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Block 7; Week 5-Michelle > Duan-DMARDS etc > Flashcards

Duan-DMARDS etc Flashcards

1
Q

What are the important corticosteroids to keep in mind?

A

prednisone
prednisolone
dexamethasone

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2
Q

What are some important DMARDs that are anti-TNFalpha?

A

adalimumab
infliximab
etanercept
anakinra

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3
Q

What are some important DMARDs that are antimetabolites?

A

azathioprine
methotrexate
cyclophosphamide
cyclosporine

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4
Q

What are the symptoms of RA? How would you describe this disease?

A

chronic progressive systemic autoimmune disease
Symmetric synovitis
Joint inflammation, pain, swelling, stiffness, progressive erosions of bones, joint misalignment, reduced or lost function
rheumatoid nodules on the extensor surfaces of the elbows, forearms, and hands.
Multisystem extra-articular manifestations
Pulmonary and vascular involvement
Keratoconjunctivitis
Sensory peripheral neuropathy

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5
Q

What are the goals of RA therapy?

A

Control inflammation
Alleviate pain
Slow progression/rate of joint damage
Reduce disease activity and induce remission
Maintain function for essential daily activities
Maximize quality of life

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6
Q

What are the ways to admin RA meds? Other treatments?

A

systemic oral meds
intra-articular injections
joint exercises & rest
joint surgery

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7
Q

What are the 2 functional groups that RA medicines fall into?

A
  1. drugs that treat pain & inflammation but don’t limit joint damage
  2. drugs that help control disease & limit joint damage
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8
Q

Where do NSAIDS & Corticosteroids (glucocorticoids) & DMARDS fall into functional categories?

A

NSAIDS & Corticosteroids–drugs that treat pain & inflammation
DMARDS–limit joint damage

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9
Q

What is combination therapy?

A 
widely used
several oral DMARDS
OR
oral + biological DMARDS
OR
DMARDS + Corticosteroids (systemic or injection)
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10
Q

Phospholipase A2 turns Membrane phospholipids into eicosanoids. Which 2 enzymes are involved next?

A

LOX: turns eicosanoids into leukotrienes.
COX: turns them into prostaglandins.

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11
Q

What are some drugs that target Phospholipase A2?

A

Corticosteroids: prednisone & dexamethasone

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12
Q

What are some drugs that target COX?

A

NSAIDS

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13
Q

Which drugs target LOX?

A

5-lox inhibitors
sulfasalazine
leukotriene receptor antagonist

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14
Q

What does the presence of leukotrienes do? Prostaglandins cause inflammation.

A

phagocyte mobilization
changes in vascular permeability
inflammation

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15
Q

Which enzyme, COX-1 or COX-2 causes inflammation, pain, fever?

A

COX-2

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16
Q

What are the advantages of using NSAIDs to manage RA?

A 
effective control of inflammation & pain
effective reduction in swelling
improves mobility, flexibility, ROM
QOL up
low cost
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17
Q

What are the disadvantages of using NSAIDS to manage RA?

A 
doesn't help disease progression
GI toxicity possible
renal problems
hepatic dysfunction
CNS toxicity with high dose
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18
Q

Where are corticosteroids made in the body?

A

adrenal cortex

including glucocorticoids & mineral corticoids

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19
Q

What is the function of glucocorticoids? WHat is an example?

A

cortisol
carb, fat, protein metabolism
prevent phospholipid release-anti-inflammatory
decrease eosinophil action

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20
Q

What is the function of mineral corticoids? What is an example?

A

Aldosterone
electrolyte & water levels
promotes sodium retention in kidney

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21
Q

Describe the hypothalamic-pituitary adrenal axis feedback.

A

CRH (vasopressin) from hypothalamus stimulates Pituitary gland to release ACTH.
ACTH causes the release of Glucocorticoids from adrenal glands.
Neg feedback to pituitary & hypothalamus.
Pos feedback to hippocampus, which is inhibitor to hypothalamus.
Additionally, stress is stimulatory to hypothalamus.

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22
Q

What is the MOA of corticosteroids?

A

diffuse into cells via simple diffusion & binds transcription factors. Enter nucleus & regulate synthesis of IFNgamma, GM-CSF & interleukins & TNFalpha
also inhibit COX-2 & phospholipase A2.

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23
Q

How do corticosteroids use lipocortin?

A

lipocortin inhibits phospholipase A2.

Corticosteroids increase lipocortin.

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24
Q

What are some clinical uses of glucocorticoids?

A 
immunosuppression
anti-inflammatory
autoimmune diseases (RA)
Asthma
Anti-cancer
Replacement THerapy (addison's disease)
Allergic disorders
collagen disease
nephrotic disease
resp distress syndrome
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25
Q

Name some corticosteroids used in RA therapy? Which have short duration? Long duration?

A 
Cortisol: 1.5-3 hrs
Cortisone: 0.5 hrs
Prednisone: 3-4 hrs
Triamcinolone: 36-54 hrs
Dexamethasone: 35-54 hrs
Fludrocortisone: 24 hrs
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26
Q

How do synthetic corticosteroids compare to endogenous ones?

A

Synthetic have stronger potency, lower dose, longer duration

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27
Q

How are corticosteroids well absorbed? How do they travel in blood? Where are they metabolized? Excreted?

A

well absorbed orally
bound to plasma proteins
metabolized in liver (Cyt P450)
excreted in kidney

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28
Q

What are some other important pharmacokinetic features of corticosteroids?

A

Plasma half-life shorter than biological halflife
Substantial lag time before onset of action
Persistence of effect after disappearance from plasma

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29
Q

What are the adverse effects of using chronic use of glucocorticoids?

A 
Fat redistribution: Cushing's syndrome, Moon face, buffalo hump
Diabetes
HPA suppression
Impaired Wound Healing
MSK: osteoporosis
Cardio: fluid retention, edema, HTN
Gastric Ulcers
Infection
Growth inhibition
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30
Q

What are the advantages of corticoid therapy?

A

anti-inflammatory & immunosuppression

helps joint flares if you use intra-articular injections

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31
Q

What are the disadvantages of corticoid therapy?

A

doesn’t affect disease progression
skin thinning, ecchymoses, Cushing appearance
cause of steroid-induced osteopenia

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32
Q

What are oral DMARDS?

A

small molecular chemical drugs

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33
Q

What are biologic DMARDS?

A

genetically engineered antibodies & proteins Ex: TNFalpha blockers
can also target IL-1, IL-6, CD20, CD28

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34
Q

How long does it take for DMARDS to have an observable clinical effect?

A

takes more than 3 months

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35
Q

What is the MOA of azathioprine?

A

purine synthesis inhibitor

36
Q

What is the MOA of cyclosporin A?

A

calcineurin inhibitor

37
Q

What is the MOA of leflunomide?

A

pyrimidine synthesis inhibitor

38
Q

What is the MOA of methotrexate?

A

purine metabolism inhibitor

39
Q

What is the MOA of abatacept?

A

T cell costimulatory signal inhibitor

40
Q

What is the MOA of adalimumab?

A

TNF alpha inhibitor

41
Q

What is the MOA of chloroquine & hydroxychloroquine? Note: these are antimalarials

A

suppression of IL-1 & TNFalpha

induce apoptosis of inflammatory cells & decrease chemotaxis

42
Q

What is the MOA of D-penicillamine?

A

reducing numbers of T lymphocytes

43
Q

What is the MOA of etanercept & golimumab? And infliximab

A

TNFalpha inhibitor

44
Q

What is the MOA of minocycline?

A

5-LO inhibitor

45
Q

What is the MOA of rituximab?

A

chimeric monoclonal antibody againstCD20on B-cell surface

46
Q

What is the MOA of sulfasalazine?

A

Suppression of IL-1 & TNF-alpha, induce apoptosis of inflammatory cells and increase chemotactic factors

47
Q

What is the MOA of tocilizumab?

A

anti-IL6

48
Q

What is the recommended dose for methotrexate in treatment of rheumatoid arthritis?

A

7.5-20 mg/wk

49
Q

What are the advantages to DMARDS?

A 
slow disease progression
improve functional disability
decrease pain
interfere with inflammation
retard joint erosions
50
Q

What is the time to benefit for methotrexate?

A

1-3 mo

51
Q

What is the potential toxicity for methotrexate?

A

moderate

on par with gold (parenteral)

52
Q

What are the toxicities to monitor for DMARDs?

A

hepatotoxicity
pulmonary
myelosuppression

53
Q

What is the general & specific MOA for methotrexate?

A

general: purine metabolism inhibitor
specific: blocks dihydrofolate reductase & thymidylate synthase

54
Q

What are the pros of using methotrexate?

A

we know what it does
ok to continue therapy with it
proven efficacy in RA

55
Q

What are the cons of using methotrexate?

A

lab monitoring every 1-2 mo

possible liver, lung toxicity, myelosuppresion

56
Q

What is the MOA of sulfasalazine?

A

COX & LOX inhibitor as well as IL-1 & TNFalpha inhibitor

57
Q

What are the pros to sulfasalazine?

A

effective

mild level of toxicity

58
Q

What are the cons to using sulfasalazine?

A

some pts sulfa intolerant
bad for patients with G6pd deficiency
monitor every 3 mo
look for myelosuppression, GI, decreased digoxin absorption

59
Q

What is the MOA of azathioprine?

A

immunosuppressive
purine synthesis inhibitor
prevents leukocyte proliferation

60
Q

What are the pros to azathioprine?

A

effective in refractory RA

metabolized to 6-mercaptopurine

61
Q

What are the cons to azathioprine?

A

risk for severe leukopenia, thrombocytopenia
risk for liver toxicity, cancer, opportunistic infections, macrocytic anemia, bone marrow depression, GI
have to monitor every 2 weeks & then every 1-3 mo.

62
Q

What shouldn’t you take azathioprine with for risk of myelosuppresion?

A

ACE-1 inhibitor or allopurinol for gout.

63
Q

What is the MOA of gold auranofin?

A

blocks phagocytosis

64
Q

What are the pros of gold auranofin?

A

good for refractory RA
can be used orally
accumulates in synovium

65
Q

What are the cons of gold auranofin?

A

6 mo before you know if effective
close monitoring
can’t take if you have liver or kidney problems
can’t combine with other immunosuppressants
shouldn’t use with X-rays

66
Q

What are the some of the toxicities associated with gold auranofin?

A 
skin lesions
stomatitis
oral ulcers
glomerulonephritis
nephrosis
thrombocytopenia
agranulocytosis
67
Q

What is the MOA of leflunomide aka ARAVA?

A

inhibits pyrimidine biosynthesis by inhibiting dihydroorotate dehydrogenase (mitochondrial enzyme)
affects T cells

68
Q

What are the pros of lefluonomide aka arava?

A

works in 1 mo
can use long term
prevents expansion of activated lymphocytes
selectively targets autoimmune lymphocytes

69
Q

What are the cons of lefluonomide?

A

less clinical experience with it
liver & GI toxicity
expensive
long half life requires loading

70
Q

Once again, what are biological DMARDS?

A

genetically engineered antibodies & proteins

block cytokines & signaling molecules

71
Q

What are the biological TNF alpha blockers?

A

Adalimumab (Humira)
Etanercept (Enbrel)
Infliximab (Remicade)

72
Q

What is the biological DMARD that blocks IL-1?

A

anakinra (kineret)

73
Q

What is the biological DMARd that blocks B cells CD20?

A

Rituximab (Rituxan)

74
Q

What is the structure of etanercept (enbrel)? Which drug is it sometimes used with? How is it administered?

A

dimeric fusion protein
extracellular ligand that binds TNFreceptor that is linked to the Fc part of IgG1
used sometimes with methotrexate
administered by injection

75
Q

What seems to be the main problem with Etanercept?

A

immunosuppressive
can get bad infections
don’t use in diabetics etc.

76
Q

WHat is the structure of infliximab aka remicade?

A

chimeric IgG1 antibody that binds to TNFalpha with high affinity
inhibits binding of TNFa to receptors by bind to it first!
can be used with methotrexate

77
Q

T/F Methotrexate could potentiate the antirheumatoid activity of infliximab while reducing its immunogenicity

A

True.

78
Q

What is the structure of adalimumab aka Humira?

A

recombinant IgG1 monoclonal antibody specific for TNFalpha
only consists of human peptide sequences
binds TNFalpha & blocks its interaction w/ p55 & p75 on cell surfaces

79
Q

When would you prescribe a biologic DMARD over an oral DMARD?

A

for patients with longstanding active RA that need to change their therapy
give a greater symptoms response & remission rate than oral DMARDS
can’t compare effectiveness yet

80
Q

IS it okay to combine 2 biologic DMARDS?

A

NO. doesn’t increase effectiveness

increases risks for bad side effects

81
Q

What are some good DMARD combos?

A

methotrexate + sulfasalazine + hydroxychloroquine
methotrexate + cyclosporine
methotrexate + leflunomide
methotrexate + biologic DMARD
**only for people with longstanding active RA, not early RA

82
Q

T/F DMARDS should be initiated early in active RA.

A

True.

83
Q

T/F DMARD combo treatment should be X + sulfasalazine.

A

False. X + methotrexate

84
Q

T/F Biologic DMARDs are indicated when oral DMARDs are not successful.

A

True.

85
Q

T/F Biologic DMARDs + Methotrexate are superior to oral DMARDs + methotrexate.

A

False.
superior to
oral DMARDS alone…that’s all we know for now.

86
Q

What is an effective firstline treatment for RA?

A

Methotrexate (oral DMARD)

87
Q

For people with longstanding active RA…what do you sometimes want to do with oral DMARDs?

A

use 2-3 oral DMARDs at once!

Block 7; Week 5-Michelle (11 decks)

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