B-30. Immunopharmacology I (cytotoxic agents, retinoids). Pharmacotherapy of autoimmune diseases.

Question 1

Cytotoxic Agents (6)

Answer 1

1. ) Cyclophosphamide
2. ) Methotrexate
3. ) Lefluomide and Teriflunomide
4. ) Azathioprine
5. ) Mycophenolate Mofetil

Question 2

When is immunosuppressive therapy used?

Answer 2

1. ) Autoimmune disease
2. ) Blocking transplant rejection
3. ) Preventing GVHD in marrow transplant

Question 3

How many different antigen receptors are there?

Answer 3

10^12, this makes it difficult to block certain antibodies/TCRs

Question 4

Mechanism of action for immunosuppression?

Answer 4

1. ) Lymphopheresis
   - Removal of lymphocytes from circulation by physical methods
2. ) Cytotoxic agents
   - To reduce lymphocyte count
3. ) IL-2 inhibition
   - IL-2 is a lymphocyte growth factor; can either inhibit its expression or its proliferative effect
4. ) Cytokine inhibition
   - Via biologics including mAbs or soluble receptors
5. ) Migration inhibition
   - Decreased movement of WBCs into tissues

Question 5

Cyclophosphamide MOA

Answer 5

Prodrug activated by CYP450 that forms phosphoramide mustard (active metabolite) and acrolein (inactive, toxic metabolite).
These metabolites alkylate the DNA (N7 of guanosine) causing cross linking inside and between DNA chains. This alkylation results in T and B cell inhibition.

Question 6

Cyclophosphamide indications

Answer 6

1. ) SLE
2. ) Systemic sclerosis
3. ) Vasculitis and AI hemolytic anemia
4. ) Kidney disease (AI glomerulonephritis and nephrotic syndrome)

Question 7

Cyclophosphamide side effects

Answer 7

1. ) Myelosuppression (check complete blood count during treatment)
2. ) Gonadal dysfunction
   - Oligospermia and ovarian issues; with increased dose over long period becomes irreversible
3. ) Hemorrhagic cystitis
   - Due to toxic acrolein metabolite; prevent with hydration and mesna treatment
4. ) Teratogen/Mutagen (CI in pregnancy)
5. ) GI symptoms including increased risk of bladder cancer, hyponatremia via SIADH

Question 8

Methotrexate (MTX) MOA

Answer 8

Acts as an antimetabolite to inhibit DHF reductase decreasing dTMP and DNA synthesis.
Also has anti-inflammatory effects via MTX-polyglutamates which inhibit AICAR transformylase (purine metabolism)
*MTX-polyglutamates persit in cell longer than MTX itself

Question 9

Methotrexate Admin

Answer 9

given orally once a week; sometimes s.c. (onset takes weeks; start with steroid/NSAIDs)

Question 10

Methotrexate Indication

Answer 10

1. ) Rheumatoid arthritis (Drug of choice in moderate/severe RA)
2. ) Psoriasis (other immune-related dermatological diseases including vasculitis, etc.)
3. ) SLE
4. ) IBD
5. ) Vasculitis
6. ) Dermatomyositis

Question 11

Methotrexate side effects

Answer 11

1. ) Myelosuppression
   - with megaloblastic anemia; reversible with leucovorin (folinic acid)
2. ) Hepatotoxic
   - Increased liver enzymes; also reversible with leucovorin (day after MTX admin.)
3. ) Pulmonary fibrosis
   - restrictive leading to decreased lung volume, FEV1 and FVC, and diffusion
4. ) GI issues
   - Including mucositis/stomatitis (with oral ulcers) and diarrhea
5. ) Teratogenic (via folate deficiency)
6. ) Rarely nephrotoxic

Question 12

Leflunomide and Teriflunomide MOA

Answer 12

Reversibly inhibit dihydro-orotate dehydrogenase which inhibits pyrimidine synthesis leading to decreased T-cell proliferation and decreased antibody production by B cells

Question 13

Leflunomide and Teriflunomide Indication

Answer 13

1. ) RA (leflunomide is as effective as MTX)
2. ) Remitting-relapsing MS (teriflunomide used which is an active metabolite of leflunomide)
3. ) Psoriatic Arthritis

Question 14

Leflunomide and Teriflunomide Administration

Answer 14

Leflunomide given orally with loading dose (half a week to 2 weeks)

Question 15

Side effects of Leflunomide and Teriflunomide

Answer 15

1. ) Liver dysfunction (can be severe)
2. ) Exanthems (widespread rash)
3. ) Alopecia
4. ) Mild hypertension and diarrhea

Question 16

Azathioprine (AZA) MOA

Answer 16

Prodrug of 6-mercaptopurine forms thio-IMP which blocks AMP/GMP (purine) synthesis

• Some of the formed thio-GTP acts as false nucleotide and halts DNA synthesis
• Results in decreased lymphocyte proliferation and increased apoptosis of lymphocytes/monocytes

Question 17

Indications for Azathioprine

Answer 17

1. ) Transplantation (decreases organ rejection)
2. ) IBD (Crohn’s)
3. ) SLE
4. ) RA (less effective than MTX for RA; mostly for refractory cases)
5. ) Vasculitis and glomerulonephritis

Question 18

Azathrioprine side effects

Answer 18

1. ) Myelosuppression with pancytopenia
2. ) Hepatoxiticity and pancreatitis (monitor LFTs)
3. ) Rarely, heaptic veno-occlusive disease

Question 19

Interaction of of Azathioprine

Answer 19

6-MP is broken down by xanthine oxidase which is blocked by allopurinol leading to azathrioprine toxicity

Question 20

Mycophenolate mofetil (MMF) MOA? Where is it isolated from?

Answer 20

Reversibly inhibits IMP dehydrogenase decreasing GMP (purine) synthesis
Lymphocytes don’t use purine “salvage” pathway, only de novo synthesis so decreased lymphocytes

Question 21

Indications for Mycophenolate mofetil?

Answer 21

1. ) Transplantation (Drug of choice for heart, liver, and kidney)
2. ) Off-label uses: GVHD, SLE, nephritis, myasthenia gravis, psoriasis, RA

Question 22

Mycophenolate mofetil side effects

Answer 22

1. ) myelosupression
   - Pancytopenia (specifically associated with invasive CMV infection)
2. ) Hypertension
3. ) Hyperglycemia
4. ) GI symptoms (very common with MMF; nausea, diarrhea, cramps)

Question 23

Retinoid drugs (3)

Answer 23

1. ) Isotretinoin
2. ) Tazarotene
3. ) Acitretin

Question 24

Isotretinoin also called?

MOA?

Answer 24

13-cis-retinoic acid
Isotretinoin binds retinoic acid (RAR) and retinoid X (RXR) nuclear receptors and may induce apoptosis in certain cells including the sebaceous glands

Question 25

Indication for Isotretinoin

Answer 25

Severe acne

Question 26

Side effects of isotretinoin?

Answer 26

1. ) Teratogenic
   - Cleft palate, cardiac issues, etc.
   - in US, requires negative pregnancy test and 2 forms of contraception before prescription
2. ) Vitamin A toxicity
   - Nausea, vomit, vertigo, blurred vision (acute); alopecia, dry skin, hepatotoxicity, arthralgia, and pseudotumor cerebri (chronic)
3. ) Myelosuppresion
   - Mostly anemia/thrombocytopenia, sometimes neutropenia

Question 27

Acitretin MOA and indication

Answer 27

MOA: also an RAR/RXR agonist; inhibits cell proliferation and differentiation
Indicated in severe psoriasis

Question 28

Acitretin side effects

Answer 28

1. ) Dry mucosa and eyes
2. ) Skin problems
   - itching, hair loss, exfoliation, dermatitis, pyogenic granuloma
3. ) Teratogenic
   - avoid pregnancy during and 3 years after treatment

Question 29

Tazarotene use?

Answer 29

Locally applied retinoid cream for psoriasis

Question 30

Tretinoin other name? Used for? In combo with?

Answer 30

All trans retinoic acid used for actue promyelocytic leukemia
Often in combo with arsenic trioxide (inducing cancer cell apoptosis)

Question 31

Antimalarial drugs that are also used in autoimmune diseases (2)

Answer 31

Chloroquine and Hydroxychloroquine

Question 32

MOA of chloroquine and hydroxychloroquine

Answer 32

Possibly via increased pH in macrophage lysosomes decreasing antigen catabolism and presentation
-Also block autophagy and proinflammatory mediator synthesis

Question 33

Kinetics of chloroquine and hydroxychloroquine

Answer 33

• Well absorbed and large Vd due to high tissue binding

- Long half life (40 days); liver metabolism

Question 34

Indication of chloroquine and hydroxychloroquine

Answer 34

1. ) SLE + discoid lupus (first choice for less complicated cases)
2. ) RA- monotherapy in mild cases; combo with other DMARDs (Disease-modifying antirheumatic drugs) is severe)
3. ) Sjogren’s syndrome

Question 35

Side effects of chloroquine and hydroxychloroquine

Answer 35

1. ) Exanthems and pruritus (especially in dark-skinned patients)
2. ) Myopathy
3. ) Vision issues
   - macular degeneration and corneal discoloration (require ophthalmological control)
4. ) Nightmares, nausea, vomiting