Sweaty has 2 many lectures: CA, BPH, overactive bladder Flashcards
anastrozole
aromatase inhibitor: REVERSIBLE (non-steroidal)
Tx: breast CA
exemestane
aromatase inhibitor: IRREVERSIBLE (steroid structure)
Tx: breast CA
letrozole
aromatase inhibitor: REVERSIBLE (non-steroidal)
Tx: breast CA
aromatase inhibitors
oral daily
block CYP19A1 mediated production of estrone and estradiol
Tx: ER+ breast CA in POST-menopausal (can’t use in pre-menopausal women: E comes from other mechanisms)
AE: post menopausal (hot flash, hair thinning), teratogen, arthralgia, diarrhea
raloxifene
monthly IM SERM ER agonist: bone ER antagonist: breast, uterus Tx: ER+ breast CA prevent: BRCA2 related breast CA
tamoxifen
daily PO SERM metabolized via CYP2D6 to more potent products: possible sub-optimal effect in poor metabolizers (no FDA requirement for testing) ER agonist: bone, uterus ER antagonist: breast Tx: ER+ breast CA prevent: BRCA2 related breast CA BBW: endometrial CA/hypertrophy, vaginal bleeding
toremifene
PO daily SERM (derivative of tamoxifen) CYP3A4 metabolism Tx: ER+ breast CA BBW: QT PROLONGATION lacks BBW of other SERM: but avoid with Hx of endometrial CA/hyperplasia and thromboembolic disease
fulvestrant
monthly IM
SERD: binds ER and prevents dimerization in the nucleus (pure antagonist)
Tx: ER+ breast CA
AE: post menopausal symptoms
SERM
selective estrogen receptor modifier
ER agonist MOA: recruits coactivators
ER antagonist MOA: recruits corepressors (HISTONE DEACETYLASE I stabilizes nucleosome and prevents mRNA production)
Tx: ER+ breast CA (more important in post menopause, but can use in pre)
prevent: BRCA2 breast CA (BRCA1 is ER-)
improves: lipid profile, increase bone mineralization
AE: teratogen, retinal degeneration
BBW: thromboembolic disease, stroke
goserelin
SC
GnRH agonist
Tx: breast CA, prostate CA
GnRH agonist in Tx of CA
use is CONTINUOUS: down regulates GnRH receptors causing fall of FSH and LH and therefore estrogen
FLARE UP of disease initially: bone pain (metastases), hypercalcemia, breast enlargement/tenderness
WEEKS to lower estrogen/androgen levels: use ANDROGEN RECEPTOR BLOCKERS until then
Tx: prostate CA, breast CA in PRE-menopausal women (not effective because ovaries aren’t working anyway)
AE: post-menopausal (including done density); decrease bone density, elevated lipids, weight gain, DM, CV risk, sexual dysfunction/ loss of libido, gynecomastia, injection site reaction
CI: PREGNANCY
pertuzumab
Her-2/neu Ab: blocks heterodimerization of HER2 with HER3/4 (EGFRs)
Tx: breast CA
AE: decreased left ventricular ejection fraction, neutropenia, leukopenia
trastuzumab
Her-2/neu Ab: binds juxtraglomerular region of extracellular domain of HER2
Tx: breast CA
AE: cardiac, renal, hepatic, pulmonary
BBW: cardiomyopathy, infusion rxn (respiratory)
ado-trastuzumab/ emtasine (T-DM1)
Her-2/neu Ab: binds receptor causing it to be internalized allowing linked chemo agent to act on microtubules
Tx: breast CA
BBW: HF/ventricular dysfunction, hepatic
her-2/neu mAb
IV
Tx: breast CA
AE: hypersensitivity (asthenia, faitugue, GI), blood dyscrasia, INFUSION RXN (dyspnea, hypotension, rash)
BBW: pregnancy
lapatinib
oral
TKI: inhibits HER1/2: binds INTRACELLULAR ErbB1/2 at ATP binding site preventing phosphorylation/activation of receptor
metabolism: CYP3A4/5
Tx: breast CA
AE: GI toxicity, hand-foot syndrome, rash, anemia/thrombocytopenia, QT PROLONGATION, LUNG (interstitial lung disease/pneumonitis)
BBW: CI in LIVER DISEASE (increase drug levels)
monitor: LFT
everolimus
mTOR inhibitor: bind FKBP-12 substrate/inhibit: CYP3A4, P-gp inhibits: CYP2D6 Tx: ER+ breast CA AE: blood dyscrasia, hyperglycemia/lipidemia, elevated creatinine, diarrhea/constipation monitor: blood glucose, CBC, LFTs, lipid-triglyceride-creatinine profiles BBW: INFECTION, NEOPLASIA (lymphoma/SCC) use with: EXEMESTANE
SERDs
selective estrogen receptor downregulator
Tx: ER+ breast CA (more important in post menopause, but can use in pre)
AE: post menopausal (hot flashes, asthenia, pain)
Why might the initial response to anti-estrogen treatment of breast CA not be sustained longterm?
SERM, SERD, aromatase inhibitors
CA finds alternative proliferation pathways
CYP3A4
tormifene
lapatinib (also 3A5)
everolimus
CYP2D6
tamoxien
everolimus
CYP19A1
aromatase inhibitors
What provides superior outcomes in postmenopausal women with breast CA compared to tamoxifen alone?
aromatase inhibitor for 5 years
or following tamoxifen up with aromatase inhibitors for 5 years total
P-gp
everolimus
How is triple neg. breast CA treated?
Sx (first for all breast CA)
drug therapy depends on tumor size, lymph involvement
adjuvant/neoadjuvant/metastatic: radiation, conventional chemo drugs
Besides determining drug choice for a patient, what is tumor genotyping used for?
determining prognosis: need for drug therapy after Sx?
good prognostic indicators: watch and wait
bad prognostic indicators: adjunctive therapy
standard adjuvant chemotherapy regimens for breast CA
ALL include cyclophosphamide and doxorubicin (with/out: taxol or fluorouracil)
exception: docetaxel and cyclophosphamide with or without doxorubicin
doxorubicin
anthracycline
MOA: intercalator, free radical generation, topo II inhibitor
Tx: triple neg. breast CA, ovarian CA, bladder CA
AE: CUMULATIVE CARDIOTOXICITY, secondary malignancy, myelosuppression, hepatic, extravasational necrosis
cyclophosphamide
Tx: triple neg. breast CA, ovarian CA
AE: renal, pulmonary fibrosis, secondary malignancy, blood dyscrasia
fluorouracil
Tx: triple neg. breast CA
Do PR+ tumors have a poor/good prognosis?
Why?
good
suppresses tumor invasion and metastasis by maintaining epithelial cell phenotype and impeding the EMT (epithelial-mesenchymal transition)
medroxyprogesterone
depo progestin
MOA: bind progestin receptors and block GnRH release
Tx: endometrial CA
AE: amenorrhea, edema, anorexia, weakness
megestrol
oral progestin
MOA: suppresses LH release, enhances estrogen degradation
Tx: endometrial CA
AE: weight gain, post menopausal, tumor flare, thrombophlebitis, thromboembolism, PE
docetaxel
taxol
Tx: triple neg. breast CA, prostate CA
carboplatin
platinum: less potent
Tx: ovarian CA, testicular CA
AE: MYELOSUPPRESSION: THROMBOCYTOPENIA, cumulative anemia, blood dyscrasia
cisplatin
MOA: platinum plus CCDP: ace on mitochondria to produce oxidative and reticular stress: cascade including pro-apoptotic BAK and BAX and VDAC; activates p53
platinum
Tx: ovarian CA, bladder CA, testicular CA
AE (actively pumped into these cells: OCT2): NEPHROTOXIC, OTOTOXIC, neuro
nephro: HYDRATE, AMIFOSTINE
oto: antioxidants
CDDP important for loss of activity
paclitaxel
taxol
Tx: ovarian CA, testicular CA
AE: MYELOSUPPRESSION
bacillus calmette-guerin (BCG)
intravesical instillation after TURBC
MOA: req. host immune response: binds urothelial cells and activates APCs to induce effector cells (CTLs, NKs, LAKs (lymphokine activated killer), BAKs (BCG activated killer) cells)
response in hours and lasts for days
Tx: bladder CA
mitomycin C
intravesical instillation
MOA: mono/bi-functional alkylating agent
Tx: bladder CA
AE: chemical CYSTITIS, contact DERMATITIS (PALMAR/PLANTAR ERYTHEMA); pancytopenia (if used IV), dyspnea/unproductive cough
thiotepa
intravescular instillation
MOA: polyfunctional alkylator with loss of aziridine (alkylator) moiety
small, lipophilic: easily penetrates urothelium: SYSTEMIC TOXICITY
Tx: bladder CA
AE: dysuria, urinary renetion, chemical/hemorrhagic CYSTITIS, RENAL dysfunction; pancytopenia (if used IV)
Tx of ovarian CA
- stage 1/2?
- stage 3/4?
- advanced?
- locally confined?
only conventional chemo (after Sx)
- stage 1/2: platinum drug with cyclophosphamide and/or doxorubicin
- stage 3/4: platinum drug with paclitaxel
- advanced: drugs given systemically
- local: option of intra-peritoneal instillation of cisplatin (1-2L, rotate side to side for coverage of peritoneal surface, then drained off)
Tx of bladder CA
- superficial disease
- with tumor progression
- trans-urethral resection of bladder CA (TURBC) followed by intravesical instillation (BCG, mitomycin, thiotepa)
- conventional chemo, csytectomy
platinum drugs
DNA intrastrand crosslinks: N7
AE: allergy, myelo-suppression
taxols
inhibits breakdown of microtubules
AE: PERIHPERAL NEUROPATHY, hypersensitivity
How can drugs for bladder CA given through intravesicular instillation become systemic?
trans-urethral resection of the bladder cancer can damage bladder integrity and containment of drugs
-phosphomides
MOA: alkylating agent: inter/intrastrand DNA crosslinks
prodrug: needs activation
AE: HEMORRHAGIC CYSTITIS
give MESNA
MESNA
use with CYCLOPHOSPHAMIDE and IFOSFOMIDE to protect against hemorrhagic cystitis
bicalutamide
androgen receptor blocker (some AGONIST activity): prostate greater than central
inhibitor: CYP3A4/2C9/19,2D6
enzalutamide
androgen receptor blocker: prostate and central
AE: MALE (and female) teratogen, CNS (seizure), URTI
flutamide
androgen receptor blocker: Prostate ONLY
AE: blood dyscrasia
BBW: HEPATOTOXICITY
Tx: hirsuitism, PCOS
nilutamide
androgen receptor blocker: prostate and central
NOT teratogenic
AE: HF/HTN, blood dyscrasia, increased time for light accommodation
BBW: LUNG
androgen receptor blocker
Tx: prostate CA
AE: TERATOGEN, HEPATOTOXICITY, GI, hot flash, aches
estramustine
Oral
targeted alkylator attached to estradiol (binds EMBP on prostate CA): inhibits microtubules, promotes dis-assembly and G2/M arrest: produces DNA strand breaks
Testosterone levels depressed due to neg. feedback on HP axis
Tx: prostate CA
AE: GI, gynecomastia, mastalgia, impotence; EDEMA, THROMBOEMBOLISM (increased CV risk due to elevated estradiol levels), elevated HEPATIC enzymes, hyperbilirubinemia
histrelin
SC
GnRH agonist
Tx: prostate CA
AE: seizure, suicide ideation
leuprolide
IM/SC
GnRH agonist
Tx: prostate CA
AE: MI/HF
triptorelin
IM
GnRH agonist
Tx: prostate CA
degarelix
SC
GnRH antagonist
Tx: prostate CA
AE: QT PROLONGATION, HEPATIC enzyme change; HTN, impotence, weight gain, hot sweats, injection site rxn
abiraterone
17-alpha reductase inhibitor (CYP17): reduce androgens by blocking pregnenolone to DHEA; progesterone to androstenedione
AE: hyper-mineralocorticoid: hypokalemia, HTN, edema (caution with pre-existing CV issues)
reduce AE: corticosteroid to suppress ACTH drive
Tx: prostate CA
other AE: HEPATIC, TERATOGEN
monitor: LFTs
sipuleucel-T
immunotherapy: stimulate T cells against PAP (prostatic acid phosphatase)
culture patient APCs with PAP: APCs take up antigens and product (T, B, NK cells) re-infused into patient
Tx: prostate CA
AE: infusion rxn (fever, chill, dyspnea, N/V), paresthesia, CITRATE TOXICITY
3B-hydroxysteroid dehydrogenase
converts dehydroepiandrostenedione to DHT
can lead to DHT mediated tumor activation
use of estrogen in prostate CA
Hx?
future?
Hx: systemic: bone protective, CV risk
future: transdermal: no CV effects
neg. feedback decreases GnRH and therefore T; ER-beta may be protective in prostate CA
carbataxel
taxol
poor P-gp substrate: decreased efflux
crosses BBB
conventional chemo for metastatic prostate CA
carbataxel, docetaxel: give corticosteroids with anti-histamines to preempt edema and injection rxns (contain surfactant)
palliative for severe pain: mitoxantrone plus prednisone
bleomycin
MOA: binds DNA in presence of iron with ferrous oxide to mediate DNA strand breaks
AE: PULMONARY, SKIN (rash, itch)
pulm fibrosis: injure lung epithelial cells and detected by Nalp3 inflammasome in macrophages: production of inflammatory mediators and ROS: IL-B to TGF-B
ifosfomide
-phosphomide
Tx: testicular CA
AE: MYELOSUPPRESSION, HEMORRHAGIC CYSTITIS, SEIZURES (neuro)
etoposide
MOA: stabilize DNA/ topo II complex: strand breaks
AE: LEUKOPENIA, hepatic, stomatitis, diarrhea
vinblastine
MOA: binds B-tubulin preventing microtubule formation
AE: PERIPHERAL NEUROPATHY
chemo for testicular CA
- primary
- second line or metastatic
- high dose
ALL: platinum agent
- cisplatin plus: etoposide with/out bleomycin or ifosfomide
- cisplatin plus: ifosfamide and microtubule drug (vinblastine or paclitaxel)
- paclitaxel/ifosfamide (can skip first step) followed by carboplatin/etoposide followed by peripheral stem cell infusion
CDDP resistance
decrease in cisplatin sensitivity by CA cells
CA cells can: lose binding to CDDP, repair damage done by it, impair transmission of signals for apoptosis, stimulate pro-survival signals that antagonize CDDP
amifostine
use with CISPLATIN to protect renal cells
What AE do most cytotoxic (conventional) chemo drugs produce?
blood dyscrasia
also: GI, alopecia
alpha 1 blockers
relaxation of sm. muscle in prostatic and penile urethra
metabolism: CYP
Tx: BPH
AE: xerostomia, nausea, CNS (dizzy, somnolence, insomnia, asthenia), floppy iris syndrome (adverse event can occur if have cataract Sx)
PDE-5 inhibitors
inhibits breakdown of cGMP by PDE-5
CYP metabolism
Tx: ED
AE: indigestion, flushing, resp. tract infection, headache, CV, LOSS of HEARING/SIGHT
CI: NITRATES, alpha blockers (hypotension), CYP drugs
5-alpha reductase inhibitors
inhibits enzyme that converts T to DHT
Tx: BPH, male pattern baldness
AE: do NOT get around pregnant women; gynecomastia, ejaculation/erectile dysfunction, decreased libido
decreases PSA (can interfere with prostate CA monitoring)
prazosin
short acting alpha 1 blocker
too short and too much variability from patient to patient for use in BPH
alfuzosin
alpha 1 blocker
NO CNS AE or ejaculatory dysfunction (not alpha-1a selective)
Tx: ED (off label)
terazosin
alpha 1 blocker
doxazosin
alpha 1 blocker
tamsulosin
partially selective alpha-1a blocker
silodosin
partially selective alpha-1a blocker
tadalafil
PDE-5 inhibitor
long T1/2
Tx: BPH and ED
finasteride
type 2 5 alpha reductase inhibitor: predominantly in urogenital tissue and genital skin
dutasteride
type 1 and 2: 5 alpha reductase inhibitor: urogenital tissue and genital skin AND skin, liver, bone
long binding time: slow reversal
metabolism: CYP3A4
beta sitosterol
SUPPLEMENT
Tx: BPH but does NOT reduce size of prostate
saw palmetto
SUPPLEMENT
not shown to be better than a placebo in BPH Tx
alpha-1a blockers
receptor predominates in prostate
Tx: BPH
alpha-1a receptor
- location?
- advantages?
- disadvantages?
- lower GU tract: including prostate, prostatic and penile urethra
- advantages: no need for dose titration (diminished effects on CV function)
- disadvantages: abnormal ejaculation (none, retrograde), block CNS transmitters
alpha-1d receptor
detrusor muscle of urinary bladder
pathway of vasodilation for cGMP
NOS produces NO which stimulates GC which increases levels of cGMP which activates PKG leading to efflux of Ca and smooth muscle relaxation
alprostadil
INTRAURETHRAL suppository, DIRECT INJECTIOn into CORPUS CAVERNOSUM: minimal systemization, rapid onset
PGE1: activates AC to increase cAMP to PKA: efflux of Ca from cell: sm. muscle relaxation
Tx: ED
AE: pain (penile, urethral, testicular), rare CV
avanafil
PDE-5 inhibitor
Tx: ED
sildenafil
PDE-5 inhibitor
Tx: ED
vardenafil
PDE-5 inhibitor
Tx: ED
AE: QT PROLONGATION with many drugs
methyltestosterone
improve response to PDE-5 inhibitors
Tx: ED
testosterone
improve response to PDE-5 inhibitors
Tx: ED
yohimbine
SUPPLEMENT (unregulated and often pharmaceutical strength rather than natural)
alpha 2 receptor inhibitor: blocke post synaptic adrenergic receptors and pre synaptic NANC (non-adrenergic, non-cholinergic) nerves: increases NO and sm. muscle relaxation
Tx: ED, promote weight loss, curb appetite
placebo effect causes part of the response
crosses BBB: anxiety, antidiuretic, dizzy, flush, HTN, irritable, restless, sinus tachy, tremor
MAOI action: TYRAMINE and CAFFEINE interactions
worsens: RENAL failure
anticholinergics
oral
Tx: overactive bladder
CYP interactions (hepatic metabolism)
AE: DRY MOUTH and eyes, mydriasis, tachycardia (monitor for prolonged QT), constipation, urinary retention, CNS (sedation, memory, slow cognition, confusion, sleep problems)
CI: close angle glaucoma, urinary/gastric obstruction, need for mental alertness, dementia
darifenacin
anticholinergic
long lasting
more selective for M3 (not clinically significant)
fesoterodine
anticholinergic
oxybutynin
anticholinergic: COMMON use
short lasting: have ER form
solifenacin
anticholinergic
long lasting
tolterodine
anticholinergic: COMMON use
short lasting: have ER form
trospium
anticholinergic
long acting
quaternary amine: does not cross BBB: fewer CNS effects
NO hepatic metabolism: NO CYP interactions
botulinum toxin
MOA: inhibits vesicle release of excitatory NT, inhibits axonal expression of SNARE complex dependent proteins in (sub)urothelium mediating intrinsic or spinal reflexes thought to cause detrusor overactivity; inhibition of expression of purinergic and SP receptors on suburothelial myofibroblasts
injection into urothelial wall
lasts months
Tx: overactive bladder in patients that are unresponsive to anticholinergics or patients that respond to anticholinergics but can’t tolerate side effects (works better in the latter set of patients)
sympathomimetics
Tx: overactive bladder
AE: HTN, tachycardia
mirabegron
sympathomimetic
B3 agonist
CYP metabolism
LONG half life
pseudophedrine
sympathomimetic (off label)
direct and indirect alpha/beta agonist: alpha greater than B
AE: tachyarrhythmia, A-fib, insominia, anxiety
ephedra, Ma Huang
sympathomimetic (off label)
indirect non-selective alpha and beta agonist
AE: tachyarrhythmia, CHF/MI, insomnia, CNS stimulation
methionine
creates ammonia free urine by acidifying urine pH
Tx: controls ODOR, dermatitis, ulceration in overactive bladder
take with FOOD/MILK/LIQUIDS
AE: drowsy, N/V
bovine collagen implant
injection into submucosa of urethra or bladder neck: increase fibers around urethral lumen
Tx: overactive bladder for those with INTRINSIC SPHINCTER DYSFUNCTION
for patients failing other therapies for more than a year
AE: urinary retention, hematuria, injection site rxn, worsening incontinence, erythema, abscess, urticaria
interactions with: immunosuppression, corticosteroids
bethanechol
MOA: muscarinic agonist
Tx: urinary retention
AE: secretions (diarrhea, tears, urinate), lightheaded/syncope, dizzy, miosis
neostigmine
MOA: AChE inhibitor
Tx: urinary retention
AE: hypotension/syncope, cardiac arrest/dysrhythmia, AV block, brady-arrhythmia, tachycardia
methylnaltrexone
Tx: opiate induced urine retention
naloxone
Tx: opiate induced urine retention
receptors on detrusor and their actions
- SNS (hypogastric n.) release NE: adrenergic: B3; relax detrusor
- PNS (pelvic n.) release Ach : muscarinic: M3; contract detrusor
- PNS nerves release ATP: contracts detrusor
receptors on sphincter and their actions
- SNS (hypogastric n.): release NE adrenergic: alpha 1; contract sphincter
- somatic (pudendal n.) release Ach: nicotinic (NOT muscarinic); contract sphincter
- PNS nerves release NO: relaxes urethral smooth muscle
What can you use to treat retention?
cholinergic agonist
opiate antagonist
What can you use to treat stress/urge incontinence?
anticholinergic
sympathomimetics
neural circuits controlling urine storage
low level vesicle afferent firing
- spinal reflex pathway
- pontine storage center in rostral pons
pontine micturition center
intense bladder afferent firing: possibly passes through the periaqueductal grey to reach pontine micturition center
- spinobulbospinal reflex pathway
- pontine mincturition center
urge incontinence
detrusor overactivity
Sx: urgency, frequency
Tx: anticholinergics: oxybutynin, tolterodine
stress incontinence
outlet incompetence
Sx: minimal urine loss with coughing, sneezing, running, laughing
Tx: topical estrogen, alpha-agonist
mixed incontinence
Sx of urge and/or stress and/or overflow incontinence
Tx: focus on predominant Sx
atonic bladder incontinence
Sx: complete loss of bladder control
Tx: catheterization
functional incontinence
Sx: vary accourding to external cause (ex: can’t get to restroom, change in mental status, UTI, meds)
Tx: eliminate cause
opiates
mu and delta receptors inhibit PNS outflow and therefore detrusor activation
AE: urinary retention
Tx: opiate antagonist (also reverses analgesia), cholinergic agonist
