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MSK Week 5 > 2.5.2. NSAIDS/DMARDS > Flashcards

2.5.2. NSAIDS/DMARDS Flashcards

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:

A

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

25
Q

What treatments do we have for NSAID-induced GI toxicity?

A
  1. proton pump inhibitors, like omeprazole
  2. misoprostol - a prostaglandin analog (for preventing gastric ulceration)
  3. mucosal protectants, like sucralfate
26
Q

NORMAL prostaglandin synthesis is important for autoregulation of renal blood flow - both non-selective and COX-2 selective inhibitors may cause the following (7)

A
  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
Q

Relate prostaglandins to vascular tone

A

vascular tone is modulated by prostaglandins; some antihypertensive and diuretic agents may stimulate PG release

28
Q

Relate NSAIDs to Hypertension

A

NSAIDs impair control of hypertension & congestive failure in Pts taking beta-adrenergic antagonists, diuretics, angiotensin receptor blockers, or ACE inhibitors

29
Q

Patient taking NSAIDs who already have hypertension should also take what?

A

Ca-channel blockers

30
Q

The more selective a drug is for Cox-__, the greater the risk for CV adverse reaction

A

COX-2

31
Q

NSAIDS and aspirin have this effect on platelet aggregation

A

Inhibit

32
Q

Mechanism for NSAID induced Asthma

A

mechanism: arachidonic acid metabolism is shifted from the COX pathway to the leukotriene pathway b/c COX enzymes are inhibited

33
Q

Problem with using Aspirin or Salicylates with certain viral infections

A

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
Q

Salicylism

A

nausea, vomiting, tinnitus caused by overdose of Aspirin or salicylates

35
Q

Effect of overdosing Aspirin or salicylates on hemostasis

A

decr platelet aggregation and hypothrombinemic effect

36
Q

Effect of overdosing on Aspirin or Salicylates on respiration?

A

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
Q

Overdose of Acetaminophen can cause what?

A

hepatotoxicity
hypoglycemic coma
renal tubular necrosis
hypersensitivity

38
Q

Detail the unique property of aspirin

A

unique property: aspirin IRREVERSIBLY INHIBITS COX enzymes. New enzyme synthesis is necessary for recovery of COX activity

39
Q

Problem with using Aspirin to cause the same effects as NSAIDs?

A

in high doses, aspirin is as effective as any other NSAID :) However, many Pts cannot tolerate the GI toxicity :(

40
Q

Effect of Aspirin on COX-1 and 2 and how we can use Aspirin therapeutically:

A

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
Q

Although it reduces cancer and MIs, what is a risk with Aspirin?

A

Increases risk of stroke

42
Q

How does Aspirin increase vasodilation? Effect on PTT and PTT in blood counts?

A

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
Q

Explain why several COX-2 inhibitors have specific adverse effects that led to their withdrawal from sale.

A
  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
Q

What does DMARD stand for?

A

DMARD = disease-modifying antirheumatic drug

45
Q

What does Rhematoid Arthritis do?

A

In RA, macrophages and other immune-related cells release lysosomal enzymes, NO, H2O2, and other free radicals that damage and disrupt cell membranes

46
Q

Effect of DMARDs on RA?

A

most DMARDs reduce symptoms slowly and delay the disease process

47
Q

What are non-biological DMARDs?

A

“non-biologics” = chemicals that are made artificially

48
Q

What are the four immunosuppressant non-biologics?

A
  1. Glucocorticoids
  2. Methotrexate
  3. Gold Salts
  4. Leflunomide
49
Q

How does Methotrexate do? What are its side effects?

A

Dihydrofolate reductase inhibitor

Side effects: anorexia, vomiting, cramps, ulcers, hepatotoxicity, thrombocytopenia

50
Q

How do Gold Salts do and what are some potential hazards?

A

Gold accumulates in macrophages, inhibiting activity

Acts as an immunosuppressant

Poses kidney toxicity

51
Q

Function and potential side effects of Leflunomide?

A

Inhibits pyrimidine synthesis by inhibiting dihydrooroate dehydrogenase

Reduces lymphocyte proliferation

Teratogenic/fetal death

52
Q

Biologics that we need to know:

A
  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
Q

How does etanercept work?

A

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
Q

Effect of etanercept?

A

given by SQ injection twice weekly, with reduced joint inflammation evident in 2 wks to 3 months

55
Q

How does infliximab work?

A

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
Q

What do we know about drugs with -“mab” or “-ab” at the end?

A

drugs with “-mab” or “-ab” refer to monoclonal antibodies (eg adalimunab, golimunab, certolizumab - don’t need to know these three, just for example)

57
Q

How does Anakinra work?

A

naturally-occurring IL-1 receptor antagonist

competitively inhibits pro-inflammatory actions of IL-1

58
Q

What are the major toxicities associated with TNF-a inhibitors?

A

serious infections like TB, other bacterial & fungal infections, and possibly HZV

allergic reactions

malignancies (potentially - will take longer to evaluate)

MSK Week 5 (7 decks)

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