Functional: Pharmacological Management of LUTS

Pharmacologic therapy to facilitate bladder storage

Background

• Detrusor muscle contracts in response to stimulation of muscarinic receptors by acetylcholine and by electric stimulation of intrinsic cholinergic nerves.
  • Pre-ganglionic parasympathetic nerves release acetylcholine (Ach)
  • This Ach acts on nicotinic receptors on post-ganglionic parasympathetic neurons on the bladder
  • In response to this Ach, post-ganglionic parasympathetic neurons release Ach which stimulates muscarinic receptors on the bladder smooth muscle, resulting in bladder contraction
  • Contractile responses can be completely abolished by atropine
• Muscarinic receptors
  • Coupled to G proteins, but the signal transduction systems may vary.
    • In general, M1, M3, and M5 receptors are considered to couple preferentially to Gq/11, activating phosphoinositide hydrolysis, in turn leading to mobilization of intracellular calcium.
    • M2 and M4 receptors couple to pertussis toxin–sensitive Gi/o, resulting in inhibition of adenylate cyclase activity.
  • 5 different subtypes based on molecular cloning and (4 different receptor subtypes based on pharmacology)
    • M1: thought to be involved in cognition.
    • M2: primary cholinergic receptor in the heart causing bradycardia when activated and tachycardia when blocked.
    • M3: primary role in salivation, bowel motility, and visual accommodation.
    • M4/M5 subtypes are not associated with dry mouth, constipation, tachycardia, drowsiness, blurred vision
    • M1 to M5 are all found in the bladder
      • M2 and M3 are the most common type of muscarinic receptors in the bladder, with M2 predominating at least 3:1 over M3 receptors
      • M3 receptors are the most important for contraction
        • Stimulation of M3 receptors by ACh induces calcium influx through L-type Ca2+ channels, as well as IP3 hydrolysis as a result of phospholipase C activation, resulting in the release of intracellular calcium, both of which contribute to a smooth muscle contraction
        • The functional role for M2 receptors is unknown.
          • M2 receptor stimulation may oppose sympathetically induced smooth muscle relaxation, mediated by β-ARs via inhibition of adenylyl cyclase
        • Muscarinic receptor subtype-mediated detrusor contractions shift from M3 to M2 receptor subtype in certain pathologic conditions, such as obstructed or neurogenic bladders

Increasing bladder storage

Anti-cholinergics

• Also known as muscarinic receptor antagonisits, anti-muscarinics, etc.
• Mechanisms of action (3):
  1. Decrease the activity in AFFARENT nerves (both C and Aδ fibers) from the bladder
     • Primary mechanism; anti-cholinergics act mainly during the storage phase (rather than the voiding phase)
       • During the storage phase
         • ACh is released from both neuronal and non-neuronal sources (e.g., the urothelium and suburothelium) and directly or indirectly (by increasing detrusor smooth muscle tone) excites afferent nerves in the suburothelium and within the detrusor
         • Normally no parasympathetic input to the LUT.
     • Since they act during the storage phase, they can be safely administered in men with bladder outlet obstruction as they do not alter urinary flow rate, voiding pressure, or incidence of urinary retention.
       • Caution should be used in large PVRs
  2. Blocking the muscarinic receptors on the detrusor muscle, which are otherwise stimulated by ACh released from activated cholinergic (parasympathetic) nerves.
     • Less significant effect than reducing AFFARENT activity
  3. Reduce the micromotions caused by the release of small packets of Ach
• In patients with involuntary bladder contractions (detrusor overactivity) of any cause, anti-cholinergics (5):
  1. Increase the volume to the first detrusor overactivity (affarent)
  2. Increase the total bladder capacity (affarent)
  3. Increase mean voided volume (affarent)
  4. Decrease urgency (affarent)
  5. Decrease the amplitude of the contraction (efferent)
• Do not affect detrusor or abdominal leak point pressure
• Produce only partial inhibition due to secondary release of a transmitter other than Ach
  • This is known as atropine resistance and is the most common hypothesis explaining the difficulty of curing detrusor overactivity with anti-cholimergic agents alone, and supports the rationale of combined treatment of detrusor overactivity with agents of different mechanisms of action. The importance or unimportance of an atropine-resistant component to detrusor contraction in the treatment of detrusor overactivity in humans remains to be established.
• In general, anti-cholinergics can be classified as tertiary vs. quaternary amines:
  • Tertiary amines:
    • Solifenacin, darifenacin, oxybutynin, fesoterodine (and its active metabolite 5-hydroxymethyl tolterodine [5-HMT]), tolterodine, atropine, imidafenacin, and propiverine
    • Well absorbed from the GI tract
    • Theoretically able to pass into the central nervous system (CNS)
      • Factors that increase the liklihood of an anti-cholinergic passing through the blood-brain barrier (3):
        1. High lipophilicity
        2. Small molecular size
        3. Low electrical charge
  • Quaternary amines:
    • Propantheline and trospium
    • Not well absorbed from the GI tract
    • Pass into the CNS to a limited extent, and have a low incidence of CNS side effects
• Metabolism
  • Many metabolized by the P450 enzyme system to active and/or inactive metabolites.
    • Most commonly involved P450 enzymes are CYP2D6 and CYP3A4
    • Metabolic conversion creates a risk for drug-drug interactions; coadministration of a potent inhibitor of this enzyme (e.g., ketoconazole) may lead to an increase in the circulating drug
• Contraindications (depends on source) (7):
  1. Untreated narrow-angle glaucoma
     • Can induce or precipitate acute angle-closure glaucoma due to their antagonistic actions on M3 and M5 receptors in the eye
  2. GI obstruction
  3. Myasthenia gravis (some sources)
  4. Dialysis dependent (solifenacin product monograph)
  5. History of urinary retention
  6. Cognitive impairment (doses of 20mg oxybutynin) (CUA OAB Guidelines)
  7. Hypersensitivity
• Adverse events
  • The clinical usefulness of available antimuscarinic agents is limited by their lack of selectivity
  • The low persistence with prescribed anti-cholinergic therapy for OAB is due to lack of efficacy and adverse effects.
    • The longest persistence has been reported for solifenacin
  • Common side effects include:
    1. Dry mouth
    2. Constipation
    3. Blurred vision
    4. CNS side effects (cognitive dysfunction, memory impairment, dizziness, fatigue, and headache)
  • Potential serious side effects are cardiac and include:
    1. Increases in HR
    2. Arrhythmia (QT prolongation and induction of polymorphic ventricular tachycardia (torsades de pointes)
       • QT prolongation is not related to muscarinic blockade but rather linked to inhibition of the hERG potassium channel in the heart. Some anti-cholinergic drugs may cause this, but this is not a class effect.
• Frequently used anti-cholinergics for LUTS
  • None of the anti-cholinergic drugs in clinical use is ideal as a first-line treatment for all OAB patients. Optimal treatment should be individualized.
  • Site and speed of anti-cholinergic metabolism has profound effects in terms of clinical efficacy and side effects; therapeutically, it is more important to be tissue selective than subtype selective
    • Oral immediate-release (IR) oxybutynin has higher risk of dry mouth than tolterodine
    • IR preparations have higher risk of dry mouth than extended release (ER) preparations of oxybutynin or tolterodine
    • IR tolterodine has lower efficacy and higher risk of dry mouth than solifenacin
    • Fesoterodine has higher efficacy but also higher risk of widhdrawal becaue of adverse events in general, in particular a higher risk of dry mouth compared to ER tolterodine
  • Darifenacin (Enablex)
    • Metabolism: extensively metabolized by the liver (cytochrome P450)
    • Selectivity: relatively selective muscarinic M3-receptor antagonist; not necessarily tissue selective, because salivary glands and other tissues also contain M3 muscarinic receptors
    • Dosing: Developed as a controlled-release formulation, which allows once-daily administration; recommended doses are 7.5 and 15 mg/day
    • Outcomes: improves frequency, urgency, and incontinence episodes, but no improvement in nocturia
    • Adverse events:
      • Most common side effects are dry mouth and constipation
      • No effect on cognition, QT interval, or heart rate
    • Symptoms improve as early at 6 to 8 days from initiation
  • Solifenacin (Vesicare)
    • Metabolism: significantly metabolized by the liver (cytochrome P450)
    • Selectivity: Modest selectivity for M3 over M2 (and M1) receptors
    • Outcomes: reduces nocturia; most of the effect is observed 2 weeks after treatment initiation
    • Adverse events:
      • Most common side effects are dry mouth and constipation
      • No effect on cognitive function or heart rate. 30-mg dose may increase QT interval
  • Fesoterodine (Toviaz)
    • Metabolism: an orally active prodrug that is converted to the active metabolite 5-hydroxymethyl tolterodine (5-HMT)
      • All of the effects of fesoterodine are thought to be mediated via 5-HMT.
      • 5-HMT is metabolized in the liver, but a significant part of 5-HMT is excreted renally without additional metabolism
    • Selectivity: no selectivity for muscarinic receptor subtypes
    • Dosing: Recommended doses are 4 and 8 mg/day, with the 8-mg dose having a greater effect at the expense of a higher rate of dry mouth.
      • The suggested starting dose, 4 mg/day, can be used in patients with moderately impaired renal or hepatic function because of the combination of renal excretion and hepatic metabolism of 5-HMT
    • Adverse events:
      • Most common side effects are dry mouth, headache, and constipation
      • No effect on QT interval
  • Tolterodine (Detrol)
    • Metabolism: The major active metabolite 5-HMT has a similar pharmacologic profile as the mother compound and significantly contributes to the therapeutic effect of tolterodine. Extensively metabolized by the liver (cytochrome P450)
      • 5-HMT is metabolized in the liver, but a significant part of 5-HMT is excreted renally without additional metabolism
    • Selectivity: tissue selective (has selectivity for the bladder compared with the salivary gland) but no selectivity for muscarinic receptor subtypes.
    • Dosing: Available in immediate release and extended release formulations. The extended release form seems to have advantages over the immediate release form in terms of both efficacy and tolerability
    • Outcomes: significant improvement in frequency and incontinence episodes
    • Adverse events:
      • No effect on QT interval
      • Low incidence of cognitive effects (relatively low lipophilicity of tolterodine and even lesser one of 5-HMT imply limited propensity to penetrate into the CNS)
  • Oxybutynin (Ditropan)
    • Mechanism of action:
      1. Blocks muscarinic receptors (main effect when given systemically)
      2. Direct muscle relaxant
      3. Local anesthetic effects
         • The latter 2 may be of importance when the drug is administered intravesically, but probably play no role when it is given orally.
    • Metabolism: Undergoes extensive upper gastrointestinal and first-pass hepatic metabolism via the cytochrome P450 system (CYP3A4) into multiple metabolites.
      • The primary metabolite, N-desethyloxybutynin, has been implicated as the major cause of the troublesome side effect of dry mouth associated with oxybutynin.
    • Selectivity: slightly higher affinity for M1 and M3 receptors than for M2 receptors
    • Dosing: Immediate release and extended release formulations available, as well as a transdermal patch and gel formulations.
      • Transdermal delivery also alters oxybutynin metabolism, reducing N-desethyloxybutynin production to an even greater extent than OXY-ER, and is associated with much less dry mouth. Side effects include application site reaction pruritus and erythema
    • Adverse events:
      • Immediate release has high incidence of side effects (dry mouth, constipation, drowsiness, blurred vision)
      • Extended release version was developed to decrease liver metabolite formulation of N-desethyloxybutynin with the presumption that it would result in decreased side effects
      • A significant dose-response relationship for both urgency incontinence episodes and dry mouth.
      • Studies show no effect on ECG
      • May have negative effects on cognitive function, particularly in the elderly population but also in children
  • Tropsium (Trosec)
    • Metabolism: mainly eliminated unchanged in the urine; not metabolized by the cytochrome P450 enzyme
      • Darifenacin, solifenacin, fesoterodine, tolterodine, and oxybutynin, are all actively metabolized in the liver by the cytochrome P450 enzyme system. Trospium chloride is not metabolized to any significant degree in the liver
    • Selectivity: no selectivity for muscarinic receptor subtypes.
    • Dosing: Extended release formulation available
    • Outcomes: reduces nocturia
    • Adverse events:
      • Most common side effects are dry mouth, constipation, and headache
      • No negative cognitive effects (quaternary amines are expected to cross the blood-brain barrier to a limited extent)
  • Propiverine (Mictoryl)
    • Mechanism of action: combined anti-cholinergic and calcium antagonistic actions.
      • The importance of the calcium antagonistic component for the drug’s clinical effects has not been established.
    • Selectivity: no selectivity for muscarinic receptor subtypes.
    • Dosing: Extended release formulation available
    • Adverse events:
      • May have equal efficacy and fewer side effects than oxybutynin
      • No significant effect on QT interval
    • Approved for use in Canada, but not US (at time of Campbell’s writing)
  • Atropine
    • Rarely used for treatment of OAB or DO because of its systemic side effects
  • Imidafenacin
    • Seems to be effective and have acceptable tolerability. However, limited data on its use; not yet available in the Western countries
  • Propantheline
    • Seems to be effective and to have acceptable tolerability. However, limited data on its use
  • Flavoxate
    • The main mechanism of flavoxate’s effect on smooth muscle has not been established.
    • Limited data on its use

β3-adrenoreceptor agonists

• 3 β-ARs subtypes (β1, β2, and β3) have been identified in the detrusor and urothelium.
  • Stimulation of β2- and β3-adrenergic receptors results in the direct relaxation of the detrusor smooth muscle
  • β3-adrenergic receptor is the most highly expressed subtype among α- and β-adrenoceptor subtypes at the mRNA level in human bladder
• Mechanism of action:
  • Stimulates β3-adrenoceptor causing activation of adenylyl cyclase with the subsequent formation of cAMP, resulting in detrusor relaxation
    • Recall that in erectile physiology, actvation of guanyl cyclase results in increased cGMP, resulting in arterial wall smooth muscle relaxation
  • Inhibits filling induced activity in both mechanosensitive Aδ and C-fiber primary bladder afferents, at least in an animal model.
• Mirabegron
  • Metabolism
    • Rapidly absorbed
    • Metabolized in the liver via multiple pathways, mainly by cytochrome P450
      • Subject to clinically relevant drug-drug interactions; should be used with caution in patients who are taking ketoconazole or other potent CYP3A4 inhibitors.
      • Metabolites are inactive
  • Outcomes:
    • Increases bladder capacity, improves frequency, urgency, incontinence episodes
    • Does not adversely affect flow rate, detrusor pressure at maximum flow rate, bladder contractile index, or residual volume
  • Contraindications (drug monograph) (3):
    1. Severe uncontrolled hypertension defined as systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg.
    2. Pregnancy
    3. Hypersensitivity
  • Dosage
    • Starting dose of 25 mg and increasing to 50 mg, if needed, is recommended.
    • Lowest dose is also recommended for renal and hepatic impairment
  • Adverse events
    • Common side effects (drug monograph):
      • Hypertension
        • The mean increase (compared with placebo) in systolic and diastolic blood pressure after therapeutic doses of mirabegron once daily was ≈0.5-1 mm Hg and was reversible on discontinuation of treatment.
        • In the clinical efficacy and safety studies, the change from baseline in mean pulse rate for mirabegron 50 mg was ≈1 beat/min and reversible on discontinuation of treatment.
      • Headache, dizziness
      • UTI
      • Constipation, dry eyes, blurry vision
      • Does not cause increase QT interval
    • Even if the cardiovascular effects of mirabegron observed in clinical studies have been minimal and clinically not relevant, effects on HR and blood pressure need to be monitored when the drug is prescribed

Toxins

• Botulinum toxin
  • A neurotoxin produced by gram-positive Clostridium botulinum
  • 7 subtypes; subtype A has the longest duration of action, making it the most relevant clinically.
    • Subtype A is available in 4 different forms: onabotulinumtoxinA (onabotA), abobotulinumtoxinA (abobotA), and incobotulinumtoxinA (incobotA) for Botox, Dysport, and Xeomin, respectively.
      • Although the toxin is the same, it is wrapped by different proteins that modify the relative potency of each brand.
      • Most of the information available about intravesical application of BoNTA derives from the use of onabotA (Botox).
    • Clinical dose conversion studies for the LUT do not exist.
  • Mechanisms of action (4):
    1. Inhibits release of acetylcholine from pre-synaptic cholinergic motor nerve endings by cleaving SNAP 25 and rendering the SNARE complex inactive, resulting in muscle paralysis
       • Acts on both striated muscle and smooth muscle
         • Striated muscle paralysis recovers within 2-4 months
    2. Terminal axonal degeneration due to accumulation of neurotransmitter-containing synaptic vesicles
    3. Inhibits the release of other neurotransmitters including ATP and neuropeptides such as substance P
    4. Reduces afferent activity from bladder
  • Efficacy
    • RCTs have documented the clinical effects of onabotulinumtoxinA both in neurogenic detrusor overactivity and idiopathic detrusor overactivity, wherein the drug decreases incontinence episodes, frequency, and urgency and improves QoL.
    • Shown to be effective in patients with OAB.
      • Successful OAB treatment with BoNTA does not appear to be related to the existence of DO. No differences in outcomes were found between those with and those without baseline DO
  • Contraindications (4):
    1. Active UTI
    2. Acute urinary retention
    3. Unwillingness or inability to self-catheterize
    4. Hypersensitivity
  • Adverse events:
    • Most common: bladder pain and urinary infections. Hematuria, usually mild, may also occur
    • Most serious: paralysis of the striated musculature caused by circulatory leakage of the toxin
      • Has never been reported.
        • Caution should be used in treating high-risk patients, including:
          1. Children
          2. Patients with low pulmonary reserve
          3. Patients with myasthenia gravis
      • Transient muscle weakness was reported with abobotA application
    • Most feared in patients with voluntary voiding: urinary retention and a transient necessity to perform CIC.
      • The proportion of patients who initiate CIC at any time during treatment cycle 1 was 6.1% versus none in the placebo group; for over half the patients who initiated CIC, the duration of CIC was 6 weeks or less.
    • Aminoglycosides should be avoided during BoNTA treatment because they might block motor plates and therefore enhance BoNTA effect
• Capsaicin and resiniferatozin (vanilloids)
  • Cause an initial excitation followed by a long-lasting blockade.
  • Resiniferatoxin is 1000 times more potent than capsaicin for desensitization and a few hundred times more potent for excitation
  • Not commonly used; there have been positive and negative trials with RTX.

Increasing outlet resistance

• Many factors seem to be involved in the pathogenesis of SUI: urethral support, vesical neck function, and function of the nerves and musculature of the bladder, urethra, and pelvic floor. Anatomic factors cannot be treated pharmacologically. However, women with SUI have lower resting urethral pressures than age-matched continent women
• The pharmacologic treatment of SUI aims at increasing intraurethral closure forces by increasing the tone in the urethral smooth and striated muscles but relative lack of efficacy and/or side effects have limited their clinical use.
• Antidepressants
  • Imipramine
    • Tricyclic antidepressant (TCA)
    • Mechanism of action: complex pharmacologic effects, including strong systemic anti-cholinergic activity and blockade of the reuptake of serotonin and noradrenaline, but its mode of action in DO has not been established; theoretically facilitates urine storage, both by decreasing bladder contractility and by increasing outlet resistance
    • Contraindications:
      • Concomitant use of monoamine oxidase inhibitors
        • Severe CNS toxicity can be precipitated, including hyperpyrexia, seizures, and coma
    • If any of the TCAs are prescribed for the treatment of voiding dysfunction, the patient should be thoroughly informed of the fact that this is not the usual indication for this drug and that potential side effects exist.
      • Imipramine is the only drug that has been widely used clinically to treat storage symptoms without good-quality RCTs that support is effectiveness
      • Has been known for a long time that imipramine can have favorable effects in the treatment of nocturnal enuresis in children.
    • Adverse events:
      • Most frequent side effects of TCAs are those attributable to their systemic anti-cholinergic activity
      • Therapeutic doses of TCAs may cause serious toxic effects on the cardiovascular system (orthostatic hypotension, ventricular arrhythmias).
        • Imipramine prolongs QTc.
        • Children seem particularly sensitive to the cardiotoxic action of TCAs.
          • It should be noted that data in the literature refer to therapeutic doses of these medications for depression and not the smaller (in comparison) doses of imipramine used for the treatment of voiding dysfunction.
      • Other adverse events include weakness, fatigue, hepatic dysfunction, allergic phenomena (including rash), obstructive jaundice, and agranulocytosis
      • Reports of significant side effects (severe abdominal distress, nausea, vomiting, headache, lethargy, and irritability) after abrupt cessation of high doses of imipramine in children would suggest that the drug should be discontinued gradually, especially in patients receiving high doses.
  • Duloxetine
    • MOA: serotonin-noradrenaline reuptake inhibitor (SNRI)
    • In a cat model, significantly increases sphincteric muscle activity during the filling and storage phase of micturition, and increased bladder capacity.
    • Lipophilic, well absorbed, and extensively metabolized by the liver
    • Has been shown to improve storage symptoms, but trials are lacking; may result in subjective more than objective improvements
    • Currently, duloxetine is licensed in the European Union for women with moderate to severe SUI. It is approved in the United States for treatment of a variety of disorders, but was withdrawn from the approval process for the treatment of SUI.
• α-adrenergic agonists (e.g. ephedrine)
  • Hypogastric nerve stimulation and α-adrenergic agonists raise intraurethral pressure. These findings provide the rationale for use of α-adrenergic agonists to promote urine storage by increasing urethral resistance.
  • The use of peripheral α-adrenergic agonists has largely been abandoned because of the adverse effects associated with these agents and the weak evidence of efficacy compared with placebo
    • Phenylpropanolamine is associated with significantly increased risk of stroke in women
• β-AR agonists and antagonists
  • Paradoxically, there are theoretic rationales for using both β-AR agonists and antagonists for treatment of SUI
    • β-AR stimulation is generally conceded to decrease urethral pressure, but β2-AR agonists have been reported to increase the contractility of striated muscle fibers.
    • Conversely, the blockade of urethral β-ARs by β-AR antagonists may enhance the effects of NA on urethral α-ARs.
    • There are few data suggesting significant efficacy.
• There is currently no effective drug for male SUI.
  • Duloxetine has been evaluated in this context but usage of duloxetine for SUI in men is universally off-label.
  • A drug is needed for male SUI.

Estrogens

• Oral estrogen
  • Plus progesterone worsened urinary incontinence in older postmenopausal women with incontinence.
  • Plus progesterone increases the risk of de novo SUI and UUI in those continent at baseline
  • And progesterone increases the frequency of incontinence in those incontinent at baseline
  • Alone or with progestin increases the risk of de novo UI in postmenopausal women
• Local (vaginal) estrogen
  • May improve OAB symptoms in postmenopausal women by treating urogenital atrophy
    • The vaginal route improves dryness, pruritus, and dyspareunia and provides a greater improvement in physical findings than oral administration.
  • Estrogen when given alone does not appear to be an effective treatment for SUI in the woman
  • Although many clinicians prescribe transvaginal estrogen or estrogen plus progestin cream for symptoms of OAB or/and SUI, there is no real evidence that vaginal estrogen, with or without progesterone, is useful in the treatment of urinary incontinence.
• Progesterone and progestogens are thought to increase the risk of UI.
  • LUTS, especially SUI, have been reported to increase in the progestogenic phase of the menstrual cycle

Pharmacologic therapy to facilitate bladder emptying

Decreasing Outlet Resistance at the Level of the Smooth Sphincter

• α1-blockers (alpha-1-adrenoreceptor antagonists)
  • Capable of reducing smooth muscle tone in the bladder outlet in both men and women and in the prostatic muscle.
    • Facilitate urine release in conditions of functionally increased urethral resistance, such as with BOO secondary to prostatic enlargement., and bladder neck dysfunction
  • Urethral tone and intraurethral pressure are influenced by α-adrenergic receptors
    • Hypogastric nerve stimulation and α-adrenergic agonists raise intraurethral pressure, which is blocked by α1-adrenergic antagonists.
    • α1 and α2 adrenoceptors have been shown in the urethra
      • α2 receptors
        • More common than α1
      • α1 receptors
        • More important for adrenergically induced lower urinary tract smooth muscle contraction and prostate smooth muscle contraction.
        • Subtypes (3): α1A, α1B, and α1D
          • Structurally and pharmacologically distinct and have different tissue distributions
          • All mediate blood vessel dilation
          • A 4th subtype, α1L, also found in human prostate is derived from the same gene as the α1A subtype, but α1L and α1A receptors have different pharmacologic properties.
          • α1A adrenoceptor is the major subtype expressed in urethral smooth muscle and prostate and mediates their contraction
            • Although the α1A adrenoceptor is the major subtype in the prostate and urethra, highly selective α1A-adrenoceptor antagonists (e.g., RS-17053) do not alter LUTS scores in men with BPH, but are effective at relaxing prostate smooth muscle and increasing urine flow
            • In contrast, α1-adrenoceptor antagonists that contain α1D-adrenoceptor blocking activity improve bladder-based symptoms, suggesting the important role of the α1D-adrenoceptors for storage symptoms associated with BOO, and receptors potentially located at the bladder or the spinal cord
              • The contribution of α1D receptors to DO observed in a variety of pathologic conditions, including obstructive uropathy and incontinence, still needs to be established
            • An individual’s response to the different α1-AR antagonists may vary based on the expression level of α1-AR subtype mRNA in their prostate
        • The α1-blockers vary in their selectivity for the different subtypes
          • Selectivity for α1B-AR has been considered disadvantageous from a cardiovascular point of view
          • Non-selective (3): TAD
            1. Terazosin
            2. Alfuzosin
            3. Doxazosin
          • Selective (3):
            1. Silodosin: (most selective) α1A > α1D > α1B
            2. Tamsulosin: α1A = α1D > α1B
            3. Naftopidil: 1d ≥ 1a > 1b)
  • Considered effective for treatment of both storage and voiding symptoms in men with LUTS associated with bladder outlet obstruction secondary to benign prostatic enlargement.
    • However, in a study in which tamsulosin was given alone or together with tolterodine to patients with male LUTS and OAB symptoms, monotherapy with the drug was not effective.
  • In women, treatment of OAB symptoms with α1-blockers seems to be ineffective and may produce stress incontinence
  • Comparing different alpha-blockers:
    • In a trial comparing silodosin 8-mg to tamsulosin 0.4-mg to placebo, silodosin overall efficacy was not inferior to tamsulosin.
    • Only silodosin showed a significant effect on nocturia over placebo.
  • Adverse events (5):
    1. Dizziness (most common, 2-10%)
       • Highest rates for terazosin and doxazosin
         • Terazosin and doxazosin require dose titration and blood pressure monitoring
    2. Orthostatic hypotension
    3. Headache
    4. Nasal congestion
    5. Retrograde ejaculation
       • Most often reported with silodosin and tamsulosin.
         • Silodosin is associated with higher rates of ejaculatory dysfunction (14%) compared to tamsulosin (2%). However, only 1.3% of silodosin-treated patients discontinued treatment because of this adverse event.

Decreasing Outlet Resistance at a Site of Anatomic Obstruction

• 5α-reductase inhibitors
  • 5α-reductase converts testosterone to DHT
    • Type 1 5α-reductase is expressed primarily in the non-genital skin and liver, and to a lesser extent in the prostate, testis, and brain
    • Type 2 5α-reductase is expressed predominantly in the prostate epithelium and other genital tissues such as the epididymis, genitalia, seminal vesicle, testis, but also in liver, uterus, breast, hair follicles, and placenta
    • Finasteride inhibits type 2, dutasteride inhibits both type 1 and 2
  • Finasteride Study Group
    • 895 men with some symptoms of urinary obstruction, an enlarged prostate gland on digital rectal examination, and maximal urinary-flow rates of less than 15 ml per second (with a voided volume of 150 ml or more).
    • Randomized to 3 arms: 1mg finasteride vs. 5mg finasteride vs. placebo once daily for 12 months
    • Results
      • The mean serum dihydrotestosterone concentrations decreased significantly in the two finasteride-treated groups (P<0.001) during the first two weeks of treatment and did not change thereafter
        • The decrease in serum dihydrotestosterone concentrations among the men who received 5 mg of finasteride daily was significantly greater than that among the men who received 1 mg of finasteride daily
      • In both finasteride-treated groups, serum testosterone concentrations increased approximately 8 to 10 percent after two weeks of treatment, and they remained increased thereafter.
        • Despite the increases, all values were within the normal range at all times.
      • Serum luteinizing hormone concentrations increased in all three groups during the first two months. However, the increases in both finasteride-treated groups were significantly higher than those in the placebo group
      • the men in both finasteride-treated groups had significant reductions in serum prostate-specific antigen for the comparison with the placebo group) at all times from month 3 through month 12 of treatment
        • The median decrease was 50 percent among the men who received 5 mg of finasteride and 48 percent among those who received 1 mg of finasteride.
      • Men treated with 5 mg of finasteride had a significant decrease in total symptom scores. The men treated with 1 mg of finasteride had no significant changes in the symptom scores.
      • During the 12 months of treatment, the maximal urinary-flow rates increased progressively in both finasteride-treated groups, but not in the group given placebo
      • During the first six months, the median size of the prostate decreased progressively in both finasteride-treated groups, after which it did not change significantly, and it was significantly smaller in both finasteride-treated groups than in the placebo group at all times. After 12 months of treatment, the prostate had shrunk by 19 percent from base line in the group given 5 mg of finasteride, by 18 percent in the group given 1 mg of finasteride, and by 3 percent in the group given placebo
    • Gormley, Glenn J., et al."The effect of finasteride in men with benign prostatic hyperplasia." New England Journal of Medicine 327.17 (1992): 1185-1191.
  • Other benefits of 5-ARIs (4):
    1. Improves sensitivity of PSA and DRE for prostate cancer detection
    2. Reduced risk of prostatitis
    3. Reduced risk of acute urinary retention
    4. Reduced risk of BPH-related surgical intervention
  • Most common adverse events of finasteride (4):
    1. Reduced volume of ejaculate (absolute risk difference 4%)
    2. Erectile dysfunction (4%)
    3. Loss of libido (3%)
    4. Gynecomastia (2%)

Decreasing Outlet Resistance at the Level of the Striated Sphincter

• There is no class of pharmacologic agents that will selectively relax the striated musculature of the pelvic floor. However, injection of botulinum toxin into the striated sphincter has been used with some clinical success, especially in patients with neurologic striated sphincter dyssynergia. The potential for spread to nearby structures is greater than with intravesical therapy, and distant effects can also occur, but these are rare

Phosphodiesterase inhibitors

• Mechanism: drugs acting through the nitric oxide (NO)/cGMP system, such as PDE5 inhibitors, can relax the smooth muscle of the bladder outflow region and may improve urinary bladder blood perfusion
• As monotherapy, PDE5 inhibitors significantly improve IPSS and International Index of Erectile Function (IIEF) scores, but not Qmax, when compared with placebo.
  • PDE inhibitors seem to improve subjective measurements but not objective ones, eg. Qmax
  • The mechanism behind the beneficial effect of the PDE inhibitors on LUTS and OAB and their site(s) of action largely remain to be elucidated.
  • Combination of PDE5 inhibitors and α-blockers led to significant improvements of the IPSS and IIEF scores as well as Qmax when compared with the use of α-blockers alone.
• As of the time of Campbell’s writing, only tadalafil has been approved for the treatment of LUTS caused by benign prostatic obstruction (BPO)
• There is insufficient information is available on the combination of PDE5 inhibitors with other LUTS medications such as 5α-reductase inhibitors.

Increasing Intravesical Pressure and Bladder Contractility

• There is currently no effective drug for the treatment of detrusor underactivity or underactive bladder
• Parasympathomimetic agents
  • ACh, which stimulates bladder contraction, cannot be used for therapeutic purposes because of its action at both muscarinic and nicotinic receptors and it is rapidly hydrolyzed by cholinesterases.
  • Many ACh-like drugs exist, but only bethanechol chloride exhibits a relatively selective in vitro action on the urinary bladder and gut with little or no nicotinic action.
    • Bethanechol is cholinesterase resistant and causes an in vitro contraction of smooth muscle from all areas of the bladder. However, there is little evidence of its efficacy.
      • At least in a "denervated" bladder, an oral dose of 200 mg is required to produce the same urodynamic effects as a subcutaneous dose of 5 mg.
• Prostaglandins
  • Synthesized both locally in bladder muscle and mucosa
    • Synthesis initiated by various physiologic stimuli such as detrusor muscle stretch, mucosal injury, and neural stimulation; directly by adenosine triphosphate; and by mediators of inflammation.
  • Have been variably reported to be useful in facilitating bladder emptying with intravesical administration. Possible roles include:
    1. Neuromodulators of efferent and afferent transmission
    2. Sensitization
    3. Activation of certain sensory nerves
    4. Potentiation of acetylcholine (but not ATP) release from cholinergic nerve terminals through prejunctional prostanoid receptors.
  • Initial reports of the use of intravesical prostanoids producing lasting favorable clinical effects have not been confirmed.

Phytotherapy

• Saw palmetto
  • RCT
    • 225 men age >49 with moderate-to-severe symptoms of benign prostatic hyperplasia
    • Randomized to to one year of treatment with saw palmetto extract (160 mg twice a day) or placebo.
    • Primary outcome: changes in the scores on the American Urological Association Symptom Index (AUASI) and the maximal urinary flow rate.
    • Secondary outcome measures included changes in prostate size, residual urinary volume after voiding, quality of life, laboratory values, and the rate of reported adverse effects.
    • Results
      • No significant difference between the saw palmetto and placebo groups in the change in AUASI scores, maximal urinary flow rate, prostate size, residual volume after voiding, quality of life, or serum prostate-specific antigen
    • Bent, Stephen, et al."Saw palmetto for benign prostatic hyperplasia." New England Journal of Medicine 354.6 (2006): 557-566.

Other drugs

• Desmopressin
  • Mechanism of action:
    • Analogue of the endogenous hormone vasopressin (also known as antidiuretic hormone).
      • Vasopressin
        • Functions (2):
          1. Causes contraction of vascular smooth muscle
          2. Stimulates water reabsorption from the collecting ducts
        • Release stimulated by:
          • Hyperosmolality
          • Hypovolemia
          • Stress
          • Nausea
          • Pregnancy
          • Hypoglycemia
          • Nicotine
          • Morphine
          • Other drugs
        • Release inhibited by:
          • Hypoosmolality
          • Hypervolemia
          • Ethanol
          • Phenytoin
  • Pharmacology
    • More powerful and longer-lasting antidiuretic action than vasopressin/anti-diuretic hormone due to selectivity for antidiuretic over vasopressor effects.
    • Fast onset of action, with urine production decreasing within 30 minutes of oral administration
    • Available in formulations for oral, parenteral, and nasal administration.
      • Because symptomatic hyponatremia with water intoxication, which is the only serious adverse event reported in children, occurred after intranasal or intravenous administration of desmopressin, the FDA and the European Medicines Agency (EMA) removed the indication for the treatment of primary nocturnal enuresis from all intranasal preparations of desmopressin. An oral lyophilisate formulation (MELT) requiring no concomitant fluid intake is currently available
  • Efficacy
    • Nocturia
      • Desmopressin is the most common vasopressin analogue used to treat nocturia in children and adults.
        • Decreased vasopressin levels are believed to be important in the pathophysiology of some forms of polyuria, specifically nocturnal polyuria.
      • Results in significant improvements in reducing nocturnal voids and increasing the hours of undisturbed sleep.
      • Generally well tolerated in all the studies on nocturia.
    • Enuresis
      • In children, effective in reducing bedwetting. However, there was no effect after discontinuation of treatment, indicating that desmopressin suppresses the symptom of enuresis but does not cure the underlying cause.
        • In addition, not all children responded sufficiently to desmopressin monotherapy.
        • The combination of desmopressin and an enuresis alarm resulted in a greatly improved short-term success rate and decreased relapse rates
  • Contraindications (drug monograph):
    • Patients with type IIB or platelet-type (pseudo) Willerbrand disease, because of the risk of platelet aggregation and thrombocytopenia
    • Any condition associated with impaired water excretion, such as:
      • Hyponatremia
      • Severe liver disease
      • [Hydro]nephrosis
      • Cardiac insufficiency
      • Chronic renal insufficiency
      • Congestive heart failure
      • Habitual or psychogenic polydypsia
    • Any medical conditions which lead to sodium losing states such as:
      • Vomiting
      • Diarrhea
      • Bulimia
      • Anorexia nervosa
      • Adrenocortical insufficiency
      • Salt losing nephropathies
    • Lactose intolerance/allergies
  • Adverse events
    • Hyponatremia
      • Can lead to a variety of adverse events ranging from mild headache, anorexia, nausea, and vomiting to loss of consciousness, seizures, and death
      • Usually occurs soon after treatment is initiated
      • Risk factors:
        1. Increasing age
        2. Female gender
        3. Cardiac disease
        4. Increasing 24-hour urine volume
  • Dosing
    • Females demonstrate increased sensitivity to demopression; recommended efficacious doses are 25 μg MELT for females and 50 to 100 μg MELT for males
    • Prior to initiation, a serum sodium should be obtained at baseline, then again after initiation. Serum sodium should be assessed regularly, at least every 6 months with long-term desmopressin administration
    • Initiation of desmopressin is currently not indicated for patients age ≥ 65 (different than CUA guidelines, see below)
    • 2018 CUA MLUTS Guidelines
      • While the risk of hyponatremia is low in men with normal baseline serum sodium, sodium must be checked at baseline and 4–8 days as well as 30 days after initiation of treatment in (2):
        1. All men taking desmopressin melts
        2. Men ≥65 years taking 50 μg oral disintegrating tablet
        • Note that these guidelines are for male LUTS and therefore recommendations for females are not provided.
• Dimethyl sulfoxide (DMSO)
  • Has been used as an industrial solvent for many years
  • Used in a 50% solution to improve symptoms in interstitial cystitis
  • Has not been shown to be useful in the treatment of:
    • Neurogenic detrusor overactivity
    • Idiopathic detrusor overactivity
    • Any patients with urgency or frequency but without interstitial cystitis
• Baclofen
  • Mechanism of action: depresses monosynaptic and polysynaptic excitation of motor neurons and interneurons in the spinal cord by activating GABAB receptors.
  • Has been tried in idiopathic detrusor overactivity but with poor efficacy
• Cyclooxygenase inhibitors
  • Although there are theoretic mechanisms by which prostaglandin synthesis inhibitors could affect filling and storage symptoms, clinical evidence for this is scarce. The interest in the use of selective COX-2 inhibitors was tempered by concerns about long-term cardiovascular toxicity with these drugs.
• Calcium antagonists
  • Activation of detrusor muscle seems to require influx of extracellular Ca2+ through Ca2+ channels as well as via mobilization of intracellular Ca2+. The influx of extracellular calcium can be blocked by calcium antagonists, blocking L-type Ca2+ channels, and theoretically this would be an attractive way of inhibiting DO and regulating detrusor smooth muscle tone. Although these in vitro data suggest a possible role for calcium channel inhibitors, in the treatment of DO and incontinence, only limited clinical studies are available
• Potassium channel openers
  • Potassium channels contribute to the membrane potential of smooth muscle cells and hence to the regulation of smooth muscle tone. Despite promising preclinical efficacy data, potassium channel openers at present are not a therapeutic option and may never become one owing to a lack of selectivity for bladder over cardiovascular tissues

Combinations

• Alpha-blockers and 5-ARIs
  • MTOPS§
    • Population: 3047 men age ≥ 50 with IPSS 8-30, PSA ≤ 10 ng/mL, Qmax ≥4 but ≤15 ml/s with minimum voided volume ≥125 ml
      • Mean prostate volume: 36mL
      • Mean PSA: 2.4ng/mL
    • Randomized to placebo, doxazosin, finasteride, or combination therapy
    • Primary outcome: overall clinical progression, defined as the first occurrence of:
      1. ≥ 4 points increase from baseline AUA symptom score
      2. Acute urinary retention
      3. Renal insufficiency
      4. Recurrent UTI
      5. Urinary incontinence
    • Secondary outcomes: changes over time in the AUA symptom score and the maximal urinary flow rate
    • Results:
      • Mean follow-up: 4.5 years
      • Rate of overall clinical progression:
        • Placebo 4.5 per 100 person-years
        • Doxazosin: 2.7 per 100 person-years (P<0.001)
        • Finasteride: 2.9 per 100 person-years (P=0.002)
        • No difference between doxazosin alone vs. finasteride alone
        • Combination therapy: 1.5 per 100 person-years (P<0.001), a significantly greater reduction than doxazosin alone (P<0.001) or finasteride alone (P<0.001)
  • CombAT§
    • Population: 4844 men age ≥ 50 with a clinical diagnosis of BPH, IPSS ≥ 12, prostate volume ≥ 30g, PSA 1.5-10 ng/ml, Qmax >5 but ≤15 ml/s with minimum voided volume ≥125 ml
      • Mean prostate volume: 55mL (larger than MTOPS)
      • Mean PSA: 4.0ng/mL (higher than MTOPS)
    • Randomized to daily tamsulosin, dutasteride, or a combination of both (no placebo)
    • Primary end point: time to first AUR or BPH-related surgery
    • Secondary end points included BPH clinical progression, symptoms, Q(max), prostate volume, safety, and tolerability
      • BPH clinical progression defined as one of the following: symptom deterioration by International Prostate Symptom Score ≥4 points on two consecutive visits; BPH-related AUR; BPH-related urinary incontinence; recurrent BPH-related urinary tract infection or urosepsis; BPH-related renal insufficiency
    • Results:
      • Combination therapy was significantly better than tamsulosin monotherapy but not dutasteride monotherapy at reducing the relative risk of AUR or BPH-related surgery
      • Combination therapy was significantly superior to both monotherapies at reducing the relative risk of BPH clinical progression
      • Combination therapy provided significantly greater symptom benefit than either monotherapy at 4 yr.
  • Summary of evidence for combination alpha-blockers and 5-ARIs from these trials:
    • Combination better reduces risk of clinical progression and symptoms benefit at 4 years
    • Monotherapy with 5-ARI and alpha-blockers are equally effective in risk of overall clinical progression
    • 5-ARI reduces risk of AUR or BPH-related surgery, addition of tamsulosin does not increase benefit
• Alpha-blockers and anti-cholinergics
  • Several RCTs have demonstrated that the combination treatment of anti-cholinergics and α1-blockers was more effective at reducing male LUTS than α1-blockers alone in men with OAB and coexisting bladder outlet obstruction
  • α1-blockers and anti-cholinergics may have an additional synergistic effect on the bladder in the neurogenic population. This suggests that targeting multiple receptors may maximize the effectiveness of pharmacologic treatment of neurogenic bladder and should be considered in patients in whom treatment with antimuscarinics alone fails
• Beta-3-agonist and anti-cholinergics:
  • Mirabegron combination therapy with solifenacin demonstrated greater efficacy than solifenacin alone on voided volume and micturition frequency.
    • The enhanced efficacy with the combination was of a magnitude that is probably similar to the enhanced efficacy one might expect from uptitrating the dose of the anti-cholinergic. However, the combination was not associated with the adverse effects one would expect to encounter with higher doses of antimuscarinics.
• Combining anti-cholinergics
  • Needs further investigation to verify its efficacy as a non-invasive alternative for patients in whom anti-cholinergic monotherapy fails.
• Anti-cholinergics and 5-ARIs
  • Anti-cholinergics are safe and effective in selected patients with OAB and BPO when used in combination with 5-ARIs

Questions

1. List benefits of 5ARIs
2. List side effects of 5ARIs

Answers

1. List benefits of 5ARIs
   1. Reduce risk of prostatitis
   2. Improves sensitivity of PSA and DRE for prostate cancer detection
   3. Reduced risk of urinary retention
   4. Reduced risk of BPH-related surgery
2. List side effects of 5ARIs
   1. Reduce volume of ejaculation
   2. Erectile dysfunction
   3. Loss of libido
   4. Gynecomastia

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 79