Tricyclic antidepressants nervous system

Research for an antidepressant among non-tricyclic compounds with pharmacological effects qualitatively different from those of the conventional tricyclic compounds led to the preparation and testing of a series of indazole derivatives for reserpine-like activity in mice. l-[3-(Dimethylamino)propyl]-5-methyl-3-phenyl-l//-indazole (FS-32 692) antagonizes reserpine-induced effects and potentiates amphetamine-induced self-stimulation and l-Dopa-induced increase in motor activity. FS-32 produces an anticholinergic action mainly on the central nervous System, while the action of imipramine occurs centrally as well as peripherally (79AF511). 

Tramadol is an opioid analgesic and when given to patients who are also receiving imipramine (a tricyclic antidepressant), there is an increased risk of central nervous system toxicity. The risk of occurrence of sedation is increased. 

Sertraline is a recent antidepressant that is called a selective serotonin reuptake inhibitor (SSRI). It is chemically unrelated to the older tricyclic antidepressants (see Section 5.3). It works by preventing the movement of the neurohormone serotonin into nerve endings. It can help to improve mood and mental alertness, increase physical activity, and improve sleep patterns. It is prescribed for obsessive-compulsive disorder and obesity. It may offer some advantage over fluoxetine by exhibiting little central nervous system (CNS) action. It has less sedation and anxiety and is shorter acting. 

Certain tricyclic compounds are found to be powerful stimulants, or antidepressants, to the central nervous system. Depressed individuals may respond with an elevation of mood, increased physical activity, mental alertness, and an improved appetite. Imipramine and amitriptyline hydrochlorides are good examples. 

Principal side effects are gastrointestinal and central nervous system symptoms, including drowsiness, dizziness, and diarrhea. Zolpidem may increase the depressant effects of other sedative drugs, such as the an-tipsychotics, tricyclic antidepressants, and antihistamines. 

FIGURE 47.1 Suggested algorithm for the use of psychotropic medications in the medically ill child or adolescent. CNS, central nervous system GI, gastrointestinal SSRI, selective serotonin reuptake inhibitor TLA, tricyclic antidepressant. 

Preskorn SH, Jerkovich GS. Central nervous system toxicity of tricyclic antidepressants phenomenology, course, risk factors and role of therapeutic drug monitoring. J Clin Psychopharmacol 1990 10 88-95. 

Imipramine, a tricyclic antidepressant drug with strong antimuscarinic actions, has long been used to reduce incontinence in institutionalized elderly patients. It is moderately effective but causes significant central nervous system toxicity. Propiverine, a newer antimuscarinic agent, has been approved for this purpose. 

Buspirone causes less psychomotor impairment than diazepam and does not affect driving skills. The drug does not potentiate the central nervous system depressant effects of conventional sedative-hypnotic drugs, ethanol, or tricyclic antidepressants, and elderly patients do not appear to be more sensitive to its actions. Tachycardia, palpitations, nervousness, gastrointestinal distress, and paresthesias may occur more frequently than with benzodiazepines. Buspirone also causes a dose-dependent pupillary constriction. Blood pressure may be elevated in patients receiving MAO inhibitors. A number of buspirone analogs have been developed (eg, ipsapirone, gepirone, tandospirone) and are under study. 

Drugs and chemicals are known to cause activated interaction. The depressant action of opioid drugs is enhanced by drugs acting on the central nervous system (CNS) such as alcohol, anesthetics, anxiolytics, hypnotics, tricyclic antidepressants, and antipsychotics. Concomitant administration of opioid analgesics and monoamine oxidase inhibitors (MAOIs) should be avoided, or extra care should be taken if such a therapy is inevitable. Fatal reactions are reported when treated along with selegiline. Interactions also are reported with cyclizine, cimetidine, mexiletine, cisapride, metoclopramide, or domperidone. 

The tricyclics, such as clomipramine (Anafranil), amitriptyline (Elavil), and imipramine (Tofranil), have been used for several decades. I have previously described their central nervous system toxic effects in some detail (Breggin, 1983b see also Breggin, 1991b). This section will therefore be abbreviated. A list of some of the older antidepressants can be found in the appendix. 

Ayd, F. J. (1974). Once-a-day dosage of tricyclic antidepressant drug therapy A survey. Diseases of the Nervous System, 35, 475-480. 

Mass spectrometric detection has also been directly interfaced with microchip separations for drug detection. These studies, detecting imipramine and desipramine in fortified human plasma, show analysis of spiked analytes in clinical sample matrices for drug detection [3]. These widely used tricyclic antidepressants inhibit the reuptake of the neurotransmitters serotonin and norepinephrine in the central nervous system. Unfortunately, the 5-mg/mL detection limit found for these antidepressants with this method is not low enough to detect typical clinical levels of the drugs. Combinatorial library characterization and preclinical drug delivery studies should benefit, however, since the concentra-... 

As many as 20% of patients taking adequate doses of a tricyclic antidepressant experience marked postural hypotension. This effect is not consistently correlated with plasma concentrations and tolerance does not develop during treatment (35-37). The mechanism for this effect is uncertain it has been attributed to a peripheral antiadrenergic action, to a myocardial depressant effect, and to an action mediated by alpha-adrenoceptors in the central nervous system (38). Studies of left ventricular function in man are conflicting. One study of systolic time intervals showed a decrement in left ventricular function with therapeutic doses (39), while two in which cardiac function was observed directly during cardiac catheterization after overdosage showed no evidence of impaired myocardial efficiency, whereas the hypotension persisted after left ventricular filling pressures and cardiac output had returned to normal (40,41). 

NERVOUS SYSTEM DRUGS ANTIDEPRESSANTS Tricyclic antidepressants... 

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