- Email: [email protected]
Urinary incontinence secondary to drugs
UROPHARMACOLOGY
URINARY
INCONTINENCE
H. G. KIRULUTA, KATHEE
ANDREWS,
SECONDARY
TO DRUGS
M.D. B.Sc.
From the Department of Surgery (Urology), Memorial University, Health Sciences Centre, St. John’s, Newfoundland, Canada
ABSTRACTWith the current rapid introduction of new drugs on the market, drug toxicity and side effects have received increasing publicity in the literature. Bladder dysfunction, however, rarely has been reported as an adverse effect. The possible mechanisms in the induction of urinary incontinence by three main groups of drugs, the neuroleptics, the antihypertensive agents, and the drugs used in the treatment of neurogenic bladder obstruction, are reviewed. These drugs are thought to act peripherally at sympathetic neurons or through a centrally-mediated effect.
Urinary incontinence as a direct side effect of commonly used drugs is becoming more frequent. Recent research in the pharmacology and physiology of bladder and urethral function has given us a clearer picture of their mechanism of action. The bladder and the urethra are innervated by both parasympathetic and sympathetic nerve fibers. Parasympathetic stimulation causes the emptying phase of bladder activity. Acetylcholine released by postganglionic parasympathetic neurons stimulates cholinergic receptors, resulting in smooth muscle contraction of the body of the bladder. Alpha-adrenergic receptors are located predominantly in the bladder base and proximal urethra, and their stimulation by the neurotransmitter norepinephrine causes contraction of the smooth muscle of the bladder neck and proximal urethra. Beta-adrenergic receptors predominate in the body of the bladder, and their stimulation results in smooth muscle relaxation, primarily of the body of the bladder. Urinary continence is thus a function of both the bladder, via its accommodating property during filling, and the proximal urethra where alpha-adrenergic receptors are located. The latter is the common site of action of most of the drugs that cause urinary incontinence as a side effect.
88
Neuroleptic
Drugs
The neuroleptic drugs are also the major tranquilizers and are widely used in the treatment of various psychoses. There are basically two types of neuroleptic drugs, phenothiazines and butyrophenones. All neuroleptics act selectively at dopamine receptors throughout the brain and body to exhibit a dopamine receptor blockade. They exhibit a wide range of central and peripheral actions including alterations in motor activity, sleep patterns, and central and peripheral nerve systems. Because of their widespread action, phenothiazines have been found to show a variety of related side effects including blood dyscrasias, dyskinesia, parkinsonian syndrome, neuroleptic hypotension, and jaundice. Bladder dysfunction has been one of the rarest reported side effects of these drugs. However, in the past decade, bladder voiding disorders, particularly urinary incontinence, have been widely reported. Urinary incontinence has been reported in several patients treated with thioridazine.1-4 More recently, nocturnal enuresis and/or daytime incontinence have been found in response to treatment with various neuroleptics including thiohexene, chloropromazine, thioridazine, and the butyrophenones, haloperidol.5-7 Patients in these studies showed
UROLOGY
i
JULY
1983
/
VOLUME
XXII,
NUMBER
1
no evidence of urinary tract abnormalities prior to treatment. and in most cases the voiding disorder disappeared immediately after discontinuance of medication. Currently, the mechanism of this urinary incontinence is unknown. Van Putten, Malkin, and Weiss’ suggest that the alpha-adrenergic blocking action. of these drugs causes internal urinary sphincter relaxation in anatomically predisposed patients. However, the absence of other systemic adrenergic blockade effects, i.e. ? hypotension, indicates that alpha-adrenergic blocking properties do not fully explain the occurrence of incontinence. A central basis for the neuroleptic-produced urinary incontinence has been suggested: since incontinence is known to occur in cases of brain stem, basal ganglia, and frontal lobe disturbances. Since phenothiazines and butyrophenones affect central biogenic amine transmitter systems and also produce a peripheral systemic effect, a centrally mediated disturbance is a likely possibility for the urinary incontinence that occurs in these patients. Drugs Used in Neurogenic Bladder Obstruction
Agents
Reserpine Reserpine is the purified alkaloids of Rauwolfia; and although a weak hypotensive drug, it is extremely useful in combination with a diuretic. It exerts its sympatholytic action by
UROLOGY
JULY
1983
!
VOI.UME
XXII.
Alpha-methyl dopa Raz’” has reported a case in which methyldopa acting alone produced urinary incontinence. Methyldopa reduces peripheral sympathetic tone by a mechanism which is still unclear. The presently accepted view is that it exerts its effect within the central nervous system. Methyldopa is metabolized to alpha-methylnorepinephrine, which stimulates inhibitory alpha-adrenergic receptors in the central nervous system. Stimulation of these receptors reduces peripheral sympathetic tone-l4 The combination of methyldopa with phenoxybenzamine, an alpha-adrenoceptor blocking agent, has been noted to be synergistic to the urethra. Fernandez et al.‘” have reported a case in which total urinary incontinence occurred while the patient was taking both drugs. Praxosin
Phentolamine and phenoxybenzamine are the commonly used drugs in this group. Phentolamine, a substituted imidazoline, produces a transient, competitive alpha-adrenergic blockade.8 It blocks alpha-receptors at the bladder neck and proximal urethra, causing smooth muscle relaxation and a decrease in the amplitude of the urethral pressure profile.g Since it is supplied for intravenous use only, it is not commonly used. However, phenoxybenzamine, which is a haloalkylamine alpha-adrenergic blocking agent, forms a stable covalent bond with alpha-receptors and thus possesses a long duration of action.1° Since first introduced by Kleeman in 1970” for the treatment of atonic neurogenic bladders, phenoxybenzamine has been used with great success in the treatment of urinary retention secondary to neurogenic bladder dysfunction. In several patients on longterm chronic treatment, stress urinary incontinence developed with the use of this drug.12 Antihypertensive
depleting the body of norepinephrine, dopamine, and serotonin. Stress incontinence has occurred in susceptible patients, particularly women.
NUSIRER
1
Prazosin hydrochloride is a quinazoline derivative which has been documented to have significant antihypertensive properties,“j and a number of reports now have been published concerning its efficacy in clinical hypertension.16-1H It produces a hypotensive effect by blocking alpha,-adrenergic receptors and thereby causing peripheral vadodilation. Urinary incontinence as a result of its blocking effect on the alpha-adrenoceptor in the proximal urethra occurs in susceptible patients, and several case reports have confirmed this effect.1g,20 We have had a similar case in which total urinary incontinence occurred in a woman taking prazosin in which the incontinence disappeared on the discontinuation of the drug. Urodynamic studies in this patient revealed a depressed urethral pressure profile while taking the medication with a return to normal when the drug was discontinued.“’ Comment The aforementioned drugs are commonly used in clinical practice. However, the incidence of drug-induced urinary incontinence is probably small in the general population. There is a group which is particularly at risk, in which precaution should be exercised when prescribing. Middle-aged women with borderline urinary stress incontinence make up a
89
large percentage of case reports in which druginduced incontinence has occurred. Bladder dysfunction in response to neuroleptic drugs does not appear to be restricted to any particular patient population or age. In some cases, the effects are transitory. St. John’s,
Newfoundland Canada AIB 3V6 (DR. KIRULUTA)
References 1. Van Putten T, Malkin MD, and Weiss MS: Phenothiazineinduced stress incontinence, J Urol 104: 625 (1973). 2. Ananth JV, et al: Urinary incontinence associated with Thiordazine administration, Can Med Assoc J 104: 326 (1971). 3. Renshaw DC: Thiordazine and incontinence, JAMA 218: 738 (1971). 4. Crittenden F: Thiordazine incontinence, ibid 219: 312 (1972). 5. Nurnberg HG, et al: Urinary incontinence in patients receivine neurolentics. I Clin Psvchol40: 271 (1979). 6. imbrosini PJ,’ ind N&berg HG: Enuresis and incontinence occurring with neuroleptics, Am J Pyschol 137: 1278 (1980). 7. Shenoy RS: Nocturnal enuresis caused by psychotropic drugs, ibid 137: 739 (1980). 8. Nickerson M, and Collier B: Drugs inhibiting adrenergic nerves and structures innervated by them in: Goodman LS, and Gilman A (Eds): The Pharmacological Basis of Therapeutics, ed 5, New York, Macmillan Co., 1975, pp 514-532.
90
9. Awad SA, et al: Sympathetic activity in the proximal urethra in patients with urinary obstruction, J Urol 115: 545 (1976). 10. Finkbeiner AE, Welch LT, and Bissada NK: Uropharmacology: XI. Adrenergic-blocking agents and drugs affecting catecholamine binding and release, Urology 13: 693 (1979). 11. Kleeman FJ: The physiology of the internal urinary sphincter, J Urol 101: 549 (1970). 12. Harrison NW, Whitfield HN, and Williams DI: The place of alpha-blocking drugs in the treatment of children with neuropathic bladders, Ural Int 32: 224 (1977). 13. Raz S: Adrenergic influence on the internal. urinary sphincter, Isr J Med Sci 10: 608 (1974). 14. Raz S, Kaufman JJ, Ellison GW, and Mayers LW: Methyldopa in the treatment of neurogenic bladder disorders, Urology 9: 188 (1977). 15. Fernandez PG, et al: Urinary incontinence due to interaction of phenoxybenzamine and alpha-methyldopa, Can Med Assot J 124: 174 (1981). 16. Richardson DW, Ramaswamy D, and Ramirez A: Effects of prazosin on arterial blood pressure and cardiac output in human hypertension, Circulation (Suppl) 38: 164 (1978). 17. Brogden RN, Heel RC, Speight TM, and Avery GS: Prazosin: a review of its pharmacological properties and therapeutic efficacy in hypertension, Drugs 14: 163 (1977). 18. Stokes GS, and Oates HF: Prazosin: new alpha-adrenergic blocking agent in treatment of hypertension, Cardiovasc Med 3: 41 (1978). 19. Straughan JL: Urinary incontinence with prazosin, S Afr Med J 53: 22; 882 (1978). 20. Thien TH, Delaere KPJ, Debruyne FMJ, and Loene RAP: Urinary incontinence caused by prazosin, Br Med J 1: 622 (1978). 21. Kiruluta HG, Mercer AR, and Winsor GM: Prazosin as a cause of urinary incontinence, Urology 18: 618 (1981).
UROLOGY
/
JULY
1983
i
VOLUME
XXII,
NUMBER
1
URINARY
INCONTINENCE
H. G. KIRULUTA, KATHEE
ANDREWS,
SECONDARY
TO DRUGS
M.D. B.Sc.
From the Department of Surgery (Urology), Memorial University, Health Sciences Centre, St. John’s, Newfoundland, Canada
ABSTRACTWith the current rapid introduction of new drugs on the market, drug toxicity and side effects have received increasing publicity in the literature. Bladder dysfunction, however, rarely has been reported as an adverse effect. The possible mechanisms in the induction of urinary incontinence by three main groups of drugs, the neuroleptics, the antihypertensive agents, and the drugs used in the treatment of neurogenic bladder obstruction, are reviewed. These drugs are thought to act peripherally at sympathetic neurons or through a centrally-mediated effect.
Urinary incontinence as a direct side effect of commonly used drugs is becoming more frequent. Recent research in the pharmacology and physiology of bladder and urethral function has given us a clearer picture of their mechanism of action. The bladder and the urethra are innervated by both parasympathetic and sympathetic nerve fibers. Parasympathetic stimulation causes the emptying phase of bladder activity. Acetylcholine released by postganglionic parasympathetic neurons stimulates cholinergic receptors, resulting in smooth muscle contraction of the body of the bladder. Alpha-adrenergic receptors are located predominantly in the bladder base and proximal urethra, and their stimulation by the neurotransmitter norepinephrine causes contraction of the smooth muscle of the bladder neck and proximal urethra. Beta-adrenergic receptors predominate in the body of the bladder, and their stimulation results in smooth muscle relaxation, primarily of the body of the bladder. Urinary continence is thus a function of both the bladder, via its accommodating property during filling, and the proximal urethra where alpha-adrenergic receptors are located. The latter is the common site of action of most of the drugs that cause urinary incontinence as a side effect.
88
Neuroleptic
Drugs
The neuroleptic drugs are also the major tranquilizers and are widely used in the treatment of various psychoses. There are basically two types of neuroleptic drugs, phenothiazines and butyrophenones. All neuroleptics act selectively at dopamine receptors throughout the brain and body to exhibit a dopamine receptor blockade. They exhibit a wide range of central and peripheral actions including alterations in motor activity, sleep patterns, and central and peripheral nerve systems. Because of their widespread action, phenothiazines have been found to show a variety of related side effects including blood dyscrasias, dyskinesia, parkinsonian syndrome, neuroleptic hypotension, and jaundice. Bladder dysfunction has been one of the rarest reported side effects of these drugs. However, in the past decade, bladder voiding disorders, particularly urinary incontinence, have been widely reported. Urinary incontinence has been reported in several patients treated with thioridazine.1-4 More recently, nocturnal enuresis and/or daytime incontinence have been found in response to treatment with various neuroleptics including thiohexene, chloropromazine, thioridazine, and the butyrophenones, haloperidol.5-7 Patients in these studies showed
UROLOGY
i
JULY
1983
/
VOLUME
XXII,
NUMBER
1
no evidence of urinary tract abnormalities prior to treatment. and in most cases the voiding disorder disappeared immediately after discontinuance of medication. Currently, the mechanism of this urinary incontinence is unknown. Van Putten, Malkin, and Weiss’ suggest that the alpha-adrenergic blocking action. of these drugs causes internal urinary sphincter relaxation in anatomically predisposed patients. However, the absence of other systemic adrenergic blockade effects, i.e. ? hypotension, indicates that alpha-adrenergic blocking properties do not fully explain the occurrence of incontinence. A central basis for the neuroleptic-produced urinary incontinence has been suggested: since incontinence is known to occur in cases of brain stem, basal ganglia, and frontal lobe disturbances. Since phenothiazines and butyrophenones affect central biogenic amine transmitter systems and also produce a peripheral systemic effect, a centrally mediated disturbance is a likely possibility for the urinary incontinence that occurs in these patients. Drugs Used in Neurogenic Bladder Obstruction
Agents
Reserpine Reserpine is the purified alkaloids of Rauwolfia; and although a weak hypotensive drug, it is extremely useful in combination with a diuretic. It exerts its sympatholytic action by
UROLOGY
JULY
1983
!
VOI.UME
XXII.
Alpha-methyl dopa Raz’” has reported a case in which methyldopa acting alone produced urinary incontinence. Methyldopa reduces peripheral sympathetic tone by a mechanism which is still unclear. The presently accepted view is that it exerts its effect within the central nervous system. Methyldopa is metabolized to alpha-methylnorepinephrine, which stimulates inhibitory alpha-adrenergic receptors in the central nervous system. Stimulation of these receptors reduces peripheral sympathetic tone-l4 The combination of methyldopa with phenoxybenzamine, an alpha-adrenoceptor blocking agent, has been noted to be synergistic to the urethra. Fernandez et al.‘” have reported a case in which total urinary incontinence occurred while the patient was taking both drugs. Praxosin
Phentolamine and phenoxybenzamine are the commonly used drugs in this group. Phentolamine, a substituted imidazoline, produces a transient, competitive alpha-adrenergic blockade.8 It blocks alpha-receptors at the bladder neck and proximal urethra, causing smooth muscle relaxation and a decrease in the amplitude of the urethral pressure profile.g Since it is supplied for intravenous use only, it is not commonly used. However, phenoxybenzamine, which is a haloalkylamine alpha-adrenergic blocking agent, forms a stable covalent bond with alpha-receptors and thus possesses a long duration of action.1° Since first introduced by Kleeman in 1970” for the treatment of atonic neurogenic bladders, phenoxybenzamine has been used with great success in the treatment of urinary retention secondary to neurogenic bladder dysfunction. In several patients on longterm chronic treatment, stress urinary incontinence developed with the use of this drug.12 Antihypertensive
depleting the body of norepinephrine, dopamine, and serotonin. Stress incontinence has occurred in susceptible patients, particularly women.
NUSIRER
1
Prazosin hydrochloride is a quinazoline derivative which has been documented to have significant antihypertensive properties,“j and a number of reports now have been published concerning its efficacy in clinical hypertension.16-1H It produces a hypotensive effect by blocking alpha,-adrenergic receptors and thereby causing peripheral vadodilation. Urinary incontinence as a result of its blocking effect on the alpha-adrenoceptor in the proximal urethra occurs in susceptible patients, and several case reports have confirmed this effect.1g,20 We have had a similar case in which total urinary incontinence occurred in a woman taking prazosin in which the incontinence disappeared on the discontinuation of the drug. Urodynamic studies in this patient revealed a depressed urethral pressure profile while taking the medication with a return to normal when the drug was discontinued.“’ Comment The aforementioned drugs are commonly used in clinical practice. However, the incidence of drug-induced urinary incontinence is probably small in the general population. There is a group which is particularly at risk, in which precaution should be exercised when prescribing. Middle-aged women with borderline urinary stress incontinence make up a
89
large percentage of case reports in which druginduced incontinence has occurred. Bladder dysfunction in response to neuroleptic drugs does not appear to be restricted to any particular patient population or age. In some cases, the effects are transitory. St. John’s,
Newfoundland Canada AIB 3V6 (DR. KIRULUTA)
References 1. Van Putten T, Malkin MD, and Weiss MS: Phenothiazineinduced stress incontinence, J Urol 104: 625 (1973). 2. Ananth JV, et al: Urinary incontinence associated with Thiordazine administration, Can Med Assoc J 104: 326 (1971). 3. Renshaw DC: Thiordazine and incontinence, JAMA 218: 738 (1971). 4. Crittenden F: Thiordazine incontinence, ibid 219: 312 (1972). 5. Nurnberg HG, et al: Urinary incontinence in patients receivine neurolentics. I Clin Psvchol40: 271 (1979). 6. imbrosini PJ,’ ind N&berg HG: Enuresis and incontinence occurring with neuroleptics, Am J Pyschol 137: 1278 (1980). 7. Shenoy RS: Nocturnal enuresis caused by psychotropic drugs, ibid 137: 739 (1980). 8. Nickerson M, and Collier B: Drugs inhibiting adrenergic nerves and structures innervated by them in: Goodman LS, and Gilman A (Eds): The Pharmacological Basis of Therapeutics, ed 5, New York, Macmillan Co., 1975, pp 514-532.
90
9. Awad SA, et al: Sympathetic activity in the proximal urethra in patients with urinary obstruction, J Urol 115: 545 (1976). 10. Finkbeiner AE, Welch LT, and Bissada NK: Uropharmacology: XI. Adrenergic-blocking agents and drugs affecting catecholamine binding and release, Urology 13: 693 (1979). 11. Kleeman FJ: The physiology of the internal urinary sphincter, J Urol 101: 549 (1970). 12. Harrison NW, Whitfield HN, and Williams DI: The place of alpha-blocking drugs in the treatment of children with neuropathic bladders, Ural Int 32: 224 (1977). 13. Raz S: Adrenergic influence on the internal. urinary sphincter, Isr J Med Sci 10: 608 (1974). 14. Raz S, Kaufman JJ, Ellison GW, and Mayers LW: Methyldopa in the treatment of neurogenic bladder disorders, Urology 9: 188 (1977). 15. Fernandez PG, et al: Urinary incontinence due to interaction of phenoxybenzamine and alpha-methyldopa, Can Med Assot J 124: 174 (1981). 16. Richardson DW, Ramaswamy D, and Ramirez A: Effects of prazosin on arterial blood pressure and cardiac output in human hypertension, Circulation (Suppl) 38: 164 (1978). 17. Brogden RN, Heel RC, Speight TM, and Avery GS: Prazosin: a review of its pharmacological properties and therapeutic efficacy in hypertension, Drugs 14: 163 (1977). 18. Stokes GS, and Oates HF: Prazosin: new alpha-adrenergic blocking agent in treatment of hypertension, Cardiovasc Med 3: 41 (1978). 19. Straughan JL: Urinary incontinence with prazosin, S Afr Med J 53: 22; 882 (1978). 20. Thien TH, Delaere KPJ, Debruyne FMJ, and Loene RAP: Urinary incontinence caused by prazosin, Br Med J 1: 622 (1978). 21. Kiruluta HG, Mercer AR, and Winsor GM: Prazosin as a cause of urinary incontinence, Urology 18: 618 (1981).
UROLOGY
/
JULY
1983
i
VOLUME
XXII,
NUMBER
1