BPH, ED & Urinary Incontinence Flashcards
Pathophys of BPH
- Circulating Testosterone:
- 90% from testes
- 10% from adrenal glands
- Adult males <40 yo
- prostate size stays the same ~15-20gm
- > 40 yo
- testosterone enters prostate cells
- type II 5 alpha reductase is converted to dihydrotestosterone (DH-T)
- testosterone enters prostate cells
- androgens (i.e. testosterone) has not direct effect on stromal tissue
-
overgrowth of muscle or stromal tissue around the urethra
- caused by testosterone → estrogen (in peripheral) → stimulates growth of stromal cells
-
overgrowth of muscle or stromal tissue around the urethra
LUTS and BPH
lower urinary tract symptoms (LUTS)
- when pt has BPH → will eventually experience LUTS
- 3 contributing factors:
- static factors:
- anatomic obstruction
- dynamic factors:
- excessive stimulation of alpha (1A)-receptors on smooth muscle of prostate and urethra → contraction
- Detrusor Factors:
- instability of detrusor muscle due to excessive hypertrophy and outlet obstruction
- static factors:
Symptoms of BPH
- obstruction due to static or dynamic factors:
- decreased force of the urinary stream
- urinary dribbling
- inability to completely empty bladder
- Detrusor instability
- irritable voiding sxs
- urinary urgency and frequency
- irritable voiding sxs
AUA-7 Score + IPSS
assessing severity of the LUTS in BPH
- AUA-7
- American urologic association score
- IPSS
- international prostate symptoms score = previous 7 question + Quality of Life
- Mildly Symptomatic: 0-7
- Moderately Symptomatic: 8-19
- Severely Symptomatic: 20-35
Treatment Algorithm for BPH
Tx for Mild Sxs of BPH
Mild Sxs = 0-7 on IPSS
Watchful waiting
Tx for Moderate to severe symptoms with no BPH complications
- prostate less than 30g?
-
alpha-adrenergic antagonist
- if response, continue
- if no response (1-2 weeks) , surgery
-
alpha-adrenergic antagonist
- Prostate ≥ 30 g?
-
5alpha-reductase inhibitor
- if response, continue
- if no response, try combo of this + alpha adrenergic antagonist or surgery
-
combo of alpha adrenergic antagonist + 5-alpha reductase inhibitor
- if response, continue
- if no response, surgery
-
5alpha-reductase inhibitor
Tx of severe symptoms of BPH and BPH complications
surgery
Alpha Antagonists Overview with BPH
- reduce the dynamic factor
- relax bladder neck, prostatic urethra, and prostate smooth muscle
- all agents in the class are equally effective
- onset = days - weeks
- good trial period = 1-2 weeks
- Mostly metabolized by the liver except silodosin (Rapaflo) -→ need to adjust for renal function
-
SEs:
- dose limiting hypotension, syncope
- less frequent with ER formulation and uroselective (alpha 1a blockers)
- ejaculation disorders (tamsulosin)
- dose limiting hypotension, syncope
- DDI:
- additive BP lowering effect
- +other antihypertensives
- +diuretics
- +phosphodiesterase inhibitors
- additive BP lowering effect
Terazosin (Hytrin)
non-selective alpha antagonist
- dose given at bedtime
- hypotensive
- extensive metabolism by liver
- floppy iris (when undergoes cataract surgery) → no need to d/c
Doxazosin
non-selective alpha blocker
- longest half life
- cardiovascular side effects
- SEs similar to terazosin:
- hypotension
- intraoperative floppy iris syndrome
Alfuzosin (uroxatral)
uroselective alpha 1A +alpha1D blocker
- better absorption with food (Alf likes to eat a lot)
- caution with renal disease
- least amount of SEs
Tamsulosin (Flomax)
uroselective alpha 1A + 1D blocker
- best absorbed on an empty stomach, “tammy is skinny b/c she does not eat food and is also extra floppy”
- caution in renal and hepatic impairment
- lowest hypotension
- can cause ejaculation disorder
- 40x higher risk of floppy iris than terazosin
Silodosin (Rapaflo)
uroselective alpha 1A +1D blocker
- food decreases extent of absorption → less hypotensive
- SEs same as tamsulosin
- causes ejaculation disorder
- CrCl = 30-50ml/min → half dose (4mg q day)
- contraindicated in CrCl <30ml/min
5-alpha reductase inhibitor MOA
prevent testosterone from being converted to DHT (DHT→which would normally promote tissue growth)
Finasteride and dutasteride
- Reduce the static factor → shrinkage of prostate by 20-25%
- 2 types of 5-alpha reductases in prostate
- type II = much more abundant than type I
5-alpha reductase inhibitors overview
- slow onset
- peak shrinkage in up to 6 months
- reduce PSA levels
- need at least 6 month to demonstrate effectiveness
- relieve sxs in 30-70% of patients
- no dose adjustment needed in renal impairment
-
SEs:
- decreased libido
- erectile dysfunction
- ejaculation disorders
- gynecomastia
- breast tenderness
- contraindicated in pregnant women → feminization of male fetus
- women should handle with GLOVES
Finasteride (Proscar)
- Type II 5 alpha reductase inhibitor
- inhibit 70-76% of serum dihydrotestosterone levels
-
half life slightly longer than dutasteride (6.2 hours vs 3-5 hours)
- lasts 6 years
Dutasteride (Avodart)
Type I and II 5-alpha reductase inhibitor
- inhibits 90-95% of serum dihydrotestosterone levels
- shorter half life than finasteride
Dutasteride/Tamsulosin (Jalyn)
5alpha reductase inhibitor + alpha blocker
-
Indications:
- high risk for BPH complications
- prostate size > 30g
- PSA > 1.5ng/mL
- relieves sxs and reduces the need for prostatectomy by 67%
- high risk for BPH complications
- may d/c alpha blocker part of medication after 6-12 month of tx
Herbal Therapies for BPH
- commonly used in europe but not approved by FDA
-
Saw Palmetto
- OTC.
- no difference from placebo on:
- urinary sx scores
- urinary flow
- prostate size
Tadalafil (Cialis) and LUTS
- approved for tx of LUTS
- relaxation of smooth muscle of urethra
- comparable to alpha blockers
- does not increase urinary flow rate or reduce post-void residual volume
- Best for BPH with ED
- CrCl< 30ml/min? DO NOT USE; if CrCl < 50 = reduce dose
Erectile Dysfunction
- commonly occurs in men with systemic disorders such as:
- DM
- HTN
- ischemic heart disease
- increased age
- identify the underlying etiology
- medication induced? → SSRI, TCA, antipsychotics
- Identify and the CV risks:
- smoking
- obesity
- HTN
- Dyslipidemia
- initiate Therapy
- PDE-5 inhibitors → 1st line
- if ineffective → other treatments available
- vacuum devices
- penile self-injectable drugs
- intraurethral alprostadil
MOA of PDE-5 inhibitors
used for erectile dysfunction
PDE-5 usually breaks down cGMP (cGMP promotes smooth muscle relaxation → increased blood flow in the corpus cavernosum) so inhibiting PDE-5 = more cGMP
Sildenafil (Viagra)
Revatio
decrease dose if CrCl <30mL/min
- 30min -1 hour before activity
- Revatio = used for pulmonary artery HTN
-
SEs:
- headaches, dizziness, flushing
- nasal congestion
- UTI, diarrhea
- reversible photosensitivity → “blue vision” – PDE-6 inhibition - retina
- MI, stroke, hypotension
- hearing loss
- Priapism (prolonged erection) seizures
- DDI:
- vasodilators – ie alpha blockers
- NITRATES → ALL CONTRAINDICATED
Vardenafil (Levitra)
(Staxyn)
- similar onset and duration as viagra 1 hour prior to activity
- QT prolongation
- high fat meals → lower peak serum concentration by 18%
- delays absorption by 1 hour
- ODT =more rapid onset
Tadalafil (Cialis)
30 min before activity
has different structure than sildenafil and vardenafil
approved for BPH-LUTS and pulmonary artery htn
avoid use if CrCl <30mL/min
Avanafil (Stendra)
- 15 min before activity
- +/- food
-
SEs:
- HA, flushing, vertigo
- nasal congestion, nasopharyngitis
- back pain
- angina, DVT
- muscle spasms, pruritus
-
DDIs :
- Nitrates = contraindication
- alpha-blockers
- antihypertensives
- 3A4 inhibitors
Types of Urinary Incontinence
Treatments of SUI
- if estrogen deficiency (atrophic urethritis or vaginitis) → vaginal estrogen (tablets and rings better than cream)
- → avoid systemic estrogen as this may actually increase risk of new onset UI
-
Alpha Receptor Agonists
- ephedrine – not recommended
- phenylephrine – lack of data
-
Pseudoephedrine → Alpha 1 agonist
- SEs: HTN, HA, dry mouth, nauseam insomnia, and restlessness
- can add when estrogen alone is not working
-
Duloxetine
- SNRI
-
off-label use
- enhances serotonergic and adrenergic tone controlling smooth muscle and sphincters
- avoid if CrCl <30mL/min
- can raise BP
- do not d/c abruptly → withdrawal syndrome
- avoid in narrow-angle glaucoma
- hepatotoxicity
- enhances serotonergic and adrenergic tone controlling smooth muscle and sphincters
-
off-label use
- SNRI
Tx of Urge Urinary Incontinence (UUI)
- first line = anticholinergic/antispasmodic
- suppressing premature detrusor contractions (overstimulation of M2 & M3 receptors)
- enhances bladder storage
- all have similar SEs and CIs
- urinary retention
- gastric retention, constipation
- uncontrolled narrow angle glaucoma
- dry mouth, HA
- orthostatic hypotension
-
immediate release:
- oxybutynin
-
Tolterodine
- higher rate of ADE esp in elderly → start at lowest dose
-
Extended Release
- oxybutynin
- trospium
- tolterodine
- fesoterodine
- darifenacin
- solifenacin
- less dry mouth compared to IR
- suppressing premature detrusor contractions (overstimulation of M2 & M3 receptors)
Tertiary Amine AntiMuscarinic Agents
Oxybutynin (highly lipophilic), tolterodine, fesoterodine, solifenacin, darifenacin
- can penetrate BBB → CNS SEs
- sedation
- mental status change
Quaternary Amine Antimuscarinic Agent
Trospium (Sanctura)
- charge → hydrophilic → cannot cross BBB → less CNS SEs
Antimuscarinic Agents DDI
- all metabolized by 3A4 and/or 2D6
- except Trospium (hydrophilic and renal clearance)
- CrCl <30mL/min = need dose reduction
- except Trospium (hydrophilic and renal clearance)
- need to reduce dose with 3A4 inhibitors
- Tolterodine
- fesoterodine
- solifenacin
- darifenacin
- avoid use with
- antagonism:
- acetylcholinesterase inhibitors
- donepezil
- acetylcholinesterase inhibitors
- additive effects
- anticholinergics
- antagonism:
Mirabegron (Myrbetriq)
- MOA: selective beta-3 agonist → relaxes smooth muscle of bladder
- Eliminated by the kidneys, avoid in ESRD
- indication: overactive bladder
- SEs: HTN, urinary retention, UTI, HA, tachycardia
-
DDI:
- +digoxin → increased dig AUC by 27% → monitor level
- 2D6 inhibitor (moderate)
- +thioridazine → QT prolongation, urinary retention
- anticholinergic → urinary retention
- colchicine → increase colchicine level → toxic myopathy, rhabdomyolysis
Tx of Overflow urinary Incontinence due to bladder underactivity
- Cholinomimetic
-
bethanechol
- mixed results
- SEs: muscle and abd cramps, hypersalivation, diarrhea, bradycardia, and bronchospasm
- mixed results
-
bethanechol
-
Alpha Blockers → help outflow
- prazosin, terazosin, doxazosin, tamsulosin, silodosin, alfuzosin
- intermittent urethral cath, indwelling urethral, suprpubic cath,
Monitoring of BPH
reduction of sxs score ≥ 3 points
perceive symptoms as not bothersome
if response → continue drug regimen and check q 6 months
- repeat PSA and DRE annually
- if no response (weeks after alpha blockers, 6 months after 5alpha reductase inhibitors) → surgery
PDE-5 Inhibitors (list)
- Sildenafil (Viagra, Revatio)
- Vardenafil (Levitra, Staxyn)
- Tadalafil (Cialis, adcirca)
- Avanafil
Duloxetine
SNRI → off label use = tx of stress urinary incontinence
- enhances serotonergic and adrenergic tone controlling smooth muscle and sphincters
- avoid if CrCl <30ml/min
- raises BP
- do not d/c abruptly → withdrawal
- avoid in uncontrolled narrow-angle glaucoma
- hepatotoxicity
Oxybutynin
anticholinergic/antispasmodic drug recommended for UUI
- tertiary amine
- active metabolite
- caution if CYP 3A4 inhibitors also being taken
Tolterodine
anticholinergic/antispasmodic drug recommended for UUI
- tertiary amine
- active metabolite
- oral Antacid interactions
Trospium Chloride
anticholinergic/antispasmodic drug recommended for UUI
- quaternary amine → does not cross BBB due to + charge
- foods decrease absorption, give on empty stomach
- altered in renal disease → dose reduction if CrCl <30ml/min
- foods decrease absorption, give on empty stomach
Solifenacin
anticholinergic/antispasmodic drug recommended for UUI
- tertiary amine
Fesoterodine
anticholinergic/antispasmodic drug recommended for UUI
- tertiary amine
- pro-drug
