Pharmacology TCAs

The important adverse effects of the various antidepressants are often a function of their underlying pharmacologic profiles7,8 (Table 35-3). TCAs cause problematic sedative, anticholinergic, and cardiovascular adverse effects owing to their interaction with dirty receptors. While these adverse effects generally are considered to be common and bothersome, they can be quite serious in certain cases. For example, constipation in its... 

The combination of antidepressants is a common clinical practice. The most usual pharmacological profile is serotoninergic-noradrenergic (96%) and the most popular combinations are selective 5-HT reuptake inhibitor (SSRI) + mir-tazapine, SSRI + reboxetine, and SSRI + TCAs (De la Gandara et al. 2005). 

It has been known for over 25 years that many of the tricyclic antidepressants (TCAs), e.g. imipramine and amitriptyline, are potent inhibitors of both norepinephrine and 5-HT reuptake. Some tricyclic antidepressants, e.g. desipramine, inhibit the uptake of norepinephrine much more potently than the uptake of 5-HT. Thus, it was unclear for some time whether the inhibition of 5-HT uptake played any role in the antidepressant action of those TCAs that possessed this pharmacological property. Recently, however, effective antidepressants such as fluoxetine, paroxetine and sertraline have been marketed and these SSRIs are much more potent inhibitors of the uptake of 5-HT than that of norepinephrine (Fig. 13-8). Thus, selective inhibition of the uptake of either norepinephrine or 5-HT can result in an antidepressant effect (Ch. 55). 

Tricyclic antidepressants (TCA prototype imipramine) have had the Lullmann, Color Atlas of Pharmacology All rights reserved. Usage subject to terms and conditions of iicense. 

Pharmacology The tricyclic antidepressants (TCAs), structurally related to the phenothiazine antipsychotic agents, possess 3 major pharmacologic actions in varying degrees Blocking of the amine pump, sedation, and peripheral and central... 

Pharmacology Cyclobenzaprine, structurally related to the tricyclic antidepressants (TCAs), relieves skeletal muscle spasm of local origin without interfering with muscle function. It is ineffective in muscle spasm caused by CNS disease. The net effect is a reduction of tonic somatic motor activity, influencing both gamma and alpha motor systems. 

Imipramine, a TCA, was the first pharmacological agent noted to treat panic disorder (Klein 1964). Other TCAs, notably clomipramine, have also been found to have significant anxiolytic properties (den Boer et al. 1990 Modigh 1992). Studies of ethnic differences in the pharmacokinetics of the TCAs in... 

Cardiovascular effects of TCAs have been of concern since recent reports of sudden death in children undergoing treatment. This effect may be due to pharmacological similarities between the tricyclics and the type lA antiarrhythmics, which cause prolongation of conduction indices and possible arrhythmias with use. The question of a possible relationship between TCA treatment and sudden unexplained death was first reported in the early 1990s (Abramowicz, 1990 Biederman, 1991 Riddle et al., 1993 Varley and McClellan, 1997). The cases in question, about which little information was available, noted that the children were on stable regimens of DM1. 

Pharmacological treatment of anxiety disorders in individuals actively abusing substances is often difficult. Two to four weeks of abstinence is recommended, during which time alternative interventions can be initiated. Agents that have low abuse liability, such as the SSRls, TCAs, or buspirone (Buspar), are recommended. If benzodiazepines are clinically indicated, it... 

The SSRIs are associated with low cardiotoxicity, particularly when compared with the TCAs, and this feature of their pharmacological profile gives them a low potential for lethality in overdose. It has been estimated from coroners reports in the United Kingdom that the SSRIs are associated with deaths in only 1-2 overdoses per million prescriptions compared with 35 per million prescriptions for the TCAs [Henry et al. 1995). 

In this chapter, we review the pharmacology of several selective serotonin reuptake inhibitors [SSRIs] and other drugs that act on the serotonergic system. That these developments have enhanced safety and tolerability is now beyond dispute, but it is also clear that these agents are no more effective than the old-style tricyclic antidepressants [TCAs]. [For a comprehensive discussion of serotonergic medication, see Montgomery, Chapter 12, in this volume.] Here, several compounds are discussed in detail. 

In pharmacodynamic interactions, the pharmacological effect of a drug is changed by the action of a second drug at a common receptor or bioactive site. For example, low-potency antipsychotics and tertiary amine TCAs have anticholinergic, antihistaminic, a-adrenergic antagonist, and quinidine-Kke effects. Therefore, concurrent administration of chlorpromazine and imipramine results in additive sedation, constipation, postural hypotension, and depression of cardiac conduction. 

The commonly used classes of antidepressants are discussed in the following sections, and information about doses and half-lives is summarized in Table 2-1. The antidepressant classes are based on similarity of receptor effects and side effects. All are effective against depression when administered in therapeutic doses. The choice of antidepressant medication is based on the patient s psychiatric symptoms, his or her history of treatment response, family members history of response, medication side-effect profiles, and comorbid disorders (Tables 2-2 and 2-3). In general, SSRIs and the other newer antidepressants are better tolerated and safer than TCAs and MAOIs, although many patients benefit from treatment with these older drugs. In the following sections, clinically relevant information is presented for the antidepressant medication classes individually, and the pharmacological treatment of depression is also discussed. The use of antidepressants to treat anxiety disorders is addressed in Chapter 3. 

SSRIs were developed in an attempt to formulate reuptake-blocking drugs that lacked the troublesome side effects of TCAs. Of the five pharmacological properties of TCAs—blockade of muscarinic receptors, blockade of histamine Hj receptors, blockade of aj-adrenergic receptors, norepinephrine reuptake blockade, and serotonin reuptake inhibition—only the last remains intact in SSRIs. This selectivity has... 

Few data are available regarding venlafaxine in overdose, but the drug s pharmacological profile suggests that it is safer than TCAs. In most of the reported cases to date, symptoms were not present. 

The TCA clomipramine and the SSRls provide the foundation of the pharmacological treatment for OCD. Although pharmacotherapy is effective against many other Axis 1 disorders, most patients with OCD experience only a 35%-60% improvement in symptoms. In addition, medication responses may not be apparent until treatment has been administered for 10 weeks, and some patients will require higher doses than are typically used to treat depression. As in the treatment of depression, SSRls tend to be better tolerated than TCAs (clomipramine is the only effective TCA for OCD). 

Paralleling these clinical developments were basic pharmacological studies, which noted that reserpine ( 5, 6, 7 and 8) and a-methyidopa produced depression in patients treated for hypertension ( 9,10 and 11). The fact that the MAOIs and TCAs functionally increased norepinephrine (NE) activity while reserpine lowered its activity led Schiidkraut (12) and Bunney and Davis (13) to independently formulate the NE hypothesis of depression. This same line of reasoning was also applied to serotonin (5-HT) (14, 15). 

The sum of the concentration of venlafaxine and ODV is probably more important than their relative ratio. Thus, CYP 2D6 deficiency, which occurs in approximately 7% of Caucasians, has fewer clinical implications for venlafaxine than for drugs that are biotransformed by this isoenzyme to either centrally inactive metabolites (e.g., paroxetine) or metabolites that have a different pharmacological profile than the parent drug (e.g., TCAs). The increase in venlafaxine plasma levels is offset by a parallel decline in ODV levels such that the sum is the same. Nevertheless, a substantial inhibition of CYP 3A3/4 could result in a meaningful increase in both venlafaxine and ODV plasma levels, particularly in patients who are CYP 2D6 deficient. Such an increase would be expected to result in an increase in the incidence or severity of the known dose-dependent effects of venlafaxine mediated by its inhibition of the neuronal uptake pumps for serotonin and NE. 

The role of TDM for different antidepressants varies from being a standard of care issue with TCAs to a discretionary laboratory test with most of the newer drugs. The reason for this difference relates to the pharmacology of the various classes of antidepressants, particularly in terms of toxicity. TDM is essential for the safe use of TCAs because of their narrow therapeutic index and the substantial interindividual differences in elimination rates. These two factors result in the risk that serious toxicity can develop in poor metabolizers on standard doses. In contrast to TCAs, most new antidepressants have such a wide therapeutic index that serious toxicity is not a concern. 

ECT should be considered for more severe forms of depression (e.g., those associated with melancholic and psychotic features, particularly when the patient exhibits an increased risk for self-injurious behavior) or when there is a past, well-documented history of nonresponse or intolerance to pharmacological intervention. Limited data indicate that bipolar depressed patients may be at risk for a switch to mania when given a standard TCA. A mood stabilizer alone (i.e., lithium, valproate, carbamazepine, lamotrigine), or in combination with an antidepressant, may be the strategy of choice in these patients. Some elderly patients and those with acquired immunodeficiency syndrome may also benefit from low doses of a psychostimulant only (e.g., methylphenidate) (see also Chapter 14, The HIV-Infected Patient ). Fig. 7-1 summarizes the strategy for a patient whose depressive episode is insufficiently responsive to standard therapies. 

Secondary amine TCAs (e.g., nortriptyline, desipramine) are better tolerated and somewhat safer than their tertiary amine parent compounds (e.g., amitriptyline, imipramine) (407, 408). This is due to differences in the relative potencies of several pharmacological actions, which include their binding affinity for the following ... 

As with most data for reboxetine, this information primarily comes from summary papers rather than primary sources (473, 474). With this caveat, the adverse-effect profile of reboxetine is consistent with its pharmacology as an NSRI. Thus, it is similar to that of desipramine and maprotiline but without the risk of serious CNS (i.e., seizures, delirium) or cardiac (i.e., conduction disturbances) toxicity. The most common adverse effects of reboxetine are dry mouth, constipation, urinary hesitancy, increased sweating, insomnia, tachycardia, and vertigo. Whereas the first three adverse effects are commonly called anticholinergic, they are well known to occur with sympathomimetic drugs as well. In other words, these effects can be either the result of decreased cholinergic tone or increased sympathetic tone, although they tend to be more severe with the former than the latter. In contrast to TCAs, reboxetine does not directly interfere with intracardiac conduction. The tachycardia produced by reboxetine, however, can be associated with occasional atrial or ventricular ectopic beats in elderly patients. 

Available evidence indicates that systematic desensitization and in vivo exposure are the most effective treatment methods available. Pharmacological treatment has not been well investigated, but studies involving antidepressants suggest that TCAs and MAOIs are ineffective ( 85, 86 and 87). In addition, three studies suggest that sedative-hypnotic anxiolytics may undermine the behavioral treatment of specific phobias (88, 89 and 90). In another study, volunteers with animal phobias were exposed to their phobic object 1.5 hours after administration of either tolamolol, diazepam, or placebo in a double-blind crossover design. Tolamolol abolished the stress-induced tachycardia but had no beneficial behavioral or subjective effects ( 91). 

Estazolam potentiates the CNS depressant effects of phenothiazines, narcotics, antihistamines, MAOIs, barbiturates, alcohol, general anesthetics, and TCAs. Use with cimetidine, disulfiram, oral contraceptives, and isoniazid may diminish hepatic metabolism and result in increased plasma concentrations of estazolam and increased CNS depressant effects. Fleavy smoking (more than 20 cigarettes/day) accelerates estazolam s clearance. Theophylline antagonizes estazolam s pharmacological effects. 

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