Drugs for Male GU disorders and Urinary incontinence Flashcards
5α-reductase
(1) Converts testosterone to dihydrotestosterone (dihydrotestosterone is the major active androgen in these tissues)
CYP19 P450 aromatase
(1) Conversion of testosterone to estradiol by aromatase occurs primarily in the liver and adipose tissue
Leuprolide - NA
= 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
abrelix, cetrorelix, degarelix, ganirelix - NA
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
ketoconozole - NA
antiandrogen steroid inhibitor
high doeses increases estradiol: testosterone ratio in plasma
finasteride - NA
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)
dutasteride - NA
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
Cyproterone - NA
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
Flutamide/ bicalutamide, nulutamide - NA
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)
spironolactone - NA
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)
prazosin *
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)
two drugs used to tx BPH?
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)
terazosin
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
doxazosin
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
Alfuzosin
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
Tamsulosin
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
saw palmetto
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
Sildenafil
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
Tadalafil
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
Vardenafil
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
Avanafil
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
Alprostadil
** 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
atropine
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
oxybutynin
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
darifenacin
selective M3 mACHR antagonist - used to tx urinary disorders
reduced incidence of xerostomia and constipation
fesoterodine
selective M3 mACHR antagonist - used to tx urinary disorders
reduced incidence of xerostomia and constipation
solifenacin
selective M3 mACHR antagonist - used to tx urinary disorders
reduced incidence of xerostomia and constipation
tolterodine
selective M3 mACHR antagonist - used to tx urinary disorders
reduced incidence of xerostomia and constipation
trospium
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
hyperthermia
think atropine overload
tx: cholinesterase inhibitor
CI for antimuscarinic agents?
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.
causes for erectile dysfunction?
- *** 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
most common drugs causing ED?
antidepressants (SSRIs)
antipsychotics (phenothiazines)
benzodiazepines (alcohol)
MOA of viagra like drugs?
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
onset of action of PDE-5 inhibitors
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”
AEs/ contraindications for PDE5 inhibitors?
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
drug used to tx BPH causing orthostatic hypotension?
prazosin
drug to tx BPH and male pattern baldness?
5-alpha reductase inhibitor = finasteride
which class of drugs will make BPH worse?
anticholinergics: i.e. oxybutynin
note: just BPH and erectile dysfunction on the test (3)
don’t need to know prostate drugs
