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Block 4 Pharm > Anti-inflammatory Agents-CT-MS > Flashcards

Anti-inflammatory Agents-CT-MS Flashcards

1
Q

Where are PGE2 and PGI 2 produced?

A

PGE2 and PGI2 are produced in gut epithelia primarily by COX1.

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2
Q

Through what protein do PGE2 and PGI2 work?

A

They act through G-protein coupled receptors which stimulate a signal cascade that limits the activity of proton pumps in the gut

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3
Q

To what are the negative GI effects of COX products attributed to?

A

COX1

  • This may underlie the improved GI toxicity profile of selective COX2 inhibitors.
  • These negative effects are increasingly managed with proton pump inhibitors.
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4
Q

Which COX product is expressed in platelets?

A

Only COX1 is present in platelets and since platelets lack a nucleus, there is no opportunity to induce COX2 expression.

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5
Q

How does COX 1 promote bleeding?

A

Production of Thromboxane A2 by COX1 mediates initiation of the clotting reaction. Therefore inhibition of COX1 in platelets will limit clotting, thereby promoting bleeding.

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6
Q

What are the renal effects of COX 1?

A

COX1 functions in control of renal hemodynamics and glomerular filtration rate.

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7
Q

What are the renal effects of COX 2?

A

COX2 functions effect salt and water excretion.

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8
Q

What are the renal effects of PGE2 and PGI2?

A

PGE2 and PGI2 regulate renal blood flow and glomerular filtration rate.

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9
Q

What are the effects of inhibiting COX products?

A
  • Inhibition of COX function leading to decreased PGE2 causes sodium retention, increased blood pressure, increased weight (likely due to water retention) and congestive heart failure (this is rare).
  • Inhibition of COX function leading to decreased PGI2 causes hyperkalemia and acute renal failure.
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10
Q

What are the 3 primary roles of COX products in pathophysiology?

A

Inflammation
Pain
Fever

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11
Q

What is the role of COX 1?

A

COX-1 is responsible for PGG2 synthesis in response to stimulation by circulating hormones, as well as maintenance of normal renal function, gastric mucosal integrity, and hemostasis.

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12
Q

What is the role of COX 2?

A

COX-2 is inducible in many cells in response to certain mediators of inflammation including interleukin-1, tumor necrosis factor, lipopolysaccharide, mitogens, and reactive oxygen intermediates.

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13
Q

Which NSAID is approved for IV and IM?

A

Only ketorolac is approved for IV and IM.

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14
Q

Which NSAID closes the ductus arteriosus in neonates?

A

Indomethacin is approved for injection to close the ductus arteriosus in neonates.

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15
Q

How do NSAIDs act as antipyretics?

A
  • COX inhibition in CNS resulting in reduced PGE2

- Inhibition of IL-1 activity

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16
Q

How do NSAIDs act as an anti-inflammatory?

A
  • COX inhibition

- Salicylates may also act a scavengers of free oxygen radicals

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17
Q

How do NSAIDs act as anti-thrombotics?

A
  • Inhibition of platelet COX (irreversible for aspirin)

- Inhibition of COX activity in Vascular endothelia

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18
Q

How od NSAIDs act as analgesics?

A
  • Peripheral effects mediated through effects on inflammation
  • May inhibit pain stimuli at a subcortical site.
  • COX inhibition decreases PGE2
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19
Q

How are NSAIDs metabolized hepatically?

A

Hepatic metabolism via CYP3A or CYP2C

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20
Q

What is the primary mode of clearance of NSAIDs?

A

Renal Excretion is the primary mode of clearance.

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21
Q

What side effects are associated with NSAIDs?

A
  • GI toxicity is combination of acidity and COX inhibition.
  • Increased Bleeding
  • CNS Toxicity
  • Aspirin irreversibly inhibits COX.
  • Salicylism: acute aspirin toxicity; ringing in the ears, nausea, vomiting
  • Anaphylactic shock.
  • Higher risk for Reyes Syndrome
  • Contraindicated in third trimester of pregnancy
  • Fluid retention and renal distress/failure.
  • Toxicity varies from patient to patient.
  • Children with viral fever (Reyes Syndrome is linked to aspirin-toxicity. It is very rare).
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22
Q

Why are NSAIDs contraindicated in the 3rd trimester?

A
  • During pregnancy, prostaglandins (mainly PGE2/I2) maintain the ductus arteriosus in an open state.
  • Therefore prolonged use of NSAIDs is contra-indicated during the third trimester.
23
Q

What contraindications are associated with NSAIDs?

A
  • Additive analgesia with opioids.
  • Caffeine enhances kinetics slightly.
  • Exacerbate GI complications of other drugs.
  • Excessive bleeding when given together with anticoagulants.
  • Reduce the effectiveness of diuretics and some antihypertensive agents.
  • Cimetidine can affect the metabolism of NSAIDs (use famotidine or proton pump inhbitor).
  • Concomitant administration of anti-virals (e.g. cidofovir) and NSAIDs, such as indomethacin, is contraindicated due to potential for increased nephrotoxicity.
  • NSAIDs interfere with lithium excretion and may lead to elevated lithium serum concentrations.
  • Steroids
24
Q

How do COX 2 inhibitors increase cardiovascular risk?

A
  • In vascular endothelia, COX2 generates prostacyclin.
  • Prostacyclin eases blood flow by relaxing blood vessels.
    • Prevents vascular endothelia from synthesizing adhesion molecules that serve as nucleation sites for platelet clumping.
    • As a result, inhibition of prostacyclin synthesis causes vascular constriction and platelet aggregation.
25
Q

What is the benefit of combining an opioid with aspirin or acetaminophen?

A

Synergistic analgesia can be produced by combining an opioid with aspirin or acetaminophen.

26
Q

What product enhances the analgesic effects of NSAIDs?

A

Caffeine can enhance the analgesic actions of NSAIDs or acetaminophen.

27
Q

How does chronic inflammation respond to NSAIDs differently than acute inflammation?

A
  • NSAIDs can provide some relief but will not resolve chronic inflammation
  • There is less vascular dilation and vascular permeability
28
Q

What are the primary cells of chronic inflammation?

A

Principal cells of chronic inflammation are lymphocytes, macrophages,and plasma cells (mature B-Cells)

29
Q

What are the therapeutic goals of NSAIDs?

A
  • Reduce Pain
  • Block inflammation
  • Retard synovial fibroblast proliferation
  • Prevent joint erosion and tissue destruction (as occurs in rheumatoid arthritis).
30
Q

What is the mechanism of action of methotrexate?

A
  • Inhibits folate metabolism which leads to decreased DNA synthesis.
  • Alleviates acute inflammation by acting as an immunosuppressive drug.
  • Used often for autoimmune diseases (lupus and RA)
31
Q

What side effects are associated with methotrexate?

A

GI distress, oral ulcerations, and progressive dose-related hepatotoxicity.

Rare: pulmonary fibrosis, hepatic fibrosis, severe hypersensitive pneumonitis in pre-existing lung disease.

32
Q

In what patients should methotrexate be used with caution?

A

age, liver or renal dysfunction, hepatitis, diabetes, obesity, low albumin

33
Q

What are the contraindications of methotrexate?

A

Contraindicated in pregnancy, lactation, alcoholism, blood disorders, immunodeficiency.

34
Q

What is the mechanism of action of leflunomide?

A
  • Major action is inhibition of dihydroorotate dehydrogenase and blockade of pyrimidine biosynthesis.
  • Prevents histamine release and COX-2 expression.
35
Q

What is the primary indication of leflunomide?

A

Similar efficacy for Rheumatoid Arthritis patients as methotrexate.

36
Q

What are the side effects of Leflunomide?

A
  • Same GI effects as methotrexate

- Slightly more common hepatic side effects than Methotrexate

37
Q

What is the mechanism of action of Sulfalazine?

A

The anti-inflammatory mechanism of mesalamine is through the inhibition of arachidonic acid metabolism in the bowel mucosa by inhibition of cyclooxygenase.

38
Q

What is Sulfalazine?

A

Prodrug used in the treatment of ulcerative colitis and rheumatoid arthritis. The drug is a combination of sulfapyridine and 5-aminosalicylic acid (mesalamine).
- Colonic bacteria metabolize the prodrug

39
Q

What is the indication of Sulfalazine?

A
  • Most commonly used in treatment of ulcerative colitis and Crohn’s disease.
  • Alternative for juvenile RA or women of child bearing age (Used in RA to reduce bone deterioration.)
40
Q

What drugs can be given with Sulfalazine?

A

Can be given with NSAIDs

41
Q

In what patient group is Sulfalazine contraindicated?

A

Not given to patients with sulfa drug or salicylate allergies.

42
Q

What side effects are associated with Sulfalazine?

A

Toxicities include rashes, nausea, vomiting, dizziness, headaches and occasional leukopenia.

43
Q

What are the biological effects of glucocorticoids?

A
  • inhibition of leukocyte infiltration at the site of inflammation
  • interference in the function of mediators of inflammatory response
  • suppression of humoral immune responses.
  • Inhibiting expression of the COX-2 gene.
44
Q

What ist he overall effects of glucocorticoids?

A

Some of the net effects include reduction in edema or scar tissue, as well as a general suppression in immune response.

45
Q

How do glucocorticoids block the transition from acute to chronic inflammation?

A
  • Deacreasing the number of circulating leukocytes
  • Induces apoptosis (programmed cell death) in leukocytes
  • Causing a redistribution of leukocytes from the vascular bed to lymphoid tissues.
  • Inhibiting the functions of macrophages and other antigen presenting cells.
  • Inhibition of Interleukin 1 expression
46
Q

How do glucocorticoids suppress the immune system?

A
  • Lymphotoxic and suppress of inflammatory mediators such as PAF, leukotrienes, prostaglandins, histamines and bradykinin.
  • In myeloid lineages they cause diminished chemotaxis and block production of IL-1 and Iterferon-
  • Can diminish or block humoral immune responses by restricting clonal selection of B-cell progenitors.
47
Q

What side effects are associated with glucocorticoids?

A
  • Cushing’s
  • Hyperhidrosis (excessive sweating)
  • Telangeictasia (dilation of capilllaries)
  • Peptic ulcers, hypomania or acute psychosis, depression
  • Mineralocorticoid effects of cortisone and hydrocortisone can lead to sodium and fluid retention.
  • Adrenal Insufficiency
  • Sodium and fluid retention
48
Q

What should be monitored in patients taking glucocorticoids?

A 
Hyperglycemia 
Glycosuria
Sodium retention with edema or hypertension
Hypokalemia
Peptic ulcer
Osteoporosis
Hidden infection
49
Q

Glucocorticids (steroids) are contraindicated in which patients?

A

Patients with:
Peptic ulcer
Heart disease or hypertension with congestive heart failure
Infections (especially herpes simplex), diabetes, osteoporosis
Psychoses
Hepatic dysfunction

50
Q

What are anti-TNF alpha biological agents?

A

Biological agents (antibodies) designed to disrupt binding of TNF-a to either receptor.

51
Q

What are the 3 main types of anti-TNF alpha biological agents?

A

1) Infliximab (Remicade): “humanized” mouse monoclonal antibody directed against TNF-a.
- Infliximab is composed of human constant and murine variable regions.
2) Adalimumab (Humira): Recombinant human anti- TNF-a antibody.
- More thoroughly humanized monoclonal altibody leads to greater stability of the antibody and improved clinical tolerance.
3) Etanercept (Enbrel): Recombinant fusion protein consisting of two TNFReceptor moieties linked to the Fc portion of human IgG1.

52
Q

How is Etanercept administered

A

Administered subcutaneously (SC) or intravenously.

53
Q

What is the indication of Etanercept?

A

Used alone or with methotrexate to manage moderate to severe chronic inflammation.

54
Q

Caution in Etanercept prescription should be taken in which patients?

A
  • Caution must be used when prescribing Etanercept with myelosuppressive anti-rheumatic agents such as azathioprine, cyclophosphamide, leflunomide, or methotrexate. These combinations have been associated with pancytopenia, including aplastic anemia, in some patients.
  • Caution should be used for patients who have recently received vaccines.

Block 4 Pharm (5 decks)

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