Topic B32 Flashcards
Cyclophosphamide
MoA and Main effect
Alkylating agent that forms cytotoxic DNA cross links
Suppresses T and B cell production.
List the cytotoxic immunosuppressive drugs (5)
Methotrexate Leflunomide Azathioprine Mycofenolate mofetil Cyclophosphamide
List the inhibitors of cytokine gene expression
Calcineurin inhibitors, mTOR inhibitors, JAK inhibitors
Calcineurin
- Cyclosporin A
- Tacrolimus
- Pimecrolimus
mTOR
- Sirolimus/Rapamycin
- Everolimus
- Temsirolimus
JAK
- Tofacitinib
- Baricitinib
1st gen retinoids and their use
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
What drug is given to decrease the side effects of MTX?
Leucovorin, Folinic acid.
2nd gen retinoid and its use, significant SE
2nd gen
- Acitretin
3rd gen retinoids and their use
3rd gen for cutaneous T cell lymphoma
- Bexarotene
3rd gen topicals for acne and psoriasis
- Adaplene
- Tazarotene
Methotrexate MoA
Inhibits dihydrofolate reductase
Leflunomide MoA and main effect, main indications
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.
Azathioprine MoA
A prodrug that generates the active 6-Mercaptopurine.
Inhibit GPAT, glutamine prpp amidotransferase,
Inhibits IMP synthesis,
inhibits de novo purine synthesis.
Mycophenolate Mofetil MoA
Inhibits IMP dehydrogenase
Inhibiting GMP synthesis specifically.
Medicines for graft vs host disease
Cyclosporine and Methotrexate
Transplant immunosuppressing agents
Azathioprine, Mycophenolate
Cyclosporine
Cyclophosphamide
List other alkylating drugs besides cyclophosphamide
Busulfan
Nitrosoureas
- Carmustine
- Lomustine
Cyclophosphamide SEs
What agent can reduce the major SE?
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
Leflunomide kinetics and SEs
Half life of 2 weeks, administered with a loading dose.
SEs: Potentially severe liver damage Rashes Alopecia Mild hypertension
Azathioprine Indications and SEs
Aza Rx: Transplants Inflammatory bowel disease SLE, RA Vasculitis
SEs:
Liver toxicity
Budd Chiari syndrome
Marrow suppression.
Mycophenolate indications and SEs
Mycophenolate Rx:
- 1st line for most transplant suppression
- GVHD
- SLE
- Psoriasis
- Myasthenia G.
SEs:
- Marrow suppression
- Hypertension
- GI upset
Cyclophosphamide indications
Autoimmune disease, SLE, RA
Organ transplant
Leukemias and Lymphomas.
Cyclosporine A indications and SEs
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
Cyclosporine kinetics
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.
Tacrolimus
Mechanism
Indication
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
Tacrolimus
Kinetics
SEs
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.
Sirolimus
MoA
Indications
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.
General transplant immunosuppression regimine
Tacrolimus, Corticosteroids, and Mycophenolate
Sirolimus may be added
Sirolimus
kinetics
SEs
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
List the mTOR inhibitors
Sirolimus
Everolimus
Temsirolimus
What drugs inhibit JAK signaling?
Tofacitinib
Baricitinib
Indications for JAK inhibitors
SEs
Rheumatoid arthritis, alone or with MTX.
SEs:
Hepatotoxicity, liver enzymes
Marrow suppression
Airway infections
Hyperlipidemia
