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MSK Week 5 > 2.5.2. NSAIDS/DMARDS > Flashcards

2.5.2. NSAIDS/DMARDS Flashcards

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1
Q

What two major pathways mediate inflammatory events within the cell?

A

the NF-kappaB pathway, and the arachidonic acid cascade

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2
Q

What does phospholipase A2 (PLA2) do?

A

membrane phospholipids are mobilized and converted to arachidonic acid by phospholipase A2 (PLA2)

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3
Q

arachidonic acid can proceed into two different pathways. what are they? What do they yield?

A

COX pathway (yields prostacyclin, prostaglandins, thromboxane)

Lipoxygenase pathway (yields leukotrienes)

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4
Q

Effect of glucocorticoids on the mediation of inflammatory events within the cell?

A

glucocorticoids indirectly inhibit Phospholipase AA, preventing arachidonic acid from being made in the first place, thus inhibiting BOTH the COX and LIPOXYGENASE pathways.

Also inhibits cyclooxygenase

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5
Q

What three enzymes can act on Arachidonic acid?

A

12-lipoxygenase
5-lipoxygenase
Cyclooxygenase

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6
Q

Effect of 12-lipoxygenase on arachidonic acid?

A

Turns it into 12-HEPETE which becomes 12-HETE

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7
Q

Effect of 5-lipoxygenase on arachidonic acid?

A

Turns it into 5-HPETE which becomes 5-HETE, which THEN becomes leukotrienes (cause bronchoconstriction)

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8
Q

Effect of cyclooxygenase on arachidonic acid?

A

Turns it into endoperoxides which then become one of the following:

  1. Prostacyclin/PGX/PGI2 which are antiaggregating factors
  2. PGE2 which causes edema, erythema, pain and fever
  3. PGF2a which causes uterine contraction
  4. Thromboxane which causes platelet aggregation
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9
Q

Difference between NSAIDS and glucocorticoids on the inflammatory process?

A

Glucocorticoids directly inhibit phospholipase A2 and cyclooxygenase whereas NSAIDS only impact the cyclooxygenase

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10
Q

In comparing Cox-1 and Cox-2 enzymes, when are they expressed?

A

COX-1 is constitutively expressed in most tissues. COX-2 is inducible, expressed in high concentrations after inflammatory mediators act on cells

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11
Q

Synthesis product of COX-1 vs. COX-2 enzymes?

A

COX-1 synthesizes relatively low amounts of prostaglandins in the presence of arachidonic acid whereas COX-2 synthesizes large amounts of prostaglandins and thromboxanes, and prostacyclins at some sites

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12
Q

Major inflammatory mediator produced by COX-2 enzymes?

A

PGE2

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13
Q

What do prostaglandins, thromboxanes and prostacyclins do in broad terms?

A

Cause inflammation and initiate wound healing

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14
Q

Effect of Aspirin on COX enzymes

A

an irreversible non-selective inhibitor of COX enzymes; it acetylates the enzyme

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15
Q

Effect of NSAIDs on COX enzymes

A

reversible non-selective inhibitors of COX-1 and COX-2; anti-inflammatory potency corresponds to COX inhibitor potency

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16
Q

Effect of Celecoxib on COX enzymes

A

selective -2 inhibitor.

platelet aggregation is NOT impaired

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17
Q

Possible bad side product of acetaminophen (esp when combined w/ETOH)

A

it can be metabolized to a highly reactive intermediate and a potent hepatotoxin, NAPQI, after induction of CYP2E1

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18
Q

What does NAPQI do to the body?

A

NAPQI drains the body’s glutathione pool by reacting w/the SH groups, leading to impaired Ca++ handling, necrosis, and ultimately hepatotoxicity

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19
Q

What does NSAIDS mean?

A

non-steroidal anti-inflammatory drugs

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20
Q

How and where are non-selective NSAIDs digested?

A

metabolized in the liver via OXIDATIVE and CONJUGATION rxns

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21
Q

When are steady state concentrations in the plasma achieved with NSAIDs?

A

steady-state plasma concentrations aren’t achieved until after 4-5 half lives

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22
Q

What NSAIDS have short half lives?

A

Less than 6 hours - Aspirin, ibuprofen and indomethacin

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23
Q

What NSAIDS have long half lives?

A

Greater than 6 hours - Naproxen, Phenylbutazone and salicylate

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24
Q

Order of GI toxicity of NSAIDs on the GI tract:

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A

naproxen > ibuprofen > diclofenac > coxibs (a drug class)

25
What treatments do we have for NSAID-induced GI toxicity?
1. proton pump inhibitors, like omeprazole 2. misoprostol - a prostaglandin analog (for preventing gastric ulceration) 3. mucosal protectants, like sucralfate
26
NORMAL prostaglandin synthesis is important for autoregulation of renal blood flow - both non-selective and COX-2 selective inhibitors may cause the following (7)
1. reversible reduction of glomerular filtration rate 2. edema 3. papillary necrosis 4. inhibition of loop diuretics (requires PGs) 5. acute or chronic renal failure 6. interstitial nephritis 7. hyperkalemia
27
Relate prostaglandins to vascular tone
vascular tone is modulated by prostaglandins; some antihypertensive and diuretic agents may stimulate PG release
28
Relate NSAIDs to Hypertension
NSAIDs impair control of hypertension & congestive failure in Pts taking beta-adrenergic antagonists, diuretics, angiotensin receptor blockers, or ACE inhibitors
29
Patient taking NSAIDs who already have hypertension should also take what?
Ca-channel blockers
30
The more selective a drug is for Cox-__, the greater the risk for CV adverse reaction
COX-2
31
NSAIDS and aspirin have this effect on platelet aggregation
Inhibit
32
Mechanism for NSAID induced Asthma
mechanism: arachidonic acid metabolism is shifted from the COX pathway to the leukotriene pathway b/c COX enzymes are inhibited
33
Problem with using Aspirin or Salicylates with certain viral infections
use of these during certain viral infections (influenza, varicella) may lead to Reye’s Syndrome. Use acetaminophen preferentially to aspirin FOR CHILDREN w/fever of UNKNOWN CAUSE
34
Salicylism
nausea, vomiting, tinnitus caused by overdose of Aspirin or salicylates
35
Effect of overdosing Aspirin or salicylates on hemostasis
decr platelet aggregation and hypothrombinemic effect
36
Effect of overdosing on Aspirin or Salicylates on respiration?
respiratory alkalosis - at “low” toxic dose levels, respiratory center is overstimulated respiratory and metabolic acidosis - at “high” toxic dose levels, the respiratory center is depressed
37
Overdose of Acetaminophen can cause what?
hepatotoxicity hypoglycemic coma renal tubular necrosis hypersensitivity
38
Detail the unique property of aspirin
unique property: aspirin IRREVERSIBLY INHIBITS COX enzymes. New enzyme synthesis is necessary for recovery of COX activity
39
Problem with using Aspirin to cause the same effects as NSAIDs?
in high doses, aspirin is as effective as any other NSAID :) However, many Pts cannot tolerate the GI toxicity :(
40
Effect of Aspirin on COX-1 and 2 and how we can use Aspirin therapeutically:
Aspirin works because it doesn't affect COX-2 as much as COX-1; its ability to depress TXA2 in platelets and reduce blood clotting allows for its therapeutic use. 1. Allows reduction of myocardial infarction 2. Reduced incidence of colorectal cancer and some other cancers
41
Although it reduces cancer and MIs, what is a risk with Aspirin?
Increases risk of stroke
42
How does Aspirin increase vasodilation? Effect on PTT and PTT in blood counts?
Aspirin affects COX-1 causing little platelet aggregation and leaves COX-2 alone to compensate; causes an increase in vasodilation NO effect on PT or PTT
43
Explain why several COX-2 inhibitors have specific adverse effects that led to their withdrawal from sale.
1. Selective COX-2 inhibitors results in a lack of vasodilation, meaning that blood vessels stay smaller in diameter 2. Normally, platelets aggregate and can induce vasodilation, preventing atherosclerotic plaques from forming and occluding the vessel, but since COX-2 is inhibited, the vessel can’t dilate 3. The high risk of platelets plaques occluding vessels led to their withdrawal 4. TL;DR: most COX-2 inhibitors had a huge risk of major cardiovascular Dz
44
What does DMARD stand for?
DMARD = disease-modifying antirheumatic drug
45
What does Rhematoid Arthritis do?
In RA, macrophages and other immune-related cells release lysosomal enzymes, NO, H2O2, and other free radicals that damage and disrupt cell membranes
46
Effect of DMARDs on RA?
most DMARDs reduce symptoms slowly and delay the disease process
47
What are non-biological DMARDs?
“non-biologics” = chemicals that are made artificially
48
What are the four immunosuppressant non-biologics?
1. Glucocorticoids 2. Methotrexate 3. Gold Salts 4. Leflunomide
49
How does Methotrexate do? What are its side effects?
Dihydrofolate reductase inhibitor Side effects: anorexia, vomiting, cramps, ulcers, hepatotoxicity, thrombocytopenia
50
How do Gold Salts do and what are some potential hazards?
Gold accumulates in macrophages, inhibiting activity Acts as an immunosuppressant Poses kidney toxicity
51
Function and potential side effects of Leflunomide?
Inhibits pyrimidine synthesis by inhibiting dihydrooroate dehydrogenase Reduces lymphocyte proliferation Teratogenic/fetal death
52
Biologics that we need to know:
1. Etanercept 2. Infliximab 3. Adalimumab 4. IL-1 receptor agonists: Anakinra and Rilanocept 5. IL-6 mAb - Tocilizumab 6. Immune modulators - Abatacept and rituximab
53
How does etanercept work?
TNF-α trap in the form of a dimeric protein - prevents TNF-α from interacting w/its receptors uses the TNF-α binding domains of p75 TNF receptor coupled to immunoglobin Fc fragments
54
Effect of etanercept?
given by SQ injection twice weekly, with reduced joint inflammation evident in 2 wks to 3 months
55
How does infliximab work?
TNF-α chimeric monoclonal antibody (human Fc region w/mouse Fab region specific to anti-TNF-α antibodies) binds to free TNF-α, reducing joint swelling and damage
56
What do we know about drugs with -"mab" or "-ab" at the end?
drugs with “-mab” or “-ab” refer to monoclonal antibodies (eg adalimunab, golimunab, certolizumab - don’t need to know these three, just for example)
57
How does Anakinra work?
naturally-occurring IL-1 receptor antagonist | competitively inhibits pro-inflammatory actions of IL-1
58
What are the major toxicities associated with TNF-a inhibitors?
serious infections like TB, other bacterial & fungal infections, and possibly HZV allergic reactions malignancies (potentially - will take longer to evaluate)

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