Urology Flashcards
Erectile dysfunction
Many causes—vascular disease, diabetes,
medications, depression, complication of
prostate surgery, psychological causes
Many options for therapy—penile implants,
intrapenile injections or intraurethral
suppositories of Aloprostil [MUSE, Caverject,
Edex] and oral phosphodiesterase-5 [PDE-5]
inhibitors
Drugs to treat erectile dysfunction:
Phosphodiestrease-5 (PDE-5)
PDE-5 inhibitors
MOA—sexual stimulation causes smooth muscle relaxation of corpus cavernosum, which increases blood flow. The mediator is nitric oxide [NO], which
activates and helps in the formation of cyclic GMP—this then causes smooth muscle relaxation through a
reduction of intracellular Ca++
PDE-5 inhibits PDE-5 which is the isoenzyme responsible for breaking down of cGMP in the corpus cavernosum—the result is to increase the flow of blood into the corpus
cavernosum—these agents have NO effect in the absence of sexual stimulation
Examples of PDE-5 inhibitors
Sildenafil (Viagra)—protype
Tadafil (Cialis)
Vardenafil (Levitra; Staxyn)
Avanafil (Stendra)
Sildenafil (Viagra)
Brand name: viagra
Taken on empty stomach—at least 1 hour before anticipated sexual activity; dosed once a day
Metabolized by CYP3A4
Dose reduction when hepatic disease is present
Dose reduction when severe renal disease is present
ADE—headache, flushing, dyspepsia, nasal stuffiness, DISTURBANCES IN PERCEPTION OF BLUE AND GREENS, SUDDEN TRANSIENT HEARING LOSS (FROM VASODILATION) can cause
priapism
Use caution with CV disease and in those at risk for CV disease
Drug interactions/considerations with SILDENAFIL aka VIAGRA
Can potentiate hypotension [if patient on other agents that can lower BP—alpha blockers, vasodilators]
Contraindicated with nitrates, isosorbide (vasodilators)
Start at low dose and titrate up as needed for effect
Reduce dose of these agents if patient on CYP3A4 inhibitors—Biaxin, Ritonavir and other protease inhibitors
Generic: sildenafil
Brand: viagra Route: PO Onset of action: 60 minutes 1/2 life: 3-4 hours Food interaction: yes Caution with alpha blockers: +
Generic: tadalafil
Brand: cialis Route: PO Onset of action: 120 miutes 1/2 life: 18 hours Food interaction: no Caution with alphablockers: ++++
**ALSO APPROVED FOR BPH*
Generic: Vardenafil
brand: Levitra Route: PO Onset of action: 60 miutes 1/2 life: 4-5 hours Food interaction: no (do not take with WATER) Caution with alpha blockers: ++
Generic: Avanafil
Brand: Stendra Route: PO Onset of action: 30-45 minutes 1/2 life: 5 hours Food interaction: no Caution with alpha blockers: ++
Alprostadil
Synthetic prostaglandin E1
In the penile tissues, PGE1 allows relaxation of the smooth muscle of corpus cavernosum
Given intraurethral [supp] or intrapenile [injection]
Can be used 1st line—but most often used in those who are not candidates for oral agents
Acts locally, which decreases chance of ADEs
MOA—smooth muscle relaxants, exact physiological mechanism is unknown
Systemic absorption is minimal
Onset 5-10” [supp] or 2-25” [injection]—effects last 30-60”
ADEs—rare; hypotension, headache have been reported; local effects—penile pain, urethral
pain, testicular pain
Priapism may occur
BPH
Nonmaligant growth of the prostate—occurs with age
Three categories of drugs approved for treating
BPH
-Alpha Blockers
-5 Alpha Reductase Inhibitors
-PDE-5 Inhibitors
Alpha Blockers
Blocking Alpha1A & Alpha1B receptors in the prostate cause the smooth muscles in the gland to relax, which leads to improved urine outflow Selective agents only block Alpha1B—have no BP effects— nonselective ones decrease peripheral vascular resistance and lower BP Five agents in this class approved for BPH, a sixth one may be used but not FDA approved 4 nonselective and 2 selective alpha blockers—real prototype drug hard to identify
Generic Name: Terazosin
Trade name: Hytrin FDA approved for BPH: yes NONSELECTIVE alpha blocker NO food effect Metabolized in liver but not CYP450
Generic Name: Doxazosin
Trade Name: cardura FDA approved for BPH: yes NONSELECTIVE alpha blocker No food effecr CYP450 metabolism? yes
Generic Name: Alfuzosin
Trade name: Uroxatral FDA approved for BPH: yes NONSELECTIVE alpha blocker Food HELPS with absorption CYP450 metabolism? yes
Generic: Prazosin
Trade name: minipress FDA approved for BPH: NOOOO NONSELECTIVE alpha blocker No effect with food CYP450: yes
Generic: Tamulosin
Trade name: Flomax FDA approved for BPH: yes SELECTIVE alpha blocker Food helps with absorption CYP450 metabolism: yes
Generic: Silodosin
Trade name: rapaflo FDA approved for BPH: Yes SELECTIVE alpha blockers Food helps with absorption CYP450: yes** (also substrate for P-glycoprotein)
Alpha Blockers
½ life—8-22 hours
Peak effects seen in 1-4 hours
Rapaflo must be dose reduced for renal disease—avoid in severe CKD
ADEs—dizziness, fatigue, nasal congestion, HA, drowsiness and orthostatic hypotension [these effects are less with selective agents]; nonselective agents given at HS
Alpha blockers can effect ejaculatory ducts and impair smooth muscle contractions—inhibition of ejaculation and retrograde ejaculation have been reported with all of these drugs—these agents do NOT affect male sexual function severely like phenoxybenzamine and phentolamine [OraVerse]
Drug interaction with Alpha Blockers
Drugs that inhibit CYP3A4 and CYP2D6—Verapamil, Diltiazem may increase the drug levels of Cardura, Flomax, Rapaflo and Uroxatrol
Drugs that induce CYP450—Tegretol, Dilantin and St. John’s Wort may decrease the plasma concentrations of the aforementioned agents
Uroxatrol may prolong QT interval, use caution when giving other drugs that can prolong QTc—Biaxin, Levaquin, Cipro, Avelox, class III antiarrhymthics
Cyclosporine increases levels of Rapaflo because it is a
substrate for P-gp
5 Alpha Reductase Inhibitors
2 agents in this class—both agents work slowly—over 9-12 months [unlike alpha blockers that work in 7-10
days]—these agents reduce the size of the gland
Prostate MUST be enlarged for these agents to work, these agents are used in COMBINATION with alpha blockers
Types:
- finastride (proscar)
- dutasteride (avodart)
MOA of 5 alpha reductase inhibitors
inhibit 5 alpha reductase—which converts
testosterone to dihydrotestosterone[DHT], the more
potent, active compound that stimulates the prostate
to grow. By decreasing DHT the gland shrinks and urine
outflow improves.
5 Alpha Reductase Inhibitor
FINASTERIDE (Proscar)
Food does not affect absorption
½ life 6-12 hours [terminal ½ life of Avodart is 5 weeks, once the steady state is reached in 6 months]
ADEs—decreased ejaculate, decreased libido, ED, gynecomastia, oligospermia
All drugs in this category are teratogenic for women—those of child bearing age or those that are pregnant should not handle or ingest 5 alpha reductase inhibitors as they may lead to birth defects in the
genitalia of male fetus
Rare drug interactions
Finasteride is used [in small doses] for alopecia—
reduces DHT in scalp and serum which prevents hair
loss
PDE-5 inhibitors
TADALAFIL (Cialis)
FDA approved for s/s of BPH
-inhibition of PDE 5 allow vasodilation and relaxation of smooth muscles of the prostate and bladder-which improves the symptoms of BPH
Effect of BPH urethra
As the prostate enlarges, it can obstruction of the urethra
As a result, the man can present with urgency, postvoid dribbling or overflow incontinence
More common in men
Men can have urethral obstruction—from a cystocele, stricture or meatal stenosis [but most common in men]
Conservative therapy includes bladder retraining and prompted voiding, which can be used if none of the following are present
Hydronephrosis, large PVR, recurrent UTI or hematuria
Alpha blockers that decrease tone in prostatic capsule and urethra-really helpful in BPH
- Terazosin (hytrin)
- Doxazosin (cardura)
- Alfuzosin (uroxatral)
- Tamsulosin (flomax)
- Silodosin (rapaflo)
5 alpha reductase inhibitors are also added
Last resort for BPH
intermittent or indwelling catheter then can do a voiding trial and then if that does not work, surgery
Detrusor Underactivity
If the patient has a prolonged outflow obstruction, a neurogenic type situation can develop; this patient has a large PVR and overflow leakage
Goals—drain urine from the bladder; decrease UI; present hydronephrosis & urosepsis
Trial of indwelling/intermittent catheterization to decompress bladder, allowing it to recover its contractile ability; left in for 2 weeks; then removed to see if voiding recurs normally
If not, catheter can be reinserted for 4
weeks & a voiding trial reattempted;
Valsalva maneuvers can be tried to induce
bladder contractions
Bethanechol, a cholinergic agonist, can be
tried at 10-50 mg QID
Testosteron Deficiency
Evaluation of ED should include a testosterone level
Testosterone deficiency can be part of male hypogonadism and can lead to osteoporosis—in addition to sexual issues.
Refer to URL and EBG cited on slide #2; refer to detail
document that reviews testosterone products
Urinary Incontinence
Involuntary loss of urine that leads to hygienic or social problems
Affects at least 10 million Americans
UI is associated with pressure ulcers, skin irritation and falls
UI can lead to anxiety, depression, embarrassment and isolation
Prevalence of UI
- more in men than women
- affects men and women equally after 80 years old
Lower urinary tracts (LUT) consists of
Detrusor
Internal sphincter
External sphincter
Detrusor (bladder)
Muscular storage and contractile organ
Smooth muscle that accommodates large volume at low intravesical pressure
What makes up the internal sphincter?
Essentially smooth muscle in proximal urethra
In men it has no landmarks
In women, ill defined and extends throughout most of urethra
What makes up the external sphincter?
More distal periurethral striated muscle
Well defined in men with striated muscle arranged in an annular style in urogenital diaphragm
Continence is maintained by?
the urethra
PNS (cholinergic): parasympathetic
-nerves come from spinal cord segments S2-S4 & travel by pelvic nerve to bladder
Cholinergic stimulation increases force and frequency of bladder contractions
SNS (sympathetic nervous system)(adrenergic)
-regulated by presacral or hypogastric nerves in the spine at T10-L2
Bladder base [trigone] and proximal urethra rich in alpha adrenergic receptors and stimulation increases
contraction of internal sphincter
How urination occurs
Somatic nerves stem from cord at levels S2-S4 and are carried via pudendal nerve to innervate urogenitaldiaphragm and external sphincter
Pons coordinates bladder contraction with sphincter relaxation
Bladder fills passively, sphincters remain closed
Filling is facilitated by CNS inhibition of parasympathetic
activity
At the same time, increase in alpha adrenergic and somatic tone maintains the sphincters in a closed
position
For urination to occur, PNS mediates bladder contraction with coordinated sphincter relaxation
Causes of urinary incontinence
All other causes of UI are from problems in bladder, urethral outlet or both Bladder contracts prematurely Detrusor overactivity Bladder contracts too weakly Detrusor under activity Urethral outlet resistance too high Obstruction Urethral outlet resistance too low Incompetent
What happens in detrusor overactivity?
Usual mechanism of urge incontinence
Most common cause of geriatric UI
Inhibition of bladder contractions is impaired and bladder contracts on its own, leading to leakage
Patient feels urge to void and before can get to toilet, wets on self
Moderate to large amounts of urine
May be associated with nocturia
Detrusor hyperreflexia If patient has a neuro lesion, overactivity is
Detrusor hyperreflexia
-frequency, urgency, and incontinence
If no neuro lesion is present, it is called
Detrusor instability
What happens in Detrusor overactivity with normal contraction
bladder can empty most of its contents
what happens in Detrusor hyperactivity with impaired contractility
Bladder can’t empty and >100 cc of urine remains in bladder after contraction
Detrusor Underactivity
Bladder’s contractions so diminished that overflow incontinence ensues
Bladder contracts [if at all] only when patient tries to void
Uncommon in geriatrics
It can be:
-Neurogenic in origin
-Secondary to nerve damage from DM, ETOH or vertebral disease
-From long standing obstruction
Outlet Incompetence
Also known as stress incontinence
Common in women
Patient has involuntary loss of urine with physical activity or coughing
Leakage is small and rare when patient is recumbent
Usually from weakening of supporting structures of
pelvic floor
Uncommon in men
Except after transurethral surgery or XRT that damages sphincter
Outlet Obstruction
Common cause of UI in elderly men Can lead to urinary retention, bladder distention and overflow incontinence Post-void dribbling or urge incontinence due to detrusor overactivity Causes -BPH -Alpha agonists -Tumors -Strictures -Spinal cord lesions
Treatment for detrusor overactivity
-voiding trails
-Anticholinergics or smooth muscle relaxants can be used to decrease involuntary contractions of the overactive detrusor and increase volume needed to elicit involuntary contractions
Propantheline: 15-30 mg TID or QID
Dicyclomine : 10-30 mg TID or QID. Has anticholinergic and smooth muscle relaxant properties
TCA (tricyclic antidepressants): Tofranil or Doxepin at 25-50 mg TID or at HS; **Evaluate for orthostatic hypotension and confusion
Ditropan: 2.5-5 mg QD or QID
Systemic side effects of anticholinergics
Systemic side effects—xerostomia, confusion, constipation, urinary retention
Anticholinergics for detrusor overactiviy
Detrol- 2 mg BID Detrol LA- 4 mg daily Ditropan XL-5-10 mg daily Levbid- 1 tab BID Symax Oxytrol Patch- change twice weekly Gelnique- 1 gram gel q 24 hrs Vesicare Sanctura Sanctura XR Enablex Toviaz
Antimuscarinic Medications—
Prototype—Oxybutynin (ditropan)
4 formulations:
- Immediate release: 2.5–5 mg BID–QID, up to 20 mg/day
- Extended release (ER) (Ditropan XL): 5–20 mg/day
- Topical patch (Oxytrol): 3.9 mg, applied 2x/week
- Topical gel (Gel): 1 gram applied every 24 hours
• Side effects (less frequent with ER and topical): Dry mouth Blurry vision Constipation Possibly cognitive
Interactions with CYP34A and 2D6
• Monitor PVR if UI worsens
Antimuscarinic Medications—
Tolterodine [Detrol]
Initial dose: 1–2 mg BID immediate release, 2–4 mg
QD for ER (Detrol LA)
Side effects similar to those of oxybutynin-ER; possible decreased xerostomia (dry mouth)
Interactions with CYP34A and 2D6
Antimuscarinic Medications—
Trospium [Sanctura]
Dose is 20 mg twice daily; can dose once daily in elderly because of renal clearance
Does come in an extended release form—Santura XR 60 mg daily
Must be taken on an empty stomach
Associated with 56%–60% reduction in weekly urge incontinence episodes
No data in long-term-care populations
Adverse events: dry mouth, constipation, headache, abdominal pain
Antimuscarinic Medications—
Darifenacin [Enablex]
Dose is 7.5 or 15 mg/day
Median reduction in weekly UI episodes 55%–58% in patients on 7.5 mg and 60%–70% in patients on 15 mg
No data in long-term-care populations
Adverse events: dry mouth, constipation; may have limited cognitive effects
Interactions with CYP34A and 2D6
Antimuscarinic Medications—
Solifenacin [VESIcare]
Dose is 5 mg/day; may be titrated to 10 mg/day
Reduction in daily UI episodes 57%–69%, depending on dose
No data in long-term-care populations
Adverse events: dry mouth, constipation, nausea, and blurred vision; possible
QTc
Interactions with CYP34A and 2D6
Antimuscarinic
Oxybutynin-Ditropan
Cost: generic
Dosing: BID-QID
Considerations: quick onset; P450 interactions
SE: Dry mouth, constipation, cognitive issues
Antimuscarinic
Oxybutynin- Ditropan XL
Cost: generic
Dosing: QD
Considerations: wide titration range: p450 interactions
SE: dry mouth
Antimuscarinic
Oxybutynin- Oxytrol (patch form)
Cost: no generic
Dosing: twice a week
Considerations: skin irritation; single dose
SE: dry mouth
Antimuscarinic
Tolterodine: Detrol LA
Cost: no generic
Dosing: QD
Consideration: titration; p450 interactions
SE: dry mouth, constipation: QTc, and there have been case reports of cognitive issues
Antimuscarinic
Trospium-Sanctura
Cost: no generic
Dosing: QD-BID
Considerations: renal clearance; must give NPO
SE: dry mouth, constipation, INCREASED HEART RATE, less cognitive issues
Antimuscarinic
Darifenacin-Enalbex
Cost: no generic
Dosing: QD
Considerations: p450 interactions; titration
SE: dry mouth, constipation, less likely to have cognitive issues
Antimuscarinic
Solifenacin-Vesicare
Cost: no generic
Dosing: QD
Considerations: P450 interactions; titration; long half life
SE: dry mouth, constipation, effects on QTc
Fesoterodine [Toviaz]
Atropine like agent that is used to treat OAB—this quaternary amine has the fewest cholinergic effects—working mostly on muscarinic and nicotonic receptors in the detrusor
Increases bladder capacity
For those on drugs that may increase
cholinergic neurotransmitters [agents
for dementia]—this is one of the DOC (drug of choice)
for OAB in those individuals
**first line for person with cognitive deficits
β 3 Agonist—Mirabergron [Myrbetriq]
This agent relaxes the detrusor smooth muscle and increases bladder capacity
Used for OAB [in patients that have failed other agents or have a contraindication to the use of the anticholingergics
Myrbetriq 25-50 mg daily
- Can increase BP [this effect is more marked at lower doses]
- It increases digoxin levels; can decrease Metoprolol levels; can inhibit CYP2D6
- If GFR is <30 cc/min—use the 25 mg dose
Other Treatments for OAB
Botulinum toxin
Sacral Nerve Stimulation
Percutaneous Tibial Nerve Stimulation
Stress Incontinence
Outlet incompetence is manifested by stress incompetence Can be treated nonsurgically or surgically Nonsurgical therapy -Weight loss -Kegel exercises -Use of vaginal cones -Biofeedback -Adjusting fluid intake -Voiding frequently
Nonsurgical treatments for stress incontinence with medication
Estrogen
-Especially in females with atrophic urethritis or vaginosis
-0.3-0.625 mg qd and/or 2 grams vaginal cream qod
Oral—shown to increase UI in randomized trials
Topical—may reduce atrophic vaginitis, urethritis; impact on UI is unclear
Alpha agonists
-Pseudoephedrine 15-30 mg BID or TID
⍺-Adrenergic Agonists
- Stimulate urethral smooth-muscle contraction
- No pure ⍺-agonists are available
Stress Incontinence—Post-prostatectomy
Milder cases: pelvic muscle exercises, periurethral injections
More severe cases: protective garments, catheters
Artificial sphincter replacement can be effective but has high re-operation rate
Emerging data on sling operations
Mixed Incontinence
Many women show evidence of 2 kinds of incontinence
- Urge
- Stress
Empirical treatment can be based on clinical history
Pediatric Enuresis
Involuntary discharge of urine at night by children older enough to be expected to have bladder control
Causes: Hormones, bladder problems, genetics, sleep problems, caffeine, medical conditions, psychological problem
Treatment options:
-alarm therapy that teaches children to respond to a full bladder while asleep. Alarm goes off when child starts to void.
-behavior therapy
-avoid caffeine before bed
Medication: desmopressin acetate
Considerations: not rec for children under 6; use caution with children having issues with osmoregulation or fluid balance, cystic fibrosis, no fluids for one hour before and 8 hours after taking desmopressin
Phosphodiesterase-5 Inhibitors (PDE-5)
- FOR ERECTILE DYSFUNCTION (ED)
MOA: sexual stimulation causes smooth musclerelaxation of corpus cavernosum, which increasesblood flow. The mediator is nitric oxide [NO], whichactivates and helps in the formation of cyclic GMP—this then causes smooth muscle
PHARMACOKINETICS: All of these agents inhibit PDE-5 which inhibitsthe isoenzyme responsible for breaking downof cGMP in the corpus cavernosum—the result
is to increase the flow of blood into the corpuscavernosum—these agents have NO effect in the absence of sexual stimulation
ADE: headache, flushing, dyspepsia, nasal stuffiness, disturbances in perception of blues and greens, sudden transient hearing loss [from vasodilation], can cause priapism
DRUG INTERACTIONS:
Can potentiate hypotension [if patient on other agents that can lower BP—alpha blockers, vasodilators]
Contraindicated with nitrates, isosorbide
Start at low dose and titrate up as needed for effect
Reduce dose of these agents if patient on CYP3A4 inhibitors—Biaxin, Ritonavir and other protease inhibitors
Examples of Phosphodiesterase-5 Inhibitors
- Sildenafil
2 Vardenafil - tadalafil
- Avanafil
Which PDE-5 can be FDA approved for BPH as well as ED?
tadalafil (Cialis)
What can you use to treat BPH?
- alpha blockers
- alpha reductase inhibitors
- PDE-5 inhibitors
Functional incontinence
address behavior, no meds
