2.1 Pharm Exam3: Dmards

Front 1

Q: 32 yr female diagnosed w RA was given NSAIDs, which did not provide relief. Her physician then prescribed Prednisone. After a few months pt returns complaining of side effects & asking for a different medication. What are some likely side effects?

Back 1

A: truncal obesity & moon face

(chronic corticosteroid use can also cause osteoporosis in women bc they downregulate Ca2+ binding proteins & upregulate osteoclasts, much better to use for flare-up & NOT chronically)

Front 2

RA triggered by:

Back 2

- Genetic disposition
- Age related “wear and tear” (athletes inc.)
- Hypothermia
- Infection

Front 3

RA pathogenesis:

Back 3

Synovial lining thickens-->

Stimulates Inflammatory influx of T-lymphocytes-->

T cells induce inflammatory cascade:
Release of cytokines (IL-2, IL-6, IFN)
↓
Attracting B cells & macrophages
↓
Macrophages release of enzymes (MMP) (& additional IL-2, IL-6, TNF) causing localized connective tissue degradation and stimulation of B lymphocytes.
--> Hydroxyl superoxide & free radicals worsen inflammation & cause systemic effects

Subsequent production of Rheumatoid Factor (RhF) by B cells

Front 4

RA: Proinflammatory cytokines:

Back 4

Proinflammatory Cytokines:
TNF-α
IL-1
IL-6
IL-17

Stimulation of synovial fibroblasts & release of matrix metalloproteinases

Front 5

In addition to increased cytokine production, what other mediators would be present in a blood culture that indicate RA?

Back 5

RF (+)

high C-reactive Protein

Front 6

RA: Progression

Back 6

Synovial inflammation
↓
Cartilage destruction
↓
Bone Erosions
↓
Changes in joint integrity

Front 7

RA: Clinical Presentation:

Back 7

1. Rheumatoid nodules (forearm & hands)

2. Vasculitis (nail beds)

3. Ocular dysfxn (vision)

4. Pulmonary (pleural effusion)

5. Pericarditis--> Fibrosis--> CHF

6. Splenomegally & Thrombocytopenia = syndrome

Front 8

RA: Therapeutic Goals

Back 8

- Analgesia-pain relief
- Reduction of inflammation
- Protection of articular structures
- Maintain joint function
- Control systemic involvement/infection
(All Palliative)

*Inhibit cytokines (TNF-alpha, IL-1, IL-6, IL-17) to prevent synovial fibroblast proliferation & MMP release--> slow deterioration, RA progression********

Front 9

RA: Treatment options

Back 9

NSAID’s
Glucocorticoids
DMARD’s
Biological Response Modifiers

Front 10

RA: Therapeutic Goals of non DMARDs

Back 10

- NSAID’s to control initial inflammation and pain and prostaglandinds
- Low dose oral glucocorticoids to slow disease progression--> flare-ups

= CONTROL inflammatory symptoms (& pain)

(DO not stop progression of RA joint destruction)

Front 11

RA: NSAIDs

Back 11

Acute relief of inflammatory symptoms by NSAID’s: (usually 2X daily dosing)

indomethacin*
diclofenac*
piroxicam*
ibuprofen*

Sulindac

Celecoxib

(less SE than corticosteroids, use first for relief)

Front 12

RA: NSAIDs- MOA

Back 12

NSAID’s will provide some analgesic relief and

antiinflammatory benefits, via;

Inhibition of cyclooxygenase (COX) activity-->
Reduction in inflammatory mediators-->

interfere w/ NADPH oxidase activity in neutrophils & w/ phospholipase C activity in macrophages

Front 13

RA: Do you use NSAIDs alone?

Back 13

NO, always combo w DMARD

*they do not alter dz progression

Front 14

RA: NSAIDs help by inhibition of...

Back 14

inhibition of neutrophil activation
inhibition of leukotriene production
inhibition of T & B cell proliferation

Front 15

(Glucocorticoids/NSAIDs) can be used for pain in combo w/ DMARDs for long-term RA tx

Back 15

NSAIDs

(DO NOT EVER give glucocorticoids long term!)

Front 16

RA: Glucocorticoids

Back 16

More efficient than NSAID’s for temporary management of pain & stiffness (but more SE)

-oral prednisolone

-Intraarticular instillation (triamcinilone, methylprednisolone)

(*joint injections avoid undesirable systemic SEs)

Front 17

RA: Therapeutic Goals of DMARDs

Back 17

-slow or stop synovial disease progression

-NO analgesic effect!!!

Front 18

RA: DMARDs- MOA

Back 18

Anti-inflammatory actions via:
-Inhibition of cytokines (TNF, IL-2, IL-6 )-->

inhibition of synovial & systemic inflammation

Slow-acting –may take months for their benefits to become apparent.

Front 19

RA: Timing of DMARD administration

Back 19

BEGIN ASAP
Initiation of DMARD’s within first 3 months of diagnosis.
↓
Single or combination DMARD
↓
Prevention of joint erosion. (dx progression)

Front 20

RA: DMARDs

Back 20

Methotrexate (Rheumatrex)* DOC
Hydroxycloroquine (Plaquenil)
Sulfasalazine (Azulfidine)*
Leflunomide (Arava)

Front 21

Methotrexate: MOA

Back 21

Inhibition of dihydrofolate reductase
-->Lymphocyte proliferation
-->Chemotaxis
-->RhF production
-->Cytokine production

Inhibits BOTH purines & pyrimidines

DMARD of choice

Front 22

Methotrexate: Course of tx

Back 22

Use of NSAID’s should be continued unless remission occurs.
Once weekly doses, until symptomatic improvement occurs (max- 20mg/week) + supplemental folic acid.

Monotherapy or combination with other DMARD’s (usually Sulfasalazine)

Front 23

RA: Methotrexate Contraindications

Back 23

thrombocytopenia
immune compromised patients
100% contraindicated in pregnant and nursing women

Front 24

Patients who take methotrexate should be counselled that they must avoid __________ intake!

Back 24

alcohol intake!

Front 25

Methotrexate: Side effects

Back 25

(Essential to monitor liver function)

hepatotoxicity and pulmonary fibrosis.

Front 26

___________ is the DOC to ADD in combo with Methrotrexate for RA tx, if disease continues to progress.

Back 26

Sulfasalazine

*not used preferentially (instead of methotrexate due to GI side effects)

Front 27

DMARDs: Sulfasalazin- MOA

Back 27

- Converted in intestine to sulfapyradine (antibacterial) & mesalamine (antiinflamm)
- Inhibition of prostaglandin production.
- Metabolites highly distributed.

- Commence with low dose.
- Therapeutic effect takes up to 2 months.

Front 28

Hydroxychloroquine: Clinical Use

Back 28

Antimalarial*

Acute & chronic RA (in combo w/ methotrexate)

(^cheap but not common RA drug)

Front 29

DMARDs: Hydroxychloroquine- MOA

Back 29

- Inhibit lymphocyte function
- Stabilize lysosomal membranes
- Reduce chemotaxis and phagocytosis.
- Reduce production and release of IL-1

*long half-life (3-4 days) & delayed results (6 mth)

Front 30

Q: A pt being tx for RA w/ methotrexate has increasing joint pain & stiffness. An additional DMARD is added to control disease progression. Pt soon develops tinnitus, dizziness, & blurred vision. What is the likely DMARD added?

Back 30

A: Hydroxychloroquine

(contains quinidine, causes same SEs)

Front 31

__________ may also be used in combo w/ methotrexate, but is not an ideal choice bc of the high risk of hepatotoxicity

Back 31

Leflunomide

- Contraindicated in hepatic dysfunction.
- Must monitor liver function

Front 32

DMARDs: Leflunomide- MOA

Back 32

Inhibition of mitochondrial dihydroorotate dehydrogenase
↓
Inhibition of T-lymphocyte response to inflammatory stimuli.

- Metabolized to active metabolite (Half-life-19 days).
- Commence with loading dose followed by maintenance dose

Front 33

RA: Biological Response Modifiers

Back 33

Indicated as combination regimen with DMARD therapy or replacement therapy in patients with DMARD failure

*VERY EFFECTIVE in RA, but VERY expensive

Front 34

Biological Response Modifiers: Contraindications

Back 34

- patients with acute, serious infection.
- immunocompromised patients and those with tuberculosis.

Front 35

Biological Response Modifiers: SE

Back 35

Can get injection site reaction--> infection or anaphylaxis

Fever, rash, headache, nausea

(always do test run to prevent major SEs & consider risk of infection)

Front 36

Biological Response Modifiers:

Back 36

TNF Antagonists:
Etanercept (Enbrel)
Infliximab (Remicade)
Adalimumab (Humira)

IL-1 Receptor Antagonist:
Anakinra (Kineret)

Costimulation Blockers:

Abatacept (Orencia)

Anti-CD20 Monoclonal Antibody:

Rituximab (Rituxan)

Front 37

TNF Antagonist: ____________prevents binding of TNF-alpha to receptors

Back 37

Etanercept prevents binding of TNF to receptors

- SC administration twice weekly.
- Elimination half-life: 5 days.
- Highly effective as monotherapy.
- Symptomatic improvement in 1-4 weeks
- May be combined with DMARD. (except Anakinra).

Front 38

TNF Antagonist:__________ solubilizes (soaks up) TNF-alpha

Back 38

Infliximab (IgG1 monoclonal antibody) binds to soluble and bound TNF-α (solubilizes TNF)

- Combination regimen with methotrexate.
- IV infusion 4 to 8 weeks.
- Elimination half-life: 9 days.
- Symptomatic relief within 1-4 weeks.

Front 39

TNF Antagonist: _________prevents binding of TNF with receptors AND reduces TNF-alpha production

Back 39

Adalimumab prevents binding of TNF with receptors, causes ysis of TNF expressing cells & reduces TNF-α production by macrophages.

- SC administration every 2 weeks.
- Half-life: 10-20 days.
- Symptomatic relief within 1 week.
- Monotherapy or combination with DMARD.

Front 40

IL-receptor antagonist: _________prevent IL-1 receptor binding

Back 40

Anakinra (Recombinant form of IL-1 receptor antagonist) prevents IL-1 receptor binding.

- Daily SC administration.
- Half-life: 4-6h
- Monotherapy or combination with DMARD.
- Contraindicated with TNF antagonists

Front 41

Costimulation blocker:___________blocks T-cell signaling & activation

Back 41

Abatacept blocks T-cell signaling & T-cell activation.

- Lack of response to antigen.
- IV administration over 30 mins every 4 weeks.
- Half-life: 13 days
- Monotherapy or combination with DMARD.
- Contraindicated with TNF-antagonists & anakinra.

Front 42

Anti-CD20 Monoclonal Antibody:___________depletes B cell invasion of inflammed joint

(also used for non-Hodgkens Lymphoma)

Back 42

Rituximab causes rapid and sustained depletion of B-lymphocyte.

- Administered IV over 4 hours, then at 2 weeks.
- Half-life: 60-150h
- Therapeutic effects last for at least 40 weeks after initial treatment.
- Indicated as monotherapy or in combination with methotrexate.

Front 43

Rituximab has many adverse SE including; _______& _________

&

___________ therapy should be withheld 12 hours, prior to Rituximab administration

Back 43

- Adverse effects include; angioedema & hypotension

- Antihypertensive therapy should be withheld 12 hours prior to administration of rituximab.

Front 44

RA: AGGRESSIVE therapy plan

Back 44

Early diagnosis of rheumatoid arthritis and prognosis (RhF & Radiography)
↓
DMARD’s + NSAID’s (withrawl NSAIDs if able)
↓
Low-dose systemic Corticosteroids if
required for flare-up
↓
If inadequate response after 3 months change/add DMARD’s or consider biologics.

Arrest progression and prevent permanent joint damage ASAP (via early dx & tx)