Block 1: IBD and PERT Pharm Flashcards
1
Q
What type of condition is IBD?
A
Chronic, idiopathic, intestinal inflammatory
2
Q
Differentiate the subtypes of IBD?
A
Ulcerative colitis: Confluent mucosal inflammation of the colon starting from the anal and extending proximally
Crohn’s disease: Transmural inflammation at any part of the GI, can skip areas with normal mucosa
3
Q
What are factors that contribute to IBD?
A
- Has genetic and environmental components
- Genetically suspectible individuals have abnormal inflammatory responses to environmental triggers
- Triggers lead to inflammation by the release of inflammatory mediators (TNF-a, IL12, IL23)
4
Q
What are the chracteristics of drugs that treat IBD?
A
- Belong to different therapeutic classes
- Different but nonspecific mechanisms of anti-inflammatory action
5
Q
What are aminosalicylates?
A
5-aminosalicylic acid (5-ASA) used topically of GI mucosa
6
Q
What is the difference between unformulated and special formulated 5-ASA?
A
Unformulated: aqueous is absorbed in small intestin and DOES NOT reach the distal small bowel or colon in the required amount
Specially formulated: used to oversome rapid absorption from proximal small intestine
7
Q
What is an azo-compound?
A
5-ASA is tagged with an inert compound or another 5-ASA by an azo (N=N) that is cleaved by bacterial azoreductase to release 5-ASA
8
Q
What are the azo 5-ASA products? Describe their tags?
A
- Sulfasalzine: sulfapyridine - 10% of parent, 85% carrier absorbed
- Balsalazide: 4-aminobenzoyl-β-alanine - <1% of the parent drug (balsalazide), 70% carrier in feces
- Olsalzine: two 5-ASA molecules
9
Q
How does mesalamine differ from azo?
A
Used to deliver 5-ASA to different segments of the small or large bowel
10
Q
What are the formulations of mesalamine?
A
- Modified-release
- pH sensitive resin
- Enema/suppository
11
Q
What are modified-release formulation for mesalamine?
A
Pentasa is a timed release microgranules that release 5-ASA throughout small intestine
12
Q
What are pH sensitive resin formulation for mesalamine? How do they work?
A
Dissolutes in colon, water slowly penetrates into drugs hydrophillic/lipophilic core → slow release in colon
Asacol & Apriso: dissolves in pH 6-7 (distal ileam and proximal colon)
Lialda: Encases a multimatrix core
13
Q
What are enema/suppotitory formulation for mesalamine? How do they work?
A
Delivered in high concentrations to the rectum and sigmoid colon:
Rowasa (enema) and Canasa (suppository)
14
Q
What is the MOA of ASA?
A
- Modulate inflammatory mediators from cyclooxyrgenase and lipoxygenase pathways
- Interfere with the production of inflammatory cytokines by inhibiting nuclear factor-κB (NF-κB)
- Inhibit cellular functions of natural killer cells, mucosal lymphocytes, and macrophages
15
Q
What is the first line for UC (mild-moderate)? Why?
A
ASA induce and maintain remission in UC
16
Q
How is ASA used in CD?
A
Effectiveness is dependent on high drug concentrations at site of disease
17
Q
When are ASA suppositories and enemas useful in UC and CD?
A
Confined in rectum or distal colon
18
Q
When are azo and mesalamine useful in UC and CD?
A
Extend to the proximal colon
19
Q
What are the ADRs of sulfasalazine?
A
- Systemic effects with NAT2 slow acetylators that fast
- Dose related: N, GI upset, HA, arthralgia, myalgias, bone marrow suppression and malaise
- Sufa allergy hypersensitivity: fever, exfoliative dermatitis, pancreatitis, pneumonitis, hemolytic anemia, pericarditis, or hepatitis
- Folate absorption impairment
20
Q
What are rare aminosalicylate ADRs?
A
Intestinal nephritis with high doses
21
Q
What are the GCs and indication?
A
Prednisone and prednisolone: PO for intermediate DOA QD
Hydrocortisone enemas, foam, suppositories for mild UC minimizing systemic absorption
Budesonide: potent sythetic prednisone analog → higher affinity for GC receptor
22
Q
Describe the ADME process of Budesonide?
A
Rapid first-pass hepatic metabolism → low oral bioavailability
Cleared by liver minimizing adrenocortical supperession and CS ADRs
23
Q
What are the formulations of Budesonide and how do they differ?
A
pH controlled DR PO
Entocort: DR it the distal ileum and colan (pH >5.5) treating CD
Uderis: Release in colon (pH>7) treating UC
24
Q
What is the MOA of GC?
A
- Inhibit production of inflammatory cytokines (TNF-α, IL-1) and chemokines (IL-8).
- Reduce expression of inflammatory cell adhesion molecules
- Inhibit gene transcription of nitric oxide synthase, phospholipase A2, cyclooxygenase-2, and NF-κB.
25
What are the indications for GC?
1. Mild-severe IBD
2. Prednisone or prednisolone PO for active disease
3. Severely ill IV
4. Mild-moderate IBD → PO CR budesonide
26
What are the categories of ADRs for GC?
1. Withdrawal of steroid therapy
2. Continued use at supraphysiological doses
27
What happens during GC withdrawal?
1. Flare-up of underlying disease for which steroids were prescribed
2. Acute adrenal insufficiency → rapid withdrawal of corticosteroids after prolonged therapy has suppressed the HPA axis
28
What are the ADRs associated with continued use at supraphysiological doses?
1. Fluid and electrolyte abnormalities
2. HTN
3. Hyperglycemia
4. Infection risk
5. Peptic ulcer
6. Osteoporsis
7. Behavioral disturbances
8. Cataracts
9. Growth arrest
10. Fat redistribution
11. Striae
12. Eccymoses
29
What are the types of immunosuppressive agents used for IBD? Why?
Thiopurine Derivatives (Azathioprine, 6-Mercaptopurine [6-MP], 6-thioguanine [6TGN] )
Prodrugs for 6-thioguanine nucleotides (active) → incorporated into DNA and RNA → inhibits DNA replication and cytotoxicity
30
What is the MOA of immunosuppressive agents?
Impair purine biosynthesis & inhibit cell proliferation → inducing T-cell apoptosis
31
What are the indications for immunosuppressive agents?
1. Severe IBD interchangeably or GC unresponsiveness
2. Autoimmune disease (lupus, RA)
3. Thioguanine → acute myeloid leukemia
4. 6-MP → childhood acute lymphoblastic leukemia
32
What are the ADRs of immunosuppressive agents?
1. Pancreatitis
2. Bone marrow suppression
3. Cholestatic hepatitis (rare)
33
What are the pathways for thiopurine metabolism?
1. Primary: Hypoxanthine Phosphoribosyltransferase (HPRT) → active 6TGN → ↑ cytotoxicity
2. Xanthine Oxidase (XO) metabolizes 6MP → inactive thiouric acid (TUA)
3. Thiopurine Methyltransferase (TPMT) converts 6MP → 6MMP
Enzyme deficiency → toxicity
High enzymatic activity → ↓ 6TGN
34
Describe genomics of TPMT?
TPMT*2, TPMT*3A, TPMT*3B, TPMT*3C
Caucasians → TPMT*3A
Africans and Southeast Asians → TPMT*3C
South American and Middle Eastern → TPMT*2
Decreased TPMT activity can be caused by with thiopurine-related toxicity mainly bone marrow suppression
35
What is Methotrexate?
Trexall is an antimetabolite for CD and RA
PO (50-90% F), SQ/IM (100%)
36
What is the MOA of Trexall?
1. Inhibition of dihydrofolate reductase → important enzyme in the production of thymidine and purines → resulting depletion of nucleotide pool
2. High doses coause cellular proliferation
3. Interfere with inflammatory actions of IL1
4. Stimulate adenosine → anti-inflammatory autacoid
5. Stimulate apoptosis and death of activated T-cell
37
What are the indications of Immunosuppressive Agents?
1. Induce & maintain remission in CD
2. Uncertain efficacy in UC
38
What are the ADRs of immunosuppressive agents?
High doses for non-IBD → bone marrow depression, megaloblastic anemia, alopecia
Folate supplementation reduces the risk of these events w/o impairing anti-inflammatory action
39
What is cyclosporine?
1. Potent immunomodulator used most frequently after organ transplantation
2. Severe IBD unresponsive to GC
3. TDM (300-400 ng/mL)
40
What is the MOA for cyclosporine?
1. Binds to the immunophilin, FK Binding Protein-12 (FKBP-12) → immunosuppressive complex
2. Complex binds and inhibits mTOR (key regulatory kinase)
3. Inhibition suppress cytokine-driven T-cell proliferation, inhibiting the progression from the G1 to the S phase of the cell cycle
41
What are the cacineurin inhibitors (immunomodulators)? Indication?
Prograf, Astagraf XL, Envarsus XR (Tacrolimus)
Organ transplant and IBD
TDM required
42
What is the MOA of Tacrolimus?
1. Inhibits T-lymphocyte activation (i.e., immunosuppression) through binding to an intracellular protein (FKBP-12)
2. A complex of tacrolimus-FKBP-12, intracellular calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin inhibited
3. Dephosphorylation & translocation of nuclear factor of activated T-cells (NF-AT
43
What is TNF?
1. Key pro-inflammatory cytokines in IBD
2. Soluble TNF and membrane-bound TNF
3. Mediated by binding to TNF receptors
44
What is the mechanism of activated TNF?
1. Release of proinflammatory cytokines.
2. T-cell activation and proliferation.
3. Fibroblast collagen production.
4. Up-regulation of endothelial adhesion molecules responsible for leukocyte migration
45
What are the TNF monoclonal antibodies for IBD? How do they differ?
Infliximab, Adalimumab, Golimumab: IgG1 subclass
Certolizumab: rAb with conjugated Fab fragment to polyethylene glycol (PEG) and no Fc portion
Infliximab: IV infusion
Aadalimumab, golimumab & certolizumab: SQ
46
Describe binding of a-TNF Ab?
1. Soluble & membrane-bound TNF receptors with high affinity
2. Prevent the cytokine from binding to receptors
3. Suppress cytokine release → mediated by membrane-bound TNF
47
What Ab are indicated for acute and chronic treatment of patients with moderate to severe CD who fail to respond to conventional therapies?
Infliximab, adalimumab, certolizumab
48
What are Ab indicated for acute and chronic treatment of moderate to severe UC?
Infliximab, adalimumab, golimumab
49
What infections can anti-TNF Ab cause?
1. Bacterial sepsis, tuberculosis, invasive fungal organisms, reactivation of hepatitis B, listeriosis, other opportunistic infections
2. Reactivation of latent tuberculosis, with dissemination → patients must get skin test or interferon gamma release assays → positive test → prophylaxis
50
What are the more common ADRs can anti-TNF Ab cause?
URI: sinusitis, bronchitis, pneumonia
Antibodies may develop
51
What are interns?
Adhesion molecules on the surface of leukocytes that interact with selectins (adhesion molecules on the surface of the vascular endothelium)
Help circulating leukocytes adhere to vascular surface and move through the vessel
52
Integrins consist of ____ with subunits __ and __?
heterodimer; a and b
53
What are examples of anti-integrins?
Natalizumab
54
What is the MOA of Natalizumab?
Humanized IgG4 monoclonal antibody that target a4 subunits → blocks integrins on circulating inflammatory cells → prevents binding to vascular adhesion molecules → inhibits migration into tissues
55
What is the indication for Natalizumab?
Moderate-to severe CD
56
What are the the ADRs of Natalizumab?
Progressive multifocal leukoencephalopathy (PML) from reaction of human polyomaviras (JC virus) found latent in 80% of adults
57
How are IBD drugs often chosen? Step-up approach?
Basis of :
1. Disease severity
2. Responsiveness
3. Drug toxicity
58
What are the pancreatic enzymes?
Lipase, amylase, protese (trypsin and chymotrypsin)
59
Describe lipase function and what happens if there was an impairment secretion?
Hydrolysis and degradation of fat.
Dysfunction leads to malabsorption of fat
60
Describe amylase function and what happens if there was an impairment secretion?
Hydrolysis and digestion of starches
Dysfunction leads to complex carb malabsorption
61
Describe protease function and what happens if there was an impairment secretion?
Breakdown of proteins and amino acids
62
What is exocrine pancreatic insufficiency?
EPI is a condition where the pancreas is impaired to deliver digestive enzymes to the duodenum → maldigestion and malabsorption of nutrients
63
What disease state can cause EPI?
1. CF
2. Chronic pancreatitis
3. Pancreatectomy
64
What is the standard of care for EPI?
PERT (Creon-Pancrelipase)
65
Describe how PEP ar prescribe and how they differ from one another?
1. Exogenous versions of the pancreatic enzyme mixture from porcine
2. Only licensed for sale in US
3. 6 products with different ratios
4. Prescribed on the basis of the lipase content
66
Describe the formulation of Pancrelipase?
Enteric-coated to resist destruction or inactivation in gastric acid, and releases enzymes in the duodenum at a pH greater than 5.5
67
When does lipase remain inactive?
pH lower than 4
68
What enzymes are in PEP?
Lipase, amylase, protease
69
What is the MOA of pancrelipase?
Acts in duodenum due to enteric coat → alkaline pH activates drug
70
Describe the replenishment of lipase with Creon?
Hydrolysis of TG to monoglycerides, fatty acids, and glycerol:
1. Colipase anchors lipase to the lipid-water membrane of the micelle producing a change in the structure of that surface
2. Hydrophobic active site is exposed to TG binding and interaction with catalytic triad → Hydrolization of the esters of the FA
71
Describe the replenishment of amylase with Creon?
1. Hydrolyzes the alpha 1-4 linkages in the polysaccharides of three or more linked glucose units.
2. Starch is only reduced to a lower compound as alpha 1-6 linkages are not hydrolyzed
3. Starch breaks down into dextrins and lower sugars
72
Describe the replenishment of proteases with Creon?
1. Comprises trypsin and chymotrypsin → belong to serine proteases family.
2. Proteases act as the digestive enzymes secreted by the pancreas
73
What is trypsin?
Acts on the arginine and lysine residues which are hydrophilic
74
What is chymotrypsin?
Acts on the hydrophobic residues tryptophan, tyrosine, and phenylalanine
75
What is the catalytic triad?
Serine, histidine, and aspartate
76
Describe the ADME of pancrelipase?
Enzymes are released only if the pH is greater than 5.5
Enzymes are not absorbed from the GIT and excreted in the feces
77
What are the counseling points of EC capsules of pancrelipase?
1. Administered with a meal or immediately before it with sufficient fluids
2. Swallow whole, should not be crushed
3. If swallowing is difficult, capsule can be opened and contents can be mixed in small amounts of liquid or soft food → don't chew
4. Don't mix contents with alkaline food or liquid (milk, tea)
78
What are the ADRs of pancrelipase?
1. HA, oral irritation, abdominal pain, lymphadenopathy, nasal congestion, neck pain
2. Beta-hemolytic streptococcal infection, hyperuricosuria and malabsorption of folate and iron
79
What are the indications of pancrelipase?
Chronic pancreatitis, Cystic fibrosis and Pancreatic surgery
80
