Anti-inflammatory Agents-CT-MS

Question 1

Where are PGE2 and PGI 2 produced?

Answer 1

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

Question 2

Through what protein do PGE2 and PGI2 work?

Answer 2

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

Question 3

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

Answer 3

COX1

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

Question 4

Which COX product is expressed in platelets?

Answer 4

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

Question 5

How does COX 1 promote bleeding?

Answer 5

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

Question 6

What are the renal effects of COX 1?

Answer 6

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

Question 7

What are the renal effects of COX 2?

Answer 7

COX2 functions effect salt and water excretion.

Question 8

What are the renal effects of PGE2 and PGI2?

Answer 8

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

Question 9

What are the effects of inhibiting COX products?

Answer 9

• 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.

Question 10

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

Answer 10

Inflammation
Pain
Fever

Question 11

What is the role of COX 1?

Answer 11

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.

Question 12

What is the role of COX 2?

Answer 12

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.

Question 13

Which NSAID is approved for IV and IM?

Answer 13

Only ketorolac is approved for IV and IM.

Question 14

Which NSAID closes the ductus arteriosus in neonates?

Answer 14

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

Question 15

How do NSAIDs act as antipyretics?

Answer 15

• COX inhibition in CNS resulting in reduced PGE2

- Inhibition of IL-1 activity

Question 16

How do NSAIDs act as an anti-inflammatory?

Answer 16

• COX inhibition

- Salicylates may also act a scavengers of free oxygen radicals

Question 17

How do NSAIDs act as anti-thrombotics?

Answer 17

• Inhibition of platelet COX (irreversible for aspirin)

- Inhibition of COX activity in Vascular endothelia

Question 18

How od NSAIDs act as analgesics?

Answer 18

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

Question 19

How are NSAIDs metabolized hepatically?

Answer 19

Hepatic metabolism via CYP3A or CYP2C

Question 20

What is the primary mode of clearance of NSAIDs?

Answer 20

Renal Excretion is the primary mode of clearance.

Question 21

What side effects are associated with NSAIDs?

Answer 21

• 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).

Question 22

Why are NSAIDs contraindicated in the 3rd trimester?

Answer 22

• 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.

Question 23

What contraindications are associated with NSAIDs?

Answer 23

• 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

Question 24

How do COX 2 inhibitors increase cardiovascular risk?

Answer 24

• 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.

Question 25

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

Answer 25

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

Question 26

What product enhances the analgesic effects of NSAIDs?

Answer 26

Caffeine can enhance the analgesic actions of NSAIDs or acetaminophen.

Question 27

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

Answer 27

- NSAIDs can provide some relief but will not resolve chronic inflammation - There is less vascular dilation and vascular permeability

Question 28

What are the primary cells of chronic inflammation?

Answer 28

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

Question 29

What are the therapeutic goals of NSAIDs?

Answer 29

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

Question 30

What is the mechanism of action of methotrexate?

Answer 30

- 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)

Question 31

What side effects are associated with methotrexate?

Answer 31

GI distress, oral ulcerations, and progressive dose-related hepatotoxicity. Rare: pulmonary fibrosis, hepatic fibrosis, severe hypersensitive pneumonitis in pre-existing lung disease.

Question 32

In what patients should methotrexate be used with caution?

Answer 32

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

Question 33

What are the contraindications of methotrexate?

Answer 33

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

Question 34

What is the mechanism of action of leflunomide?

Answer 34

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

Question 35

What is the primary indication of leflunomide?

Answer 35

Similar efficacy for Rheumatoid Arthritis patients as methotrexate.

Question 36

What are the side effects of Leflunomide?

Answer 36

- Same GI effects as methotrexate | - Slightly more common hepatic side effects than Methotrexate

Question 37

What is the mechanism of action of Sulfalazine?

Answer 37

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

Question 38

What is Sulfalazine?

Answer 38

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

Question 39

What is the indication of Sulfalazine?

Answer 39

- 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.)

Question 40

What drugs can be given with Sulfalazine?

Answer 40

Can be given with NSAIDs

Question 41

In what patient group is Sulfalazine contraindicated?

Answer 41

Not given to patients with sulfa drug or salicylate allergies.

Question 42

What side effects are associated with Sulfalazine?

Answer 42

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

Question 43

What are the biological effects of glucocorticoids?

Answer 43

- 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.

Question 44

What ist he overall effects of glucocorticoids?

Answer 44

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

Question 45

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

Answer 45

- 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

Question 46

How do glucocorticoids suppress the immune system?

Answer 46

- 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.

Question 47

What side effects are associated with glucocorticoids?

Answer 47

- 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

Question 48

What should be monitored in patients taking glucocorticoids?

Answer 48

``` Hyperglycemia Glycosuria Sodium retention with edema or hypertension Hypokalemia Peptic ulcer Osteoporosis Hidden infection ```

Question 49

Glucocorticids (steroids) are contraindicated in which patients?

Answer 49

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

Question 50

What are anti-TNF alpha biological agents?

Answer 50

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

Question 51

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

Answer 51

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.

Question 52

How is Etanercept administered

Answer 52

Administered subcutaneously (SC) or intravenously.

Question 53

What is the indication of Etanercept?

Answer 53

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

Question 54

Caution in Etanercept prescription should be taken in which patients?

Answer 54

- 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.