Tricyclic amine

The answer is b. (Katzung, p 499. Hardman, p 4.3.3.) Amitriptyline is a tertiary amine tricyclic antidepressant. It functions as a norepinephrine... 

The tertiary amine tricyclics have similar effects on norepinephrine and serotonin transmission, while the two secondary amines have more specific effects on norepinephrine, with much smaller effects on serotonin. This can be seen in the fCj (inhibitory constant) values for the TCAs, as listed in Table 23.1. is the concentration of drug required to block transport of the neurotransmitter (in this case, norepinephrine or serotonin). Lower fCj equals greater relative ability to block transport. Desipramine and NT have the greatest inhibitory effects at the receptor site, while CMI has... 

Tricyclics Tertiary amine tricyclics Amitriptyline Clomipramine Elavil Anafranil 25-50 25 100-250 25, 50, 75 16 (27) 32 (69)... 

Imipramine, amitriptyline, clomipramine, trimipramine, and doxepin are tertiary amine TCAs. Desipramine, nortriptyline, and protriptyline are secondary amine TCAs. Tertiary amine tricyclics have more potent serotonin reuptake inhibition, and secondary amine tricyclics have more potent noradrenergic reuptake inhibition. Tertiary amine TCAs tend to have more side effects than do... 

The results for this tertiary amine tricyclic are less convincing in terms of efficacy but quite robust with regard to toxicity. The optimal range for this medication in terms of antidepressant efficacy is approximately 80 to 150 ng/mL (amitriptyline plus nortriptyline). Studies generally found a nonsignificant trend with a remission rate of 48% within versus 29% outside this range. 

Adverse effects of various antidepressants are summarized in Table 30-5. Most common unwanted effects are minor, but they may seriously affect patient compliance the more seriously depressed the patient is, the more likely it is that unwanted effects will be tolerated. Most normal persons find that even moderate doses of many antidepressants cause disagreeable symptoms, especially the classic tertiary amine tricyclics amitriptyline, imipramine, clomipramine, and doxepin. With the SSRIs, transient nausea is the most frequent complaint, and decreased libido and sexual dysfunction create the greatest concerns during maintenance treatment. 

N. Narsimhachari and R. O. Friedel, N.-Alkylation of secondary amine tricyclic antidepressants by GC-MS-MS technique, Anal. Lett., 725 77(1979). 

Toxicity. Relatively few cases of serious intoxication have been attributed to nortriptyline in comparison to the tertiary amine tricyclic antidepressants. Toxic effects are usually associated with blood concentrations greater than 0.25 pg/ml and concentrations above 1 pg/ml may produce coma. Recovery has occurred after the ingestion of 2.5 g. 

The increase in tricyclic concentrations following valproate is probably partly due to inhibition of CYP2C isozymes, preventing demethylation of tertiary tricyclic antidepressants to the corresponding secondary amines (desmethylimipramine in the case of clomipramine). However, valproate can also increase the plasma concentrations of secondary amine tricyclics, such as nortriptyline (183). The current data suggest that the combined use of tricyclic antidepressants and valproate should be undertaken with caution. 

Thus there appear to be significant mechanistic differences the hydrazines inhibit MAO, the tertiary amine tricyclics seem to inhibit the serotonin amine pump, whereas the secondary amine ones seem better in switching off the NE reuptake mechanism. Table 12-18, however, shows that there is some overlap. Nevertheless, there is a thread of commonality—the net increase of amine neurotransmitters in the synaptic area—yet all these drugs require several weeks of treatment before objective results are noted. The biogenic amine hypothesis does not satisfactorily explain this. It is even more difficult to explain the antidepressant action of some of the second-generation drugs, such as mianserin (Fig. 12-26), that seem to have no significant effect on amine reuptake mechanism of either... 

With some notable exceptions, inactivation and elimination of most antidepressants occurs over a period of several days. Generally, secondary-amine tricyclic antidepressants and the N-demethylated derivatives of serotonin reuptake inhibitors have elimination half-lives about twice those of the parent drugs. Nevertheless, most tricyclics are almost completely eliminated within 7 to 10 days. An exceptionally long-acting tricyclic antidepressant is protriptyline (half-hfe of about 80 hours). Most MAO inhibitors are long acting because recovery from their effects requires the synthesis of new enzyme over a period of 1 to 2 weeks. 

Norepinephrine Reuptake Inhibitors Tertiary Amine Tricyclics... 

Several psychosomatic disorders may respond at least partly to treatment with tricyclic antidepressants, MAO inhibitors, or SSRIs among these are chronic pain disorders, including diabetic and other peripheral neuropathic syndromes (for which tertiary-amine tricyclics probably are... 

Table 21.4. Common Side Effects with Secondary Amine Tricyclic Antidepressants and Recommendations...

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