Transcript Bladder Pharmacology Campbell-Walsh Ch. 56: 1948-1972

Bladder Pharmacology
Campbell-Walsh
Ch. 56: 1948-1972
Stephen Miller, DO
Peripheral Pharmacology
Muscarinic
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4 different receptor subtypes based on
Pharmacology (M1-M5)
Human Bladder
– M1
– M2 (Predominate)
– M3:
 Mediate cholinergic contractions

Key roles in:
– Salivary secretion
– Pupillary constriction
– Digestive tract
M3R Action
Acetylcholine  M3R  IP3 hydrolysis
(PLC)  Intracellular Ca2+ Release =
Smooth Muscle Contraction
 L- type Ca2+ channels have also been
indicated in M3R mediated detrusor
contractions
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M2R
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Coactivation could enhance
response to M3:
1. Inhibition of adenylate cyclase =
suppressing sympathetic mediated
depression of detrusor
2. Inactivation of K+ channels
3. Activation of nonspecific cation channels
Prejunctional Muscarinic Receptors
M1R facilitate Acetylcholine release
 M2-M4R inhibit release
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Purinergic Mechanisms
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Parasympathetic stimulation
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ATP acts on 2 Receptors
– P2X (ion channel) with 7 subtypes
– P2Y (G-Protein coupled receptor) with eight subtypes
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May play a role in Pathological conditions
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Unstable bladders
BOO
Increased amount of P2X1R in obstructed bladders
P2X3R in small diameter afferent neurons of the DRG
are also found in the wall of bladder and ureter
 Mechanosensory and Nociceptive signaling
Adrenergic Mechanisms
Isoproterenol, Terbutiline
 β- Adrenergic
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– β 2 and β 3 Receptors results in direct relaxation of
detrusor smooth muscle
–  3 main receptor
Mediated through stimulation of Adenylate
cyclase and accumulation of cyclic AMP
 PDE inhibitors?
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– Selective inhibition of bladder PDE  Increase cAMP
 Relax detrusor and/or enhance the sensitivity/efficacy of 
adrenergic agonists
– Bladder Isoform of PDE?
-Adrenergic
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Ephedrine, Phenylpropanolamine, Midodrine,
Psuedoephedrine
Bladder: (Not prominate in nml bladder)
– -adrenergic density is increased in pathological conditions
– NE induced responses convert from relaxation to contraction
– 1dR subtype
Urethra:
 Promote urine storage by increasing Urethral resistance
– Hypogastic nerve stimulation and -adrenergic agonists produce
a rise in intraurethral pressure
– blocked by 1- adrenergic antagonists
– 1a major subtype in Urethra/Prostate
Nitric Oxide
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Major inhibitory transmitter mediating relaxation
of the urethral smooth muscle during
micturation
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Involved in controlling bladder afferent nerve
activity
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Increase production of intracellular cGMP =
Smooth muscle relaxation
– Inactivated by PDE’s
– Role for PDE-inhibitors?
Afferent Neuropeptides
Substance P
Neurokinin A
Calcitonin gene- related peptide (CGRP)
Vasoactive Intestinal polypeptide (VIP)
Pituitary adenylate cyclase-activating peptide (PACAP)
Enkephalins
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Contained in capsaicin-sensitive, C-Fiber bladder
afferents
– Released in bladder by noxious stimulation
– Inflammatory response  plasma extrav., vasodilation,
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and alter bladder smooth muscle activity
– transmitters at afferent terminals of the spinal cord
Receptors of Tachykinins
– NK1R  blood vessels to induce plasma extrav.
– NK2R  bladder contractions
– NK2R  increase excitability during bladder filling or
inflammation
Prostanoids
Prostaglandins, Thromboxane
 Manufactured throughout the lower urinary tract
 Bladder Mucosa Contains:
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– PGI2, PGE2, PGE2a, Thromboxane A
– PGF2, PGE, PGE2 = Contraction
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Mediated by specific receptors on cell
membranes
– DP, EP, FP, IP, and TP
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Slow onset of action
– Modulatory role
– Affect neural release of transmitters or inhibit
acetylcholinesterase activity
Endothelins
21 amino acid peptides produced in endothelial
cells
 ET-1 (ET-2, ET-3)
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– Control of bladder smooth muscle tone
– Regulation of local blood flow
– Bladder wall remodeling in pathological conditions
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involved in detrusor hyperplasia and overactivity
seen in pts with BOO resulting from BPH
Receptors: ETA , ETB
Also have a role in nociceptive mech. in
peripheral and Central Nervous System
– Peripheral = induce detrusor activity
– Spinal Cord = inhibit micturition through Opioid’s
Parathyroid Hormone Related
Peptide
Manufactured by bladder smooth muscle
 Detrusor relaxation
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Sex Steroids
Do not directly affect bladder contractility,
but modulate receptors and influence
growth of bladder tissues
 Estrogen: Effect on urinary continence in
females probably reflects multiple actions
on adrenergic receptors, vasculature, and
urethral morphology
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– Increasing adrenergic receptors
– NOS
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Progesterone: increases electrical and
cholinergic contractions of bladder
Transducer function of Urothelium
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Urothelial cells display properties of
nociceptors and mechanoreceptors
– Release NO, ATP, Acetylcholine, Substance P,
Prostaglandins
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local chemical/mechanical stimuli 
chemical signals to bladder
afferents CNS
Serotonin (5-HT)
Neuroendocrine cells along urethra and
prostate
 Contraction in concentration dependent
manner
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C-Fiber Pharmacotherapy
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Unmyelinated C-fibers are normally silent
– Activated by noxious stimuli
– Irritated state they become responsive to low
pressure bladder distention
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Capsaicin and Resiniferatoxin (RTX)
– Vanilloids that stimulate and desensitize C
fibers to produce pain and release
neuropeptides
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TRPV1 (transient receptor potential)
 Spinal cord, DRG, bladder, Urethra, Colon
 Activated  calcium/Na influx  afferent terminals  CNS
Capsaicin selectively excites and subsequently
desensitizes C-fibers
 RTX causes desensitization without prior
excitation
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Normal Conditions
Pathologic Conditions
Botulinum Toxin
Inhibit acetylcholine release at the presynaptic
cholinergic nerve terminal = Inhibiting striated and
smooth muscle contractions
Also shown to inhibit afferent nerve activity
4 steps required for Paralysis
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Toxin heavy chain  Nerve terminal receptor(?)
Internalization of toxin into nerve terminal
Translocation of light chain into the cytosol
Inhibition of neurotransmitter release
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Spinal cord injury suffering from detrusor-external sphincter
dyssynergia and detrusor overactivity
Pelvic floor spasticity
BPH
Urological uses (BTX-A)
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Actions of Drugs on Smooth Muscle
Calcium Channel Blockers
 Potassium Channel Openers
 TCA
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Calcium Channel Blockers
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Diltiazem, Verapamil
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Less effective in suppressing nerve-mediated
contractions
Spontaneous and evoked contractile properties
are mediated by membrane depol. And
movement of calcium into the smooth muscle
cell through L-type Ca channels
– Dependent on both Extracellular Ca and Intracellular
Calcium
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Develop a selective Ca channel blocking agent to
eliminate spontaneous contractions without
effecting micturition contractions?
K channel Openers
Cromakalim, Pinacidil
 Move K+ out of cell  membrane
hyperpolarization = reduction in
spontaneous contractile activity
 3 K channels identified
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– Katp, SKCa, BKCa
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Intravesicular instillation of bladder
selective Katp = reduced detrusor activity
in rats with BOO
TCA
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Imipramine, Amitriptyline
– Antimuscarinic activity
– Inhibition of Ca translocation
– Direct smooth muscle relaxant
Spinal Ascending/Descending Paths
Glutamatergic
 Inhibitory Amino Acids
 Adrenergic
 Serotonergic
 Opioid
 Purinergic
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Glutamatergic
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Glutamate
– Bladder Contraction
– Excitatory transmitter in afferent limb of
micturation reflex
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Suppressed by NMDA receptor
antagonists
Inhibitory Amino Acids
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Intrathecal injection of GABAa or GABAb
agonists increases bladder capacity and
decreases voiding pressures (rats)
Baclofen
 Glycine levels low in rats with chronic
spinal cord injuries
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– Increasing dietary stores of glycine can
restore bladder function
Adrenergic
 adrenoceptors can mediate excitatory
and inhibitory influences on the lower
urinary tract
 Efferent and Afferent limbs of the
Micturition reflex receive excitatory and
inhibitory input, respectively from spinal
noradrenergic systems
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Serotonergic
Raphe nucleus of the caudal brainstem
autonomic and sphincter motor nuclei in the
lumbosacral spinal cord
 Inhibitory
 Duloxetine
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– Combined Norepinephrine/5 HT reuptake inhibitor
– Increase neural activity to external urethral sphincter
and decreases bladder activity through the CNS
Opioids
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Inhibitory action of reflex pathways in the
spinal cord
Purinergic
Adenosine A1
 Inhibitory action
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PMC and Supraspinal
Mech.
Glutamate
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Excitatory in Micturition pathway
Cholinergic
Excitatory/Inhibitory
 M1R and Protein Kinase C
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GABA
Inhibitory
 Acts on GABAa/GABAb Receptors
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Dopaminergic
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Inhibitory Reflex
– D1
– D5
– Substantia nigra
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Facilitatory
– D2
– D3
– D4
Opioids
Inhibitory
  and δ Receptors
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Mechanisms of Detrusor
Overactivity
Spinal Cord Injury/Neurogenic
Detrusor Overactivity
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Damage above the Sacral level = detrusor
overactivity
– reorganization of synaptic connections in spinal cord
– Alteration of bladder afferents
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Nml Micturition by lightly myelinated Aδ
afferents
Post injury
– Capsaicin-sensitive C- fiber mediated spinal reflex =
Detrusor overactivity
 UMN: MS, PD
– NGF (nerve growth factor) : Implicated as Chemical
mediator of disease-induced changes
– NGF Antibodies?
Bladder Outlet Obstruction
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Changes:
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Detrusor hypertrophy
No change of myofilaments
Axonal degeneration
Decrease in percentage volume of Mitochondria
Increase in sarcoplasmic reticulum
Gap junctions are absent
Enlarged density of afferent and efferent nerve fibers
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Unstable Contraction
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CNS alterations
Obstruction-Induced detrusor overactivity with irritative
voiding symptoms has been attributed to denervation
supersensitivity.
– New spinal circuits
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NGF
– Increase precedes enlargement of bladder neurons and
development of urinary frequency
Aging
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Contractility
– α – adrenergic stimulation increase and
decrease in β – adrenergic inhibitory
responses?
– Innervation and development of Gap
Junctions?
– Low energy production?
Future
Pharmacogenetics
 Tissue Engineering
 Gene Therapy
