Topic B32

Question 1

Cyclophosphamide

MoA and Main effect

Answer 1

Alkylating agent that forms cytotoxic DNA cross links

Suppresses T and B cell production.

Question 2

List the cytotoxic immunosuppressive drugs (5)

Answer 2

Methotrexate
Leflunomide
Azathioprine
Mycofenolate mofetil
Cyclophosphamide

Question 3

List the inhibitors of cytokine gene expression

Answer 3

Calcineurin inhibitors, mTOR inhibitors, JAK inhibitors

Calcineurin

• Cyclosporin A
• Tacrolimus
• Pimecrolimus

mTOR

• Sirolimus/Rapamycin
• Everolimus
• Temsirolimus

JAK

• Tofacitinib
• Baricitinib

Question 4

1st gen retinoids and their use

Answer 4

Vitamin A, aka Retinol

1st gen
- Tretinoin
used for acne, commonly along with Salicylic acid

• Isotretinoin
  Systemic retinoid, for severe, cystic acne.
• Alitretinoin
  Injected into the lesions of AIDs-Kaposi sarcoma

Question 5

What drug is given to decrease the side effects of MTX?

Answer 5

Leucovorin, Folinic acid.

Question 6

2nd gen retinoid and its use, significant SE

Answer 6

2nd gen

- Acitretin

Question 7

3rd gen retinoids and their use

Answer 7

3rd gen for cutaneous T cell lymphoma
- Bexarotene

3rd gen topicals for acne and psoriasis

• Adaplene
• Tazarotene

Question 8

Methotrexate MoA

Answer 8

Inhibits dihydrofolate reductase

Question 9

Leflunomide MoA and main effect, main indications

Answer 9

Leflunomide prodrug is processed to Teriflunomide, active metabolite.

Inhibits Dihydroorotate dehydrogenase,
an early step in pyrimidine synthesis.

Potent inhibition of T-cell proliferation and Antibody production by B cells

Rx: Rheumatoid arthritis and Multiple Sclerosis.

Question 10

Azathioprine MoA

Answer 10

A prodrug that generates the active 6-Mercaptopurine.

Inhibit GPAT, glutamine prpp amidotransferase,
Inhibits IMP synthesis,
inhibits de novo purine synthesis.

Question 11

Mycophenolate Mofetil MoA

Answer 11

Inhibits IMP dehydrogenase

Inhibiting GMP synthesis specifically.

Question 12

Medicines for graft vs host disease

Answer 12

Cyclosporine and Methotrexate

Question 13

Transplant immunosuppressing agents

Answer 13

Azathioprine, Mycophenolate
Cyclosporine
Cyclophosphamide

Question 14

List other alkylating drugs besides cyclophosphamide

Answer 14

Busulfan

Nitrosoureas

• Carmustine
• Lomustine

Question 15

Cyclophosphamide SEs

What agent can reduce the major SE?

Answer 15

Hemorrhagic cystitis - due to Acrolein.

Mesna, mercaptoethane sulfonate binds urinary acrolein, preventing the hemorrhagic cystitis.

BUT, it increases subsequent risk for bladder cancer

Other SEs:
Marrow suppression
Testicular and Ovarian toxicity and infertility
Premature menopause
Teratogenic and mutagenic
Pulmonary fibrosis
SIADH, hyponatremia

Question 16

Leflunomide kinetics and SEs

Answer 16

Half life of 2 weeks, administered with a loading dose.

SEs:
Potentially severe liver damage
Rashes
Alopecia
Mild hypertension

Question 17

Azathioprine Indications and SEs

Answer 17

Aza Rx: 
Transplants
Inflammatory bowel disease
SLE, RA
Vasculitis

SEs:
Liver toxicity
Budd Chiari syndrome
Marrow suppression.

Question 18

Mycophenolate indications and SEs

Answer 18

Mycophenolate Rx:

• 1st line for most transplant suppression
• GVHD
• SLE
• Psoriasis
• Myasthenia G.

SEs:

• Marrow suppression
• Hypertension
• GI upset

Question 19

Cyclophosphamide indications

Answer 19

Autoimmune disease, SLE, RA
Organ transplant
Leukemias and Lymphomas.

Question 20

Cyclosporine A indications and SEs

Answer 20

Cyclosporin Rx:
Organ transplant and stem cell transplants

SEs;
- Dose dependent kidney toxicity. Kidney function monitoring is manditory

• Hepatotoxicity. Liver function should also be regularly monitored.
• Infections, potentially life threatening. Especially CMV and Herpes viral infections
• Lymphomas
• gingival hyperplasia
• hirsutism
• tremor and CNS effects
• hypertension and hyperglycemia

Question 21

Cyclosporine kinetics

Answer 21

CYP3A4 metabolized
About 50% bound by RBCs
Pumped out of GI epithelial cells by P-glycoprotein
-because of all this, oral dose is unpredictable, and should be carefully monitored/administered.

Grapefruit juice inhibits CYP3A4 and increases dose.

Question 22

Tacrolimus
Mechanism
Indication

Answer 22

Calcineurin inhibitor
Binds to FKBP proteins and then inhibits calcineurin

Inhibits IL-2 release and T cell activation.

Rx:
Preferred agent of cyclosporine for liver and kidney transplant, also used for rescue therapy in other transplants.
3rd line for severe refractory atopic dermatitis

Question 23

Tacrolimus
Kinetics
SEs

Answer 23

Kinetics are like cyclosporine, variable bioavailability
CYP3A4 metabolism

SEs
1- Nephrotoxicity, actually more severe than in cyclosporine, kidney function must be monitored.
2- CNS toxicity is also more potent.
- Tremors, Seizures, Hallucinations
3- Insulin dependent diabetes, especially in blacks and hispanics.
4- Alopecia

No hirsutism or gingival hyperplasia. 
lower incidence of 
hypertension
hyperglycemia
hyperlipidemia
than cyclosporine.

Question 24

Sirolimus
MoA
Indications

Answer 24

Sirolimus aka Rapamycin

Binds to FKBP proteins, but inhibit mTOR, blocking IL-2 signal transduction.

Inhibits both T and B cell function,
Also inhibits fibroblasts and angiogenesis.

Indications

• Kidney transplants
• Coated stents, as an anti-proliferative agent.

Question 25

General transplant immunosuppression regimine

Answer 25

Tacrolimus, Corticosteroids, and Mycophenolate

Sirolimus may be added

Question 26

Sirolimus
kinetics
SEs

Answer 26

Also CYP3A4 metabolized
P-gylcoprotein substrate
Unpredictable dose needs monitoring

SEs:
Significant hyperlipidemia

Nephrotoxicity - especially when co-adminstration with cyclosporin or tacrolimus

Marrow suppression

Pneumonitis

Question 27

List the mTOR inhibitors

Answer 27

Sirolimus
Everolimus
Temsirolimus

Question 28

What drugs inhibit JAK signaling?

Answer 28

Tofacitinib

Baricitinib

Question 29

Indications for JAK inhibitors

SEs

Answer 29

Rheumatoid arthritis, alone or with MTX.

SEs:
Hepatotoxicity, liver enzymes
Marrow suppression

Airway infections
Hyperlipidemia