Lecture 12: Emerging Therapies: Roflumilast for COPD Flashcards

1
Q

What class of drug is Roflumilast?

A

Phosphodiesterase inhibitor

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2
Q

What is PDE?

A

Enzyme that breaks down cAMP - a messenger molecule that plays a role in regulating inflammatory responses in the body.

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3
Q

What is the mechanism of action of Roflumilast?

A

Inhibits PDE4 and increases the levels of cAMP, which in turn reduces the production of pro-inflammatory cytokines such as TNF-alpha, IL-1, and IL-6. This leads to a decrease in the inflammatory response in the lungs, which can help to reduce symptoms of COPD such as shortness of breath and coughing.

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4
Q

How does raising cAMP levels inhibit inflammation?

A

cAMP can inhibit the production of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), by immune cells.

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5
Q

What does roflumilast work synergistically with?

A

Salbutamol

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6
Q

What are the effects of roflumilast?

A
  • Decrease in inflammatory cell activity
  • Inhibition of fibrosis
  • Relaxation of smooth muscle
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7
Q

What are the effects of PDE4 inhibition on epithelial cells?

A

Mucus production

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8
Q

What are the effects of PDE4 inhibition on monocytes?

A

TNF alpha release

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9
Q

What are the effects of rofluminast in vitro?

A
  • Decreased release of inflammatory cytokines, mediators, chemotactic factors.
  • Reduced neutrophil migration
  • Increased apoptosis
  • Increased expression of anti-inflammatory cytokines
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10
Q

What are the effects of rofluminast in vivo?

A
  • Reduced the accumulation of neutrophils in bronchoalveolar lavage fluid.
  • Prevented bleomycin-induced lung infiltration of neutrophils.
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11
Q

What is the active form of roflumilast?

A

Roflumilast N-oxide

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12
Q

How is roflumilast converted to its active metabolite?

A

By cytochrome P450 (CYP) 3A4 and 1A2

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13
Q

How is roflumilast absorbed?

A

Rapidly and almost completely absorbed

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14
Q

What is the bioavailability of roflumilast?

A

80%

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15
Q

What is the theraputic dose of roflumilast?

A

500ng taken once daily

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16
Q

What is the plasma protien binding of rofumilast

A

97%

17
Q

What is a side effect of roflumilast?

A

Weight loss, GI disturbances

18
Q

How does roflumilast lead to weight loss?

A

PDE3B and PDE4 regulate cAMP pools that affect the activation/
phosphorylation state of AMP-activated protein kinase, thereby influencing lipolysis.

19
Q

What is the main isoform assosiatied with emisis?

A

PDE4

20
Q

Name other PDE4 inhibitors

A
  • Cilomilast
  • Oglemilast
  • Tetomilast
    -ONO-6126
21
Q

Describe cilomilast

A

improved lung function and reduced exacerbation rates in COPD. Associated with gastrointestinal disturbances such as emesis and nausea

22
Q

What is the function of oglemilast?

A

inhibited pulmonary cell infiltration, including eosinophilia and neutrophilia

23
Q

What is tetomilast under the development of?

A

COPD and ulcerative colitis

24
Q

What other drugs are used in COPD?

A
  • Infliximab
25
Q

What is the target for infliximab?

A

TNF alpha antagonist