Pharm E3- Urology

How does the blood flow in an erection?

Increased arterial flow IN & decreased venous flow OUT

What is testosterone converted into?

DHT by 5a reductase

Estradiol by aromatase

What antidepressants can cause ED (in order of most likely to and least like to)?

TCAs > SSRIs > SNRIs > bupropion

What anticholinergics can cause ED?

Antihistamines (can use 2nd gen), antiparkinsonian agents, TCAs, phenothiazines

How can dopamine antagonists (phenothiazine & metoclopramide) cause ED?

Dopamine blockade increases prolactin levels → decreases testosterone production

What drugs can cause ED by suppressing testosterone mediated libido stimulation?

Estrogens, anti androgens, digoxin, spironolactone, ketoconazole, cimetidine

What CNS depressants can cause ED by suppressing perception of psychogenic stimuli?

Benzodiazepines, opiates, large doses of ethanol, anticonvulsants

What agents can cause ED by decreasing penile flow which reduces arteriolar flow to corpora?

Diuretics, BBs, central sympatholytics (methyldopa, clonidine)

What antihypertensive agents are less likely to cause ED?

ACEi, ARBs, CCBs

What other miscellaneous drugs can cause ED?

Finasteride, dutasteride, lithium carbonate, MAOIs, gemfibrozil

ED treatment algorithm

How do vacuum erection devices work to treat ED?

Pump generates negative vacuum pressure to draw arterial blood into cavernosa

*onsets 3-20 minutes

In what ED patients would it be good to use a vacuum erection device?

Can’t use PDE-5i or other oral agents

can be used in combo or before surgery; effective but not discreet

How do phosphodiesterase inhibitors (PDEi) work to treat ED?

inhibits metabolism of cGMP → increases cGMP → less Ca gets into cells → more vasodilation → produces erection

What metabolizes cGMP into GMP (inactive) & inhibits erections?

Phosphodiesterase (PDE)

What drugs are phosphodiesterase inhibitors (PDEi)?

Sildenafil (Viagra)

Vardenafil (Levitra/Staxyn)

Tadalafil (Cialis)

Avanafil (Stendra)

Which PDEIs inhibit PDE-6 (in rods & cones of eye)?

*test Q

Sildenafil

Which PDEI inhibits PDE-11 (striated muscle)?

*test Q

Tadalafil

Which PDEI’s have a delayed onset if taken within 2 hours of a fatty meals if taken w/in 2 hours (pt needs to take earlier)?

** test Q

Sildenafil & Vardenafil

Which PDEI has a slower onset but the longest duration of 24-36 hours?

** test Q

Tadalafil

What is first line for ED, especially in younger patients?

PDE inhibitors

What is likely to cause a failure of PDEIs when using for ED?

*try atleast 5-8 doses

Comorbid conditions (DM, PVD, etc), excess alcohol, food interactions

In what patients should PDEIs be avoided due to risk of priapism?

Healthy patients (no issues with erections), sick cell, leukemia, multiple myeloma, currently taking other ED meds

Which PDEIs are more likely to have to have ocular symptoms (blurred vision, cyanosis)?

Sildenafil > vardenafil = avanafil > tadalafil

Which PDEI is most likely to cause myalgias?

Tadalafil

How are PDEIs metabolized?

CYP3A4

*sildenafil & tadalafil need renal adjustment

What SEs are seen with PDEIs?

Vasodilation → HA, facial flushing, dyspepsia, nasal congestion, dizziness

8-10 mmHg drop in SBP (avoid if on multiple antihypertensives, nitrates & high risk cardiac patients)

The following SE is caused by what drug?

• nonarteritic anterior ischemic optic neuropathy (NAION)

• drop in blood flow to optic nerve → sudden U/L painless blindness

• emergency! → irreversible

Sildenafil

What reversible ocular SEs are seen with sildenafil?

Photophobia, blurred vision, loss of blue green color discrimination

Which PDEI is more likely to cause QTc prolongation?

Vardenafil

How should the dose of PDEI be adjusted if a patient is also taking a CYP3A4 inhibitor?

Decrease dose

Why are nitrates CI in a patient who took a PDEI?

Severe hypotension from too much cGMP

*treat w/ trendelenburg position & fluids

How long must a patient wait to take a nitrate after taking a PEDI?

24 hours (48 hours for tadalafil)

What drug is a synthetic prostaglandin E1 used to treat ED by intracavernosal injection or intraurethral insert?

Alprostadil

What ED medication is good for patients with an impaired nitric oxide pathway (DM, prostatectomy, failed PDEI tx)?

Alprostadil

How does alprostadil work to treat ED?

Stimulates adenyl cyclase → increased cAMP production → dec intracellular Ca → smooth muscle relaxation → erection

*not nitric oxide dependent

Which is alprostadil preferred in ED over other vasodilator intracavernosal agents (papaverine, phentolamine, atropine)?

Less risk of prolonged erections & priapism

How should alprostadil be administered?

5-10 min before intercourse → T ½ of 1 minute

Duration < 1 hr (12-44 minutes)

Inject into 1 cavernous w/ aseptic technique

Why might alprostadil be a a better option for ED in high risk cardiac patients?

Less systemic absorption → less SEs

Would psychogenic ED or vasculogenic ED respond to lower doses of alprostadil?

Psychogenic ED

What SEs are seen with intracavernosal alprostadil?

Local burning/dull pain, injection site infection, cavernosal plaques or fibrotic areas (switch injection site around), priapism (rare)

What are SEs of alprostadil intraurethral suppository?

Urethral damage, stricture, difficulty voiding, fibrosis

*less bioavailability than intracavernosal

What is the MC adverse effect of penile prostheses / implant (malleable or inflatable)?

Post op infection

What are treatment options for BPH?

Watchful waiting, alpha 1 antagonists, 5a reductase inhibitors, PDEIs, anticholinergic, surgery

What stimulates the epithelial (glandular) tissue of the prostate?

Androgens (DHT)

What stimulates the stromal (smooth muscle) tissue of the prostate?

a1 adrenergic receptors (NE, estrogen)

Static or dynamic factors of BPH?

• size → prostatic enlargement physically blocks bladder neck & obstructs urinary flow

• slower changes

• can be caused by

  • androgen stimulation on epithelial tissue

  • estrogen stimulation on stromal tissue

Static

Static or dynamic factors of BPH?

• squeeze → excessive a-adrenergic tone on stromal tissue, bladder neck & posterior urethra

• prostate can be normal in size

• faster changes

• can be triggered under stress or pain

Dynamic

What medications can worsen symptoms of BPH?

Testosterone replacement → inc DHT, more prostate growth

Adrenergic agonists (pseudoephedrine, ephedrine, phenylephrine) → activates stromal tissue

Anticholinergics (antihistamines, phenothiazines, TCAs) → dec detrusor muscle contraction, inc urinary retention

A patient with a history of BPH recently had a cold and took OTC pseudoephedrine. What symptom would you expect them to experience?

*example from lecture

Difficulty voiding bc pseudoephedrine is an adrenergic agonist & stimulates stromal tissue, causing constriction

BPH treatment algorithm

test questions!!!

A patient with an enlarged prostate (BPH) and history of ED comes in to the office. What medication do you start them on?

**test Q

PDEI and/or a adrenergic antagonist

A patient with BPH has an enlarged prostate and increased PSA. What medication do you start them on?

**test Q

5 a reductase inhibitor +/- a adrenergic antagonist

A patient with BPH has a small prostate and low PSA. What medication do you start them on?

**test Q

a adrenergic antagonist

A patient with BPH has predominant irritative voiding symptoms (frequency, urgency, bedwetting, nocturia). What medication do you start them on?

**test Q

a adrenergic antagonist + anticholinergic

The following sx are seen in what condition?

• Obstructive: bladder outlet obstruction, dec flow rate, incomplete & slow bladder emptying, hesitancy, bladder overdistension

• Irritative: bladder hypertrophy & hypersensitivity, urinary frequency, urgency, bedwetting, nocturia

• Lower urinary tract sx (LUTS): neurogenic bladder, UTI

BPH

What are the pharmacologic treatment options for BPH?

Dynamic sx → a1 blockers to relax smooth muscle

Static sx → 5 a reductase to inhibitors to dec testosterone stimulation, shrink prostate

irritative sx → antimuscarinics to relax detrusor

What meds are generally first line for BPH because they are rapid acting and have fewer SEs?

a1 antagonists

What meds are preferred for BPH in CV patients or significantly enlarged prostates?

5a reductase inhibitors

What must you ensure a BPH patient does not have before prescribing anticholinergics?

High post void residual (relaxes bladder & increases urinary retention)

What drug is a first generation a1 adrenergic antagonist that is generally avoided in BPH treatment due to tachycardia & arrhythmia SEs?

Phenoxybenzamine

Which generation of alpha 1 adrenergic antagonists are better for BPH because they are euro-selective for blocking a1A receptors (less SEs)?

Third generation

Do a1 adrenergic antagonists affect prostate size?

No

What drugs are second generation a1 adrenergic antagonists?

Prazosin (Minipress)

Terazosin (Hytrin)

Doxazosin (Cardura)

Alfuzosin (UroXatral)

What are the main SEs of second gen a1 blockers?

First dose syncope, orthostatic hypotension, dizziness

(dose at nighttime to avoid)

Which 2nd gen a1 blocker is the shortest acting, requires BID-TID dosing, & has the most significant CV effects?

Prazosin

Which 2nd gen a1 blockers are the longest acting & have lower average serum concentrations?

Doxazosin & alfuzosin

Which 2nd gen a1 blocker has the lowest risk of systemic SEs and does not require dose titration?

Alfuzosin

What drugs are 3rd generation a1 adrenergic antagonists?

Tamsulosin (Flomax)
Silodosin (Rapaflo)

Which 3rd gen a1 blocker is used most often, needs to be taken on an empty stomach, & should be avoided in a sulfa allergy?

Tamsulosin

What SEs are seen with 3rd gen a1 blockers?

Flu like sx, nasal congestion, inability to ejaculate

*no orthostasis/dizziness

What is the safest combo of PDEIs & a1 blockers to use in BPH?

*least likely to cause cause synergistic drops in BP

Tadalafil & tamsulosin

What drugs are 5a reductase inhibitors?

Finasteride (Proscar) - type II inhibitor

Dutasteride (Avodart) - non selective

What drug for BPH is good for patients who cannot tolerate a1 blockers and ma reduce the prevalence of prostate cancer over time?

5a reductase inhibitors

What should be used in BPH for enlarged prostates > 40 g to shrink prostate by blocking the conversion of testosterone into DHT?

5a reductase inhibitors

What drug is 2nd line for BPH in sexually active men due to the increased incidence of sexual SEs (gets rid of DHT which is potent form of testosterone)?

5a reductase inhibitors

Which has a slower onset, a1 blockers or 5a reductase inhibitors?

5a reductase inhibitors

Why is it necessary to continue use of 5a reductase inhibitors long term for BPH?

Prostate size & sx will return if stopped

What SEs are associated with 5a reductase inhibitors?

ED, decreased libido, ejaculation disorders, HA, N, abd pain, gynecomastia, pregnancy category X

How do PDEIs work to treat BPH?

Prevent breakdown of cGMP and cause smooth muscle relaxation around prostate & bladder neck

Which PDEI is preferred to use in BPH treatment?

Tadalafil

What is the gold standard treatment for moderate to severe BPH unresponsive to drug therapy?

Prostatectomy

What is stress urinary incontinence?

Urethral underactivity→ inadequate urethral closing pressure causes episodic low volume leakage with activity (sneeze, exercise, etc)

What drugs aggravate urethral under activity (stress urinary incontinence)?

Alpha antagonists → releases smooth muscle & decreases closing pressure

ACEI → can cause coughing

A patient with stress urinary incontinence is started on an ACEI, but experiences increased coughing. Which drug should they be switched to?

ARB

What is urge urinary incontinence?

bladder overactivity → leakage w/ urgency (desire to void) due to involuntary contractions of detrusor

What can worsen urge urinary incontinence (bladder overactivity)?

Diuretics & alcohol

What is overflow incontinence?

Leakage d/t filled bladder unable to empty (chronic urinary retention)

urethral hyperactivity (MCC BPH) & bladder under activity (outlet obstruction, DM, etc)

What medications can worsen urethral hyperactivity (overflow incontinence)?

TCAs→ anticholinergic properties

Alpha-agonists→ squeezing on a receptors to close urethra

What medications can decrease bladder contractility (overflow incontinence)?

Anticholinergics, TCAs, CCBs, antipsychotics

What kind of urinary incontinence has the following presentation?

• leakage with physical exertion

Stress UI (urethral UNDERactivity)

What kind of urinary incontinence has the following presentation?

• urinary frequency (>8 times a day)

• urgency

Urge UI (bladder OVERactivity)

What kind of urinary incontinence has the following presentation?

• lower abdominal fullness

• hesitancy

• incomplete bladder emptying

• ± frequency & urgency

Overflow UI (urethral OVERactivity & bladder UNDERactivity)

What is the first line treatment for mild-mod UI?

Non pharmacologic- behavioral interventions, lifestyle mods, toilet scheduling regimens, pelvic floor rehabilitation

What drugs are anticholinergics used to treat urge UI?

Oxybutynin

Tolterodine

Trospium

Solifenacin

Darifenacin

Fesoterodine

What is first line RX for urge UI?

Anticholinergics

How do anticholinergics work to treat urge UI?

Antagonize muscarinic receptors & suppress premature detrusor contractions → allows bladder to relax & accommodate bigger volumes of urine

What SEs are seen with anticholinergics?

Blind as a bat: mydriasis, blurred vision

Mad as a hatter: AMS

Red as a beet: flushing/vasodilation

Hot as a hare: hyperthermia, dec sweating

Dry as a bone: dry mouth, skin, mucus membranes

Bowel & bladder lose their tone: urinary retention, constipation

Heart runs alone: tachycardia

What are CIs to anticholinergics?

Urinary retention, gastric retention, decreased GI motility, uncontrolled narrow angle glaucoma, MG

Why are anticholinergics not good for elderly?

AMS, falls