Amitriptyline effects

Rowan PR, Paykel ES, Parker RR. Phenelzine and amitriptyline effects on symptoms of neurotic depression. Br J Psychiatry 1982 140 475-483. 

Landauer AA, Milner G, Patman J. Alcohol and amitriptyline effects on skills related to driving behavior. Science (1969) 163, 1467-8. 

Venkatakrishnan K, Von Moltke LL, Obach RS, Greenblatt DJ (2000) Microsomal binding of amitriptyline effect on estimation of enzyme kinetic parameters in vitro. J Pharmacol Exp Ther 293 343-350... 

Trigclic Antidepressants. Imipramine (38) was introduced in the late 1950s as one of the first pharmacotherapies for depression. At that time, chlorproma2ine [50-53-3] was the first effective antipsychotic treatment to be discovered. Researchers looked for similar chemical stmctures and imipramine was found to be effective in the symptomatic treatment of depression. Over the years, other congeners, such as desipramine (39), amitriptyline (40), and dothiepin (41), were synthesized and shown to be clinically efficacious antidepressant dmgs (121). These substances, known under the general mbric of tricycHc antidepressants, share a basic chemical stmcture comprising... 

Two recently introduced antidepressants are notable m that they are selective serotonin uptake inhibitors Citalopram (19) is reported to be as effective as amitriptyline m the treatment of endogenous depression [75, 16] Fluoxetine (20) as the hydrochlonde is approved for major depressive disorders mcludmg those with concomitant anxiety Interestmgly, it also appears useful m the treatment of obesity [17]... 

FIGURE 9.18 Multiple receptor effects (ordinates denote pK values for antagonism or receptor occupancy) of (a) yohimbine and (b) amitriptyline. 

Antidepressants are used in the treatment of neuropathic pain and headache. They include the classic tricyclic compounds and are divided into nonselective nor-adrenaline/5-HT reuptake inhibitors (e.g., amitriptyline, imipramine, clomipramine, venlafaxine), preferential noradrenaline reuptake inhibitors (e.g., desipramine, nortriptyline) and selective 5-HT reuptake inhibitors (e.g., citalopram, paroxetine, fluoxetine). The reuptake block leads to a stimulation of endogenous monoaminer-gic pain inhibition in the spinal cord and brain. In addition, tricyclics have NMDA receptor antagonist, endogenous opioid enhancing, Na+ channel blocking, and K+ channel opening effects which can suppress peripheral and central sensitization. Block of cardiac ion channels by tricyclics can lead to life-threatening arrhythmias. The selective 5-HT transporter inhibitors have a different side effect profile and are safer in cases of overdose [3]. 

All TCAs are either secondary- or tertiary-amines of a dibenzazepine nucleus (Fig. 20.3), and they all inhibit neuronal reuptake of noradrenaline and/or 5-HT but are much less potent as dopamine reuptake blockers. A common claim is that secondary amines (e.g. desipramine) are preferential inhibitors of noradrenaline uptake whereas the tertiary derivatives (e.g. imipramine, doxepin and amitryptyline) preferentially inhibit 5-HT uptake. However, when Richelson and Pfenning (1984) actually compared the effects of a wide range of antidepressants on the synaptosomal uptake of [ H]monoamines in vitro, and compared their A s, instead of merely ranking /C50S collected from different studies, they found that tertiary- and secondary-substituted compounds were equi-potent inhibitors of [ H]noradrenaline uptake. Moreover, all the TCAs turned out to be more potent inhibitors of [ H]noradrenaline than of [ H]5-HT uptake. Tertiary amines are even less convincing inhibitors of 5-HT reuptake in vivo, because any such action is diminished by their metabolism to secondary amines (e.g. imipramine to desipramine amitriptyline to nortriptyline). Only clomipramine retains any appreciable 5-HT uptake blocking activity in vivo with (an unimpressive) five-fold selectivity for 5-HT versus noradrenaline. 

Tricyclic antidepressants (TCAs) such as amitriptyline and doxepin have been used with some success in the treatment of IBS-related pain (Table 18-5). They modulate pain principally through their effect on neurotransmitter reuptake, especially norepinephrine and serotonin. Their helpfulness in functional gastrointestinal disorders seems independent of mood-altering effects normally associated with these agents. Low-dose TCAs (e.g., amitriptyline, desipramine, or doxepin 10 to 25 mg daily) may help patients with IBS who predominantly experience diarrhea or pain. 

Chen, L. X., Wang, Z. G., Ai, M. et al. (2005). Effect of CYP2C19 genotypes on demethylation of amitriptyline in Chinese patients with depression. Chinese Journal of Nervous and Mental Diseases, 31(1), 33-6. 

Until the introduction of selective serotonin reuptake inhibitors (SSRIs) in the 1980s, tricyclic antidepressants were the most widely used drugs. The therapeutic effect of amitriptyline and imipramine are related to their ability to inhibit the presynaptic reuptake of both NA and 5-HT. They are referred to as non-selective reuptake inhibitors, whereas many of the other tricyclics are more selective thus, clomipramine is a selective reuptake inhibitor for 5-HT and desipramine and nortriptyline are selective... 

The answer is a. (Katzung, p 499.) Of the listed a n tide press ants, only amitriptyline, a tricyclic, causes adverse effects related to blockade of muscarinic acetylcholine receptors. Both trazodone and amitriptyline cause adverse effects related to a-adrenoreceptor blockade... 

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). 

Amitriptyline and imipramine, and the MAOI phenelzine, can be considered second- or third-line drugs for PTSD after SSRIs have failed. Mirtaza-pine and venlafaxine may also be effective. 

Amitriptyline, doxepin, and nortriptyline are effective, but side effects include anticholinergic effects, adrenergic blockade, and cardiac conduction prolongation. 

Nakamura, M., Fukushima, H., and Kitagawa, S. (1976) Effect of amitriptyline and isocarboxazid on 5-hydroxytryptophan induced head twitches in mice. Psychopharmacology, 48 101-104. 

Tricyclic drugs have, as the name implies, a three-ring structure, and interfere with reuptake of norepinephrine and/or serotonin into axon terminals. Tricyclic drugs include imipramine (Tofranil), amitriptyline (Elavil), clomipramine (Anafranil), and nortriptyline (Pamelor, Aventil). Tricyclics have the occasional but unfortunate cardiovascular side effects of arrhythmia and postural hypotension. Newer, nontricyclic antidepressants have been developed that are collectively referred to as SSRIs. These have a potent and selective action on serotonin, and lack the cardiovascular side effects of the tricyclics. These include fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), and fluvoxamine (Luvox). A fifth SSRI, citalopram (Celexa) has been used in Europe and has recently been approved in the United States. Venlafaxine (Effexor) blocks reuptake of norepinephrine and serotonin, while bupropion (Wellbutrin) acts on both dopamine and norepinephrine. 

Pharmaceutical Comparison. At least 8 studies to date have examined the effectiveness of hypericum compared to the pharmaceutical antidepressants imipramine, amitriptyline, and maprotiline. Preliminary results indicate that hypericum is equivalent to standard antidepressants in effectiveness (Linde et al. 1996 Vorbach 1997). Similar to the pharmaceutical antidepressants, there is a 10-14 day lag for therapeutic effects of hypericum (Harrer et al. 1994). Indeed, the differences seen between hypericum and placebo groups becomes apparent between 2 and 4 weeks (Sommer and Harrer 1994). Hypericum has been reported to have a more favorable side-effect profile than several pharmaceutical antidepressants as well (Vorbach et al. 1994 Harrer et al. 1994). In double-blind studies, subjects have reported fewer and less-severe side effects. Although these initial results are promising, Linde and colleagues (1996) have concluded that the present evidence is inadequate to establish... 

The true tricyclics are often subdivided into tertiary and secondary amine groups. Structurally, the difference lies in the length of side chains branching off the basic three-ringed hub of the molecule. Clinically, side effects are most common and most severe with the tertiary amine medications such as amitriptyline, imipramine, and doxepin. The secondary amines are generally better tolerated. It should be added that two of the tertiary amine TCAs, amitriptyline and imipramine, are metabolized... 

Tricyclic Antidepressants (TCAs). Because of their effectiveness not only for depression but for anxiety disorders such as panic disorder as well, TCAs were the first medications formally tested in the treatment of PTSD. Three TCAs, amitriptyline, imipramine, and desipramine, have been studied in small trials, producing modest benefit for reexperiencing and hyperarousal symptoms, without any relief of avoidance/numbing symptoms. Given this limited benefit in conjunction with the side effect burden and potential for toxicity in a suicide prone population, TCAs are infrequently used in the treatment of PTSD. Please refer to Chapter 3 for more information regarding TCAs. 

Tricyclic Antidepressants (TCAs). The TCAs have been nsed to treat ADHD for 30 or more years. Most often used are imipramine (Tofranil) and desipramine (Norpramin), mainly becanse they are the TCAs that most specihcally increase norepinephrine activity. Remember, boosting norepinephrine activity in the brain shonld improve attention. Other TCAs, namely, amitriptyline (Elavil, Endep) and nortriptyline (Pamelor), have been used, though they also increase norepinephrine activity. TCAs do offer a modest benefit for both the inattention and the hyperactivity of ADHD. In addition, they are often effective at doses mnch lower than those required to treat depression. However, their effectiveness nsnally falls short of the stimulant medications. In addition, TCAs have considerable side effects including dry mouth, constipation, drowsiness, weight gain, and adverse cardiac effects. 

When treating insomnia without depression, doxepin and amitriptyline (both tricyclic antidepressants) can be administered in low doses (25-100 mg) at bedtime. These antidepressants, however, do have troublesome anticholinergic side effects (dry mouth, constipation, blurred vision, dizziness) and adverse effects on the heart, and they can be lethal if taken in overdose. Because of their effect on heart function, these antidepressants should be avoided in patients with heart problems and administered cautiously, if at all, to those who are already receiving one of any number of newer antidepressants that inhibit the metabolism of the TCAs. 

The metabolism and elimination of TCAs takes several days to occur, the elimination half-life ranging from 20 hours for amitriptyline to 80 hours for protriptyline. The half-life values for the desmethylated metabolites such as desmethylimipramine and nortriptyline are approximately twice those of the parent compounds imipramine and amitriptyline. It is also well established that the half-life values of the TCAs are considerably greater in the elderly, which predisposes such patients to a greater possibility of severe side effects. 

Selective serotonin re-uptake inhibitors such as paroxetine tend to cause less antimuscarinic side-effects and are less toxic in overdose than the tricylic antidepressants, such as amitriptyline. However, selective serotonin re-uptake inhibitors are more likely to cause gastrointestinal disturbances, such as nausea and vomiting, than tricylic antidepressants. Selective serotonin re-uptake inhibitors and tricylic antidepressants are equally effective. 

One of the main side-effects of opioid analgesics, such as codeine and tramadol, is constipation. Amitriptyline (tricyclic antidepressant) and orphenadrine tend to have antimuscarinic properties, resulting in side-effects such as constipation. Senna is a stimulant laxative indicated in constipation. 

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