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Pulmonary > Drugs for Restrictive Lung Diseases and PAH > Flashcards

Drugs for Restrictive Lung Diseases and PAH Flashcards

1
Q

What is the treatment for pneumoconiosis (e.g. silicosis, asbestosis, coal miner’s pneumoconiosis, berylliosis)?

A

There is no curative treatment for deposited material

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2
Q

Excessive doses of which drugs are known to preceipitate ARDS in susceptible individuals?

A

Aspirin, cocaine, opioids, phenothiazines, and tricyclic antidepressants

Idiosyncratic rxns can also occur with certain chemotherapeutic agents and with radiologic contrast media.

EtOH abuse increases riks of ARDS d/t other causes (e.g. sepsis, trauma) but doesn’t cuase ARDS

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3
Q

Are drugs for ARDS helpful?

A

None of the drugs has demonstrated a consistent and unequivocal benefit.

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4
Q

List the various drugs used for ARDS

A
  • B-2 agonist (Albuterol, IV) and Inhaled NO
    • preferential vasodilation of pulmonary vessels that perfuse functioning alveoli
  • Inhaled prostacyclin (PGI2) - vasodilator
  • Corticosteroids - anti-inflammatory
  • Dietary oil supplementation - anti-inflammatory action (modulation of arachidonic acid metabolism)
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5
Q

What is NRDS?

A

Most common cuase of respiratory failure in newborns and the most common cause of death in premature infants. Arises from surfactant deficiency in immature lung tissue leading to **increased surface tension, V/Q mismatch and shunting. **

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6
Q

What is the treatment for NRDS?

A
  • Antenatal corticosteroids to all women at risk of delivery <34 weeks; enhances synthesis and release of surfactant
  • Exogenous surfactant is administerd to preterm (<30 weeks) neonates to reduce surface tension.
  • Natural products (Poractant alfa, Calfactant and Beractant) are purified animal products rich in surfactant proteins, neutral lipids, and DPPC
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7
Q

What is DDPC?

A

Primary surface-active component that lowers alveolar surface tension

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8
Q

What is the hallmark of sarcoidosis?

A

Non-caseating granulomas, which often involve multiple organs

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9
Q

What is the treatment for sarcoidosis and what does it depend on?

A

Treatment with anti-inflammatory glucocorticoids or immunosuppresive methotrexate depends upon the degree of functional impairement

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10
Q

How do glucocorticoids work?

A

Binding to glucocorticoid receptors in the nucleus

  • Inhibit production of pro-inflammatory cytokines (IL-1B and TNF) while promoting the production of anti-inflammatory cytokines (IL-10) by macrophages and dendritic cells
  • Promote apoptosis of macrophages, dendritic cells and T cells, leading to inhibition of immune responses
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11
Q

What are the adverse effects associated wtih chronic corticosteroid use?

A
  • hypothalamic-pituitary-adrenal (HPA) axis suppresion
  • osteoporosis
  • pancreatitis
  • steroid-induced diabetes mellitus
  • cataracts
  • galucoma
  • physcosis
  • oral candidiasis (opporutnisitc infections)
  • immunosupprssion
  • weight gain
  • skin atrophy
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12
Q

What are the actions of Methotrexate?

A
  • DHFR inhibition and an antineoplastic action
  • Increase in adenosine-mediated immunosuppression via a cAMP increase.
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13
Q

What are the adverse effects of taking methotrexate and what are their implications?

A

A significant side effect profile means that MTX is NOT front-line therapy for its anti-inflammatory effects.

  • Severe (and sometimes fatal) dermatologic rxns
  • Brith defects
  • Malignant lymphoma
  • Increased risk of infection (contraindicated in pts with preexisting immunosuppresion)
  • Potentially fatal adverse pulmonary effects (acute or chornic interstital pneuonitis and pulmonary fibrosis)
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14
Q

Is Idiopathic Pulmonary Fibrosis (IPF) a chronic inflammatory disease?

A

NO! Represents 15% of chronic interstitla lung disease.

Even the most potent antiinflammatory drugs yield little or no therapeutic effect. Some clinicans use response and/or non-response to corticosteroid treatment as a differential diagnosis from other lung inflammatory fibrotic diseases.

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15
Q

Explain the pathogenesis of IPF

A

Altered mesenchymal cell phenotype and blockade of apoptosis gives rise to an altered stromal cell population and the activated epithelium release a series of profibrogenic factors (TGF-B and PDGF) which interact wtih deposited matrix at the site of abnormal repair. This creates a new microenviornment in patchy areas (other areas remain normal in structure and envrionment) of the lung and can give rise to remodeling of the blood vessel walls, resulting in PAH

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16
Q

Is there a clinical benefit in IPF for existing drug trials?

A

NO!

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17
Q

Goodpasture syndrome

Pathogenesis and Treatment

A
  • type II HSR agaisnt alpha-3 chains of type IV collagen in basement membranes of lungs and kidneys
  • plasmapheresis for treatment
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18
Q

What is Wegner’s Granulomatosis?

A

ANCA-positive autoimmune vasculitis (small-medium vessels), primarily of the upper respiratory tract, lungs and kidney.

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19
Q

What is the treatment for Wegner’s Granulomatosis?

A

Variety of anti-inflammatory agents

  • Rituximab
  • Off label usage of
    • Azathioprine
    • Cyclophosphamide
    • Corticosteroids
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20
Q

Rituximab MOA

A

immunosuppressing monoclonal antibody that binds the CD20 cell surface antigen on B-cell precursors and mature B-lymphocytes. Cell populations are depleted, and depletion is long-lasting (6-9 months follwing a single drug course; 3 doses).

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21
Q

What are the three mechanism that rituximab uses to induce cell death?

A
  1. Antibody-dependent cell-mediatted cytotoxicity: recruits macrophages and NK cells by binding to their Fcy receptors
  2. Complement-mediated cytotoxicity: activates complement and generates membrane attack complexes
  3. **Induction of apoptosis **
22
Q

What are the adverse effects associated wtih Rituximab?

A

HTN, asthenia, pruritis, urticarial, rhinitis and arthralgia

23
Q

Azathioprine MOA

A

DNA and RNA synthesis inhibitor that also produces immunosuppression, possibly by facilitating apoptosis of T cell populations.

24
Q

Azathioprine Adverse Effects

A
  • neoplastic, mutagenic, leukopenic and thrombocytopenic toxicity
  • increases risk of infection
25
Q

Cyclophosphamide MOA

A

alkylating agent that also produces (B & T cell) lymphopenia, selective suppresion of B-lymphocyte activity and decreased immunoglobulin secretion

26
Q

Cyclophosphamide Adverse Effects

A

Associated wtih neutropenia and thrombocytopenia, bladder cancer, myeloproliferative or lymphoproliferative malignancies

27
Q

What are the 4 causes that lead to PAH?

A
  1. imbalance between vasoconstriction and vasodilation (d/t decrease in prostacyclin and NO production and increased production of endothelin-1 and greater presence of TXA2)
  2. smooth muscle and endothelial cell proliferation, propagation, and hypertrophy (d/t production fo growth inhibitors and mitogenic factors)
  3. **thrombosis **
  4. **fibrosis **
28
Q

What is the histiologic hallmark of PAH

A

Plexiform lesions, which are thickened arterioles as a result of sheer stress. These lesions result in proliferation of monoclonal endothelial cells, smooth muscle cells, and accumulation of circulating cells (e.g. macrophages and progentior cells) and lead to significant obstruction of blood flow

29
Q

Explain the neurohormonal imbalances

  • Prostacyclin
  • NO
  • Endothelin-1
  • TXA2
A
  • Prostacyclin: inhibits platelet activation and smooth muscle growth
    • lack of prostacyclin allows for increased TXA2
  • Endothelin-1: induces smooth muscle cell proliferation.
  • TXA2: propoagator of platelet aggregation
  • NO: inhibits platelet stimulation adn smooth muscle cell activity
30
Q

The approach to drug therapy for PAH is based on what?

A

Severity of patient disease

NYHA 1: no limitations

NYHA 2: mild Sx and/or slight limitation during normal physical activity

NYHA 3: marked limitation d/t Sx during physical activity; comfortable only at rest

NYHA 4: severe limitation; Sx experienced at rest

31
Q

What is the function of prostanoids and what 3 drugs are characterized as prostanoids?

A

Induce pulmonary artery vasodilation, retard smooth muscle growth and disrput platelet aggregation.

  1. Epoprostenol
  2. Iloprost
  3. Treprostinil
32
Q

Epoprostenol

Route and Adverse Effects

A

Route: t1/2 is 3-5m; requires continuous IV infusion

Adverse Effects: hypotension, muscle pains, headaches and flushing. Risk of catheter infection. Monitor for bleeding especially if recieving antithrombotic drugs (commonn).

33
Q

Iloprost

Route and Adverse Effects

A

Route: t1/2 is 25 min; requires 6-9 inhaled doses/day using approved pulmonary delivery device; takes 10m for each dose

Adverse Effects:

  • cough, flushing and headaches are most common adverse effects
  • hypotension, muscle cramps and tongue/back pains
  • monitor for bleeding, especially if recieving antithrombotic drugs (common)
  • _monitor d/t reports of hemoptysis _
34
Q

Treprostinil

Route and Adverse Effects

A

Route: t1/2 is 4 hours; continuous SC (can be irritation) or IV infusion; more stable in solution

Adverse Effects:

  • injection site erythema, rash and pain
  • headache, nausea, dirrhea, vasodilation, jaw pain
  • monitor for bleeding, espeically if recieving antithrombotic drugs (common)
  • CYP2C8 drug-drug interactions possible (e.g. decreaed clearence with gemfibrozil and increased clearence with rifampin)
35
Q

What is the disadvantage of prostanoids?

A

Abscence of an oral drug

36
Q

Which drug class has the advantage over prostacyclins of being orally active drugs?

A

Endothelin-1 Receptor Antagonists

37
Q

Endothelin-1 Receptor Antagonist MOA and Drugs

A

MOA: block the smooth muscle proliferation and pulmonary arterial vasoconstriction produced by this vasoactive molecule upon binding to endothelin-1 type A (on smooth muscle) or type B (on endothelial cells) receptors

Drugs: Bosentan and Ambrisentan

38
Q

What is the disadvantage of Endothelin-1 receptor antagonists?

A
  • Expensive
  • Both bosentan and ambrisentan are teratogenic (category X)
  • Bosentan is also associated with **liver and blood toxicities. **
39
Q

Bosentan

Route and Adverse Effects

A

Route: t1/2 5-8 hours; PO BID

Adverse Effects:

  • Significantly elevated LFTs, monitor
  • Anemia
  • Nasopharyngitis, headache
  • Extensive hepatic metabolism; interactions wtih CYP2C9 and 3A4 substrates
  • CYP inducer leading to drug-drug interactions
40
Q

Ambrisentan

Route and Adverse Effects

A

Route: t1/2 is 15 hours; PO QD

Adverse Effects

  • Significantly less likely to cause elevated LFTs, no need to monitor but not to be used in patients wtih signficiant hepatic dysfunction, as this is major elimination route
  • Peripheral edema and headache are most common adverse effects
  • Extensive hepatic metabolism; CYP2C9, 3A4, OATP, and P-gp substrate; drug-drug interactions possible but not recorded
41
Q

Phosphodiesterase Type 5 Inhibitors MOA and Drugs

A

MOA: perpetuate endogenously generated cGMP leading to vasodilation and reduced cellular proliferation

Drugs: sildenafil and tadalafil

42
Q

Who should not take PDE Type 5 Inhibitors?

A

patients taking organic nitrates

43
Q

Sildenafil

Route and Adverse Effects

A

Route: t1/2 is 3-4 hr; PO or IV TID

Adverse Effects:

  • headache is most common adverse effect
  • epistaxis (nosebleed)
  • flushing, insomnia, dyspepsia
  • rarely a dizziness with sudden hearing loss
  • CYP3A4 > 2C9 substrate; drug interactions with 3A substrates/inducers/inhibitors
44
Q

Tadalafil

Route and Adverse Effects

A

Route: t1/2 17 hr; PO QD

Adverse Effects

  • headache is most common adverse effect
  • back pain, dyspepsia
  • change in color vision (non-arteritic anterior ischemic optic neuropathy; NAION)
  • CYP3A4 substrate; drug interactions with 3A substrates/inducers/inhibitors
45
Q

What is the MOA of CCBs and Drugs

A

MOA: prevent access of calcium into cells during membrane depolarization, thus block the key mediator of smooth muscle contraction and permitting a vasodilation

Drugs:

  • Diltiazem
  • Nifedipine
  • Amlodipine
46
Q

Do all patients respond to CCBs?

A

NO, some develop potentially fatal hemodynamic decompensation while others have short-term benefit (reduced mPAP and PVR). Perform a vasodilator challenge to determine.

47
Q

Explain the vasodilator challenge

A

Drugs: Epoprostenol (IV), Adenosine (IV), NO (Inhale)

Recieve escalated dosing rate and pulmonary arterial pressure (PAP) and CO are monitored for 2-3h. A patient who responds positively to a vasodilator challenge (i.e. decreased PAP and decreased CO) may then be prescribed certain CCBs.

48
Q

Why is verapamil avoided in PAH?

A

Strong negative inotropic properties, which makes it more likely to induce symptomatic bradycardia than amlodipine, diltiazem, or sustaiend-release nifedipine.

49
Q

What is the goal of CCB therapy?

A

For the patient to achieve NYHA-FC I or II after 3-4 months. If this is not achieved, alternative therapy needs to be considered.

50
Q

Diltiazem intermediate release

Route and Adverse Effects

A

Route: t1/2 3-6 hr; PO TID

Adverse Effects

  • bradycardia, hypotension, headache, edema
  • CYP3A4 substrate
51
Q

Nifedipine extended release

Route and Adverse Effects

A

Route: t1/2 2-5 hr; PO QID

Adverse Effects

  • Flushing, edema, hypotension, heartburn
  • CYP3A4 substrate
52
Q

Amlodipine

Route and Adverse Effects

A

Route: t1/2 35-50 hr; PO QID

Adverse Effects

  • edema, fatigue, hypotension
  • CYP3A4 substrate

Pulmonary (10 decks)

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