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Bladder Pharmacology Campbell-Walsh Ch. 56: 1948-1972 Stephen Miller, DO.

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Presentation on theme: "Bladder Pharmacology Campbell-Walsh Ch. 56: 1948-1972 Stephen Miller, DO."— Presentation transcript:

1 Bladder Pharmacology Campbell-Walsh Ch. 56: Stephen Miller, DO

2 Peripheral Pharmacology

3 Muscarinic 4 different receptor subtypes based on Pharmacology (M1-M5) 4 different receptor subtypes based on Pharmacology (M1-M5) Human Bladder Human Bladder –M1 –M2 (Predominate) –M3:  Mediate cholinergic contractions Key roles in: Key roles in: –Salivary secretion –Pupillary constriction –Digestive tract

4 M 3 R Action Acetylcholine  M 3 R  IP 3 hydrolysis (PLC)  Intracellular Ca 2+ Release = Smooth Muscle Contraction Acetylcholine  M 3 R  IP 3 hydrolysis (PLC)  Intracellular Ca 2+ Release = Smooth Muscle Contraction L- type Ca 2+ channels have also been indicated in M 3 R mediated detrusor contractions L- type Ca 2+ channels have also been indicated in M 3 R mediated detrusor contractions

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6 M2RM2RM2RM2R Coactivation could enhance response to M3: 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

7 Prejunctional Muscarinic Receptors M1R facilitate Acetylcholine release M1R facilitate Acetylcholine release M2-M4R inhibit release M2-M4R inhibit release

8 Purinergic Mechanisms Parasympathetic stimulation Parasympathetic stimulation ATP acts on 2 Receptors ATP acts on 2 Receptors –P2X (ion channel) with 7 subtypes –P2Y (G-Protein coupled receptor) with eight subtypes May play a role in Pathological conditions May play a role in Pathological conditions –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

9 Adrenergic Mechanisms Isoproterenol, Terbutiline Isoproterenol, Terbutiline β- Adrenergic β- Adrenergic –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 Mediated through stimulation of Adenylate cyclase and accumulation of cyclic AMP PDE inhibitors? PDE inhibitors? –Selective inhibition of bladder PDE  Increase cAMP  Relax detrusor and/or enhance the sensitivity/efficacy of  adrenergic agonists –Bladder Isoform of PDE?

10  -Adrenergic Ephedrine, Phenylpropanolamine, Midodrine, Psuedoephedrine 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 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

11 Nitric Oxide Major inhibitory transmitter mediating relaxation of the urethral smooth muscle during micturation Major inhibitory transmitter mediating relaxation of the urethral smooth muscle during micturation Involved in controlling bladder afferent nerve activity Involved in controlling bladder afferent nerve activity Increase production of intracellular cGMP = Smooth muscle relaxation Increase production of intracellular cGMP = Smooth muscle relaxation –Inactivated by PDE’s –Role for PDE-inhibitors?

12 Afferent Neuropeptides Substance P Neurokinin A Calcitonin gene- related peptide (CGRP) Vasoactive Intestinal polypeptide (VIP) Pituitary adenylate cyclase-activating peptide (PACAP) Enkephalins Contained in capsaicin-sensitive, C-Fiber bladder afferents Contained in capsaicin-sensitive, C-Fiber bladder afferents –Released in bladder by noxious stimulation –Inflammatory response  plasma extrav., vasodilation, and alter bladder smooth muscle activity –transmitters at afferent terminals of the spinal cord Receptors of Tachykinins Receptors of Tachykinins –NK1R  blood vessels to induce plasma extrav. –NK2R  bladder contractions –NK2R  increase excitability during bladder filling or inflammation

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14 Prostanoids Prostaglandins, Thromboxane Prostaglandins, Thromboxane Manufactured throughout the lower urinary tract Manufactured throughout the lower urinary tract Bladder Mucosa Contains: Bladder Mucosa Contains: –PGI2, PGE2, PGE2a, Thromboxane A –PGF2 , PGE, PGE2 = Contraction Mediated by specific receptors on cell membranes Mediated by specific receptors on cell membranes –DP, EP, FP, IP, and TP Slow onset of action Slow onset of action –Modulatory role –Affect neural release of transmitters or inhibit acetylcholinesterase activity

15 Endothelins 21 amino acid peptides produced in endothelial cells 21 amino acid peptides produced in endothelial cells ET-1 (ET-2, ET-3) ET-1 (ET-2, ET-3) –Control of bladder smooth muscle tone –Regulation of local blood flow –Bladder wall remodeling in pathological conditions involved in detrusor hyperplasia and overactivity seen in pts with BOO resulting from BPH involved in detrusor hyperplasia and overactivity seen in pts with BOO resulting from BPH Receptors: ETA, ETB Receptors: ETA, ETB Also have a role in nociceptive mech. in peripheral and Central Nervous System Also have a role in nociceptive mech. in peripheral and Central Nervous System –Peripheral = induce detrusor activity –Spinal Cord = inhibit micturition through Opioid’s

16 Parathyroid Hormone Related Peptide Manufactured by bladder smooth muscle Manufactured by bladder smooth muscle Detrusor relaxation Detrusor relaxation

17 Sex Steroids Do not directly affect bladder contractility, but modulate receptors and influence growth of bladder tissues 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 Estrogen: Effect on urinary continence in females probably reflects multiple actions on adrenergic receptors, vasculature, and urethral morphology –Increasing adrenergic receptors –NOS Progesterone: increases electrical and cholinergic contractions of bladder Progesterone: increases electrical and cholinergic contractions of bladder

18 Transducer function of Urothelium Urothelial cells display properties of nociceptors and mechanoreceptors Urothelial cells display properties of nociceptors and mechanoreceptors –Release NO, ATP, Acetylcholine, Substance P, Prostaglandins local chemical/mechanical stimuli  chemical signals to bladder afferents  CNS local chemical/mechanical stimuli  chemical signals to bladder afferents  CNS

19 Serotonin (5-HT) Neuroendocrine cells along urethra and prostate Neuroendocrine cells along urethra and prostate Contraction in concentration dependent manner Contraction in concentration dependent manner

20 C-Fiber Pharmacotherapy Unmyelinated C-fibers are normally silent Unmyelinated C-fibers are normally silent –Activated by noxious stimuli –Irritated state they become responsive to low pressure bladder distention Capsaicin and Resiniferatoxin (RTX) Capsaicin and Resiniferatoxin (RTX) –Vanilloids that stimulate and desensitize C fibers to produce pain and release neuropeptides TRPV1 (transient receptor potential) 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 Capsaicin selectively excites and subsequently desensitizes C-fibers RTX causes desensitization without prior excitation RTX causes desensitization without prior excitation

21 Normal Conditions

22 Pathologic Conditions

23 Botulinum Toxin Inhibit acetylcholine release at the presynaptic cholinergic nerve terminal = Inhibiting striated and smooth muscle contractions Inhibit acetylcholine release at the presynaptic cholinergic nerve terminal = Inhibiting striated and smooth muscle contractions Also shown to inhibit afferent nerve activity Also shown to inhibit afferent nerve activity 4 steps required for Paralysis 4 steps required for Paralysis 1.Toxin heavy chain  Nerve terminal receptor(?) 2.Internalization of toxin into nerve terminal 3.Translocation of light chain into the cytosol 4.Inhibition of neurotransmitter release  Urological uses (BTX-A)  Spinal cord injury suffering from detrusor-external sphincter dyssynergia and detrusor overactivity  Pelvic floor spasticity  BPH

24 Actions of Drugs on Smooth Muscle Calcium Channel Blockers Calcium Channel Blockers Potassium Channel Openers Potassium Channel Openers TCA TCA

25 Calcium Channel Blockers Diltiazem, Verapamil Diltiazem, Verapamil Spontaneous and evoked contractile properties are mediated by membrane depol. And movement of calcium into the smooth muscle cell through L-type Ca channels Spontaneous and evoked contractile properties are mediated by membrane depol. And movement of calcium into the smooth muscle cell through L-type Ca channels Less effective in suppressing nerve-mediated contractions Less effective in suppressing nerve-mediated contractions –Dependent on both Extracellular Ca and Intracellular Calcium Develop a selective Ca channel blocking agent to eliminate spontaneous contractions without effecting micturition contractions? Develop a selective Ca channel blocking agent to eliminate spontaneous contractions without effecting micturition contractions?

26 K channel Openers Cromakalim, Pinacidil Cromakalim, Pinacidil Move K+ out of cell  membrane hyperpolarization = reduction in spontaneous contractile activity Move K+ out of cell  membrane hyperpolarization = reduction in spontaneous contractile activity 3 K channels identified 3 K channels identified –Katp, SKCa, BKCa Intravesicular instillation of bladder selective Katp = reduced detrusor activity in rats with BOO Intravesicular instillation of bladder selective Katp = reduced detrusor activity in rats with BOO

27 TCA Imipramine, Amitriptyline Imipramine, Amitriptyline –Antimuscarinic activity –Inhibition of Ca translocation –Direct smooth muscle relaxant

28 Spinal Ascending/Descending Paths Glutamatergic Glutamatergic Inhibitory Amino Acids Inhibitory Amino Acids Adrenergic Adrenergic Serotonergic Serotonergic Opioid Opioid Purinergic Purinergic

29 Glutamatergic Glutamate Glutamate –Bladder Contraction –Excitatory transmitter in afferent limb of micturation reflex Suppressed by NMDA receptor antagonists Suppressed by NMDA receptor antagonists

30 Inhibitory Amino Acids Intrathecal injection of GABAa or GABAb agonists increases bladder capacity and decreases voiding pressures (rats) Intrathecal injection of GABAa or GABAb agonists increases bladder capacity and decreases voiding pressures (rats) Baclofen Baclofen Glycine levels low in rats with chronic spinal cord injuries Glycine levels low in rats with chronic spinal cord injuries –Increasing dietary stores of glycine can restore bladder function

31 Adrenergic  adrenoceptors can mediate excitatory and inhibitory influences on the lower urinary tract  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 Efferent and Afferent limbs of the Micturition reflex receive excitatory and inhibitory input, respectively from spinal noradrenergic systems

32 Serotonergic Raphe nucleus of the caudal brainstem autonomic and sphincter motor nuclei in the lumbosacral spinal cord Raphe nucleus of the caudal brainstem autonomic and sphincter motor nuclei in the lumbosacral spinal cord Inhibitory Inhibitory Duloxetine Duloxetine –Combined Norepinephrine/5 HT reuptake inhibitor –Increase neural activity to external urethral sphincter and decreases bladder activity through the CNS

33 Opioids Inhibitory action of reflex pathways in the spinal cord Inhibitory action of reflex pathways in the spinal cord

34 Purinergic Adenosine A1 Adenosine A1 Inhibitory action Inhibitory action

35 PMC and Supraspinal Mech.

36 Glutamate Excitatory in Micturition pathway Excitatory in Micturition pathway

37 Cholinergic Excitatory/Inhibitory Excitatory/Inhibitory M1R and Protein Kinase C M1R and Protein Kinase C

38 GABA Inhibitory Inhibitory Acts on GABAa/GABAb Receptors Acts on GABAa/GABAb Receptors

39 Dopaminergic Inhibitory Reflex Inhibitory Reflex –D1 –D5 –Substantia nigra Facilitatory Facilitatory –D2 –D3 –D4

40 Opioids Inhibitory Inhibitory  and δ Receptors  and δ Receptors

41 Mechanisms of Detrusor Overactivity

42 Spinal Cord Injury/Neurogenic Detrusor Overactivity Damage above the Sacral level = detrusor overactivity Damage above the Sacral level = detrusor overactivity –reorganization of synaptic connections in spinal cord –Alteration of bladder afferents Nml Micturition by lightly myelinated Aδ afferents Nml Micturition by lightly myelinated Aδ afferents Post injury 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?

43 Bladder Outlet Obstruction Changes: Changes: –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 Unstable Contraction Unstable Contraction Obstruction-Induced detrusor overactivity with irritative voiding symptoms has been attributed to denervation supersensitivity. Obstruction-Induced detrusor overactivity with irritative voiding symptoms has been attributed to denervation supersensitivity. CNS alterations CNS alterations –New spinal circuits NGF NGF –Increase precedes enlargement of bladder neurons and development of urinary frequency

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45 Aging Contractility Contractility –α – adrenergic stimulation increase and decrease in β – adrenergic inhibitory responses? –Innervation and development of Gap Junctions? –Low energy production?

46 Future Pharmacogenetics Pharmacogenetics Tissue Engineering Tissue Engineering Gene Therapy Gene Therapy


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