Drugs for Male GU disorders and Urinary incontinence

Question 1

5α-reductase

Answer 1

(1) Converts testosterone to dihydrotestosterone (dihydrotestosterone is the major active androgen in these tissues)

Question 2

CYP19 P450 aromatase

Answer 2

(1) Conversion of testosterone to estradiol by aromatase occurs primarily in the liver and adipose tissue

Question 3

Leuprolide - NA

Answer 3

= androgen suppression = Gonadotropin-releasing hormone (GnRH) and analogs
** Leuprolide is the prototypical GnRH analog (others include goserelin, histrelin, nafarelin, triptorelin, and gonadorelin, a synthetic human GnRH)

dose: pulsatile for increased T, constant for decreased T

USE:

(1) Occasionally used for stimulation of gonadotropin production but more commonly used for suppression of gonadotropin release
(2) Clinical situations in males where stimulation of gonadotropin production is useful include male infertility
(3) Clinical situations in males where suppression of gonadotropin production is useful include prostate cancer

AE’s:
hot flushes, sweats, edema, gynecomastia, decreased libido, decreased hematocrit, reduced bone density, and asthenia

Question 4

abrelix, cetrorelix, degarelix, ganirelix - NA

Answer 4

GnRH antagonists –> inhibition of FSH And LH

USE: suppression of T, and for advanced prostate cancer

• Abarelix and degarelix are used to treat advanced prostate cancer

AE’s:
hot flushes, sweats, edema, gynecomastia, decreased libido, decreased hematocrit, reduced bone density, and asthenia

Question 5

ketoconozole - NA

Answer 5

antiandrogen steroid inhibitor

high doeses increases estradiol: testosterone ratio in plasma

Question 6

finasteride - NA

Answer 6

c) 5α-reducatase inhibitors
i) MOA: inhibition of 5α-reductase reduces levels of dihydrotestosterone within 8 hours of administration
ii) Developed to treat benign prostatic hyperplasia (BPH)

Common adverse effects are impotence and decreased libido

(1) Preferentially antagonizes type II 5α-reductase
(2) Also approved for use in the treatment of male pattern baldness (effect presumably mediated via type I)
(3) Been shown to successfully treat hirsutism in women (unlabeled/investigational use)

Question 7

dutasteride - NA

Answer 7

c) 5α-reducatase inhibitors
i) MOA: inhibition of 5α-reductase reduces levels of dihydrotestosterone within 8 hours of administration
ii) Developed to treat benign prostatic hyperplasia (BPH)

Common adverse effects are impotence and decreased libido

Longer half-life than finasteride

Question 8

Cyproterone - NA

Answer 8

androgen receptor inhibitor

USE: tx of prostate carcinoma and hirsuitism

(2) Used for palliative treatment of advanced prostate carcinoma
(3) Acetate form has a marked progestational effect that suppresses the feedback enhancement of LH and FSH, leading to a more effective antiandrogen effect

Question 9

Flutamide/ bicalutamide, nulutamide - NA

Answer 9

androgen receptor inhibitor

USE: tx of prostate carcinoma and hirsuitism

(1) Nonsteroidal antiandrogens
(2) Used for metastatic advanced prostate carcinoma
(3) May be used in combination with a GnRH analog to suppress tumor flare
(4) Common adverse effect is gynecomastia (reversible upon discontinuation)

Question 10

spironolactone - NA

Answer 10

androgen receptor inhibitor

USE: tx of prostate carcinoma and hirsuitism

(1) Antagonist effects at multiple nuclear receptors (androgen, aldosterone/mineralocorticoid) and reduces 17α-hydroxylase activity, which lowers plasma levels of testosterone and androstenedione
(2) Most common use is in the management of heart failure; may be used to treat hirsutism (investigational)

Question 11

prazosin *

Answer 11

alpha-adrenergic antagonist

• Smooth muscle tone in the prostate is mediated by α1 receptors (primarily α1A)
• Antagonism of α1 receptors is more efficacious in treatment of BPH compared to α2 receptors due to the increased density of α1 receptors in the prostate

USE: more effective for short-term treatment of BPH compared to 5α-reductase inhibitors

(b) More commonly used for the treatment of hypertension
(c) Adverse effects include palpitations and orthostatic hypotension (postural hypotension and syncope are sometimes seen 30-90 minutes after a patient takes an initial dose)
(d) 2-3 hour half-life requires twice-daily dosing (duration of action typically 7-10 hours)

Question 12

two drugs used to tx BPH?

Answer 12

i) 5α-reductase inhibitors
* **(1) Have demonstrated the potential for long-term reduction in prostate volume compared to α-antagonists
* ** (2) Shown to reduce the need for surgery compared to α-antagonists
(3) There are two 5α-reductase inhibitors approved in the United States, finasteride and dutasteride (see above for more information)

α1-adrenergic receptor antagonists

(2) Smooth muscle tone in the prostate is mediated by α1 receptors (primarily α1A)
(3) Antagonism of α1 receptors is more efficacious in treatment of BPH compared to α2 receptors due to the increased density of α1 receptors in the prostate
* ** (4) more effective for short-term treatment of BPH compared to 5α-reductase inhibitors
(5) Five long-acting agents (terazosin, doxazosin, alfuzosin, tamsulosin, and silodosin) are approved for treatment of BPH (Prazosin, a short-acting α1-antagonist, may be used for BPH but requires more frequent dosing)

Question 13

terazosin

Answer 13

alpha-adrenergic antagonist

• Smooth muscle tone in the prostate is mediated by α1 receptors (primarily α1A)
• Antagonism of α1 receptors is more efficacious in treatment of BPH compared to α2 receptors due to the increased density of α1 receptors in the prostate

USE: more effective for short-term treatment of BPH compared to 5α-reductase inhibitors

(a) Similar profile to prazosin but half-life is 9-12 hours and less adverse effects

Question 14

doxazosin

Answer 14

alpha-adrenergic antagonist

• Smooth muscle tone in the prostate is mediated by α1 receptors (primarily α1A)
• Antagonism of α1 receptors is more efficacious in treatment of BPH compared to α2 receptors due to the increased density of α1 receptors in the prostate

USE: more effective for short-term treatment of BPH compared to 5α-reductase inhibitors

(b) Few adverse effects compared to prazosin

Question 15

Alfuzosin

Answer 15

alpha-adrenergic antagonist

• Smooth muscle tone in the prostate is mediated by α1 receptors (primarily α1A)
• Antagonism of α1 receptors is more efficacious in treatment of BPH compared to α2 receptors due to the increased density of α1 receptors in the prostate

USE: more effective for short-term treatment of BPH compared to 5α-reductase inhibitors

Question 16

Tamsulosin

Answer 16

alpha-adrenergic antagonist

• Smooth muscle tone in the prostate is mediated by α1 receptors (primarily α1A)
• Antagonism of α1 receptors is more efficacious in treatment of BPH compared to α2 receptors due to the increased density of α1 receptors in the prostate

USE: more effective for short-term treatment of BPH compared to 5α-reductase inhibitors

(e) Major adverse effect is abnormal ejaculation

Question 17

saw palmetto

Answer 17

i) Most often promoted for the treatment of BPH although the active constituents in saw palmetto berries are not well defined
ii) Studies performed in vitro show saw palmetto inhibits 5α-reductase I and II and inhibits dihydrotestosterone binding to androgen receptors
iii) Clinical trial data are mixed

Question 18

Sildenafil

Answer 18

Viagra

PDE-5 inhibitor
i) MOA: selective inhibition of PDE-5 increases intracavernosal cGMP levels and causes relaxation of the nonvascular smooth muscle of the corpora cavernosa

v) As potent vasodilators, concomitant use of PDE-5 inhibitors and nitrates can lead to severe hypotension and syncope (myocardial infarctions have also been reported)
vi) In men treated for BPH with α-antagonists, symptomatic hypotension may occur
vii) Rare adverse effects include visual changes (color changes, blurred vision, or increased sensitivity) and hearing loss

Question 19

Tadalafil

Answer 19

Cialis - may last 36 hours!

PDE-5 inhibitor
i) MOA: selective inhibition of PDE-5 increases intracavernosal cGMP levels and causes relaxation of the nonvascular smooth muscle of the corpora cavernosa

v) As potent vasodilators, concomitant use of PDE-5 inhibitors and nitrates can lead to severe hypotension and syncope (myocardial infarctions have also been reported)
vi) In men treated for BPH with α-antagonists, symptomatic hypotension may occur
vii) Rare adverse effects include visual changes (color changes, blurred vision, or increased sensitivity) and hearing loss

Question 20

Vardenafil

Answer 20

Levitra
PDE-5 inhibitor
i) MOA: selective inhibition of PDE-5 increases intracavernosal cGMP levels and causes relaxation of the nonvascular smooth muscle of the corpora cavernosa

v) As potent vasodilators, concomitant use of PDE-5 inhibitors and nitrates can lead to severe hypotension and syncope (myocardial infarctions have also been reported)
vi) In men treated for BPH with α-antagonists, symptomatic hypotension may occur
vii) Rare adverse effects include visual changes (color changes, blurred vision, or increased sensitivity) and hearing loss

Question 21

Avanafil

Answer 21

Stendra

PDE-5 inhibitor
i) MOA: selective inhibition of PDE-5 increases intracavernosal cGMP levels and causes relaxation of the nonvascular smooth muscle of the corpora cavernosa

v) As potent vasodilators, concomitant use of PDE-5 inhibitors and nitrates can lead to severe hypotension and syncope (myocardial infarctions have also been reported)
vi) In men treated for BPH with α-antagonists, symptomatic hypotension may occur
vii) Rare adverse effects include visual changes (color changes, blurred vision, or increased sensitivity) and hearing loss

Question 22

Alprostadil

Answer 22

** must be injected **

i) Prostaglandin E1 (PGE1) analog that relaxes trabecular smooth muscle by dilation of cavernosal arteries when injected along the penile shaft, allowing blood flow to and entrapment in the lacunar spaces of the penis
ii) Commonly used in patients who do not respond to PDE-5 inhibitors
iii) Major adverse effect is penile pain
iv) Lasts up to 1 hour

Question 23

atropine

Answer 23

anticholinergic agent used for urinary incontinence (rarely used now)

CNS: sedation, parkinson tremor, motion sickness

eye: block of papillary constrictor mm. - weakens contraction of ciliary mm, reduced lacrimal secretion

CV: tachycardia

resp: bronchodilation and reduced secretion

GI: decreased salivary, decreased gastric emptying

GI tract: relax smooth mm. of uterters and bladder wall and slow voiding

sweat glands: suppression of sweating –> atropine fever

Question 24

oxybutynin

Answer 24

selective M3 mACHR antagonist - used to tx urinary disorders

side effects that include dry mouth, dizziness, constipation, blurred vision, dry eyes, and urinary tract infections among others

Question 25

darifenacin

Answer 25

selective M3 mACHR antagonist - used to tx urinary disorders

reduced incidence of xerostomia and constipation

Question 26

fesoterodine

Answer 26

selective M3 mACHR antagonist - used to tx urinary disorders

reduced incidence of xerostomia and constipation

Question 27

solifenacin

Answer 27

selective M3 mACHR antagonist - used to tx urinary disorders

reduced incidence of xerostomia and constipation

Question 28

tolterodine

Answer 28

selective M3 mACHR antagonist - used to tx urinary disorders

reduced incidence of xerostomia and constipation

Question 29

trospium

Answer 29

nonselective M3 mACHR antagonist - used to tx urinary disorders

side effects that include dry mouth, dizziness, constipation, blurred vision, dry eyes, and urinary tract infections among others

Question 30

hyperthermia

Answer 30

think atropine overload

tx: cholinesterase inhibitor

Question 31

CI for antimuscarinic agents?

Answer 31

galucoma (d/t reduced secretions)

should be used with caution in elderly men with a history of prostatic hyperplasia (difficult to differentiate between symptoms attributable to detrusor over-activity and those caused by bladder-outlet obstruction secondary to benign prostatic enlargement). Men with hyperplasia would be at risk for acute urinary retention.

Question 32

causes for erectile dysfunction?

Answer 32

• *** Vascular (e.g., atherosclerosis)
• Neurologic (e.g., cerebrovascular accident, spinal cord damage, autonomic and peripheral neuropathy)
• Endocrine (e.g., diabetes, hypogonadism, prolactinomas, hyper- and hypo-thyroidism
• Iatrogenic (e.g., pelvic radiation, prostatectomy)
• Psychogenic (e.g., performance anxiety, depression)

Common drug induced:

• *Antidepressants – **SSRIs, TCAs
• Spironolactone and thiazide diuretics
• Centrally-acting sympatholytics (clonidine, methyldopa, guanethidine, etc)
• Nonselective beta-blockers (~100% at high doses; try switching to selective beta blocker)
• Antipsychotics* – phenothiazines (50%)* and other dopamine receptor antagonists
• Benzodiazepines, alcohol** cocaine, marijuana, hallucinogens –biphasic
• Opioids

Question 33

most common drugs causing ED?

Answer 33

antidepressants (SSRIs)
antipsychotics (phenothiazines)
benzodiazepines (alcohol)

Question 34

MOA of viagra like drugs?

Answer 34

inhition of PDE-5 –> decreased breakdown of cGMP –> increased NO –> increased relaxation of erectile tissues

ex. sildenafil, tadalafil, vardenafil, avanafil

no trials showing a difference in effectivness

Question 35

onset of action of PDE-5 inhibitors

Answer 35

All PDE-5 inhibitors have a similar onset of action:

“take 30 min before sexual activity” - tadalafil & avanafil

“take 1 hour before sexual activity” - sildenafil & vardenafil

Duration of action: tadalafil 36 hours, others 4 hours

Tadalafil is available for “daily use”

Question 36

AEs/ contraindications for PDE5 inhibitors?

Answer 36

AE: flushing, h/a, “blue vision”

**can potentiate hypotension (esp. in pts. using alpha blockers - tamulosin, doxazosin)

** conraindicated with nitrates! (nitroglycerin, isorbide dinitrate) - can cause myocardial ischemia

Question 37

drug used to tx BPH causing orthostatic hypotension?

Answer 37

prazosin

Question 38

drug to tx BPH and male pattern baldness?

Answer 38

5-alpha reductase inhibitor = finasteride

Question 39

which class of drugs will make BPH worse?

Answer 39

anticholinergics: i.e. oxybutynin

Question 40

note: just BPH and erectile dysfunction on the test (3)

Answer 40

don’t need to know prostate drugs