Fig. 15.1 Aspects of the bladder/prostate structures and the innervation involved in the micturition reflex.
Bladder filling provides neuronal signals to the micturition centre via sensory input from purinoceptors on neurons in the urothelium. To accommodate filling and continence, sympathetic stimulation both relaxes the smooth muscle of the bladder via β2– and β3-adrenoceptors and stimulates sphincter mechanisms through α1-adrenoceptor subtypes. Somatic control of the external sphincter also aids continence. Voluntary urination involves parasympathetic stimulation of bladder smooth muscle through M3 and M2 muscarinic receptor subtypes (M) and inhibition of the sympathetic and somatic outflow. Aspects of bladder control may involve other less understood transmitter substances. For example, γ-aminobutyric acid (GABA) interneurons inhibit bladder contraction. P2X, purinergic receptors.
During bladder filling, sympathetic nervous system stimulation via the hypogastric nerve relaxes the bladder smooth muscle (via β2– and β3-adrenoceptors in the detrusor which generate intracellular cAMP). At the same time sympathetic stimulation of α1-adrenoceptors (α1A– and to a lesser extent α1B-adrenoceptor subtypes), via the vesical nerve, contracts the smooth muscle of the internal urethral sphincter. Stimulation of the striated muscle of the external urethral sphincter, which is under voluntary control via the pudendal nerve, and aided by pelvic muscle control in women, contributes to maintenance of internal urethral sphincter tone and continence. The sensation of urge to micturate occurs in adults at a bladder volume of 200–300 mL.
Bladder emptying is initiated by myogenic stretch receptor activity produced by distention of the trigone, and by sensory signals from the urothelium (the epithelial cell lining of the bladder). Release of ATP from the urothelium stimulates P2X purinoceptors which along with other local receptor modulators initiate sensory impulses in the afferent nerves (see Ch. 1). The afferent sensory nerves project to the pontine micturition centre, which then initiates activity in efferent motor pathways. Stimulation of the pelvic nerve, acting through parasympathetic muscarinic M3 receptors in the detrusor muscle, leads to bladder contraction and voiding. Acetylcholine, acting through these receptors, leads to generation of intracellular inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). At the same time, stimulation of muscarinic M2 receptors on presynaptic nerve terminals inhibits intracellular cAMP production, and therefore opposes the effects of sympathetic activity. Non-cholinergic-mediated efferent impulses (ATP neurotransmission acting via P2X purinoreceptors) also contribute to bladder contraction, and this component becomes more prominent in unstable bladders. Contraction of the detrusor is coordinated with inhibition of the tonic control of distal sphincter mechanisms and the bladder neck, thus relaxing the bladder outflow tract. Bladder emptying may be augmented by contraction of the diaphragm and abdominal muscles. M3 and M2 receptors are present in detrusor muscle but the M3 subtype appears to be more important for detrusor contraction.
Disorders of micturition
Disorders of micturition can arise from a disturbance of bladder function or from abnormalities affecting bladder outflow. Although there are distinct clinical syndromes, many people with incontinence have mixed incontinence; for example, both stress and urge incontinence (see below). Management of disorders of micturition should also consider possible contributory factors, such as diuretics, α1-adrenoceptor antagonists used for treatment of hypertension, and stool impaction, which inhibits sacral parasympathetic neurotransmission.
Overactive bladder syndrome
Detrusor instability produces uncontrolled bladder contractions during normal filling. Symptoms from this include urinary urgency, nocturia and frequency (overactive bladder syndrome), often accompanied by urge incontinence (a sudden compelling desire to urinate). Most cases in women are idiopathic but probably have a neurogenic component, while in men bladder outflow obstruction is the commonest cause. Upper motor neuron lesions, such as those produced by stroke, spinal cord injuries or multiple sclerosis, can also produce an overactive bladder. First-line approaches to management include reduction in excessive fluid intake, weight loss, smoking cessation and behavioural training that includes pelvic floor muscle rehabilitation and suppression of urge.
Drugs for treatment of overactive bladder syndrome
Increased understanding of the neural pathways involved in initiating micturition is opening up new avenues for drug therapy to augment the relatively ineffective treatments currently available. Those used at present to treat overactive bladder act at peripheral muscarinic receptors to decrease bladder activity.
Muscarinic receptor antagonists
These drugs act with various degrees of selectivity at muscarinic receptor subtypes. Antimuscarinic unwanted effects (Ch. 4) are most troublesome with oxybutynin, particularly central nervous system (CNS) effects such as sedation, insomnia, confusion and cognitive problems (from M1 receptor blockade) and dry mouth (from M3 receptor blockade in salivary glands). The need for continued use of these drugs should be reviewed after 6 months.
Oxybutynin is a selective antagonist of M1 and M3 receptors and has additional weak muscle relaxant properties through calcium channel blocking actions and local anaesthetic activity. Oxybutynin is rapidly absorbed from the gut and metabolised in the liver to an active metabolite. Modified-release and transdermal formulations are available because oxybutynin has a short half-life (1–3 h) and use of standard formulations can result in large fluctuations in plasma drug concentrations and increase the severity of unwanted effects.
Tolterodine, fesoterodine and trospium are non-selective muscarinic receptor antagonists with no additional properties and less lipophilicity than oxybutynin. They cross the blood–brain barrier less readily and have fewer cognitive unwanted effects. Both tolterodine and trospium have short half-lives. Tolterodine is better tolerated in a modified-release formulation.
Beta3-adrenoceptor agonist
Example: mirabegron: Stimulation of β3-adrenoceptors in the bladder trigone flattens and lengthens the bladder base, which facilitates urine storage. Mirabegron reduces symptoms of urinary frequency and urgency with similar efficacy when compared to the muscarinic receptor antagonists. The main adverse effects are an increase in blood pressure and heart rate. It may be an option for those who fail to respond to muscarinic receptor antagonists, or who cannot tolerate them.
Other drugs
Topical vaginal oestrogen-replacement therapy (Ch. 45) reverses atrophic changes in the lower genital tract in postmenopausal women and may be helpful for overactive bladder syndrome.
Desmopressin, a synthetic antidiuretic hormone (ADH) analogue (Ch. 43), is sometimes helpful to reduce nocturia in unstable bladder syndrome. It is taken orally; the nasal spray is no longer licensed for this indication because of the risk of water intoxication in children.Hypotonic bladder
Hypotonic bladder is often a result of lower motor neuron lesions, or can arise from bladder distension following chronic urinary retention. Drugs with antimuscarinic properties (such as tricyclic antidepressants; Ch.22) and the specific antimuscarinic drugs above can make the symptoms worse. Hypotonic bladder leads to incomplete bladder emptying, with urinary retention and overflow incontinence. Treatment depends on the cause.
Chronic urinary retention is often caused by bladder outlet obstruction. If renal function is impaired, it should be managed by bladder catheterisation and correction of the underlying cause.
Neurogenic problems are sometimes treated with anticholinesterases (such as distigmine) which may increase the force of detrusor contraction (Ch. 4), although they are probably ineffective. Cholinergic drugs should not be used in the presence of urinary outflow obstruction.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
