Therapeutics I Exam III - BPH/ED/Testosterone

what are the static factors of BPH

anatomic obstruction of the bladder neck caused by an enlarged prostate gland (as gland grows around urethra, prostate occludes the urethral lumen)

what are the dynamic factors of BPH

excessive stimulation of α1A-adrenergic receptors (~70% of prostate) in the smooth muscle of the prostate, urethra, and bladder neck, which results in smooth muscle contraction

what are the detrusor factors of BPH

-bladder detrusor muscle hypertrophy in response to prolonged bladder outlet obstruction

-hypertrophic detrusor muscle becomes irritable, contracting abnormally in response to small amounts of urine in the bladder => storage voiding symptoms

why does hypertrophy occur in the bladder

so bladder can generate higher pressure to overcome bladder outlet obstruction

what happens if the hypertrophic detrusor muscle is not treated

bladder muscle with decompensate and be unable to empty completely

what are 3 facts about the dynamic factors of BPH

-reduces the caliber of the urethral lumen and causes obstructive voiding symptoms

-stromal tissue is the primary focus of alpha-1A adrenergic receptors in the prostate

- ~98% of alpha adrenergic receptors in the prostate are found in prostatic stromal tissue

what are the signs of BPH

-enlarged prostate on digital rectal exam

-check for prostate nodules or indurations (suggest prostate cancer instead of BPH)

-distended urinary bladder

-rule out meatal stenosis or urethral stricture

-check anal sphincter tone as indirect assessment of peripheral innervation to detrusor muscle of bladder

what are the symptoms of BPH

-urinary hesitancy (obstructive)

-decreased force of urinary stream (obstructive)

-straining to void (obstructive)

-intermittency (obstructive)

- urinary frequency (irritative)

- nocturia (irritative)

- urgency with or without incontinence (irritative)

- dribbling (post micturition)

- incomplete bladder emptying (post mictrurition)

treatment goals for patients with BPH

- slowing disease progression; when compared with baseline, symptoms and signs of BPH, serum blood urea nitrogen (BUN), and creatinine should improve, stabilize, or decrease to the normal range with treatment

- preventing disease complications and reducing the need for surgical intervention

- avoiding or minimizing adverse treatment effects

- providing economical therapy

- maintaining or improving quality of life

how do you go about stratifying the severity of symptoms of BPH

what are some non-pharmacologic therapies and medications to avoid in BPH

- stop drinking fluids 3-4 hours before bedtime and pee before going to sleep

- time urination every 2-3 hours

- avoid excessive intake of caffeine-containing beverages, sugar sweetened drinks, and alcohol

- avoid taking non-prescription meds that can worsen obstructive urination symptoms (antihistamines and decongestants)

- take diuretic in morning

- smoking cessation

- lose excessive weight

which medications relax prostatic smooth muscle

alpha adrenergic antagonists and tadalafil

which medications reduce size of enlarged prostate

5-alpha reductase inhibitors

which medications are useful in patients with enlarged prostates

alpha-adrenergic antagonists (works independent of the size of the prostate), 5-alpha reductase inhibitors, anticholinergics, and tadalafil

which medications reduce the frequency of BPH-related complications

5-alpha reductase inhibitors

which medications reduce the frequency of BPH-related surgery

5-alpha reductase inhibitors

what is the frequency of dosing of alpha-adrenergic antagonists

once or twice daily, depending on the agent and the dosage formulation

what is the frequency of dosing of 5-alpha reductase inhibitors

once daily

what is the frequency of dosing of anticholinergic agents

once or twice daily, depending on the agent

what is the frequency of dosing of tadalafil

once daily

what is the frequency of dosing of mirabegron

once daily

do alpha adrenergic antagonists require up-titration of dose

yes (for terazosin and doxazosin IR); no (for alfuzosin or silodosin, possibly for doxazosin ER and tamsulosin)

what is the peak of onset of alpha-adrenergic antagonists

days to 6 weeks, depending on need for dose titration

what is the peak of onset of 5-alpha reductase inhibitors

6 months

what is the peak of onset of anticholinergic drugs

days

what is the peak of onset of tadalafil

days

what is the peak of onset of mirabegron

2-8 weeks

which medications decrease PSA

5-alpha reductase inhibitors

which medications have cardiovascular side effects

alpha adrenergic antagonists (hypotension), anticholinergic agents (tachycardia), tadalafil (hypotension), mirabegron (hypertension and tachycardia)

which medications cause drug-induced sexual dysfunction

alpha adrenergic antagonists (ejaculation disorders), 5-alpha reductase inhibitors (decreased libido, ED, ejaculation disorders), anticholinergic agents (ED)

what are the significant drug interactions with alpha adrenergic antagonists

antihypertensives, CCBs, beta-adrenergic antagonists, CYP3A4 inducers and inhibitors

what are the significant drug interactions with 5-alpha reductase inhibitors (dutasteride only)

CYP3A4 inhibitors

what are some significant drug interactions with anticholinergic agents

drugs with anticholinergic effects/side effects, drugs that prolong QT interval, CYP3A4 inhibitors and inducers

what are some significant drug interactions with tadalafil

nitrates, drugs that prolong QT interval, CYP3A4 inhibitors and inducers, and alpha-adrenergic antagonists

what are some significant drug interactions with mirabegron

CYP2D6 substrates and drugs that prolong the QT interval

what are some common adverse effects of mirabegron

headache, HTN, tachycardia, constipation, and nasopharyngitis

what patient population is most likely to be affected by BPH

men over 40 years old (increasing risk with increasing age)

what effects do testosterone and estrogen have on the prostate

-testes and adrenal glands produce 90% and 10% of circulating testosterone

-testosterone enters prostate cells, where predominantly Type II 5α-reductase converts testosterone to dihydrotestosterone, which combines with a cytoplasmic receptor

-an alteration in the testosterone: estrogen ratio occurs in overweight men because of testosterone conversion to estrogen in adipose tissue, which may contribute to the development of BPH

-unused testosterone is converted to estrogen peripherally, which contributes to gynecomastia

-stromal tissue growth may be stimulated by estrogen, which is derived from peripheral tissue conversion of testosterone

what are obstructive urination symptoms

urinary hesitancy, decreased force of urinary stream, straining to urinate, and intermittency

what are irritative urination symptoms

urinary frequency, nocturia, and urgency with or without incontinence

how much should the AUA symptom score be reduced

30-50% or at least by three or more points

what is AUA symptom score for the mild category

0-7

what is the AUA symptom score for the moderate category

8-19

what is the AUA score for the severe category

20+

what are some common medication classes that can cause or worsen urination symptoms

- androgens

- alpha adrenergic agonists

- anticholinergic agents (antiarrhythmics, antihistamines, anti parkinson's, TCAs)

- caffeine

- CCB

- anticonvulsants

- thiazide diuretics and loop diuretics

- antidepressants, SSRIs

- opiates

- sedatives

which alpha adrenergic antagonists are uroselective

alfuzosin (functionally/clinically), tamsulosin (pharmacologically), and silodosin (pharmacologically)

what are the non-selective alpha-1 blockers

tamsulosin and silodosin

what do terazosin and doxazosin target

alpha 1A and 1B (vasodilation -> lower BP)

what are non-selective alpha-1 blockers good for

patients with both BPH and hypertension

what is a big side effect of terazosin and doxazosin

orthostatic hypotension (especially first dose)

what can be done to minimize first-dose hypotension

take at bedtime

how does titration work for non-selective alpha-1 blockers

require slow titration

what are some pros about uroselective alpha-1 blockers

fewer cardiovascular side effects and less concern with timing related to hypotension

what are the uroselective alpha-1 blockers

tamsulosin and silodosin

what are the titration parameters of uroselective alpha-1 blockers

often without titration

which alpha-adrenergic antagonists are preferred for patients at risk of hypotension, tolerate hypotension poorly, or have CAD or orthostatic hypotension

tamsulosin and silodsin

what is finasteride

selective type II isoenzyme inhibitor of 5-alpha reductase

what is dutasteride

nonselective inhibitor of both isoenzymes of 5-alpha reductase

what does dutasteride do differently than finasteride

dutasteride produces a faster and more complete inhibition of 5-alpha reductase in prostate cells

is there a difference in clinical efficacy between finasteride and dutasteride

no, takes a minimum of 6 months t evaluate the full clinical effectiveness of treatment (disadvantage in patients with moderate to severe symptoms)

are finasteride and dutasteride therapeutically equivalent

yes

what are the side effects of finasteride and dutasteride

sexual dysfunction, decreased libido, ED, ejaculation disorders, and gynecomastia

what side effects does finasteride cause that dutasteride does not

chronic fatigue, penile and scrotal shrinkage, persistent sexual dysfunction and gynecomastia after discontinuation

if needed, how long should a patient receive combo therapy for BPH

minimum of 4 years

why are 5-alpha reductase inhibitors teratogenic

may cause feminization of a male fetus

what precautions are recommended for women handling 5-alpha reductase inhibitors

use gloves when handling

when are anticholinergics indicated to treat BPH

when a patient has bothersome irritative urination symptoms despite treatment with an alpha-1 adrenergic antagonist

when are PDE-5 inhibitors indicated to treat BPH

reserved for patients with both BPH and ED, or those patients with LUTS that are not responsible for alpha-adrenergic antagonists (can be alone or with alpha-antagonists/5-alpha reductase inhibitors)

when is mirabegron indicated to treat BPH

in patients who poorly tolerate or are at high risk of anticholinergic adverse effects, or when irritative urinations symptoms do not respond to an anticholinergic agent

what patient populations are most likely to develop ED

61% in men aged 40-69 years and 77% in men older than 70 years

what is organic dysfunction

abnormalities in the vascular, hormonal, or neurologic systems or may be medication induced

what is psychogenic dysfunction

performance anxiety, strained relationships, lack of sexual arousability, and overt psychiatric disorders such as depression and schizophrenia

what types of lifestyle modifications may improve ED symptoms

- a healthy diet

- increases in regular physical activity

- weight loss

- smoking cessation

- reduction in excessive alcohol intake

- the discontinuation of illicit drug use

what is a vacuum device

creating a vacuum around the penis; the negative pressure draws blood into the penis by passively dilating arteries and engorging the corpora

what are some advantages of vacuum devices

can be used as often as needed; more acceptable to older patients in stable relationships and infrequent sexual encounters; do not have to deal with cost barrier of oral meds; high efficacy rates (90%)

what is a disadvantage of vacuum devices

don't use longer than 30 minutes

what are some advantages of alprostadil

onset of action is within 5 to 10 minutes and it is effective for 30 to 60 minutes; most appropriate for patients in long-term stable relationships (or people who are paralyzed)

what are some disadvantages of alprostadil

slow onset of action (limits spontaneity); cold, lifeless, discolored penis; painful ejaculation or the inability to ejaculate

what is the time to onset of sildenafil and vardenafil

60 minutes

what is the time of onset of tadalafil

30-60 minutes

what is the time of onset of avanafil

15 minutes

which PDE-5 inhibitors have their onset delayed by a high-fat meal

sildenafil and vardenafil (not ODT version though)

what is the duration of effect of sildenafil

up to 4 hours

what is the duration of effect of tadalafil

up to 36 hours

what is the duration of effect of vardenafil and avanafil

up to 6 hours

what is the half life of sildenafil

3-4 hours

what is the half life of tadalafil

18 hours

what is the half life of vardenafil

4-6 hours

what is the half life of avanafil

5 hours

what is the metabolism of sildenafil

CYP3A4 (major) and CYP2C9 (minor)

what is the metabolism of tadalafil

CYP3A4

what is the metabolism of verdenafil

CYP3A4 (major), CYP3A5 (minor), CYP2C9 (minor)

what is the metabolism of avanafil

CYP3A4 (major) and CYP2C9 (minor)

what are clinically relevant drug interactions of sildenafil

nitrates, alpha-1 blockers, protease inhibitors, azole antifungals, erythromycin, and grapefruit

what are clinically relevant drug interactions of tadalafil

nitrates, alpha-1 blockers, protease inhibitors, azole antifungals, and erythromycin

what are clinically relevant drug interactions of vardenafil

nitrates, alpha-1 blockers, anti-arrhythmic agents, erythromycin, and grapefruit

what are clinically relevant drug interactions of avanafil

nitrates, alpha-1 blockers, protease inhibitors, azole antifungals, erythromycin, and grapefruit

what is the recommendation regarding use of PDE inhibitors with nitrate therapy

all four PDE-5 inhibitors are absolutely contraindicated in patients taking any form of nitrate, whether scheduled or as needed for acute situations

what does the combo of PDE 5 inhibitors and nitrates cause

severe hypotension and sometimes death

what are some chronic medical conditions contraindications to PDE 5 inhibitor therapy

HTN, diabetes, BH, CAD and PAD, neurologic disorders, endocrine disorders, psychiatric disorders, dyslipidemia, renal failure, liver failure, and penile disease