Inflammation Drugs Flashcards

1
Q

T or F. Nonsteroidal anti-inflammatory agents (NSAIDS) and corticosteroids both have nonspecific actions and are sometimes ineffective.

A

T. AND can have deleterious effects to other systems

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2
Q

What are the main mediators of vasodilation in inflammation?

A

PGI2, PGE1, PGE2, PGD2, NO

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3
Q

What are the main mediators of increased vascular permeability in inflammation?

A

Histamine, C3a, C5a,, Bradykinin, LTC4, LTD4, LTE4, PAF, substance P, calcitonin gene related pepide (CGRP)

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4
Q

What are the main mediators of chemotaxis and leukocyte activation in inflammation?

A

C5a, LTB4, LXA4, LXB4, bacterial products

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5
Q

What are the main mediators of tissue damage in inflammation?

A

neutrophil and macrophage lysosomal productsoxygen radicalsNO

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6
Q

What are the main mediators of fever in inflammation?

A

IL-1, IL-6, TNF-a, PGE2, PGI2, LBT4, LXA4, LXB4

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7
Q

What are the main mediators of pain in inflammation?

A

PGE2, PGI2, LTB4, Bradykinin, CGRP

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8
Q

Asthma, a bronchial condition, is characterized by two distinct phases:

A

bronchospastic (caused by histamine) and inflammatory (not caused by histamine).

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9
Q

What is the bronchospastic nature of asthma caused by?

A

due to the preformed mediator histamine that is ready and packaged in mast cells in the bronchial system. Histamine stimulates cholinergic receptors that result in smooth muscle contraction in the lungs

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10
Q

Release of histamine from mast cells in the bronchial system in relation to asthma causes what?

A

causes the initial bronchospasm and initiates the synthesis and release of a slew of inflammatory mediators, including. These include PGD2, LTC4, PAF (these are anti-inflammatory agents used to control this process and return cell physiology to normal as soon as possible), and ECP (eosinophil cationic protein), MBP (major basic protein) and proteases.

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11
Q

T or F. Whereas a series of anti-inflammatory drugs are appropriate for asthma, antihistamines are not. Why or why not?

A

T. Anti-histamines block the effects of histamine binding to H1 receptors, but currently no antihistamine has utility in preventing its release from mast cells.

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12
Q

Whereas corticosteroids were once the only anti-inflammatory drugs used for asthma, a number of other drugs are now used for specific patients who remain inadequately responsive to corticosteroids. Name them.

A

Leukotrience receptor blockers (Montelukast)Leukotriene synthesis inhibitors (Zileuton)IgE-antibody (Omalizumab)PDE4 Inhibitor (Roflumilast)

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13
Q

What is GATA-3?

A

a transcription factor that is specifically expressed in TH2 cells and plays a critical role in the differentiation of Th2 cells from uncommitted CD4+ lymphocytes.

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14
Q

What else does GATA-3 do?

A

In addition GATA-3 is essential for the gene expression of the cytokines IL-4, IL-5 and IL-13 that mediate allergic inflammation.

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15
Q

Where is GATA-3 present in the cell of a naive T lymphocyte?

A

In human T lymphocytes GATA-3 is normally localized to the cytoplasm,

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16
Q

What happens to GATA-3 when a T cell is activated?

A

GATA-3 is phosphorylated by p38 MAP kinase and translocates to the nucleus via the nuclear import protein importin-alpha.

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17
Q

How does Corticosteroids inhibit GATA-3 movement to the nucleus upon T cell activation?

A

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.So they are accidentally controlling T cell activation from preventing GATA-3 getting into the nucleus by competitive inhibition

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18
Q

GATA-3 is inhibited by the Th1 master regulatory transcription T-bet but in turn inhibits STAT-4 and thus T-bet so that Th2 polarization is maintained.

A

GATA-3 is inhibited by the Th1 master regulatory transcription T-bet but in turn inhibits STAT-4 and thus T-bet so that Th2 polarization is maintained.Since GATA-3 appears to be a critical transcription factor for allergic inflammation it is an obvious target for inhibition. However, direct inhibition by inhaled specific oligonucleotides or interference RNA is not yet possible. Corticosteroids act as indirect inhibitors and in patients with corticosteroid resistance p38 MAP kinase inhibitors may also prove to be useful in the future.

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19
Q

Describe the Ngb pathway.

A

There are two major signaling pathways that lead to upregulation of transcriptional activity that are mediated by inflammatory cytokines, this is one. Under resting conditions, NF-κB (a heterodimer of p50 and p65 subunits) is tightly bound to an inhibitor called IκB that sequesters NF-κB in the cytoplasm. Engagement of one of the TLRs or the signal transducing receptors for interleukin 1 (IL-1) or tumor necrosis factor (TNF) family members leads to induction of IκB kinase activity that phosphorylates IκB on critical serine residues. Phosphorylated IκB becomes a substrate for ubiquitination, which triggers degradation of IκB by the 26S proteasome. Loss of IκB results in release of NF-κB, which permits it to move to the nucleus and activate transcription of genes whose promoters contain κB recognition sites.

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20
Q

The second major transcription regulating pathway is the JAK/STAT pathway. Describe it.

A

Binding of human IFN-γ (a dimer) to its receptor brings about oligomerization of receptor complexes composed of α and β chains. The nonreceptor protein tyrosine kinases Jak1 and Jak2 are activated and phosphorylate critical tyrosine residues in the receptor such as the tyrosine at position 440 of the α chain (Y440). STAT1α molecules are recruited to the IFN-γ receptor based on the affinity of their Src homology 2 (SH2) domains for the phosphopeptide sequence around Y440. Receptor-associated STAT1α molecules then dimerize through reciprocal SH2-phosphotyrosine interactions. The resulting STAT1α dimers translocate to the nucleus and stimulate transcription of IFN-γ-regulated genes.

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21
Q

T or F. corticosteroids downregulate the activity of NFkb responsive gene expression.

A

T

22
Q

What is the only current drug that can regulate the NfkB pathway?

A

bortezomib

23
Q

How does Bortezomib regulate the NfkB pathway?

A

it does this through controlling ubiquination and 26S proteosomal degradation of the critical inhibitory partner of Ngb, namely Ikb.at low conc it can inhibit transcription of IL-6, VEGF, and VCAM-1

24
Q

What do NSAIDs do?

A

inhibit cyclooxygenase 1 and 2

25
Q

Are NSAIDS reversible or irreversible?

A

these drugs are reversible inhibitors of COX activity, with the sole exception of acetylsalicylic acid (aspirin) which modifies the enzyme irreversibly by depositing an acetyl residue in the catalytic site. Most of the drugs are non-selective in their action, affecting both COX-1 and COX-2.

26
Q

What is a COX-2 selective inhibitor?

A

Celecoxib

27
Q

How do corticosteroids influence the arachidonic acid pathway?

A

They prevent cleaving of AA from phospholipids in membranes via phospholipase A2

28
Q

What is a potent leukotriene synthesis inhibitor? How does it work?

A

Zileuton. This prevents the formation of leukotrienes via lipoxygenase activity

29
Q

How is montelukast different from zileuton?

A

it is a leukotriene receptor antagonist that prevents formation of LTB4 (and subsequent neutrophil attraction)

30
Q

How does Omalizumab (Xolair) work?

A

Mast cells are chock full of preformed histamine and that this mediator is responsible for the initial bronchospastic phase of asthma. Histamine is also the mediator that is released in response to anaphylactic shock, following binding of IgE to mast cell surface receptors. One means of reducing the likelihood of histamine release is to prevent the IgE from binding, thorough the application of an anti-IgE antibody. The mast cells remain full of histamine, yet the signal never arrives. Such a drug is reserved for hard to treat cases, not least because it requires injection and is very expensive in comparison.this is a monoclonal antibody

31
Q

What effect does IL-13 have on allergic inflammation in asthma?

A

including production of immunoglobulin E (IgE) from B lymphocytes, increased expression for the low-affinity receptor for IgE (FCRII, CD23) on several inflammatory cells, increased mucus secretion and fibrosis and eotaxin release from airway epithelium. In addition, IL-13 induces steroid resistance (probably by activating p38 mitogen-activated protein kinase).

32
Q

How can IL-13 be blocked?

A

by a high-affinity soluble receptor (shuIL-13R2), a blocking antibody or an inhibitor of STAT6, which is also activated by IL-4.

33
Q

Clinical trials with modulators of interleukin pathways have met with mixed success. IL-5 antagonists have been successful where?

A

severe, steroid-resistant, eosinophilic astema (no effect in milder cases)

34
Q

The release of histamine from mast cells cause what symptoms to occur?

A

Lungs- bronchoconstriction (asthma symptoms)Vascular smooth muscle- post-capillary venule dilation (erythema)Vascular endothelium- contraction and separation of cells (erythema)Peripheral nerves- nerve sensitization (itchiness, pain)

35
Q

What are antihistamines commonly used to treat?

A

Whereas antihistamines are not used for treatment of asthma, they are used in many other medical conditions, including insect bites and stings, urticaria (hives), pruritus (itching), rhinorrhea, and contact dermatitis. Some antihistamines, by virtue of their ability to access the CNS, are used in the treatment of insomnia, Parkinson disease and motion sickness.

36
Q

There are two generations of antihistamines. What is the difference between them?

A

The first generation access the BBB and can produce anticholinergic effects in the CNS as an adverse effect. The second generation drugs were designed to lack the ability to pass the BBB, hence they are considered non-sedating in normal clinical use and they lack the CNS adverse effects.1st gen- Diphenhydramine, Chlorpheniranime, Dimenphydrinate, Promethazine

37
Q

What is Roflumilast? Action?

A

approved for the treatment of COPD. It selectively inhibit the actions of phosphodiesterase-4 (PDE4).

38
Q

Inhibition of PDE4 by Rofumilast causes what?

A

This medication is not a bronchodilator. Instead inhibition of the PDE4 enzyme blocks the hydrolyses and inactivation of cAMP, resulting in intracellular cAMP accumulation. This is thought to decrease inflammatory activity, though the exact mechanism of action is not fully elucidated.Phosphodiesterase-4 (PDE4) inhibitors inhibit the recruitment and activation of key inflammatory cells, including mast cells, eosinophils, T lymphocytes, macrophages and neutrophils, as well as the hyperplasia and hypertrophy of structural cells, including airway smooth-muscle cells, epithelial cells and sensory and cholinergic nerves (this nerve causes the initial bronchospasm)

39
Q

How does TNF-a signaling occur?

A

Cell I produces soluble TNF and also expresses membrane-bound TNF (from which soluble TNF is cleaved). Soluble TNF binds to type I and type II TNF receptors on TNF- responsive cell types (cell III). The net effect of TNF depends on the relative proportion of type I and type II receptors, and can be activating or pro-apoptotic. Cell-surface TNF can also bind and signal to adjacent cells (cell II), and soluble TNF can also act in an autocrine manner if cell I also expresses TNF receptors (not illustrated). b) The ‘simple’ scenario in which the effects of soluble and membrane-bound TNF are prevented by neutralization with monoclonal antibody (mAb) or soluble receptor. Thus, receptor-expressing cells II and III consequently remain in a basal state.c) Inhibition of TNF results in cell death, either through cytokine deprivation (cells II and III); through antibody-facilitated cell death (complement-mediated cytotoxicity (CDC) or antibody dependent cell-mediated cytotoxicity (ADCC)); or through reverse signaling. Both of the latter mechanisms affect cells expressing membrane TNF.d) A recently identified mechanism by which fragment crystalizable- receptors (FcR)- expressing cells can use anticytokine mAb to convert soluble cytokine to cell-surface- arrayed cytokine. In this way an anticytokine mAb could actually enhance rather than reduce cytokine potency. Distinct TNF inhibitors might harness different mechanisms, depending on their affinity for TNF and FcRs and, potentially, other characteristics (mono- versus bivalency, hinge flexibility and so on).

40
Q

Shown here are the common anti-TNF drugs in clinical use. Three of these are monoclonal antibodies (Etanercept, Infliximab, Adalimumab), as denoted by the names. The third is a fusion protein that consists of the extracellular ligand-binding portion of the human 75 kD (p75) tumor necrosis factor (TNF) receptor linked to the Fc portion of human IgG1 The antibody drug provide an interesting observation regarding structural requirements for activity. Both infliximab and adalimumab contain an Fc region and are thus capable of fixing complement and inducing antibody dependent cytotoxicity, as I described in the immunosuppressant presentation. Are these processes actually needed for clinical activity, or will simple removal of TNF from the signaling process suffice? The answer may lie with certolizumab actions. Unlike etanercept, infliximab, and adalimumab, certolizumab pegol does not contain a fragment crystalizable (Fc) region and thus, does not fix complement or cause antibody-dependent cell- mediated cytotoxicity. Nevertheless, this drug is capable of controlling disease processes mediated through increased TNF-a signaling.

A

Shown here are the common anti-TNF drugs in clinical use. Three of these are monoclonal antibodies (Etanercept, Infliximab, Adalimumab), as denoted by the names. The third is a fusion protein that consists of the extracellular ligand-binding portion of the human 75 kD (p75) tumor necrosis factor (TNF) receptor linked to the Fc portion of human IgG1 The antibody drug provide an interesting observation regarding structural requirements for activity. Both infliximab and adalimumab contain an Fc region and are thus capable of fixing complement and inducing antibody dependent cytotoxicity, as I described in the immunosuppressant presentation. Are these processes actually needed for clinical activity, or will simple removal of TNF from the signaling process suffice? The answer may lie with certolizumab actions. Unlike etanercept, infliximab, and adalimumab, certolizumab pegol does not contain a fragment crystalizable (Fc) region and thus, does not fix complement or cause antibody-dependent cell- mediated cytotoxicity. Nevertheless, this drug is capable of controlling disease processes mediated through increased TNF-a signaling.

41
Q

What is Telcagepant?

A

a CGRP antagonist

42
Q

What does CGRP do?

A

sensitizes glutamatergic synapses in the CNS, leading to migrane

43
Q

What is the current treatment for migraine?

A

Triptans these can constrict blood vessels and sometimes produce deleterious CV effectsCGRP antagonists don’t have this effect

44
Q

Has Telcagepant been effective in trials?

A

Yes but produces hepatic toxicity

45
Q

What are second generation anti-histamines and how are they different from the first generation?

A

Cetirizine, Fexofenadine, and Loratadine. The first generation access the BBB and can produce anticholinergic effects in the CNS as an adverse effect. The second generation drugs were designed to lack the ability to pass the BBB, hence they are considered non-sedating in normal clinical use and they lack the CNS adverse effects.

46
Q

What is Anakinra?

A

an analog for IL-1 that can competitively compete for binding to receptors

47
Q

What is Tocilizumab?

A

a monoclonal antibody drug that binds to IL-6 receptors to prevent the action of IL-6

48
Q

What is Rituxamib?

A

a monoclonal antibody drug that binds to B cells and prevents their proliferation

49
Q

What are some side effects of corticosteroids?

A

decreased bone density (prolonged use can cause stunted growth), weight gain, lipid profile change, muscle weakness, mood swings, high BP, risk of diabetes, cataract glaucoma

50
Q

What is a side effect of topical application of corticosteroids?

A

thinking of skin

51
Q

Why might corticosteroid effectiveness vary from patient to patient?

A

difference in sensitivity due to mutations in receptors or different transcriptional regulators