IC18 BPH + ED Flashcards
What is the definition of BPH? (3 points)
Benign Prostatic Hyperplasia
Definition:
- Lower urinary tract signs and symptoms (LUTS)
- Negatively impact on QOL
- Non-malignant growth of prostate components e.g. transitional zone
What is the physiology of the prostate?
Physiology of prostate:
- Epithelial (glandular) tissue –> androgens stimulate its growth
a. Testosterone is converted to dihydrotestosterone (DHT) by Type II 5α-reductase in prostate
b. DHT is needed in normal growth and enlargement of prostate - Stromal (smooth muscle) tissue –> innervate by α1 adrenergic receptors
What is the pathogenesis of BPH?
Pathogenesis
- Mainly age and hormonal factors
- Static component:
Hormonal factors
testosterone –> DHT
Enlargement of prostate tissue - Dynamic Component:
Increase smooth muscle tissue and agonism of α1-receptors (vasoconstriction)
Narrowing of urethra outlet
–> Urethral obstruction / Signs and symptoms
Long Term
- Bladder response to obstruction
o Early phase: bladder muscle force urine through narrowed urethra by contracting more forcefully
o Over time: bladder muscle gradually becomes thicker (hypertrophy) to overcome obstruction
o Once reach highest state of hypertrophy, muscle decompensates
o Detrusor muscle becomes irritable and/or overly sensitive (detrusor overactivity or instability), contracting abnormally in response to small amounts of urine –> increase frequency of urine
What are the S&S of BPH?
Signs and Symptoms
Commonly asymptomatic, symptoms only occur in 1/3 men who are >65y/o
LUTS:
- Weak stream
- Increase frequency
- Nocturia
- Intermittent stream (urinary stream is not continuous)
- Incomplete emptying
- Straining
- Increase urgency
*LUTS not specific to BPH, other things can cause LUTS
e.g. prostate/bladder cancer, UTIs, diabetes mellitus
Obstructive /Voiding Symptoms
(early BPH):
- Hesitancy
- Weak stream
- Sensation of incomplete emptying
- Dribbling
- Straining
- Intermittent flow
Irritative/Storage symptoms
(Late BPH)
[Occurs after several years of untreated BPH]:
- Dysuria
- Nocturia
- Increase frequency (overly sensitive so can’t control when you have a small amt of urine)
- Increase urgency
- Urinary Incontinence (loss of bladder control, involuntary peeing)
What are the classifications of symptoms (severity) for BPH?
Severity AUA – SI score Usual Signs and Symptoms:
- Mild <= 7 Asymptomatic or mildly symptomatic
- Moderate 8-19 All of the above s/s AND Have obstructive voiding and irritable voiding symptoms
- Severe >= 20 Signs and symptoms AND complications
Complications:
- Recurrent UTI
- Bladder stones
- Acute urinary retention
- Urinary incontinence
- Hematuria
(Consider transurethral resection of prostate (TURP) when have complications)
What are the test and cut offs when evaluating BPH?
Assessment of BPH:
- Digital Rectal exam – normal prostate should be smooth
- Ultrasonography
- Maximum urinary flow rate (Qmax) – if there is some sort of obstruction, will have weak stream
- Prostate Specific Antigen (PSA)
a. The bigger the prostate, the higher the PSA
b. Predict progression of BPH –> PSA > 1.5 ng/mL
c. Higher risk of prostate cancer - Postvoid Residual (PVR)
a. <100 mL normal
b. >200 mL – inadequate emptying
What are the medications that can worsen BPH? (5 meds)
- Anticholinergics
e.g. antihistamines, tricyclic antidepressants, anti-muscarinic
- Decrease bladder muscle contractability -> increase urinary retention
- Alpha1 adrenergic agonist e.g. decongestant
- Contraction of prostate smooth muscles
- Opioid analgesic –> Increase urinary retention
- Diuretics –> Increase urine frequency
- Testosterone –> Increase prostate growth
When to start therapy for BPH? What to do if mild symptoms?
Management + when to start pharmacological therapy:
- As long as BPH does NOT affect QOL/not bothered, just watch and assess annually + non-pharm (be it mild, moderate or severe)
- START medications when moderate to severe and are bothered by symptoms
- Assess using AUA-SI score annually
- Advise regarding non-pharmacological
What are the non-pharm management of BPH?
Non-pharmacologicals
- Drink less water in the evening –> reduce urine frequency
- Eat less caffeine and drink less alcohol –> reduce urine frequency
- Take time to completely empty bladder
- Avoid medications that worsens BPH (anticholinergics, alpha receptor agonist, opioids analgesics, diuretics, testosterones)
What is the MOA of alpha 1 Receptor antagonist?
MOA
Mod-severe with small prostate (<40g)
Reversibly inhibit alpha1 adrenergic receptors
–> reduce smooth muscle contraction and cause vasodilation (dynamic component)
Non-selective (blood vessels, heart, peripheral, LUT)
- E.g. Doxazosin, Terazosin, Prazosin (not reco in BPH)
- Titrate dose slowly –> due to hypotension and syncope
Uroselective (blood vessel, prostate, LUT)
- E.g. Alfuzosin, Tamsulosin, Silodosin
NO effect on prostate size, prevention of BPH progression, need for surgery and PSA
Fast onset (days to weeks)
What are the non-selective alpha blockers?
Doxazosin, terazosin, prazosin
What are the uro-selective alpha blockers?
Alfuzosin, tamsulosin, silodosin
What are the ADRs of the class, non-selective and selective alpha blockers?
ADR
- Muscle weakness
- Fatigue
- Ejaculatory disturbance
- Headache (thus give bedtime dose)
Non-selective:
- Orthostatic hypotension
- 1st dose Syncope
- Dizziness
Uroselective:
- Ejaculatory disturbances (delayed or retrograde ejaculation)
- Silodosin > Tamsulosin > Alfuzosin
- (Tamsulosin) Intraoperative floppy iris syndrome
- CI in cataract surgery
- Block a1 receptors in iris dilator muscle
- Avoid starting until surgery is complete
What are the special considerations for using non-selective alpha blockers and selective alpha blockers?
Special Considerations
- Non-selective ARA:
o Use if need additional blood pressure lowering effect
o Avoid in patients at risk of syncope
o Should NOT be given as monotherapy for patients with BPH and HTN, need give with other meds - Selective ARA
o Used if don’t need extra anti-hypertensive effects
When to consider adding 5aRI? What is the MOA of 5aRI?
MOA
Mod-severe with large prostate (>40g)
Consider adding if PSA > 1.5ng/mL
Competitively bind to 5alpha reductase
- prevent the conversion of testosterone to DHT by 5alpha reductase
- less DHT
- reduce size of prostate (static component) + slows BPH progression + need for surgery
- Reduces PSA (obtain PSA before starting therapy)
E.g. Finasteride, dutasteride
Slow onset (6 months to a year)
What is the ADR of 5aRI?
ADR (More sexual dysfunction that Alpha1 ARA)
- Ejaculatory disorders
- Loss of libido
- ED (due to less DHT)
- Gynecomastia and breast tenderness
What is the CI for 5aRI?
Special Considerations CI:
- Women, children, pregnancy
Which PDE5i is used for BPH? How is PDE5i often used in clincial practise for BPH?
ONLY Tadalafil allowed for BPH
Adjunct therapy for BPH
What is the counselling tips for use of PDE5i? (When to take in general)
Counselling tips
- Take without regard to timing of sexual activity (becos it will only cause an erection when have sexual stilmulation)
What is the MOA of anti-muscarinic?
MOA:
Used ONLY when have irritable or overly sensitive bladder (late BPH, urinary frequency and nocturia)
Given when PVR < 250mL(can’t be more than this if not burst)
Blocks the muscarinic receptors in detrusor muscles of bladder
- Reduce involuntary contraction of bladder
- Reduce urinary incontinence
An anti-cholinergic medication (counterintuitive since these meds cause BPH)
- But works since this medication can help to reduce urine frequency
When do we use combi therapy for BPH?
What are the diff combis?
Combination Therapy:
When to use:
- Moderate LUTS symptoms (8-19) AND prostate > 25g
1. Alpha1 ARA + 5aRI
2. 5aRI + PDE5i
3. Alpha1 ARA + PDE5i
What are examples of A blockers + 5aRI? What is the benefit?
Alpha1 ARA + 5aRI
- E.g. Doxazosin (NS) + Finasteride OR Tamsulosin (S) + Dutasteride
- One acts on dynamic (within weeks) while the other works on the static component (require months)
What is 5aRI + PDE5i best used for? Why?
5aRI + PDE5i
- Best combi for patients with BPH and ED
- Cancel each other out wrt ED (5alpha RI cause ED while PDE5i treats ED)
What to look out for when using A blocker + PDE5i?
Alpha1 ARA + PDE5i
- Rare
- High risk of severe life-threatening hypotension
- Use uroselective Alpha1 ARA
- Want to use lowest dose for both
- Start with Alpha1 ARA and stabilize on it before adding PDE5i
- Would NOT address prostate enlargement
Define ED and which group of people is it most common in?
Definition:
- Persistent (6 months) inability to achieve or maintain an erection of sufficient duration and firmness to complete satisfactory intercourse
- ED increases with age
- Common among men > 40y/o
Describe the flaccid state and physiology of erection.
Physiology:
Flaccid State
- blood flow into and out of penis is balanced
Erection
- arterial blood flow into penis > venous outflow
- Parasympathetic system activated – by acetylcholine (ACh)
o ACh increase NO production –> increase guanylate cyclase activity –> increase cyclic guanosine monophosphate (cGMP)
o ACh and prostaglandins E –> increase adenyl cyclase activity –> increase cAMP - Causes smooth muscle to relax + vasodilation
o Corpora cavernosa fills up with blood (increase inflow)
o Swelling causes compression of the venules against tunica albuginea (decrease outflow) - Testosterone
o encourages libido
o normal amounts: 300-1100ng/dL (10.4-38.2 nmol/L)
o low amounts of testosterone alone does not indicate ED –> thus mainly look if have ED symptoms
Describe the physiology of detumescence.
Detumescence
- Deactivate Parasympathetic system
- Phosphodiesterase type 5 (PDE-5) deactivates cGMP –> stops vasodilation
- PDE-5 predominantly found in penis
- Activate sympathetic system
- Activation of α2 adrenergic receptors on arterioles –> induce smooth muscle contraction –> reduce blood flow
- Serotonin
- Inhibit sexual arousal
What are the 4 broad possible causes of ED?
- Organic ED
(physical, 80% of all ED causes) - Psychogenic ED
(mental) - Mixed ED
- Others
(risk factors)
What are the possible causes of organic ED?
Organic ED:
(physical, 80% of all ED causes)
- Vascular systems compromised (vessels become narrow)
o Arteriosclerosis
o Peripheral vascular disease (PVD)
o HTN
o Diabetes - Nervous systems compromised (parasympathetic affected)
o Central:
Spinal cord trauma or disorders
Stroke
CNS tumours
o Peripheral:
Diabetes
Neuropathy
Urethral surgery - Hormonal systems compromised
o Hypogonadism (not enough testosterone)
o Hyperprolactinemia (too much prolactin suppresses testosterone production) - Medication induced **(table below)
What are the possible psychogenic ED causes?
Psychogenic ED
(mental) - due to thoughts or feelings (psychological reasons) rather than physical pathology
o malaise
o loss of attraction
o stress
o performance anxiety
o mental disorders
o sedation
What are the other causes of ED?
Others
(risk factors)
- Social habits: smoking,
- excessive ethanol intake,
- illicit drug use
- Obesity
What are the medications that can cause ED?
Medications that induce ED Possible MOA Alternatives
- BP meds:
- Clonidine, methyldopa, beta blockers (except nebivolol), thiazides diuretics
- Decrease penile blood flow
- Nevibolol, ACEi, ARBs, Loop diuretics
- Anticholinergics (TCAs, 1st gen antihistamines, phenothiazines etc.)
- Decrease ACh activity –> decrease parasympathetic system activity
- Bupropion, trazodone, 2nd gen antihistamines, 2nd gen atypical antipsychotics - Dopamine antagonist (e.g. metoclopramide)
- Dopamine related to cause sexual arousal or stimulation
- PPIs, erythromycin
- Selective serotonin reuptake inhibitors (SSRIs)
- Increase serotonin in brain / decrease testosterone - Bupropion, trazadone
- Finasteride, Dutasteride
- Decrease testosterone
- Terazosin, alfuzosin etc.
- CNS depressants e.g. benzodiazepines, anticonvulsants
- Suppress perception of psychic stimulus
- Anticonvulsant: valproic acid or gabapentin
What to look out for when evaluating for ED?
Evaluation of ED:
- Signs and Symptoms/Complications:
a. Inability to achieve an erection
b. Loss of interest in sexual activities
c. Depression
d. Performance anxiety
e. Embarrassment
f. Angry
g. Low self-esteem
h. Disharmony in relationship - Sexual Health Inventory for Men:
- Mild to No ED: 17-21 points
- Moderate to severe: < 11 points - Find underlying causes
- Evaluate for CVD
a. ED might be an early symptoms of CVD
b. Sexual activity –> increase BP + HR –> increases risk of MI
c. If low risk: ok
d. If unknown risk / not low risk:
i. Exercise stress testing to evaluate exercise capacity
e. If unstable or severe symptomatic CVD:
i. hold off until condition stabilized - Cardiac rehabilitation + regular exercise –> reduce risk of CV complications with sexual activity
What are the non-pharm management of ED?
Non-pharmacological
- Modify risk factors
a. Smoking cessation
b. Control weight
c. Control glucose / BP / lipids
d. Exercise
e. Decrease alcohol - Psychotherapy
- Vacuum erection devices
- Surgery e.g. penile implant
What is the MOA of PDE5i?
MOA 1st line for ED
Inhibit PDE5 (concentrated at the penis)
e.g. Sildenafil, vardenafil, tadalafil, avanafil
reduce deactivation of cGMP
more cGMP
smooth muscle relaxation + vasodilation
erection
ONLY after sexual stimulation, then will cause erection
Good for those with BPH and ED
Fast onset (days to weeks)
What are the ADR of PDE5i?
ADR
- Hypotension
- Muscle and back pain
- Flushing
- Rhinitis
- Headache
- Dizziness
- Priapism (emergency if >4hrs)
- Sudden hearing loss
- QTc prolongation (vardenafil)
- Muscle pain (tadalafil with PDE 11 affinity)
- Ocular problems (sildenafil, vardenafil)
- Color discrimination
- Light sensitivity
- If sudden vision loss or decreased vision –> seek medical attention immediately
What are the DDIs of PDE5i?
DDI:
- GTN in angina (since both meds increase cGMP, can cause severe hypotension)
- 12 hours after avanafil
- 24 hours after sildenafil and vardenafil
- 48 hours after tadalafil - Multiple anti-hypertensive drugs
- Alcohol –> hypotension
- CYP3A4 inhibitors
What are the counselling tips for PDE5i? When to use low dose PDE5i?
Counselling tips Sildenafil:
- Empty stomach
- Hepatic and renal dose adjustment needed
- prn
Vardenafil:
- Empty stomach
- Hepatic dose adjustment needed
- prn
Tadalafil
- Regardless of food
- Hepatic and renal dose adjustment needed
- Take daily
- 36hrs before sexual activity (due to its long lasting effect)
Avanafil:
- Regardless of food
- prn
Lower dose:
- > 65 y/o (due to risk of orthostatic hypotension)
- On alpha blockers
- Renal failure
- CYP3A4 inhibitor e.g. erythromycin, cimetidine, ketoconazole, grapefruits or juice, ritonavir increase PDE5i concentrations
What to monitor for when using PDE5i?
Monitoring Efficacy:
- If failure reported
o Administration with food? (Sildenafil, vardenafil)
o Timing and frequency of dosing
o Lack of adequate sexual stimulation
o Titration to max dose
Safety:
- BP
- ADR
- DDI
- Change in cardiac health status
When do we use testosterone replacement?
What is the ROA?
What is the MOA?
What is the normal range of testosterone?
MOA:
Normal range: 300-1100ng/dL
1st line for ED AND symptomatic hypogonadism –> symptoms e.g. reduced libido + low testosterone levels
IM route
What are the ADRs of testosterone replacement therapy?
ADR
- Irritability
- Aggressive behaviour
- Hair growth
- Increase BP
- Hepatotoxicity
- Dyslipidemia
- Polycythemia (high RBC)
- Prostatic hyperplasia
What is the CI for testosterone replacement therapy?
CI:
- Patients with prostate cancer
What is the MOA for Alprostadil? When should patients administer it?
MOA Stimulate adenylyl cyclase
- Increase cAMP
- Induce smooth muscle relaxation
- Erection
Do NOT require sexual stimulation to work (give right before sexual activity)
Fast onset
What are the ADRs of Intraurethral and intracarvernosal alprostadil?
ADR Intraurethral alprostadil
- Pain
- Warmth
- Burning sensation in urethra
- Voiding difficulties
- Bleeding and spotting
- Priapism
- Partners have vaginal burning and itching
Intracavernosal alprostadil (better efficacy, common)
- Priapism
- Bleeding
- Hematoma (pool of clotted blood)
- Fibrosis
What is the DDI of alprostadil?
DDI:
- PDE5i
What is a counselling tip for the use of alprostadil?
For the intracavernosal alprostadil, inject at the sides of the penis and not the top or base
What is the MOA of yohimbine?
Alpha2 antagonist for ED
NOT recommended
