MOA Flashcards
Thioamides- PTU and MMI
Prevent hormone synthesis by inhibiting TPO-catalyzed rxns to block iodide organification
Block coupling of iodotyrosines
Drug binds to and inactivates TPO
Slow onset (takes 4- wks to deplete), excreted in urine
Anion Inhibitors- ClO4- and TeO4-
Compete with sodium ion transporter for uptake
Iodide
Inhibit organification and hormone release and ↓ size of hyper plastic gland
Effect reverses with time (escape) if used alone
Radioactive Iodine
I131
Taken orally → rapidly
concentrated in thyroid follicle cells, where
β particles selectively destroy gland w/o injury to adjacent cells →
become euthyroid in 6-8 wks
Biguanides
Enhances effects of insulin “sensitizer”
Activates AMP-dependent protein kinase (AMPK) causing ↑ glucose uptake by fat and muscle and ↓ production by liver
Sulfonylureas
↑ Insulin release from pancreas beta cells by binding to K+ channel (requires functional beta cells)
Mimic Glucose to Close ATP-sensitive K+ Channels and Stimulate Insulin Secretion
Non-Sulfonylurea Secretagogues (Meglitinides)
Mimic glucose to close K+ ch and stim insulin secretion
↑ Insulin release from pancreas beta cells by bindi to beta K+ cells (require fn beta cells)
Thiazolidenediones (TZDs)
↑ Insulin sensitivity in target tissues by activating receptor gamma (PPAR-gamma) liganda
GLP-1 Receptor Agonists
↑ glucose-dependent insulin secretion
Dipeptidyl Peptidase-4 (DPP-4) Inhibitors
Prolong endogenous GLP-1 action
↑ glucose-mediated insulin secretion
α-Glucosidase Inhibitors
Stays in intestine and ↓ GI glucose absorption
↓ Postprandial glycemia (must be taken with meal)
Canagliflozin
Glucose co-transporter inhibitor
Inhibition of SGLT-2 → suppresses renal glucose re-absorption → lowers blood glucose
Estrogen/progestin combo pill
Hypothal
↓ GnRH pulses (P) → no LH surge
Pituitaty
↓ responsiveness to GnRH (combo)
↓FSH/LH release (E) → ↓ follicular devel
Other
thickening of cervical mucus (P) → ↓ sperm penetration
Atrophic endometrium ( P) to implantation
↓ transport of sperm/egg through fallopian tub (combo)
Overall blocks ovulation, atrophies endometrium, thick cervical mucus, altered traans in fallopian tube
Ulipristal
Selective
Delays ovulation
Alters cervical mucus and endometrium
Mifepristone
RU486
Competitive antagonist
Blocks uterine progesterone receptors → decidual breakdown → blastocyst detachment (↓hCG)
↑ sensitivity of myometrium to PG → contractile, softens cervix
Generally how do combo estrogen/progestins work?
by suppressing follicle development, thickening cervical mucus, and inhibiting ovulation
Copper IUD
reduces sperm motility and viability
LNG-IUD
inhibits ovulation, thickens cervical mucus, reduces sperm motility and viability
Hormonal EC
acts by delaying ovulation and may also interfere with sperm migration and fn at all levels of genital tract
Tamoxifen
Metabolized by CYP2D6 to active metabolites endoxifen and 4- hydroxyTAM that bind to ER-alpha, acting as antagonists in breast tissue to inhibit gene transcription, inhibit cell proliferation and promote apoptosis
Acts as a partial agonist in endometrium to promote endometrial hyperplasia
Toremifene
Active antagonist at ER-alpha/beta
Does NOT require activation by CYP2D6
Insufficient clinical data at this time, but may act as partial agonist in endometrium to promote endometrial cancer
Leuprolide
Disrupts normal pulsatile stimulation of GnRH receptor by endogenous GnRH
→ desensitization of GnRH receptor in the pituitary→ ↓ release of FSH and LH from the pituitary→ ↓ estrogen synthesis in the ovaries
Anastrozole
Reversible inhibitor
Prevent conversion of testosterone to estrogen by inhibiting aromatase (CYP19A1) in adipose tissue
Exemestane
Suicide inhibitor
Prevent conversion of testosterone to estrogen by inhibiting aromatase (CYP19A1) in adipose tissue
Trastuzumab
“Armed” monoclonal Ab that has been coupled with DM1 (emtansine)
Ab binds to HER2 extracellular domain IV → Ab is internalized into lysosomal stores → DM1 is released
DM1 is a mitotic spindle poison, binds beta-tubulin to inhibit microtubule polymerization
Pertuzumab
Monoclonal Ab binds HER2 extracellular domain II to prevent ligand-dependent dimerization with EGFR
ALKYLATING AGENTS (Cyclophosphamide and Cisplatin)
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
ANTIBIOTICS
Insert btwn base pairs of DNA → Δ DNA configuration → strand breakage/ enzyme interference
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
Inhibits XO → prevent uric acid production
