Pharm: Drug Targets of Inflammation Flashcards
Describe the MOA of the following anti-inflammatory drug(s):
Corticosteroids
Transcriptional regulation inhibitor
Describe the MOA of the following anti-inflammatory drug(s):
NSAIDS
Zileuton
Synthesis inhibitors
Describe the MOA of the following anti-inflammatory drug(s):
Certolizumab
Adalimumab
Soluble cytokine receptor
Blocking monoclonal antibody
Describe the MOA of the following anti-inflammatory drug(s):
Antihistamines
Montelukast
Receptor blockers
Asthma is characterized by two distinct phases:
Bronchospastic phase: histamines (bronchospasm)
Inflammatory phase: PGs, LTs, PAF, MBP, eosinophil cationic protein (ECP), proteases
Why are antihistamines not appropriate for treatment of asthma?
Antihistamines block the effects of histamine binding to H1 receptors, but currently no antihistamine has utility in preventing degranulation of mast cells. There are many other inflammatory products in mast cell granules that cause asthma symptoms in addition to histamine.
GATA-3, a transcription factor that is specifically expressed in T helper 2 (Th2) cells, is essential for the gene expression of these 3 cytokines that mediate allergic inflammation.
IL-4, IL-5, and IL-13
GATA-3 is activated by ACPs via the TCR ______ and co-stimulatory receptor _____ after which is is phosphorylated by p38 MAP kinase and translocates to the nucleus via the nuclear import protein _________ .
CD3; CD28; importin-alpha
Corticosteroids bound to glucocorticoid receptors inhibit GATA-3 function by:
Competing for nuclear entry via importin-alpha and also by inhibiting p38 MAP kinase through the induction of MAP kinase phosphatase-1. Corticosteroids act as indirect inhibitors of GATA-3.
Briefly describe the two major signalling pathways that lead to upregulation of transcriptional activity and how they work.
Nf-kB pathway:
Nf-kB (p50/p65 heterodimer) is bound to inhibitor called IkB. Binding of IL-1 or TNF to TLR on surface of cell causes IkB to be phosphorylated, releasing Nf-kB which travels to nucleus and initiates transcription of Nf-kB responsive genes.
Jak/STAT pathway:
IFN-gamma binds surface receptor of alpha subunit of heterodimer Jak. Jak subunits (alpha/beta) join and Jak1/Jak2 (non-receptor protein tyrosine kinases) are activated and phosphorylate critical tyrosine residues, signalling to STAT to come on over and get in on some of that phosphorylating action. STAT molecules dimerize and translocate to the nucleus and stimulate transcription of IFN-gamma regulated genes.
At present, bortezomib is the only drug that targets Nf-kB levels by inhibiting its activation through stabilization of the inhibitor protein _____ .
IkB
The Nf-kB pathway plays a central role in both inflammation and ________ .
Cancer
Is it advisable to use corticosteroids over an extended period of time?
No. Can increase susceptibility to multi-system pathology to include: Infection Myopathy Osteonecrosis/porosis Neuro/psych symptoms Metabolic disorders Gastric ulcers Hair in wrong places/thinning skin Eye problems Cardiovascular issues vascular impermeability
Glucocorticoid (GCC) resistance is a problem. Name a few mechanisms by which cells can become resistant to GCCs?
Familial resistance
Receptor modification
Increased levels of pro-inflammatory TFs (AP1, JNK, STAT, JAK3)
Increased efflux of steroids from cell
Which NSAID irreversibly acetylates the catalytic site of COX?
Aspirin
Ibuprofen is a selective or non-selective COX inhibitor? (meaning it inhibits either COX 1 or COX 2)
Non-selective inhibitor, can inhibit production of PGs and Thromboxane
Name a COX-2 specific inhibitor.
Celecoxib (Celebrex, Celebra)
What are autacoids?
A family of cell signalling molecules that include prostaglandins (from COX) and leukotrienes (from LOX)
Montelukast is a:
Leukotriene receptor antagonist
Zileuton is a:
Leukotriene synthesis inhibitor
Omalizumab is a drug reserved for hard-to-treat asthma cases that acts by binding and neutralizing _______ (Ig) before it binds to mast cells to inhibit histamine release.
IgE
Interleukins have become a drug target to treat asthma. An example is ____, which induces steroid resistance and increases B cell secretion of IgE, IgE receptor expression on several inflammatory cells, increased mucus secretion and fibrosis and eotaxin (eosinophil chemotaxis) release from airway epithelium.
IL-13
With regard to H1 receptor activation by histamine what is the clinical manifestation of activation of the following tissue:
Lungs
Asthma symptoms
With regard to H1 receptor activation by histamine what is the clinical manifestation of activation of the following tissue:
Vascular smooth muscle
Erythema (redness of the skin or mucous membranes, caused by hyperemia of superficial capillaries)
With regard to H1 receptor activation by histamine what is the clinical manifestation of activation of the following tissue:
Vascular endothelium
Erythema Wheal response (A wheal is a rounded or flat-topped, pale red papule or plaque that is characteristically evanescent, disappearing within 24 to 48 hours)
With regard to H1 receptor activation by histamine what is the clinical manifestation of activation of the following tissue:
Peripheral nerves
Itchiness
Pain
There are two generations of antihistamines. The first generation access the blood-brain barrier (BBB) and can produce ____________ effects in the CNS as an adverse effect.
anti-cholinergic effects
There are two generations of antihistamines. The second generation drugs were designed to lack the ability to pass the ______, hence they are considered non-sedating in normal clinical use and they lack the CNS adverse effects.
BBB (blood-brain barrier)
List 4 1st generation antihistamines
Promethazine
Dimenhyrinate
Chlorpheniramine
Diphenhydramine
List 3 2nd generation antihistamines
Cetirizine
Fexofenadine
Loratadine
Roflumilast is a new treatment for COPD. It selectively inhibits the action of ____________, which blocks the hydrolases and inactivation of cAMP, resulting in intracellular accumulation of cAMP, an action thought to decrease inflammatory activity, somehow.
phosphodiesterase-4 (PDE4)
By Roflumilast inhibition of PDE4, the recruitment and activation of key inflammatory cells, including these 5 key playas, as well as the hyperplasia and hypertrophy of structural cells, including airway smooth-muscle cells, epithelial cells and sensory and cholinergic nerves.
Mast cells macrophages T-lymphocytes neutrophils eosinophils
Name the two cellular sources of TNF-alpha.
New production of soluble TNF-alpha and membrane-bound expression of TNF from which soluble TNF is cleaved.
Is TNF-alpha capable of initiating either apoptosis or cell proliferation? What is this based upon?
Yes. The net effect of TNF depends on the relative proportion of type I and type II receptors, and can be activating or pro-apoptotic. No, he didn’t say what the difference is between Type I and Type II receptors.
List 4 drugs that inhibit the activity of TNF-alpha.
Etanercept
Infliximab
Adalimumab
Certolizumab pegol
Which of the 4 TNF-alpha inhibitors we discussed are capable of fixing complement? How are they able to do this?
Infliximab
Adalimumab
They are mAbs that contain an Fc region and are thus capable of fixing complement and inducing antibody dependent cytotoxicity.
Which TNF-a inhibitor has the broadest disease spectrum of use? Name a few of the conditions they treat.
Adalimumab followed closely by Infliximab and Etanercept.
Diseases they treat: Ankylosing spondylitis, Crohn’s disease, other arthritic conditions, ulcerative colitis, psoriasis.
T/F: Current drugs for treatment of inflammatory conditions are often ineffective or they adversely affect the patient through indiscriminate inhibition of multiple cross-connected cytokine signaling systems.
True
