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Janimine

Imipramine (sold as Antideprin®, Janimine®, Tofranil®) is an antidepressant medication belonging to a class called tricyclic antidepressants of the dibenzazepine group, mainly used in the treatment of clinical depression and enuresis. more...

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Imipramine was, in the late 1950s, the first tricyclic antidepressant to be developed (by Ciba-Geigy). Initially, it was tried against psychotic disorders (e.g. schizophrenia), but proved insufficient. During the clinical studies its antidepressant qualities, unsurpassed until today, became evident. Subsequently it was extensively used as standard antidepressant and later served as a prototypical drug for the development of the later released tricyclics. It is not as commonly used today but sometimes used to treat major depression as a second-line treatment. It has also seen limited use in the treatment of migraines, ADD and post concussive syndrome. Imipramine has additional indications for the treatment of panic attacks and chronic pain. In pediatric patients it is relatively frequently used to treat pavor nocturnus and enuresis.

Mechanism of Action

Imipramine, a tertiary amine, inhibits the reuptake of serotonin more so than most secondary amine tricyclics, meaning that it blocks the reuptake of neurotransmitters serotonin and noradrenaline almost equally.

Metabolism

Imipramine is converted to desipramine, another TCA, in the body.

Contraindications and Precautions

See Tricyclic antidepressants

Side Effects

Some common side effects of the drug include: tremors, dry mouth, blurred vision, constipation, insomnia, drowsiness, perspiration, flushing and weight gain. Agitation, irritability, confusion, and delirium are also possible, particular in the elderly.

Dosage

  • Ambulatory patients : starting with 25 to 75mg daily, increasing up to a maximum of 200mg daily, after remission dose is often reduced to 50-100mg daily.
  • Hospitalized patients : starting with 3 time 25mg, increasing to 200mg. Up to 300mg may be given in resistant cases. After remission dose is often reduced to 50-100mg daily.
  • Pediatric patients : starting with 10mg daily the dose is adjusted according to the severity of the symptoms to be treated, the side-effects encountered and the weight of the patient.

Overdose

The symptoms and the treatment of an overdose are largely the same as for the other tricyclic antidepressants. Cardinal symptoms are cardial and neurological disturbances. Any intake by children should be considered as serious and potentially fatal.

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Pharmacotherapy of urinary incontinence - includes patient information sheets
From American Family Physician, 8/1/96 by James W. Mold

Urinary incontinence is an extremely common and frequently undiagnosed problem in primary care patients of all ages.[1,2] Appropriate treatment almost always resolves or improves the problem. However, the development of an effective treatment plan depends on accurate identification of the type or types of incontinence in the individual patient. This process is well within the scope and expertise of family physicians.[3,4]

The treatment of urinary incontinence often involves educational and behavioral strategies, specific exercises and the elimination of aggravating factors, such as fecal impaction, polyuria or impaired mobility.[4] This article focuses on the pharmacologic issues that are relevant to the treatment of urinary incontinence and the pharmacotherapeutic approaches for the four most common causes of urinary incontinence.

Normal Physiology

AUTONOMIC CONTROL OF BLADDER FUNCTION

The bladder and internal urethral sphincter are capable of functioning automatically through neural reflex arcs involving spinal sensory and motor neurons, the autonomic nervous system and the detrusor nucleus located in the brain stem.[5] Current pharmacotherapy frequently targets the autonomic nervous system.

The detrusor muscle of the bladder is stimulated to contract by the parasympathetic nervous system, which uses acetylcholine as its major neurotransmitter. Conversely, sympathetic nervous system activation of beta-adrenergic receptors inhibits detrusor muscle contraction. Sympathetic stimulation of alpha-adrenergic receptors causes contraction of the internal involuntary urethral sphincter.[1]

Voluntary control of bladder function occurs through cerebral cortical connections that modulate the involuntary reflex arc. The external urethral sphincter and the pelvic floor muscles are also under voluntary control.[5] This is important pharmacologically because medications that depress or impair the function of the cerebral cortex may interfere with voluntary control mechanisms.

HORMONAL EFFECTS

Estrogen receptors are found throughout the urethra, in the trigone area and, more sparsely, in the rest of the bladder. Estrogen deficiency causes atrophy of the epithelial lining of the urethra, and the resulting loss of coaptation of the urethral mucosa reduces the effectiveness of the sphincters. Estrogen deficiency also predisposes women to urethritis, trigonitis and cystitis, all of which may exacerbate urge incontinence.

The frequency of urinary tract infections in postmenopausal women with recurrent cystitis can be reduced by estrogen replacement therapy. Estrogen also seems to increase the number and sensitivity of alpha-adrenergic receptors, which results in greater sensitivity to sympathetic stimulation.[6,7]

The roles of other sex hormones, such as progesterone and testosterone, in the control of bladder function have not been as well studied as the role of estrogen. Dihydrotestosterone, but not testosterone, contributes to prostatic enlargement and benign prostatic hyperplasia, which can eventually result in obstruction and overflow incontinence. As more is learned about the effects of decreasing testosterone levels in aging men, testosterone, like estrogen, may be found to have other roles in the maintenance of urinary continence.

AGE-RELATED CHANGES IN BLADDER STRUCTURE AND FUNCTION

The aging process is associated with several important changes in bladder structure and function, in addition to those changes directly related to postmenopausal estrogen deficiency (Table 1). Because of decreased elasticity, bladder capacity is often reduced.[8,9] In addition, the bladder becomes less able to distend beyond the point at which maximum pressures are reached. As a result, older people must void more frequently and promptly.[8] This lack of elasticity in combination with some reduction in detrusor muscle strength also results in less complete emptying.

Appropriate therapeutic agents for the treatment of urge incontinence include estrogen (for postmenopausal women), anticholinergic medications and smooth muscle relaxants. In addition, selected patients seem to benefit from alpha-adrenergic agents, which may act, in part, by increasing the sphincter tone and elevating the threshold of intravesical pressure required for incontinence.

Some of the more frequently used medications for urge incontinence and their purported mechanisms of action are listed in Table 3. Calcium channel blockers, such as verapamil (Calan, Isoptin) and nifedipine (Adalat, Procardia), and beta-adrenergic agonists, such as terbutaline (Brethine, Bricanyl), are not included, although these agents have been shown to be efficacious in several small clinical trials.[7,13,14] Theoretically, some prostaglandin synthetase inhibitors may be helpful. At this time, however, there is little clinical research evidence to support their use.[7]

[TABULAR DATA 3 OMITTED]

Caution should be exercised when treating a patient with a pretreatment postvoid urine volume of more than 75 mL. To avoid iatrogenic urinary retention, measurements of the postvoid urine volume should be repeated while these patients are receiving medication.

A syndrome of detrusor hyperactivity with impaired contractile function has been identified, primarily in the very old. This syndrome is particularly difficult to treat, since medications for the urge component further exacerbate the tendency to retain urine.[15]

All of the pharmacologic agents listed in Table 3 have anticholinergic effects. Therefore, they are all likely to cause dry mouth, constipation, sedation and, sometimes, blurred vision. Furthermore, it is not uncommon for older patients, particularly those with preexisting cognitive impairment, to have central nervous system side effects ranging from mild confusion to delusions and hallucinations. Because the anticholinergic effects may cause the heart rate to increase somewhat, patients with symptomatic coronary artery disease may experience an increase in angina. Since a variety of prescription and over-the-counter medications have anticholinergic properties, it is important to be sure that patients for whom anticholinergic drugs are prescribed for urge incontinence are not taking other anticholinergic agents.

The tricyclic antidepressants imipramine Janimine, Tofranil) and desipramine (Norpramin, Pertofrane) may cause additional side effects. The most frequent and potentially serious of these is orthostatic hypotension, which can easily be detected by routinely measuring blood pressure and pulse in the lying, sitting and standing positions both before and after the patient begins taking the medicine.

Tricyclic agents also have a tendency to slow atrioventricular nodal conduction and to decrease cardiac contractility. Furthermore, these drugs have both antiarrhythmic and proarrhythmic effects, similar to those of quinidine (Quinaglute). However, these cardiac effects are usually a problem only for patients with preexisting heart failure or conduction system disease.

Overflow Incontinence: Detrusor Hypotonicity

Weakness or hypotonicity of the detrusor muscle usually results from a neurologic disorder, such as diabetic autonomic neuropathy, but medications with anticholinergic or beta-adrenergic effects can worsen the problem. Therefore, in the treatment of overflow incontinence due to hypotonicity, drugs such as antihistamines, tricyclic antidepressants, anticholinergic sedatives and systemic beta agonists should be discontinued, if possible. Smooth muscle relaxants such as calcium channel blockers should also be avoided. In addition, alpha-adrenergic agents generally should be discontinued, since they increase outflow resistance by increasing sphincter tone.

Pharmacologic therapy for detrusor hypotonicity is relatively ineffective. In some patients, however, cholinergic agonists and beta-adrenergic blockers can be useful. The only cholinergic agent available for treatment of this problem is bethanechol (Urecholine), which can be taken in a dosage of 10 to 25 mg three to four times a day.[16] Side effects include abdominal pain and diarrhea, bradycardia, hypotension, diaphoresis and bronchoconstriction. Generally, bethanechol should be avoided in patients with asthma, coronary artery disease, peptic ulcer disease and parkinsonism. Beta-adrenergic blockers can be given in the usual antihypertensive doses, but their effectiveness in patients with detrusor hypotonicity has not been adequately evaluated. Postvoid residual urine volumes should be checked before and after treatment to document efficacy.

Overflow Incontinence: Bladder Outlet Obstruction

Urethral obstruction is most often caused by enlargement of the prostate due to infection, benign hyperplasia or cancer. Less common causes of urethral obstruction include urethral stricture related to infection or instrumentation, periurethral abscess and congenital anomalies.

Infections of the prostate gland, while difficult to eradicate, often respond to fluoroquinolones including ciprofloxacin (C)pro), norfloxacin (Noroxin), lomefloxacin (Maxaquin) and ofloxacin (Floxin). Prostatic infections also respond to trimethoprim-sulfamethoxazole (Bactrim, Septra) and carbenicillin (Geocillin). Benign prostatic hyperplasia can be reduced over a six-month period with finasteride (Proscar).

Many cases of bladder outlet obstruction associated with prostatic infection and hyperplasia occur because of increased internal sphincter tone. Consequently, alpha-adrenergic blockers may be quite helpful until the mechanical obstruction can be reduced.

Alpha-adrenergic blockers that are effective in the treatment of bladder outlet obstruction due to prostatic hyperplasia are listed in Table 4. The peripheral alpha blockers are usually more effective than the centrally active agents, although the latter may be useful in some circumstances.[17] As with any medication, the initial dosage should generally be low in older patients, with increases in the dosage made gradually until the desired effects occur. To reduce the risk of severe orthostatic hypotension, peripheral alpha blockers generally should be taken at bedtime.

[TABULAR DATA 4 OMITTED]

Nocturnal Incontinence

Nocturnal incontinence presents some unique challenges when it is associated with increased urine production at night. Most healthy children and young adults produce urine twice as rapidly during the daytime as nighttime. There is some evidence that this circadian pattern is lost in many older people. In some cases, this may be due to a failure of increased arginine vasopressin secretion at night.[18] Desmopressin (DDAVP) nasal spray, two to four sprays (without sniffing) at bedtime, has been found to reduce nocturnal urine production in such individuals.[19]

In others, the cause of increased nocturnal urine production is mobilization of interstitial fluid that has accumulated, mainly in the lower extremities, during the daytime. In such cases, efforts to reduce daytime urine retention with the use of support stockings, careful salt restriction, diuretics or other appropriate measures can be quite helpful. Alternatively, these individuals can lie down with their legs elevated for an hour or two in the late afternoon or early evening so that the fluid is mobilized at a more convenient time of day.

Individuals with combined stress and urge incontinence are more likely to have incontinence at night than those with either stress or urge incontinence alone. There is some evidence to suggest that the use of hypnotics (but not alcohol) is associated with an increased risk of nocturnal incontinence.[20]

Final Comment

A large number of patients in primary care settings have significant problems associated with urinary incontinence. To identify these patients, family physicians must routinely make specific inquiries about problems with bladder function. Once a problem is discovered, an attempt should be made to identify potential aggravating factors, such as medications, infection, impaction and mobility impairment.

When necessary, specific treatment should be prescribed, based on the type or types of incontinence. In most patients, nonpharmacologic therapies, including exercises, behavioral strategies and the reduction of caffeine intake, should be considered before pharmacotherapy. Hormonal and autonomic agents are the principal pharmacologic approaches to the management of urinary incontinence. The primary types of urinary incontinence and the pharmacologic agents that can be useful in their management are listed in Table 5. Referral is necessary when diagnostic confusion exists, simple measures have been ineffective or a surgical procedure is necessary.

REFERENCES

[1.] Bissada NK, Finkbeiner AK. Pharmacology of continence and micturition. Am Fam Physician 1979;20(5):128-36. [2.] Lagace EA, Hansen W, Hickner JM. Prevalence and severity of urinary incontinence in ambulatory adults: an UPRNet study. J Fam Pract 1993;36 (6):6104. [3.] Urinary incontinence in adults. Natl Inst Health Consens Dev Conf Consens Statement 1988;7(5):1-11. [4.] Urinary incontinence in adults. Agency for Health Care Policy and Research. Clin Pract Guidel Quick Ref Guide Clin 1992;(2):1-27. [5.] Williams ME, Pannill FC 3d. Urinary incontinence in the elderly. physiology, pathophysiology, diagnosis, and treatment. Ann Intern Med 1982;97:895-907. [6.] Elia G, Bergman A. Estrogen effects on the urethra: beneficial effects in women with genuine stress incontinence. Obstet Gynecol Surv 1993;48:509-17. [7.] Wein AJ. Pharmacologic treatment of incontinence. J Am Geriatr Soc 1990;38:317-25. [8.] Brocklehurst JC, Dillane JB. Studies of the female bladder in old age. I. Cystometrograms in nonincontinent women. Gerontol Clin [Baser] 1966,8: 285-305. [9.] Andersen JT, Jacobsen O, Worm-Petersen J, Hald T. Bladder function in healthy elderly males. Scand J Urol Nephrol 1978;12:123-7. [10.] Green TH Jr. Urinary stress incontinence: differential diagnosis, pathophysiology, and management Am J Obstet Gynecol 1975;122:368-400. [11.] Graber EA. Stress incontinence in women: a review--1977. Obstet Gynecol Surv 1977;32:565-77. [12.] Cardozo L. Role of estrogens in the treatment of female urinary incontinence. J Am Geriatr Soc 1990;38:326-8. [13.] Sourander LB. Treatment of urinary incontinence: the place of drugs. Gerontology 1990;36(Suppl 2):19-26. [14.] Sand PK, Brubaker L. Nonsurgical treatment of detrusor overactivity in postmenopausal women. J Reprod Med 1990;35:758-64. [15.] Resnick NM, Yalla SV. Detrusor hyperactivity with impaired contractile function. An unrecognized but common cause of incontinence in elderly patients. JAMA 1987;257:3076-81. [16.] Finkbeiner AK. Is bethanechol chloride clinically effective in promoting bladder emptying? A literature review. J Urol 1985;134:443-9. [17.] Rao MS, Bapna BC, Vaidyanathan S, Chary KS. Use of clonidine in the management of patients with neurogenic bladder dysfunction. Eur Urol 1980;6:2614. [18.] Kirkland JL, Lye M, Levy DW, Banerjee AK. Patterns of urine flow and electrolyte excretion in healthy elderly people. Br Med J [Clin Res] 1983;287:1665-7. [19.] Seiler WO, Stahelin HB, Hefti U. Desmopressin reduces night urine volume in geriatric patients: implications for treatment of nocturnal incontinence. Clin Investig 1992;70;619. [20.] Burgio KL, Locher JL, Ives DG, Hardin JM, Newman AB, Kuller LH. Nocturnal enuresis in community-dwelling older adults. J Am Geriatr Soc 1996;44:139-43.

The Author

JAMES W. MOLD, M.D. is professor and director of the research division in the Department of Family Practice and Preventive Medicine at the University of Oklahoma College of Medicine, Oklahoma City. He is a graduate of Duke University School of Medicine, Durham, N.C., and completed a residency in family practice at Highland Hospital, an affiliate of the University of Rochester, Rochester, N.Y.

Address correspondence to lames W Mold, M.D., Department of Family Practice and Preventive Medicine, University of Oklahoma Health Sciences Center, 900 N.E. 10th St., Oklahoma City, OK 73112.

RICHARD W. SLOAN, M.D., R.PH., coordinator of this series, is chairman and residency program director of the Department of Family Medicine at York (Pa.) Hospital and clinical associate professor in family and community medicine at the Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pa.

COPYRIGHT 1996 American Academy of Family Physicians
COPYRIGHT 2004 Gale Group

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