Normal Pharmacology

In General

  • Most of the drugs available in clinical practice are those agents with targeted peripheral pharmacological effects.
  • Centrally acting agents are not yet widely available pending more data on the effects of CNS activity on urinary tract function. Some agents in clinical use for urethral and bladder dysfunction have clear central effects (e.g. some antidepressants which prolong the central effects of serotonin, and norepinephrine)
  • Most of the drugs, in clinical use, have effects on both post-ganglionic and preganglionic neurons. [Braverman 1998]
  • There are several important pharmacologic mechanisms in the bladder contraction and relaxation. Among them, cholinergic mechanism is the most important for detrusor contractility.

Cholinergic Mechanisms

  • Detrusor muscle will contract when exposed to cholinergic muscarinic receptor agonists. This contractile response can be completely, but reversibly, abolished by atropine.
  • Pharmacologic subtypes of muscarinic, acetylcholine receptors, labeled M for muscarinic, have been identified and characterized: these are M1 through M 5. [Caulfield 1998].
  • The human urinary bladder smooth muscle contains a mixed population of M2 and M3 subtypes,
    • M2 receptors: being predominant in the human bladder (80% of the total muscarinic receptor population) [Chapple 2000]
    • M3 receptors: primarily responsible for bladder contraction [Chapple 2000]
  • Mechanisms of detrusor contractions
    • Activation of M3 receptors: phosphoinositol hydrolysis -> intracellular calcium mobilization -> smooth muscle contraction.
    • Activation of M2 receptors: inhibition of adenyl cyclase ->
      • Major action: inhibit sympathetically mediated (via beta adrenergic) augmentation of cAMP levels -> inhibiting bladder relaxation
      • Minor action: activation of nonspecific cation channels, Rho proteins, and inactivation of potassium channels.
    • Activation of presynaptic M1 receptors: -> acetylcholine release during neural stimulation
  • M3 receptor subtype is abundant in salivary gland. This fact is clinically very relevant regarding the side effects ‘dry mouth’ during the treatment with anticholinergic agents.

Adrenergic Mechanisms

  • Both alpha and beta involved in the urinary bladder or urethral smooth muscle

β-Adrenergic

  • β2 and β3 receptors are present in the human detrusor muscle.
  • Stimulation results in the direct relaxation of the detrusor smooth muscle [Levin 1995]
  • β-Adrenergic–stimulated relaxation is mediated through adenyl cyclase (cAMP)

α-Adrenergic

  • Predominant distribution of α-adrenergic receptors:
    • Smooth muscle of the bladder base
    • proximal urethra
    • blood vessels
  • α1A subtype is primarily mediated in the human prostate and urethra [Docherty 1998] Urethra
    • α-adrenergic mechanisms are very important in urethral function.
      • α-adrenergic agonist: promote urine storage by increasing urethral resistance
      • α-adrenergic antagonists: block urethral contraction
  • Detrusor
    • Normal condition: not very prominent
    • Pathologic conditions: receptor density can increase in the urinary bladder
      • Bladder outlet obstruction:
        • normal β-adrenergic response of canine bladder body smooth musculature was changed to an α-adrenergic response [Rohner 1978]
        • α-adrenergic response instead of the usual β-adrenergic response in BPH patients [Perlberg 1982].
      • Unstable bladder: significantly lower muscarinic receptor and higher α-adrenoceptor densities [Lepor 1989]
    • For more information, please refer to this

NANC Mechanism

  • Cholinergic mechanism is a main component of bladder contraction. However, not all the contractile activities are solely contributed by cholinergic mechanism. The rest of the contractile activities is called atropine-resistant components (nonadrenergic noncholinergic, NANC)
  • Recently, several NANC mediators have been recognized to play a significant role in the physiology of the lower urinary tract.
  • Purinergic (medicated by ATP, acting on P2X receptor) and nitrergic (mediated by NO) mechanisms are two major NANC mechanisms.
  • Nonadrenergic noncholinergic components
    • Normal human bladder muscle: present in normal human detrusor but relatively unimportant [Ruggieri 1990]
    • Functionally altered bladder: more important [Andersson 1999]
      • Unstable bladder [Bayliss 1999]
      • neurogenic bladder [Wammack 1995

1) Purinergic Mechanism

  • An increase in purinergic function in overactive bladder (approximately 50%) [O'Reilly 2001]
  • Explanation for the reason why antimuscarinic treatment fails in many patients

2) Nitrergic Mechanism

  • Producing smooth muscle relaxation in human bladder neck [Mumtaz 2000]
  • There are significant implications in clinical situations.

Key Points of This Section
  • Lower urinary tract pharmacology is complex, although the agents we have are mainly cholinergic, anticholinergic and alpha adrenergic agonists and antagonists.
  • Available agents work better in neuropathic conditions (e.g. spincal cord injury) than idiopathic conditions (e.g. the overactive bladder)
  • In most cases the best effects of drug therapy are: an increase in the volume required to excite a bladder contraction, increased bladder capacity, and lower storage pressures.
  • These effects in neuropathic conditions are achieved with combined treatment anticholinergic and alpha receptor antagonists, as both muscarinic and alpha receptors are involved in the detrusor response to filling
  • Emerging evidence suggests that anticholinergic agents do not directly affect the strength and character of detrusor contractility but rather affect the storage phase of bladder activity in effect prolonging it.

References

  • Andersson KE. Changes in bladder tone during filling: pharmacological aspects. Scand J Urol Nephrol Suppl. 1999;201:67-72.
  • Bayliss M, Wu C, Newgreen D, Mundy AR, Fry CH. A quantitative study of atropine-resistant contractile responses in human detrusor smooth muscle, from stable, unstable and obstructed bladders. J Urol. 1999 Nov;162(5):1833-9.
  • Braverman AS, Kohn IJ, Luthin GR, Ruggieri MR. Prejunctional M1 facilitory and M2 inhibitory muscarinic receptors mediate rat bladder contractility. Am J Physiol. 1998 Feb;274(2 Pt 2):R517-23.
  • Caulfield MP, Birdsall NJ. International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev. 1998 Jun;50(2):279-90.
  • Chapple CR. Muscarinic receptor antagonists in the treatment of overactive bladder. Urology. 2000 May;55(5A Suppl):33-46
  • Docherty JR. Subtypes of functional alpha1- and alpha2-adrenoceptors. Eur J Pharmacol. 1998 Nov 13;361(1):1-15
  • Lepor H, Gup D, Shapiro E, Baumann M. Muscarinic cholinergic receptors in the normal and neurogenic human bladder. J Urol. 1989 Sep;142(3):869-74.
  • Levin RM, Wein AJ, Saito M, Longhurst PA. Factors that modulate the initiation of micturition. Scand J Urol Nephrol Suppl. 1995;175:3-10.
  • Mumtaz FH, Khan MA, Thompson CS, Morgan RJ, Mikhailidis DP. Nitric oxide in the lower urinary tract: physiological and pathological implications. BJU Int. 2000 Mar;85(5):567-78.
  • O'Reilly BA, Kosaka AH, Chang TK, Ford AP, Popert R, Rymer JM, McMahon SB. A quantitative analysis of purinoceptor expression in human fetal and adult bladders. J Urol. 2001 May;165(5):1730-4.
  • Perlberg S, Caine M. Adrenergic response of bladder muscle in prostatic obstruction. Its relation to detrusor instability. Urology. 1982 Nov;20(5):524-7.
  • R. Wammack, E. Weihe, H.P. Dienes et al., Die neurogene blase in vitro. Aktuel Urol 26 (1995), pp. 16–18.
  • Rohner TJ, Hannigan JD, Sanford EJ. Altered in vitro adrenergic responses of dog detrusor msucle after chronic bladder outlet obstruction. Urology. 1978 Apr;11(4):357-61.
  • Ruggieri MR, Whitmore KE, Levin RM. Bladder purinergic receptors. J Urol. 1990 Jul;144(1):176-81.

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