Anti-inflammatory Drugs Flashcards
T or T: glucocorticoids and cytotoxic drugs act in a specific manner to prevent inflammation.
False, Monoclonal antibodies are examples of more targeted therapy
Are anti-histamines appropriate for controlling asthma?
- why or why not?
- What is appropriate for asthma treatment?
No, because they do not block histamine release from mast cells, they only prevent histamine binding to receptors
- Anti-inflammatories are what is needed to control inflammation in asthma patients
What are the two key phases in the asthma response, what molecules are involved in each phase?
Bronchospastic Phase:
- Involves Histamine
Inflammatory Phase:
- PDG2, LTC4, PAF
- ECP (eosinophil cationic protein), MBP (major basic protein)
- Proteases, PAF
What is the only drug that currently works on the Nfkb?
- how does it work?
- what is the importance of drug design centered around this pathway?
Bortezomib
- Prevents Ub being added to Ikb (inhibitor of Ikb) preventing degradation
It allows us to alter a single pathway while leaving others unaffected
What are some downsides of using corticosteriods?
- Specificity
Overaching Concept is that they act on too many cellular processes and are very non-specific.
Side effects:
CV risk, Cataract Glaucoma, Hirsutism, Cushings, Insulin resistance, Osteoporosis(necrosis), Infections
What are some ways in which people develop resistance to even powerful coriticosteriods?
- Receptor Modification
- Compensatory Pathways
- Upregulation of Counter-regulatory pathways
- Efflux mechanisms
What enzymes do NSAIDs work on?
COX-1/COX-2
What inflammatory Processes are instigated by IL-13, how can these be IL-13 be blocked?.
- IgE secretion by B cells
- Upregulation of Low-aff. CD 23 FcRII IgE receptor
- Mucus secretion inc.
- Eotaxin secretion by Respiratory cells
- Fibrosis
- STEROID RESISTANCE.
- *IL-13 blocked by:
1. High affinity Shuttle Receptor (ShulL-13R2)
2. STAT 6 inhibitor
What was the result of using IL-5 antagonists?
Only useful in patients with severe, steroid-resistant, eosinophilic asthma
What was the result of using anti-IL-4/IL-3 antibody?
not too fruitful, only helped in a subgroup of severely affected patients
What was the result of using anti-TNF-alpha antibody to treat asthma?
- Not effective
- Patients experienced pneumonia and TB and Malignancies
What are the affects of H1 (histamine 1) receptor activation in the following tissues:
- Lungs
- Vascular Smooth Muscle
- Vascular Endothelium
- Peripheral Nerves
Lungs:
- Bronchoconstriction
Vascular Smooth Muscle:
- Post-capillary venule Dilation
- Terminal Arteriole Dilation
- VENOCONSTRICTION
Vascular Endothelium:
- Contraction causing separation
Peripheral Nerves:
- Afferent Nerve Sensitization
What is the difference in first and second generation antihistamines?
1st generation antihistamines cross the BBB and act as ANTICHOLINERGICs on CNS
2nd generations don’t pass BBB
What are four 1st generation antihistamines?
- Diphenhydramine
- Chlorpheniramine
- Dimenhydrinate
- Promethazine
What are three 2nd generation antihistamines?
- Cetirizine
- Fexofenadine
- Loratadine
How does Roflumilast work?
- PDE4 (phosphodiesterase-4) inhibitor, this prevents PDE4 from turning active cAMP into 5-AMP
this leads to:
- Relaxation of Airway smooth muscle
- Suppression of Inflammatory Cell function
- Inhibition of airways smooth muscle proliferation
What group of diseases do TNF-alpha inhibitors work best on?
- why?
- What diseases specifically?
- Arthritic type conditions and GI disorders are predominantly the targets for this treatment.
- TNF-alpha concentrations are elevated in the blood, SYNOVIUM, and JOINTS, which is what these inflammatory conditions involve
Diseases:
- Ankylosis Spondylitis
- Crohn’s Disease
- Juvenile RA or IA
- Psoriasis
- Psoriatic Arthritis
- Rheumatoid Arthritis
- Ulcerative Colitis
What was Telcagepant designed to do?
- why was it dropped off the market?
- CGRP antagonist to reduce migraines but taken off the market because it produced hepatic toxicity
What are Pro-resolving molecules?
- why are they the future?
- These mimick the effects of molecules that naturally TERMINATE the production of SPECIFIC inflammatory response.
- Mimicking these molecules would hopefully lead to more specific effects
T or F: Leukotriene inhibitors have no effect on PG pathways
True
What is the role of the mAb drugs against TNF-alpha?
- Etancercept
- Infliximab
- Adalimumab
- Certolizumab Pegol
All except Certolizumab Pegol the last blocks Soluble TNF-alpha, Binds Transmembrane TNF-alpha, Increase Transmembrane Cytokine Cleavage, Promote ADCC and CDC, Apoptosis, and PMN death (aka OPSONIZATION)
What are the COX-2 specific inhibitors?
CELECOXIB
what are the non-selective COX inhibitors?
- Ibuprofen
- Indometacin (GI toxicity)
- Naproxen
What drug acts to inhibit the synthesis of Leukotrienes?
Zileuton
T or F: Antihistamines and Montelukast both work as receptor blockers.
True
In what two ways doe corticosteroids block GATA-3 from getting to the nucleus?
- Inhibit p38 MAP kinase (and induce MAP kinase phaosphatase)
- note: p38 Map Kinase acts to phosphorylate GATA-3 - Compete for Nuclear Entry at Importin Alpha
T or F: Coricosteroids indiscriminately down regulate NfkB in addition to blocking GATA-3 from the nucleus.
True
What drug acts to block IkB from getting degraded?
- Preventing NfkB prevents transcription of what genes?
Bortezomib
IL-6, VEGF, VCAM-1
How do we limit the shitty systemic effects of antiinflammatories?
- Topical or Inhaled Treatments
- Prodrugs that can be targeted to specific tissues
- Taper the dose
What condition is Roflumilast used to treat?
COPD
What is the role of Lipoxins in inflammation?
- They are important for resolving inflammation
***Messing with the Leukotriene pathway could then be messing with potential resolution of the inflammatory response
What is Rituximab?
- what does it do?
Targets CD20 on B cells
- Useful in B cell lymphoma
Describe the possible outcomes of TNF signaling and the techniques we use to down-regulate this signaling.
- TNF binding to surface receptors can be activating or pro-apoptotic depending on the amount of signal received
ways to down regulate:
- Neutralizing TNF-alpha
- can be done via mAb
- Also can be done by Soluble Receptor
- Inhibiting TNF leads to cell death
- can happen by cytokine deprivation
- can also happen by anti-body facilitating cell death via ADCC, or CDC
What are the TNF-alpha blocking drugs?
- Etancercept
- Infliximab
- Adalimumab
- Certolizumab Pegol
What likely plays the biggest role in the TNF blockers, neutralization of TNF or antibody mediated cell death?
Neutralizing TNF is likely more important we know this because Certolizumab Pegol lacks and Fc region but is still effective at keeping down inflammation
What condition are leukotriene blockers indicated for?
asthma
