MOA Flashcards
Prostaglandin E1 (alprostadil)
Vasodilation
Sildenafil
Viagra
PDE5 inactivates cGMP so viagara blocks this to maintain relaxation and penile erection
Anti-ED drugs
relaxation of smooth muscle in corpora cavernosa
Calcium
↑ in Ca2+ absoprtion →
↑ bone deposition
and
↓ PTH release
Vitamin D
↑ in Vit D →
↑ Ca2+ absorption in GI tract →
↑ bone deposition and
↓ PTH release
“Teriparatide
(hPTH 1-34)”
↑ osteoblasts and osteoclasts number
and
Indirectly ↓ osteoclast activation by ↑ RANKL and ↓ OPG
Calcimimetic
Binds to Ca2+ sensitizing receptors →
↑ sensitivity of receptor to Ca2+ →
↓ PTH production and release
Raloxifen
↓ Osteoclast number
and
↓ osteoclast activation by RANKL
Biphosphonates
Incorporated into bone and comes out w/ osteoclast activity → becomes incorporated in osteoclasts→
apoptosis of osteoclasts→
↓ Osteoclast number
Denosumab
Binds to RANKL and ↓ RANKL - RANK interaction →
↓ osteoclast activation→
↓ osteoclast #
Salmon Calcitonin
↓ plasma Ca2+ levels → ↓ Ca reabsorption in kidney and ↓Ca2+ abs in GI tract and ↑ Ca2+ deposition in bone
Cortisol/Glucocorticoids
Binds glucocorticoid receptor (GR)→ dimerizes → goes to nucleus → dimers bind to GRE → transcriptional repression
Suppress T-and B-cell transcription of pro- inflammatory mediator genes and cytokine genes (TNF- a, IL-2)
Suppress inflammatory immune cell (monocytes, macrophages) production of prostaglandins and thromboxane A2 by:
Up-regulating lipocortin gene transcription → Lipocortin protein inhibits PLA2 → preventing arachidonic acid mobilization
Down-regulating COX-2 transcription
Cytotixic Antimetabolites
Inhibit clonal expansion of lymphocyte population
Azathioprine
Azathioprine taken up in liver → cleaver → converted non- enzymatically to 6-MP (a purine analog) → converted to Thio-dGTP by de novo purine synthesis pathway.
Thio-dGTP incorporated into DNA of replicating immune cells→DNA breaks → suppression of T- and B-cell proliferation
Mycophenolate Mofetil
More selective in suppressing B and T cells (less SE)
Prodrug hydrolyzed to mycophenolate (active form)→ taken up by de novo purine pthwy→ inhibits IMP dehydrogenase (IMPDH) in B- and T- cells → decrease purine biosynthesis → Ab formation by B-cells is inhibited and cellular adhesion and migration is inhibited
Cyclosporine
Calcineurin inhibitor
Binds to cyclophilin to inhibit calcineurin → inactive NFAT and ↓ IL-2 gene transcription in T-cells
Tacrolimus
Calcineurin inhbitor
Binds to FKBP-12 to inhibit calcineurin → inactive NFAT and ↓ IL-2 gene transcription in T-cells
Sirolimus
Binds to FKBP-12 to inhibit mTOR → ↓ translation of proteins needed for proliferation of T- cells
Abatacept
Fusion protein that neutralizes the co- stimulatory ligand CD80/86 on antigen presenting cells → thus preventing T-cell activation → T-cell hyporesponsiveness → apoptosis
(Anergy)
Adalimumab
Humira
Human monoclonal Ab that neutralizes TNF-alpha → ↓ regulation of macrophage and T-cell fn
Etanercept
Enbrel
Fusion protein (fusion of TNF receptor and Fc domain of IgG) that neutralizes TNF-alpha by binding to it and preventing its interaction w/ cellular receptor
Infliximab
Remicade
Chimeric human/mouse monoclonal antibody that neutralizes TNF-alpha → ↓ regulartion of T cell and macrophage fn
Rituximab
Humanized monoclonal Ab against CD20 on the surface of B-cells → depletes →CD20 + B cells
Tocilizumab
Humanized monoclonal antibody that neutralizes IL-6 receptor on immune cells → blocks activation of JAK-STAT pthwy → prevents transcription of proinflammatory proteins
ALKYLATING AGENTS
CCNS drugs
Greatest anti-ca activity in S phase
Bi-functional
Alkylates guanine
residues → produces
interstrand crosslinks
Guanine has abnrml base-pairing w/ thymine during replication → protein miscoding and apoptosis
ANTI-METABOLITES
CCS drugs (active in S-phase of cell cycle)
Structurally similar to endogenous molecules → act as antagonists of biosynthetic pthwys
Ca cells are more sensitive than nrml cells bc of high growth fraction and higher levels of certain enzymes
Methotrexate
CCS
Folic acid
analog
Binds to and inhibits DHFR → prevents formation of THF from folate → prevents thymidylate, purine & amino acid synthesis→ interruption of DNA, RNA and protein syntheses
5-Fluorouracil
CCS
Analog of uracil
Prodrug → converted to 5FdUMP,
which inhibits TS activity which is required for de novo pyrimidine synthesis → slows ca cell replication and causes DNA damage
6-Mercaptopurine
CCS
HGPRT metabolizes 6 mercap into TIMP →
converted to Thio-dGTP
Thio-dGTP is incorporated
into DNA of replicating
cancer cells→ leading to
apoptosis
Vinca Alkaloids (Vinblastine and Vincristine)
Binds to β-tubulin→
prevents
polymerization of
microtubules → causes blocking of mitotic spindle formation → tumor cell death
Paclitaxel
CCS
Binds with high
affinity to β-tubulin and
stabilizes microtubules
(prevents depolymerization)→ cells blocked at G2/M phase
Etoposide
CCS
Inhibits
topoisomerase II → prevents DNA uncoiling → DNA strand breakage
Irinotecan
CCS
(CCNS at higher
concentration)
Inhibits topoisomerase I → prevents uncoiling → DNA strand breakage
Doxorubicin
CCNS
DNA intercalation that
interferes with DNA &
RNA synthesis
Inhibits topoisomerase II→ DNA fragmentation
Free radical formation
→ DNA scission (responsible for cardiotox)
Bleomycin
CCS
Intercalation, scission and fragmentation of DNA due to oxidation by a DNAbleomycin-Fe(II) complex
Allopurinol
Purine analog
Inhibits XO → prevent uric acid production
