NSAIDs & Non-Opioid Analgesics (Exam V)

Question 1

What is the cause of chronic inflammation?

What additional mediators are released?

Answer 1

WBC infiltration of the tissue in response to acute inflammation.

Interleukins
GM-CSF
TNF
Interferons
PDGF

Question 2

What can block arachidonic acid production?

Answer 2

Corticosteroids

Question 3

What is the most important autocoid involved in acute inflammation?

What are the other autocoid involved with acute inflammatory response?

Answer 3

Prostaglandin (most important)

Histamine
Serotonin
Bradykinin
Leukotrienes

Question 4

What is the main pathway target when using NSAIDs?
What is the secondary pathway?

Answer 4

• COX pathway
• LOX pathway

Question 5

Differentiate COX-1 & COX-2.

Essay Question

Answer 5

COX1 - Constitutive “always on” (stomach mucous secretion, renal blood flow, platelet function, macrophage differentiation “good effects”)

COX2 - Stimulus dependent, inflammatory response.

Question 6

What drug class are usually the first line defense to relieve mild to moderate pain?

What can glucocorticoids suppress?

What drug can reverse the signs and symptoms on rheumatic disease?

Answer 6

Non-steroid Anti-inflammatory Drugs (NSAIDs)
Can treat acute or chronic pain.

Glucocorticoids can suppress immune response, chronic use can lead to toxicity.

Disease modifying antirheumatic drugs (DMARDs)- slow acting

Question 7

What is the pharmacodynamics of NSAIDS?

What are the kinetic properties of NSAIDS?

Toxicity and side effects of NSAIDS?

Answer 7

Inhibit PG synthesis through COX-inhibition

Weak acids and well absorbed.

All NSAIDS can cause gastric irritants and can cause nephro/hepatotoxicity.

Question 8

What function group on aspirin will bind irreversibly to COX-1 to prevent platelet aggregation?

How does ASA go through phase 1 metabolism?

How does ASA go through phase 2 metabolism?

Answer 8

acetyl group

Phase 1 through CYP450

Phase 2 through UGTs

Question 9

How do NSAIDs treat headaches?

Answer 9

• Decrease sensitivity of brain vessels to bradykinin & histamine = CNS vasoconstriction.

Question 10

Which NSAID irreversibly blocks COX-1, thus preventing platelet aggregation?

How long will this platelet inhibition last?

Answer 10

• Aspirin
• 8-10 days (the lifespan of the platelet)

Question 11

Which NSAID is COX-1 selective?

Which NSAID is COX-2 selective?

Which NSAIDs block COX-1 & COX-2 with equal efficacy?

Which NSAIDs are both COX & LOX inhibitors?

Essay Question

Answer 11

COX-1 Selective:
-Aspirin (irreversible)
-Sulindac
-Piroxicam

COX 2 Selective: Celecoxib (Celebrex)

COX1 and COX2
- Ibuprofen
- Toradol
- Meclofenamate

COX and LOX
- Indomethacin
- Diclofenac

Question 12

What are clinical uses of aspirin?

What are adverse effects of aspirin?

How was aspirin extracted prior to modern medicine?

Answer 12

Widely used to treat mild/moderate pain (12-1500 mg TID)
Rheumatoid Arthritis, Fever
Clot Prevention (81-325 mg/day)

GI upset d/t inhibition of GI protective PG
Increase gastric ulcers d/t decrease buffering

• Willow Bark extraction

Question 13

Leukotrienes have power chemotactic effect on ______, ________, and ______.

Leukotrienes promote broncho_________.

Leukotrienes alters _____________.

Answer 13

Eosinophils, Neutrophils, and Macrophages

constriction

vascular permeability

Question 14

Neutrophils produce _________.

How does this damage the membrane?

Answer 14

ROS (reactive oxygen species)

Hydrogen peroxide and hydroxyl radicals

Question 15

ROS + AA =

Answer 15

Chemotactic metabolites

Question 16

What can occur with chronic use of COX-2 selective agents?

Answer 16

• Thrombosis from ↑ PLT aggregation

COX-2 has prostaglandins that inhibit platelet aggregation.

Question 17

What are the effects of COX-2 Selective Inhibitors?

Answer 17

Analgesic
Antipyretic
Anti-inflammatory

Question 18

Adverse cardiovascular events are related to all NSAIDs except ________.

Answer 18

aspirin

Question 19

Celecoxib (Celebrex)
Use:
Adverse:
Pharmacokinetics:
Other:

Answer 19

Celecoxib (Celebrex) - Selective COX-2 Inhibitor
Use: Arthritis
Adverse: CV Black Box Warning
Pharmacokinetics: Less GI issues , CYP2C9
Other: Sulfonamide, Very $$$

Question 20

Diclofenac (Voltaren)
Use:
Adverse: What can you give to decrease GI issues?

Answer 20

Diclofenac (Voltaren) - Inhibits COX and LOX
Use: Pain, inflammation, fever
Adverse: 20% of pt have GI effects, but decrease incidence with misoprostol/cytotec (a synthetic prostaglandin)

Question 21

Ibuprofen
Use:

Answer 21

Ibuprofen: Inhibits COX1 and COX2
Use: Pain, Inflammation

Question 22

Indomethacin
Use:
Adverse:

Answer 22

Indomethacin: Inhibits COX and LOX
Use: Patent Ductus Arteriosus , Arthritis, Gout,
Adverse: GI issues

Question 23

Acetaminophen
Use:
Adverse:
Other:

Answer 23

Acetaminophen: NOT A NSAID
Use: Pain and Fever
Adverse: Toxic levels @15 grams, Hepatotoxicity, ATN
Other: COX-2 inhibitor (primary effect is in the CNS, no significant anti-inflammatory effect)

Question 24

What is the primary short-term use of glucocorticoid?

Answer 24

Suppression of Inflammation
Mobilize energy stores
Improve Cognitive Function - cortisol release
Salt and Water Retention
Crave carbohydrates for energy utilization.

Question 25

What are the adverse effects of chronic glucocorticoid usage?

Answer 25

• Immunosuppression
• DM, obesity, muscle wasting
• Depression
• HTN

Question 26

When glucocorticoids bind to glucocorticoid receptors in the cell what will increase in transcription (3 molecules)?

What will decrease in transcription (1 molecule)?

Answer 26

Increase transcription in substances involved in immune suppression:
1. Annexin-1 (lipocortin-1): suppresses PLA2, inhibit leukocyte response
2. Secretory Leukoprotease Inhibitor (SLPI)
3. IL-10: immunosuppressive enzyme

Decrease transcription in pro-inflammatory cytokines:
-Inhibition of NFkappaB

Question 27

What is Rheumatoid Arthritis?

What drug class will reverse the effects of rheumatoid arthritis?

What is also given in conjunction with this drug?

Answer 27

RA is a progressively worsening joint disorder involving rheumatic factors.

Disease Modifying Anti-Rheumatic Drugs (DMARDs) will reverse the effects of RA and decrease inflammation.

NSAIDs

Question 28

What lab tests measure Rheumatoid Arthritis inflammation (3 lab test)?

Answer 28

• Sed rate
• C-Reactive Protein
• Rheumatoid Factor (measure immune complexes)

Question 29

Non-biologic DMARDs are useful for what?
Name 3 Examples

Answer 29

Non-biological DMARDs: useful for immunosuppression and as anti-cancer drug

1. Methotrexate- targets adenosine production that activates WBC (anticancer, ↓ dose for RA)
2. Cyclophosphamide - B&T cell suppression
3. Cyclosporine - inhibition of interleukins
   overall, these drugs are non-specific

Question 30

what are biologic DMARDs and how are they different from non-biologic DMARDs?

Name 3 examples.

Answer 30

Biologic DMARDs are antibodies or fragment of antibodies (very $$$) - target on particular protein in one particular pathway, more specific than non-biological DMARDs.

1. Abatacept (Orencia)- Blocks T-cell activation
2. Rituximab (Rituxan)- Depletes B-lymphocytes (anti-cancer)
3. Adalimumab (Humira)- inhibits pro inflammatory cytokine TNF-alpha, a popular choice for RA patients.