA of Natalizumab?
Inhibits the interaction of α4β1 with VCAM-1 and of α4β7 with MAdCAM-1
Which integrin was developed first and why?
Natalizumab, it was used for treatment of Multiple Sclerosis
What are the examples of anti - IL12/23?
Ustekinumab
Risakizumab
What are the subunit of IL-23?
p19 and p40
What are the subunits of IL-12?
p35 and p40
What is Ustekinumab?
Fully human monoclonal antibody
What is the MOA of Ustekinumab?
Targets the p40 subunit of IL-12 and IL23
When is Ustekinumab used?
In moderate to severe cases (non-responsive ti anti-TNFa and immunosuppressant)
What is the PK of Ustekinumab?
IV administration
What is the MOA of Risankizumab?
Targets p19
Which cases is Risankizumab used in?
Psoriasis
What are the adverse effects of Infliximab?
Risk of TB
Flu-like symptoms
Liver injury
Dyspepsia
Bronchitis
What are the adverse effects of Adalimumab?
Bone marrow suppression
Raised creatinine kinase
Respiratory tract infections
TB
Why is there less of a reaction when it comes to Adalimumab?
It is the first full human monoclonal antibody
Which antibodies target plasma proteins?
Infliximab
Adalimumab
Which antibodies are surface antigens?
Vedolizumab
What is the administration routes of antibodies?
Not orally
IV, IM or SC
What is the resistance of monoclonal antibodies like?
Resistance to the therapeutic effects can occur either due to altered disease biology or to the development of neutralizing antibodies
WHat is the elimination of monoclonal antibodies like?
They are large molecules and cannot be eliminated by the kidney, so there is almost no interaction with CYP450
What is the uptake of monoclonal antibodies like?
Receptor-mediated endocytosis or pinocytosis through Fc
How are monoclonal antibodies metabolised?
Through proteolysis to small peptides and amino acids in the reticule-endothelial system by circulating phagocytic cells, mainly in the liver and spleen
What is Ozanimod?
Another medication, previously used for multiple sclerosis but is now also approved for UC/CD
What is the MOA of Ozanimod?
- Sphingosine 1P is a lipid molecule
- Ozanimod is a ligand for Sphingosine 1P receptor 1 and S5P receptors, binds to receptors and induces internalization and degredation
- Stimulation of S1P1 receptors sequesters lymphocyte subsets in peripheral lymphoid organs, preventing their trafficking to inflamed tissue sites, modulating immunity
What is the PK of Ozanimod?
IV administration
What are Jak Inhibitors ?
They are a kind of molecule that decreases the signaling by cytokine and growth factors
Cytokines will work on cytokine receptors and cause inflammation, and Jak inhibitors inhibit that
WHat are the counter indications for Jak inhibitors?
Acute infection, cardiovascular, and thrombotic risk
