DMARDS (Disease-Modifying Anti-Rheumatic Drugs) Flashcards
1
Q
Biological DMARDS (Disease Modifying Anti-Rheumatic Drugs)
A
- TNA-a blocker
- B-cell depleter (CD20 mAb)
- T-cell activation inhibitor
- IL6-R mAb
- JAK-3 inhibitor
- Recbominant IL-1 ANT
2
Q
TNF-a blocker Biologic DMARD
A
- Etanercept
- Adalimumab
- Infliximab
3
Q
B-cell depleter (CD20 mAb) Biologic DMARD
A
- Rituximab
4
Q
T-cell activator inhibitor: Biologic DMARD
A
- Abatacept
5
Q
IL-6R mAb: Biologic DMARD
A
- Tocilizumab
6
Q
JAK-3 Inhibitor Biologic DMARD
A
Tofacitinib
7
Q
Recombinant IL-1 ANT: Biologic DMARD
A
- Anakinra
8
Q
Miscellaneous drugs for pain/inflammation in Rhematoid Arthritis
A
- Acetominophen
- NSAIDS (naproxen, celecoxib)
- Glucocorticoids (prednisone)
- Opioids (generally NOT used)
9
Q
Traditional/non-biologic DMARDS (Disease Modifying Anti-Rheumatoid Drugs)
A
- Methotrexate
- Hydroxychloroquine
- Sulfasalaznie
- Leflunomide
10
Q
What are the 3 goals of RA therapy?
A
- Stop inflammation (put disease in remission)
- Relieve symptoms
- Prevent joint and organ damage
11
Q
Manifestation of RA
A
- 40% have involvement of MSK system other than joinits and non-articular organs
- Bone loss due to prostaglandins + cytokines + exogenous glucocorticoids
- Muscle weakness
- Pleurisy and parenchymal lung disease
- Anemia
12
Q
Non-pharmacologic and Preventative therapies for RA
A
- Education and counseling
- Rest (bc causes fatigue) and exercise (pain and stiffness)
- PT/OT
- Nutrition and diet therapy
- Bone protection
- CV risk reduction
- Vaccinations
13
Q
Drugs for 1st choice for RA, due to efficacy and rapid onset of action
A
- NSAIDS (either 1st generation; COX1 (ASA) & COX2 inhibitors (Naproxen) OR 2nd generation COX2-I (Celecoxib)) = anti-inflammatory action AND pain relief
14
Q
When using NSAID analgesis for RA, does it alter the progression of the disease?
A
No
15
Q
Drug of choie if additional pain relief is required for RA.
A
Acetominophen
16
Q
Glucocorticoids - Prednisone
- MOA
A
- Goes into cell - binds to glucocorticoid receptor
- GR dimer is formed in cytpoplasm => NTRS nucleus
- GR complexes with NF-kB and AP-1 TF=>
- Activates genes, like lipocortin, PLA2-I => immunosupression
17
Q
How do glucocorticoids cause immunosupression?
A
- Blocks synthesis of eicosanoids (PG, TX,LT, etc)
- Reduces activity of immune system via suppressionof IL-1 -6, IL-8 and IFN-γ
- Lymphocytes sequestration and apoptosis
- Suppresses neutrophil migration
- ↓ eosinophil numbers in blood and tissue
18
Q
Glucocorticoids - Prednisone Use for Rheumatoid Arthritis
How often?
A
- Treats pain and inflammation that occurs in flares in sicker patients with RA for a SHORT-TIME, while you are waiting for effects of DMARDS
- Use < 1 month => more effective than placebo or NSAID, but use less than 6 months. Do not use chronically without DMARD therapy, however you can take <5mg/day W/O signifant AE, but NO reduction in disease progression.
19
Q
How is the 1/2 life and potency of prednisolones ↑↑↑?
A
- Adding F (fluorine)
20
Q
Name fluorinated prednisolones
A
- Betamethasone
- Dexamethasone
- Triamcinilone
21
Q
Non-fluorenated prednisolone
A
Methylprednisolone
22
Q
When DQing exogenous glucocorticoids, what do you have to make sure to do?
A
DQ slowly: abruptly DQ them can be deadly
23
Q
Patients with pain due to RA are often administered _____ or ____ despite their lack of effect on disease progression while waiting for a drug from DMARD class to begin exertings its effects
A
NSAIDS
Glucocorticoids
24
Q
Glucocorticoid, prednisolone prodrug, short-term use is useful in therapy for RA until DMARD effects are seen
A
Prednisone
25
Describe **Mild RA**
1. _\<_ 5 inflamed joints and pain
2. NL to slighly ↑ ESR and C-reactive protein levels
3. No extra-articular disease, erosions or cartilage loss on XR of the hands, wrists, and feet
4. Low levels of measures of disease activity such as the DAS28, CDAI, SDAI, or RAPID
5. Most patients lack poor prognostic features: rheumatoid factor or Ab to cyclic citrullinated peptides
26
Describe **Moderate RA**
1. ≥ 5 inflamed joints
2. ↑↑↑ (ESR) and/or (CRP) concentration
3. Rheumatoid factor and/or anticyclic citrullinated peptide(CCP) antibodies present in most patients
4. Evidence of inflammation on XR of the hands, wrists, or feet, such as osteopenia and/or periarticular swelling….
5. Minimal joint space narrowing and small peripheral erosions
27
**_Mild RA treatment_**
28
**Moderate RA treatment**
29
_**Methotrexate**: Traditional/ non-biologic DMARD_
* MOA for RA and cancer
**_Blocks_ _thymidine_ and _purine synthesis_: purinergic GPCR mediates anti-inflammatory effects**
For RA
1. Undergoes polyglutamation =\> MTX-(glu)n, which accumulates in cells over multiple weeks
2. Also blocks thymidylate synthase and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase
3. =\> AICAR accumulation =\> adenosine efflux, which binds to purinergic GPCRs on cell surface =\> **anti-inflammatory effects**
4. =\> fastest DMARD, with effects in 3 - 6 weeks and works in 80% of pts
For cancer
1. Inhibits dihydrofolatereductase with loss of TH4 causing a thymineless death when used as antiproliferative to treat cancer
30
How efficacious is **MTX (methotrexate)?**
**Fastest DMARD,** with effects in **3-6 weeks** and works in up to **80% of patients.**
31
**Uses** of MTX (Methotrexate)
1. **Drug of 1st choice for RA,** due to efficacy, safety, low cost and extensive use
2. Use in **combo** wit other traditional DMARDS
3. **Continued** when pt is switched to **biologic** DMARD
32
**Pharmokinetics of MTX**
**1x/ per week**, either: **orally**(but variable absorption) or **injection**
33
**Methotrexate** toxicities
1. **Low doses** used for immunosuppression = **well-tolerated,** but patient should take weekly **folate supplements**
2. **Higher doses** =\> **life threatening major AE:** _bone marrow suppression_, _hepatic fibrosis_, _GI ulceration_ and _pneumonitis_
3. **Fetal death** and **congenital abnormalities**
34
**_Hydroxychloroquine_**
1. **MOA**
2. **Uses**
**_MOA_: Lipophilic weak base** that **accumulates in lysosomes** is then protonated, resulting in concentrations within lysosomes up to 1000 times higher than in culture media =\> ↑↑↑ the pH of the lysosome from **4 -\> 6 =\>** higher pH of these lysomal vesicles in APC limits the association of peptides (including autoantigens) with class II MHC molecules =\> **Slow disease progression**, but has a **delayed onset (3-6 months**
_Use_:
1. **Malaria**
2. **Mild RA in PREGNANT WOME**N w/o poor prognostic features
3. Combined with **methotrexate ±sulfasalazine** if more severe RA
4. **Lupus erythematosus**
35
Which **traditional/non-biologic DMARD** is safe to use when PG?
**_Hydroxychloroquine_**
36
**_Hydroxychloroquine_**
* Pharmacokinetics
* Toxicities
* Pharmacokinetics:
* **1/2 life = 23 days** and eliminated by kidneys
* Use **loading doses** to speed up onset
* Toxicities
* **Retinal damage,** but low doses have little risks
37
Agent used as a **traditional DMARD** _alone_ or in _combo w/ other Traditional_ _DMARDS_ and also to tx **IBD**, **GI side** effects are a **common reason for discontinuing**
**Sulfasalazine**
38
Refers to the use of **_methotrexate_**, **_hydroxychloroquine_**, and **_sulfasalazine_** together to treat RA
**Triple therapy**
39
**2nd-choice traditional DMARD** that **disrupts pyrimidine synthesis** and causes more common serious adverse effects
**Leflunomide**
40
**Methotrexate** is the _most effective_ and _fastest acting_ of the traditional DMARDs, we most ofren monitor for ___________ but generally well tolerated at low doses, often added to \_\_\_\_\_\_\_\_\_
* **Myelosupression** (fever, symptoms of infection, bleeding)
* **Biologic DMARDS**
41
As a general rule, what _can/can't **biologic DMARDs**_ be combined with?
CAN be **combined** with **non-biologic DMARDS,**
**NEVER combined** with other **biologic DMARDS**
42
What are the _pros/cons_ between **Biologic DMARDS** and **Nonbiologic DMARDS**?
* _PRO_: **Faster** onset of action and **HIGH rate of response.**
* _CONS_**: More expensive** and **↑↑↑ risk of AE.**
43
**_What does each mean?_**
* “-cept” = \_\_\_\_\_\_\_\_\_\_\_\_\_\_
* “-mab” = \_\_\_\_\_\_\_\_\_
* “-ximab” = \_\_\_\_\_\_\_\_\_\_\_
* “-zumab” = \_\_\_\_\_\_\_\_\_\_\_
* “-umab” = \_\_\_\_\_\_\_\_\_\_\_\_\_
1. “-**cept**” = fusion of a receptor to the Fc part of human IgG1
2. “-**mab**” = monoclonal antibody (mAb)
3. “-**ximab**” = chimeric mAb
4. “-**zumab**” = humanized mAb
5. “-**umab**” = human mAb origin
44
Blocking the effects of ______ inflammatory mediator is a common target in tx of RA and various other autoimmune diseases
**TNF** via _TNF-ANT._
45
**TNF-ANT** are indicated for what?
What are the AE?
* **Moderate =\> severe RA**, generally after _traditional DMARDs_ have proven to be _ineffective_
* Toxicities
* 1. All drugs =\> risk of **serious infection, like TB**
* **2. Severe allergic reactions**
46
**Chimeric (human and mouse) monoclonal Ab** directed against TNF that can be administered **IV every 6 weeks** as a biologic DMARD
**Inflixumab**
47
**Anti-TNF biologic DMARD;** this _recombinant fully humanized monoclonal Ab_ is administered _SQ every 2 weeks_; also used for _psoriatic arthriti_s, _ankylosing spondylitis_, and _Crohns disease_
**Adalimumab** = BEST SELLING DRUG IN THE WORLD
48
What is the best selling drug in the world?
**Adalimumab**
49
**Fusion protein** made from _Fc portion of IgG_ and _two TNF receptors_, a biologic DMARD administered **1-2x/week by SQ injection**; also used for _psoriasis_
**Etanercept**
50
Ab that targets **CD20 antigen on B cells, begining in the pre-B cell stage** to cause a _B cell “do-over”,_ used to _treat NHL (non-hodgekins)_ and _CLL (chronic lymphocytic leukemia)_ and can be effective in some _antibody-dependent autoimmune diseases_
**Rituximab**
51
What is **Rituximab** MOA?
1. _Targets CD20 on surface of B-cells_ but _SPARES plasma cells:_ bc CD20 is present begining at the pre-B cell stage UNTIL they differentiate into plasma cell
2. Bc plasma cells are NOT affected =\> Ig levels stay NL despite B-cell lymphopenia that persists for months after cause.
3. AutoAB that can cause disease are affected by B-cell depletion
52
**_Rituximab_**
* Use
* Who responds the highest
* **Use with** [**methotrexate**] for patients with RA _who do not respond to TNF-ANT_
* If _(+) for rheumatoid facto_r or _anti-CCP_ AB =\> responds higher.
53
**Biologic DMARD,** fusion protein blocks T cell CD80/86 co-stimulatory signal needed for activation
**Abatacept**
54
**Biologic DMARD** that is a **humanized antihuman IL-6-R AB =\> competes for membrane-bound** and **soluble forms of IL-6R,** among its effects is to
_↓ ↓↓ acute-phase response of liver_ and (+) T/B-cells, MO and osteoblasts
**Tocilizumab**
55
**Tocilizumab**
1. Use
2. Toxicities
1. Uses
1. Moderate - severe RA, _if other DMARDS and TNF-a ANT do not work_
2. Use w or w/o **methotrexate**
2. MC toxicities
1. URT infection
2. Life threatening infectiosn
56
**JAK3 enzyme ANT** used as a _biologic DMARD,_ _UNIQUE_ in that it is administered **_ORALLY_**
**Tofacitinib**
57
**Biologic DMARD** that is _least efficacious (last choice DMARD)_, _recombinant_, _non-glycolsylated version_ of **endogenous human IL-1-R ANT**
**Anakinra**
58
MOA of MTX
1. **Polyglutamine of MTX** =\> AICAR to accumulate in the cell and adenosine to acculinate outide the cell;
1. Polyglutamination is assx with its low-dose ability to tx RA and the persistence of effects AFTER DQd
2. Adenosine then binds to purigenic GCPR on surface of cell =\> anti-inflammatory response
