01b: Pharmacology

Question 1

(Biologics/non-biologics) are referred to as DMARDs and typically have MW (over/under) (X).

Answer 1

Non-biologics;
Under
X = 1000 Da

Question 2

Biologics are typically (X) molecules that are administered via which routes?

Answer 2

X = IgG

IV or SC

Question 3

Hydroxychloroquinone is in (X) class of immunosuppressants and works via which mechanisms on (Y) cells?

Answer 3

X = antimalarial (non-biologic)
Y = synovial fibroblasts and B cells

1. Sensitization to Fas-induced apoptosis
2. Inhibition of TLR-dependent cell activation

Question 4

Hydroxycholorquinone is used as immunosuppressant in which diseases?

Answer 4

Lupus, mild RA

Question 5

Side effects of Hydroxycholorquinone.

Answer 5

Accumulation in/damage to retina (requires ophthalmologic monitoring)

Question 6

T/F: One advantage of Hydroxycholorquinone is its very low potential for toxicity at lower doses.

Answer 6

True

Question 7

Sulfasalazine is in (X) class of immunosuppressants and reduces inflammation by which mechanism?

Answer 7

X = 5-aminosalicylates (non-biologics)

Parent drug increases level of adenosine

Question 8

Sulfasalazine DMARD effect is by which actions on which cells?

Answer 8

1. Suppress T cell function (IkkB inhibition blocks NFkB signaling)
2. Inhibit B cell proliferation

Question 9

Sulfasalazine is effective in (X) diseases with (greater/less/same) efficacy as hydroxychloroquine.

Answer 9

X = RA and spondyloarthropathies

Greater

Question 10

(X) (biologic/non-biologic) immunosuppressant drug should be avoided in patients with G6PD deficiency due to (Y) adverse effect.

Answer 10

X = sulfasalazine
Non-biologic

Y = hemolytic anemia

Question 11

Methotrexate is (biologic/non-biologic) that works by which mechanism at high doses?

Answer 11

Non-biologic

Inhibits TMP (thymidine monophosphate) synthesis, thus DNA replication/cell division; anti-neoplastic effect

Question 12

Methotrexate is in (X) class of DMARDs that works by which mechanism at low doses?

Answer 12

Purine synthesis inhibitors;

Inhibits DHF Reductase (de novo purine synthesis); anti-rheumatic effect; also increase adenosine (anti-inflammatory)

Question 13

List some side effects of methotrexate.

Answer 13

1. Nausea and mucositis

2. Hepatotoxicity

Question 14

T/F: Switching from parenteral to oral administration of methotrexate may decrease nausea/hepatotoxicity.

Answer 14

False - vice versa

Question 15

Folate supplementation has been shown to (increase/decrease) effects of (X) immunosuppressant drug.

Answer 15

Decrease;

X = methotrexate

Question 16

(X) immunosuppressant is teratogenic and used to induce abortion. Thus, which patients should avoid using it?

Answer 16

X = methotrexate

Pregnant women or men considering fatherhood

Question 17

Aside from high dose, list some circumstances that might increase the side effect risks of methotrexate in a patient.

Answer 17

Reduced renal clearance:

1. Renal disease
2. Use of OATP inhibitors

Question 18

Methotrexate is drug of choice for which rheumatic diseases? Star the one it’s especially effective for.

Answer 18

1. RA*
2. Lupus
3. Vasculitis
4. Psoriatic arthritis and others

Question 19

(X) is in (Y) class of immunosuppressants that is active once the prodrug is metabolized into 6-mercaptopurine (6-MP).

Answer 19

X = Azathioprine
Y = purine synthesis inhibitors (non-biologics)

Question 20

6-mercaptopurine has (X) effect on B cells and (Y) effect on T cells.

Answer 20

X = inhibits DNA replication (blocks IMP synthesis)
Y = inhibits DNA replication AND initiates T cell apoptosis

Question 21

(X) prodrug is metabolized into 6-mercaptopurine (6-MP) and then to nucleotides by (Y).

Answer 21

X = Azathioprine
Y = HGPRT (hyopxanthine quanine phosphoribosyl transferase)

Question 22

List the three main side effects of azathioprine.

Answer 22

1. Bone marrow suppression
2. Infection
3. Malignancy

Question 23

Risk of azathioprine side effects is increased by:

Answer 23

Deficiency in TPMT (thiopurine methyltransferase) enzyme, which inactivates 6-MP

Question 24

Leflunomide is in (X) class of immunosuppressants and acts by which mechanism?

Answer 24

X = pyrimidine synthesis inhibitors (non-biologics)

Converted to active metabolite that inhibits dihydroorotate dehydrogenase (inhibits T/B cell de novo pyrimidine synthesis)

Question 25

Therapeutic (anti-rheumatic) uses for Azathioprine:

Answer 25

SLE, myositis, vasculitis

Question 26

Leflunomide risk of (X) side effect is increased when it's used in combo with methotrexate.

Answer 26

X = hepatotoxicity

Question 27

(X) DMARD used to treat RA has long half-life and undergoes enterohepatic circulation. An overdose of this drug can be effectively treated with (Y).

Answer 27

``` X = Leflunomide Y = cholestyramine (bile acid binding resin to increase fecal clearance) ```

Question 28

Cyclophosphamide is in (X) class of immunosuppressants. It's (activated/inactivated) via metabolism by (Y).

Answer 28

X = DNA Alkylating agent Activated (into phosphoramide mustard) Y = Hepatic CYP450s

Question 29

(X) DMARD is a prodrug that is metabolized into phosphoramide "mustard". What's the mechanism of action of this active metabolite?

Answer 29

X = cyclophosphamide Cross-links DNA (alkylating agent) that blocks cell replication

Question 30

Cyclophosphamide used to treat which rheumatic diseases?

Answer 30

1. SLE and scleroderma (esp pulm fibrosis) | 2. Vasculitis

Question 31

T/F: Cyclophosphamide typically used in combo with Methotrexate for RA.

Answer 31

False - used in combo with glucocorticoids; NOT used for RA

Question 32

Cyclophosphamide side effects:

Answer 32

1. Bone marrow suppression 2. Infertility 3. Alopecia (hairloss)

Question 33

Glucocorticoids mechanisms of immunosuppression include:

Answer 33

1. Increase IkB transcription, which binds/blocks NFkB 2. Inhibit cytokine secretion (phages and T cells) 3. Inhibit B and T cell replication

Question 34

T/F: Low-dose corticosteroids for 6 months are recommended in RA.

Answer 34

True - ideally less tho

Question 35

JAK3 is a(n) (X) molecule that's expressed in (Y) cells. It contributes to:

Answer 35

``` X = enzyme Y = T and B cells ``` Signaling of cytokines (like IL-2)

Question 36

List the three classes of biologics used for immunosuppression (anti-rheumatic).

Answer 36

1. Cytokine (IL-1/6, TNFa) antagonists 2. T-cell costimulation inhibitor 3. Anti-CD20 B cell depleter

Question 37

Adalimumab is in (X) class of immunosuppressants and has which structure/mechanism?

Answer 37

Fully humanized IgG; binds TNFa with high affinity and blocks interaction with receptor

Question 38

TNFa antagonists are approved for which rheumatic diseases?

Answer 38

1. RA 2. Psoriatic arthritis/psoriasis 3. Ankylosing spondylitis

Question 39

T/F: Patients on TNFa antagonists must go get injections at inpatient/outpatient clinic.

Answer 39

False - preloaded devices can be bought for self administration (SC injection)

Question 40

List some important side effects of Adalimumab.

Answer 40

1. TB REACTIVATION (test for TB prior to use) 2. Injection site reaction 3. CHF aggravation 4. AutoAb development (lupus-like syndrome)

Question 41

Abatacept is in (X) class of immunosuppressants and has which structure?

Answer 41

X = T cell co-stimulation inhibitors Fusion protein (IgG Fc portion with extracellular domain of CTLA4)

Question 42

Abatacept is binds (X) and (stimulates/inhibits) (Y).

Answer 42

X = APC (B7) Inhibits Y = Interaction with CD28 on T cell

Question 43

Abatacept side effects:

Answer 43

1. Infusion-related reactions 2. Infections 3. Antagonism of immunizations

Question 44

Abatacept should not be used in combo with (X) because there's an increased risk of (Y) adverse effect without an increase in therapeutic response.

Answer 44

``` X = anti-TNFa drugs Y = infection ```

Question 45

Live vaccines must not be given prior to/during use of (X) immunosuppressant drug.

Answer 45

X = abatacept

Question 46

Patient with RA is not responding to DMARDs. What (in order) are the next two drugs you would try.

Answer 46

1. Adalimumab (TNFa antagonists) | 2. Abatacept (T cell co-stim inhibitor) OR Rituximab (B cell depleter)

Question 47

Rituximab is in (X) class of immunosuppressants and has which structure?

Answer 47

X = Anti-CD20 B cell depleter IgG binding with high affinity to CD20

Question 48

What is the effect of Rituximab binding to (X)?

Answer 48

X = CD20 on B cells Complement or Ab-dependent cytotoxicity or apoptosis

Question 49

In early RA with low disease activity (X) (mono/combo)-therapy is preferred.

Answer 49

X = methotrexate | Monotherapy

Question 50

If RA disease activity remains moderate or high despite DMARD monotherapy, what options would you consider?

Answer 50

1. DMARD combo | 2. Biologic (anti-TNFa or other) with/without MTX

Question 51

T/F: In established RA with low disease activity MTX monotherapy is preferred over a anti-TNFa.

Answer 51

True