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Flashcards in DMARDs Deck (49):
1

Methotrexate (MTX) description
DMARD

**DOC -> first DMARD prescribed for mild, moderate or severe RA**

Decreases *purine* synthesis

Decrease toxicity with **leucovorin or folic acid**

2

Methotrexate Mechanism
DMARD

Inhibits *AICAR transformylase* -> final step in de novo purine synthesis forming IMP

Also leads to the *accumulation of adenosine* which is a potent anti inflammatory mediator -> decrease NF-kB

3

Methotrexate PK/PD
DMARD

Requires much *lower dose* than what is needed to CA chemotherapy -> inhibits DHF reductase

4

Methotrexate AE/contraindications

Nausea, ulcers
Hepatotoxicity (dose related)
**Pseudolymphomatous rxn**

***Contraindicated in pregnancy***

5

Leflunomide description
DMARDS

Prodrug converted to an active metabolite

Cells are *arrested in G1*

Decreases *pyrimidine synthesis*

6

Leflunomide mechanism
DMARDS

Inhibits *dihydroorotate dehydrogenase* -> decrease UMP

Inhibits autoimmune T&B cell proliferation which have increased need for DNA precursors (other cell are able to maintain basal pyrimidine requirements through salvage pathways)

7

Leflunomide PK/PD
DMARDS

Can cause severe hepatotoxicity when combine with MTX

Monitor CBC and LFT's

8

Leflunomide AE/contraindications
DMARDS

Frequent diarrhea
Alopecia, rash
Myelosuppression
Increase aminotransferase activity
*Contraindicated in pregnancy*

9

Hydroxychloroquine description
DMARDS

Often used with MTX and sulfasalazine

10

Hydroxychloroquine PK/PD
DMARDS

Ophthalmology exam before treatment and annually thereafter for high risk pts

11

Hydroxychloroquine AE/contraindications
DMARDS

**Hemolysis in patients with decreased G6PD**
**Retinal damage** is rare

12

Sulfasalazine description
DMARDS

In contrast to use for the treatment of ulcerative colitis, Sulfapyridine is the active DMARD

13

Sulfasalazine PK/PD
DMARDS

Diazo bond metabolized by *bacteria* in colon to sulfapyridine and 5-ASA

14

Sulfasalazine AE/contraindications
DMARDS

Nausea, anorexia, rash
Hepatitis, leukopenia
*Lupus like syndrome*
*Hemolysis in decrease G6PD*
****Safe in pregnancy*****

15

Cyclosporine description
DMARDS

Inhibits Ag triggered signal transduction in T cells
Only used in severe cases

16

Cyclosporine mechanism
DMARDS

Forms a comlpex with cyclophilin -> prevents calcineurin from desphosphorylating **NFAT -> decrease IL-2**

17

Cyclosporine PK/PD
DMARDS

Many drug interactions and widespread nephrotoxicity -> limited use

18

Cyclosporine AE/contraindications
DMARDS

**Nephrotoxicity**
**Hirsutism & gum hyperplasia**
Tremor, HTN, hyperglycemia, hyperlipidemia, osteoporosis

19

Azathioprine description
DMARDS

Purine antimetabolite
Only used in cases of **refractory RA**

20

Azathioprine mechanism
DMARDS

Converted to 6-MP -> inhibition of *de novo purine* synthesis -> suppression of T & B cells

21

Azathioprine PK/PD
DMARDS

Reduce dose in pts taking *allopurinol* due to inhibition of xanthine oxidase

22

Azathioprine AE/contraindications
DMARDS

BM suppression
GI disturbance
Infection and malignancy risk

23

Cyclophosphamide description
DMARDS

Generally limited to the most *severe* cases of RA

24

Cyclophosphamide mechanism
DMARDS

Alkylating agents -> cross links DNA -> prevents cell replication

25

Cyclophosphamide PK/PD
DMARDS

*Mesna* is used to treat hemorrhagic cystitis caused by cyclophosphamide

26

Cyclophosphamide AE/contraindications
DMARDS

BM suppression, infertility
**Hemorrhagic cystitis**
Infection and malignancy risk
**Fanconi's anemia**

27

Gold sodium thiomalate & Auranofin description
DMARDS

**Macrophage poisons** with high toxicity rendering them basically obsolete

28

Gold sodium thiomalate & Auranofin mechanism
DMARDS

Suppress phagocytosis and lysosomal enzyme activity

29

Gold sodium thiomalate & Auranofin PK/PD
DMARDS

GST is given IM
Auranofin is oral

30

Adalimumab description
DMARDS

Fully human **IgG1 anti-TNF Ab**

31

Adalimumab mechanism
DMARDS

Binds to soluble TNF alpha preventing is interaction with receptors -> *downregulation of T-cell and macrophage function*

32

Infliximab mechanism
DMARDS

Binds to soluble TNF alpha preventing is interaction with receptors -> *downregulation of T-cell and macrophage function*

33

Etanercept mechanism
DMARDS

Binds to soluble TNF alpha preventing is interaction with receptors -> *downregulation of T-cell and macrophage function*

34

Anakinra mechanism
DMARDS

IL-1 receptor antagonist

35

Adalimumab PK/PD
DMARDS

Pts need to be *screened for latent TB* prior to and during treatment with any TNF alpha inhibitor (also used in IBD)

36

Infliximab PK/PD
DMARDS

Pts need to be *screened for latent TB* prior to and during treatment with any TNF alpha inhibitor (also used in IBD)

37

Etanercept PK/PD
DMARDS

Pts need to be *screened for latent TB* prior to and during treatment with any TNF alpha inhibitor (also used in IBD)

38

Infliximab description
DMARDS

Chimeric anti TNF alpha
(mouse and human)

39

Etanercept description
DMARDS

Recombinant fusion protein -> 2 TNF receptors linked to IgG1

40

Adalimumab AE/contraindications
DMARDS

Cytopenia -> monitor CBC
*Serious infection*
Do not give to patients with active infection

41

Etanercept AE/contraindications
DMARDS

Cytopenia -> monitor CBC
*Serious infection*
Do not give to patients with active infection

42

Infliximab AE/contraindications
DMARDS

Cytopenia -> monitor CBC
*Serious infection*
Do not give to patients with active infection

43

Glucocoritcoids description
DMARDS

Prompt and dramatic effect, but use is controversial
Not real DMARDS

44

Glucocorticoids mechanism
DMARDS

Used for *short term symptomatic relief* until beneficial effects of DMARDs become apparent

Inhibit PLA2 and COX-2

45

Glucocorticoids PK/PD
DMARDS

AE associated with long term use

Do not affect CV risk

46

Glucocorticoids ae/contraindications
DMARDS

Osteoporosis, weight gain, ulcers, HTN, hyperglycemia, etc.

47

DMARD therapy

More effect if combination than monotherapy without significanly increasing toxicity
Combo typically includes MTX and another agent

MTX + leflunomide can increase risk for hepatoxicity

**Never use multiple biological agents in combination therapy**

48

DMARD biological agents

Adalimumab
Infliximab
Etanercept
Anakinra

49

Relief of RA
DMARDs

NSAIDs off symptomatic relief of RA, but have little effect on progression of disease

DMARDs have no immediate analgesic effect, but can *control symptoms and delay progression* of disease

Typically takes 6 weeks to 6 months for DMARD clinical effects to be seen, but some of the biologic DMARDs can have effects within 2 weeks