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1

anastrozole

aromatase inhibitor: REVERSIBLE (non-steroidal)
Tx: breast CA

2

exemestane

aromatase inhibitor: IRREVERSIBLE (steroid structure)
Tx: breast CA

3

letrozole

aromatase inhibitor: REVERSIBLE (non-steroidal)
Tx: breast CA

4

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

5

raloxifene

monthly IM
SERM
ER agonist: bone
ER antagonist: breast, uterus
Tx: ER+ breast CA
prevent: BRCA2 related breast CA

6

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

7

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

8

fulvestrant

monthly IM
SERD: binds ER and prevents dimerization in the nucleus (pure antagonist)
Tx: ER+ breast CA
AE: post menopausal symptoms

9

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

10

goserelin

SC
GnRH agonist
Tx: breast CA, prostate CA

11

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

12

pertuzumab

Her-2/neu Ab: blocks heterodimerization of HER2 with HER3/4 (EGFRs)
Tx: breast CA
AE: decreased left ventricular ejection fraction, neutropenia, leukopenia

13

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)

14

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

15

her-2/neu mAb

IV
Tx: breast CA
AE: hypersensitivity (asthenia, faitugue, GI), blood dyscrasia, INFUSION RXN (dyspnea, hypotension, rash)
BBW: pregnancy

16

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

17

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

18

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)

19

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

20

CYP3A4

tormifene
lapatinib (also 3A5)
everolimus

21

CYP2D6

tamoxien
everolimus

22

CYP19A1

aromatase inhibitors

23

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

24

P-gp

everolimus

25

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

26

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

27

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

28

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

29

cyclophosphamide

Tx: triple neg. breast CA, ovarian CA
AE: renal, pulmonary fibrosis, secondary malignancy, blood dyscrasia

30

fluorouracil

Tx: triple neg. breast CA

31

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)

32

medroxyprogesterone

depo progestin
MOA: bind progestin receptors and block GnRH release
Tx: endometrial CA
AE: amenorrhea, edema, anorexia, weakness

33

megestrol

oral progestin
MOA: suppresses LH release, enhances estrogen degradation
Tx: endometrial CA
AE: weight gain, post menopausal, tumor flare, thrombophlebitis, thromboembolism, PE

34

docetaxel

taxol
Tx: triple neg. breast CA, prostate CA

35

carboplatin

platinum: less potent
Tx: ovarian CA, testicular CA
AE: MYELOSUPPRESSION: THROMBOCYTOPENIA, cumulative anemia, blood dyscrasia

36

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

37

paclitaxel

taxol
Tx: ovarian CA, testicular CA
AE: MYELOSUPPRESSION

38

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

39

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

40

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)

41

Tx of ovarian CA
1. stage 1/2?
2. stage 3/4?
3. advanced?
4. locally confined?

only conventional chemo (after Sx)
1. stage 1/2: platinum drug with cyclophosphamide and/or doxorubicin
2. stage 3/4: platinum drug with paclitaxel
3. advanced: drugs given systemically
4. local: option of intra-peritoneal instillation of cisplatin (1-2L, rotate side to side for coverage of peritoneal surface, then drained off)

42

Tx of bladder CA
1. superficial disease
2. with tumor progression

1. trans-urethral resection of bladder CA (TURBC) followed by intravesical instillation (BCG, mitomycin, thiotepa)
2. conventional chemo, csytectomy

43

platinum drugs

DNA intrastrand crosslinks: N7
AE: allergy, myelo-suppression

44

taxols

inhibits breakdown of microtubules
AE: PERIHPERAL NEUROPATHY, hypersensitivity

45

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

46

-phosphomides

MOA: alkylating agent: inter/intrastrand DNA crosslinks
prodrug: needs activation
AE: HEMORRHAGIC CYSTITIS
give MESNA

47

MESNA

use with CYCLOPHOSPHAMIDE and IFOSFOMIDE to protect against hemorrhagic cystitis

48

bicalutamide

androgen receptor blocker (some AGONIST activity): prostate greater than central
inhibitor: CYP3A4/2C9/19,2D6

49

enzalutamide

androgen receptor blocker: prostate and central
AE: MALE (and female) teratogen, CNS (seizure), URTI

50

flutamide

androgen receptor blocker: Prostate ONLY
AE: blood dyscrasia
BBW: HEPATOTOXICITY
Tx: hirsuitism, PCOS

51

nilutamide

androgen receptor blocker: prostate and central
NOT teratogenic
AE: HF/HTN, blood dyscrasia, increased time for light accommodation
BBW: LUNG

52

androgen receptor blocker

Tx: prostate CA
AE: TERATOGEN, HEPATOTOXICITY, GI, hot flash, aches

53

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

54

histrelin

SC
GnRH agonist
Tx: prostate CA
AE: seizure, suicide ideation

55

leuprolide

IM/SC
GnRH agonist
Tx: prostate CA
AE: MI/HF

56

triptorelin

IM
GnRH agonist
Tx: prostate CA

57

degarelix

SC
GnRH antagonist
Tx: prostate CA
AE: QT PROLONGATION, HEPATIC enzyme change; HTN, impotence, weight gain, hot sweats, injection site rxn

58

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

59

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

60

3B-hydroxysteroid dehydrogenase

converts dehydroepiandrostenedione to DHT
can lead to DHT mediated tumor activation

61

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

62

carbataxel

taxol
poor P-gp substrate: decreased efflux
crosses BBB

63

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

64

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

65

ifosfomide

-phosphomide
Tx: testicular CA
AE: MYELOSUPPRESSION, HEMORRHAGIC CYSTITIS, SEIZURES (neuro)

66

etoposide

MOA: stabilize DNA/ topo II complex: strand breaks
AE: LEUKOPENIA, hepatic, stomatitis, diarrhea

67

vinblastine

MOA: binds B-tubulin preventing microtubule formation
AE: PERIPHERAL NEUROPATHY

68

chemo for testicular CA
1. primary
2. second line or metastatic
3. high dose

ALL: platinum agent
1. cisplatin plus: etoposide with/out bleomycin or ifosfomide
2. cisplatin plus: ifosfamide and microtubule drug (vinblastine or paclitaxel)
3. paclitaxel/ifosfamide (can skip first step) followed by carboplatin/etoposide followed by peripheral stem cell infusion

69

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

70

amifostine

use with CISPLATIN to protect renal cells

71

What AE do most cytotoxic (conventional) chemo drugs produce?

blood dyscrasia
also: GI, alopecia

72

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)

73

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

74

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)

75

prazosin

short acting alpha 1 blocker
too short and too much variability from patient to patient for use in BPH

76

alfuzosin

alpha 1 blocker
NO CNS AE or ejaculatory dysfunction (not alpha-1a selective)
Tx: ED (off label)

77

terazosin

alpha 1 blocker

78

doxazosin

alpha 1 blocker

79

tamsulosin

partially selective alpha-1a blocker

80

silodosin

partially selective alpha-1a blocker

81

tadalafil

PDE-5 inhibitor
long T1/2
Tx: BPH and ED

82

finasteride

type 2 5 alpha reductase inhibitor: predominantly in urogenital tissue and genital skin

83

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

84

beta sitosterol

SUPPLEMENT
Tx: BPH but does NOT reduce size of prostate

85

saw palmetto

SUPPLEMENT
not shown to be better than a placebo in BPH Tx

86

alpha-1a blockers

receptor predominates in prostate
Tx: BPH

87

alpha-1a receptor
1. location?
2. advantages?
3. disadvantages?

1. lower GU tract: including prostate, prostatic and penile urethra
2. advantages: no need for dose titration (diminished effects on CV function)
3. disadvantages: abnormal ejaculation (none, retrograde), block CNS transmitters

88

alpha-1d receptor

detrusor muscle of urinary bladder

89

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

90

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

91

avanafil

PDE-5 inhibitor
Tx: ED

92

sildenafil

PDE-5 inhibitor
Tx: ED

93

vardenafil

PDE-5 inhibitor
Tx: ED
AE: QT PROLONGATION with many drugs

94

methyltestosterone

improve response to PDE-5 inhibitors
Tx: ED

95

testosterone

improve response to PDE-5 inhibitors
Tx: ED

96

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

97

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

98

darifenacin

anticholinergic
long lasting
more selective for M3 (not clinically significant)

99

fesoterodine

anticholinergic

100

oxybutynin

anticholinergic: COMMON use
short lasting: have ER form

101

solifenacin

anticholinergic
long lasting

102

tolterodine

anticholinergic: COMMON use
short lasting: have ER form

103

trospium

anticholinergic
long acting
quaternary amine: does not cross BBB: fewer CNS effects
NO hepatic metabolism: NO CYP interactions

104

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)

105

sympathomimetics

Tx: overactive bladder
AE: HTN, tachycardia

106

mirabegron

sympathomimetic
B3 agonist
CYP metabolism
LONG half life

107

pseudophedrine

sympathomimetic (off label)
direct and indirect alpha/beta agonist: alpha greater than B
AE: tachyarrhythmia, A-fib, insominia, anxiety

108

ephedra, Ma Huang

sympathomimetic (off label)
indirect non-selective alpha and beta agonist
AE: tachyarrhythmia, CHF/MI, insomnia, CNS stimulation

109

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

110

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

111

bethanechol

MOA: muscarinic agonist
Tx: urinary retention
AE: secretions (diarrhea, tears, urinate), lightheaded/syncope, dizzy, miosis

112

neostigmine

MOA: AChE inhibitor
Tx: urinary retention
AE: hypotension/syncope, cardiac arrest/dysrhythmia, AV block, brady-arrhythmia, tachycardia

113

methylnaltrexone

Tx: opiate induced urine retention

114

naloxone

Tx: opiate induced urine retention

115

receptors on detrusor and their actions

1. SNS (hypogastric n.) release NE: adrenergic: B3; relax detrusor
2. PNS (pelvic n.) release Ach : muscarinic: M3; contract detrusor
3. PNS nerves release ATP: contracts detrusor

116

receptors on sphincter and their actions

1. SNS (hypogastric n.): release NE adrenergic: alpha 1; contract sphincter
2. somatic (pudendal n.) release Ach: nicotinic (NOT muscarinic); contract sphincter
3. PNS nerves release NO: relaxes urethral smooth muscle

117

What can you use to treat retention?

cholinergic agonist
opiate antagonist

118

What can you use to treat stress/urge incontinence?

anticholinergic
sympathomimetics

119

neural circuits controlling urine storage

low level vesicle afferent firing
1. spinal reflex pathway
2. pontine storage center in rostral pons

120

pontine micturition center

intense bladder afferent firing: possibly passes through the periaqueductal grey to reach pontine micturition center
1. spinobulbospinal reflex pathway
2. pontine mincturition center

121

urge incontinence

detrusor overactivity
Sx: urgency, frequency
Tx: anticholinergics: oxybutynin, tolterodine

122

stress incontinence

outlet incompetence
Sx: minimal urine loss with coughing, sneezing, running, laughing
Tx: topical estrogen, alpha-agonist

123

mixed incontinence

Sx of urge and/or stress and/or overflow incontinence
Tx: focus on predominant Sx

124

atonic bladder incontinence

Sx: complete loss of bladder control
Tx: catheterization

125

functional incontinence

Sx: vary accourding to external cause (ex: can't get to restroom, change in mental status, UTI, meds)
Tx: eliminate cause

126

opiates

mu and delta receptors inhibit PNS outflow and therefore detrusor activation
AE: urinary retention
Tx: opiate antagonist (also reverses analgesia), cholinergic agonist