Prostate Cancer, Benign Prostatic Hyperplasia, ED Flashcards
Ultimate goals of therapy for BPH?
- relax smooth muscle of prostate (ex a1 blockade)
- decrease stromal tissue/hyperplasia (ex 5 alpha reductase inhibitors)
- relax prostate vasculature (PDE-5 inhibitors – used in pulmonary HTN as well)
Predominate alpha receptor in prostate? main idea of alpha receptor blockade?
a-1a (and to a lesser extent a-1d) -
- a-1a = lower GI tract
- a-1d = internal sphincter of bladder?
**inhibition = prostatic/penile urethral muscle relaxation –> allows urination
- Zosins (prazosin, alfuzosin, terazosin, doxazosin, tamsulosin, silodosin)
- – MOA, Metabolism, administration, AEs, special things?
MOA: Alpha 1 Blockers
Metabolism: CYP – significant drug-drug interaction
Administration: Oral
AEs: GI (xerostomia, nausea), CNS (dizziness, somnolence, asthenia, HA, insomnia)
**Generally LONG T1/2, EXCEPT PRAZOSIN (only 2-4 hrs)
**
Advantage and disadvantage of a-1a specific agents?
** recommended, “superior” alpha blocker? why?
Advantage: no dose titration needed
Disadvantage: retrograde anejaculation, block dopamine/CNS transmitters
**ALFUZOSIN - achieves clinically significant improvements w/out dizziness/asthenia or ejaculatory dysfunction
Which BPH therapy would you need to ask about before Cataract surgery?
– possible AE of flaccid iris in response to intraoperative irrigation + potential for prolapse of iris toward incision
** no apparent benefit to stopping a1 blocker prior to sx!
PDE-5 inhibitor MOA
inhibit cGMP breakdown –> prolonged Ca efflux / smooth muscle relaxation / vasodilation –> erection
(Normally: NOS produces NO –> stimulates guanyl cyclase –> cGMP produced –> Ca efflux –> etc.)
Tadalafil
MOA: PDE-5 inhibitor
**Longer duration = used for BPH (t1/2 = 2-4 hr)
AEs: generally well tolerated… HA, nausea, URI possible… really rare non-arteritic ischemic optic neuropathy / retinal artery occlusion / hearing loss
Contraindication: w/ NITRATES! (^hypoTN), also exacerbated by alcohol
Metabolism: cyp3A4
5 alpha Reductase, and MOA of inhibitors
5aR-ase = T –> DHT
type I = non - genital (skin, liver, bone)
type II = UG tract
MOA: xDHT –> dec prostate proliferation/hyperplasia –> urinary evacuation
Finasteride, Dutasteride: MOAs, AEs,
5 alpha Reductase Inhibitors
Finasteride = type 2 specific
Dutasteride = type 1 and 2 (non specific) – long binding time/slow removal + Cyp3A4 metabolism
AEs: category X TERATOGEN! but not carried in semen
erectile dysfunction / dec libido / gynecomastia
decrease PSA levels (can’t use as prostate ca monitor)
Possible increased rate of prostate cancer
Beta-Sitosterol
Saw Palmetto
“Natural” products for BPH relief
B-sistosterol = symptomatic relief, but does not shrink prostate
Saw Palmetto = no found benefit
Alprostadil: MOA and administration
MOA: PGE1 mimic = activates adenylate cyclase –> inc Ca efflux –> relaxes smooth muscle
administration: intraurethral suppository or direct injection into corpus cavernosum
* *Minimal systemization + rapid onset (minutes) + durable effect (1/2-several hours)
Avanafil, Sildenafil, Vardenafil, (tadafil)
MOA: PDE-5 inhibitors (prolong cGMP)
AEs: HA…some have indigestion, etc.
rare – non-arteritic ischemic optic neuropathy / hearing loss
Contraindications: DON’T USE W/ NITRATES, or alpha-blockers, drugs interacting with CYP
*Veradenafil – interaction w/ 70+ drugs = inc risk QT prolongation
Metabolism: hepatic (cyp3A4)
Testosterone replacement for erectile dysfunction?
– 65% will benefit – levels are variable for erectile dysfunction symptoms though
– may improve PDE5 inhibitor response
Yohimbine: MOAs, AEs, Contraindication
MOA: 2 mechs! –> overall = relaxes penile smooth m.
1) alpha 2 agonist –> decreases intracellular Ca
2) NANC presynaptic inhibition –> inc NO –> guanylate cyclase/cGMP activation
*NANC = non adronergic, non cholineric nerve
AEs: crosses BBB easily –> potential anxiety, antidiuresis, dizziness, flushing, HA, HTN…
Contraindication: Renal fail – worsens
Drug induced ED
280+ drugs have ED listed as adverse effect! mechanism often unknown…don’t forget about it
Caution with “natural” ED remedies?
Many have PDE-5 inhibitor action (inc cGMP) – careful of synergistic BP effects with NO!!
How does GnRH agonism and antagonism block FSH/LH secretion? What’s the difference in their effects, especially initially?
Antagonists –> decrease GnRH action –> dec FSH/LH
Agonists –> INITIAL FLARE of FSH/LH /Dz –> eventual decrease in GnRH receptors / negative feedback –> dec FSH/LH
What is a “super androgen receptor”?
– AR amplification, a point mutation or a change in the coregulators of A receptors –> increases responsiveness / receptors respond at a lower [androgen]
Goserelin, Histrelin, Leuprolide, Triptorelin: MOA, time til effect, AEs
MOA: GnRH agonists
— initial surge, but then 2-4 weeks until hypoandrogenic state/therapy
AEs:
- dec bone mineral density (dec estrogen), elevated serum lipids, weight gain, DM –> increase risk of CV disease
- dec androgens = dec libido, gynecomastia, sexual dysfunction,
- Cat X TERATOGEN
- injection site reaction
Degarelix
MOA: reversible GnRH receptor antagonist –> reduces FSH/LH –> castrates testosterone w/in 3 days
Administration: SC injection
AEs: Hot sweats, weight gain, HTN, arthralgia, chills, fatigue, inc LFTs, QT prolongation, impotence
Estramustine: MOA, AEs
MOA: conjugated drug estradiol structure binds to EMBP on prostate cancer –> delivers alkylator –> microtubule inhibitor
+
Dec testosterone levels due to estradiol negative feedback
AEs: GI upset, elevated LFTs, hyperbilirubinemia
“estrogen therapy” like AEs w/ prolonged tx = gynecomastic/mastalgia, impotence, edema, MI, PE, Stroke
Bicalutamide, Enzalutamide, Flutamide, Nilutamide
Androgen receptor blockers –>
Bic-, Enz-, Nil-utamide = CENTRAL and prostate receptors
Flutamide = only prostate receptors
AEs: HTN (nilutamide), blood dyscrasias, CNS changes, GI tox,
Androgen receptor blocker used in PCOS?
Flutamide
- *Bic, Enz, and Flutamide = Teratogens
- *
Which androgen receptor blocker is a: male teratogen? causes respiratory insufficiency? has a BBW for interstitial pneumonitis?
Enzalutamide = male teratogen
Nilutamide = respiratory insufficiency
Flutamide = Interstitial pneumonitis BBW
which androgen receptor blocker may cause increased time to accommodate transition from light to dark and may cause respiratory insufficiency?
Nilutamide
SipuLEUCel - T
MOA: Uses pt’s APCs to create T cell response (autologous cellular immunotherapy designed to stimulate T cell immunity against Prostatic acid Phosphate)
AEs: infusion rxn, paresthesias, citrate toxicity
Abiraterone
MOA: 17-hydroxylase/Cyp17 inhibitor –> dec GC and Androgen production @ adrenal cortex, but increased MCs
*MUST ADMINISTER GCs!
AEs: Hepatic dysfunction (get LFTs), teratogenic (women should not handle drug / condoms must be used during pregnancy)
Ketoconazole vs. 17-alpha-hydroxylase inhibitor (Cyp17 inhib)
– Ketoconazole = less specific –> produces hypoaldosterone, hypocortisol, hypoandrogenic state
– 17-alpha-hydroxylase inhib –> HYPERmineralocorticoid, hypocortisol, hypoandrogenic state
Could you use finasteride and dutasteride as prophylaxis for prostate cancer prevention?
(5 alpha reductase inhibitors)
Not recommended – thought was that it would decrease DHT levels –> dec cancer development
Estrogen therapy in prostate cancer
– estrogen works as negative feed back at H-P axis
– also has osteo-protective effects
– AE: negative CV effects
**TRANSDERMAL Estrogen – similar effect to GhRH agonist, w/out CV risk!!
estrogen and progesterone receptors in prostate cancer? ER-beta receptor effect?
– E-alpha and P receptors found on many prostate cancers, consistently on androgen insensitive tumors –> blockade is an area for further study!
– ER - beta = protective / tumor suppressive effect
Conventional chemo used in prostate cancer?
- Docetaxel: taxane, used w/ prophylactic GC to prevent edema/injection reaction
- Carbazitaxel: “ + poor P-glycoprotein efflux pump substrate + penetrates BBB – may be useful in multidrug resistant tumors!
- Mitoxantrone + predinsone: palliation of severe pain in hormone refractory dz
Why doesn’t Flutamide increase testosterone levels?
Doesn’t block central androgen receptors (just prostatic)
*other androgen receptor blockers bind central and prostate receptors
which alpha 1 antagonist has a short half life (comparatively)?
Parazosin
which AR antagonist is a male teratogen?
Enzalutamide
