Tricyclic antidepressants examples

Examples of the application of HPLC to the analysis of (a) acetaminophen, salicylic acid, and caffeine (b) chlorinated pesticides (c) tricyclic antidepressants and (d) peptides. (Chromatograms courtesy of Alltech Associates, Inc. Deerfield, IL). 

Another interesting example of the use of solid state extraction cartridges is the determination of the tricyclic antidepressant drugs in blood serum (2). 

Serious adverse effects of epinephrine potentially occur when it is given in an excessive dose, or too rapidly, for example, as an intravenous bolus or a rapid intravenous infusion. These include ventricular dysrhythmias, angina, myocardial infarction, pulmonary edema, sudden sharp increase in blood pressure, and cerebral hemorrhage. The risk of epinephrine adverse effects is also potentially increased in patients with hypertension or ischemic heart disease, and in those using (3-blockers (due to unopposed epinephrine action on vascular Ui-adrenergic receptors), monoamine oxidase inhibitors, tricyclic antidepressants, or cocaine. Even in these patients, there is no absolute contraindication for the use of epinephrine in the treatment of anaphylaxis [1,5,6]. 

Figure 20.3 The basic structure of tricyclic antidepressants with some well-known examples...

CYP2C19 is another example of the existence of both cross-ethnic and inter-individual variations in drug metabolism. This enzyme is involved in the metabolism of many psychotropics such as diazepam and tertiary tricyclic antidepressants, as well as one of the selective serotonin re-uptake inhibitors (SSRIs), citalopram. Using S-mephenytoin as the probe, previous studies showed that up to 20% of East Asians (Chinese, Japanese, and Koreans) are PMs, when only 3-5%... 

Some studies compare dietary supplements to sub-therapeutic dosages of prescription medicine. For example, St. John s wort is compared to some of the tricyclic antidepressants. However, the given doses of amitriptyline and imipramine were below the recommended antidepressant doses. 

Several other clinically available pharmacological agents have been tested for their potential to facilitate smoking cessation, although they are not approved by the FDA for this purpose. For example, tricyclic antidepressants, which inhibit reuptake of noradrenaline and 5-HT, promote smoking cessation in conjunction with behavioral treatment in some individuals.107 However, these medications are limited because of their significant side effects. 5-HT-selective reuptake inhibitors (SSRIs) are believed to be a safer class of antidepressants but have not demonstrated effectiveness in smoking cessation.108... 

Metabolism converts a lipophilic molecule into a more hydrophilic (water-loving) metabolite that can be excreted in urine by the kidneys. In the majority of cases the drug is detoxified, or made pharmacologically inactive by this metabolic breakdown. However, a few drugs need to be metabolised to become psychoactive for instance, the sedative-hypnotic chloral hydrate is converted to the active metabolite trichloroethanol. In this case the parent molecule is referred to as a prodrug. With many drugs, both the parent compound and its metabolites are psychoactive. An example of this is the tricyclic antidepressant imipramine which is metabolised to desipramine, with... 

In many clinical trials a positive control of a clinically established drug is often used for comparison purposes for example, a novel selective serotonin reuptake inhibitor (SSRI), may be compared with a more established tricyclic antidepressant, such as imipramine. The aim is to see whether the new SSRI is more efficacious or has fewer adverse side effects than the more established tricyclic (Chapter 12). In many such comparisons the new and older treatments are equally efficacious at relieving depression, but the newer drugs display fewer side effects this means that they are better tolerated by patients, so that they are more willing to continue taking the tablets. The high rates of compliance also mean that, in overall terms, newer drugs with fewer side effects tend to be more efficacious. 

The traditional scheme is complicated by the fact that some antidepressants exhibit characteristics of more than one class. For example, clomipramine, a tricyclic antidepressant (TCA) with side effects and toxicity similar to other TCAs, works more like the selective serotonin reuptake inhibitors (SSRls). Similarly, venlafaxine and duloxetine, which are usually grouped with the atypical antidepressants, have a side effect and safety profile comparable to the SSRls. Although a classihcation system based on mechanism of action offers some advantage (see Table 3.7), even this scheme is limited by the fact that antidepressants that work in the same way may have widely divergent side effect and safety profiles. In the following discussion, the traditional classification system is adopted. Although fraught with problems and inconsistencies. 

Tricyclic Antidepressants (TCAs). The TCAs were also introduced in the 1950s, and some were discovered to be effective anxiolytics in the 1960s. For example, early studies pioneered by Donald Klein and his colleagues indicated that imipra-mine (Tofranil) effectively relieved panic attacks. Like the MAOIs, the TCAs are not addictive but also require over 3 weeks to begin to achieve significant therapeutic benefit for anxiety. 

Many currently used antidepressants are chiral drugs (for example, tricyclic antidepressants, mianserin, mirtazepine, venlafaxine, reboxetine, fluoxetine, paroxetine, sertraline, citalopram), some of which are administered as racemates (such as the tricyclics, mianserin, mirtazepine, fluoxetine, reboxetine, venlafaxine, citalopram) while others are given as single isomers (paroxetine and sertraline). 

Serendipity has played a major role in the discovery of most classes of psychotropic drugs. For example, the observation that the first antidepressants, the tricyclic antidepressants and the monoamine oxidase inhibitors, impeded the reuptake of biogenic amines into brain slices, or inhibited their metabolism, following their acute administration to rats, provided the experimenter with a mechanism that could be easily investigated in vitro. Such methods led to the development of numerous antidepressants that differed in their potency, and to some extent in their side effects (for example, the selective serotonin reuptake inhibitors) but did little to further the development of novel antidepressants showing greater therapeutic efficacy. The accidental discovery of atypical antidepressants such as mianserin led to the broadening of the basis of the animal models... 

Nomifensine and bupropion are examples of non-tricyclic antidepressants that facilitate catecholaminergic function. These drugs have the advantage over the TCAs of being non-sedative in therapeutic doses. The... 

The word "tolerability" is perhaps a little clumsy but it describes accurately what is assessed, namely how well the drug is tolerated by those to whom it is administered. This last qualification is necessary because there are many instances in which a drug is better tolerated or less well tolerated by young healthy volunteers than by patients. For example, anxiolytics and tricyclic antidepressants are usually far better tolerated by patients with depression than by healthy volunteers. However, healthy volunteer studies generally provide useful information about tolerability even if it may under- or overestimate tolerability in patients. Many adverse reactions wiU be directly related to the known pharmacological activity of the drug and are therefore predictable. 

Altered homeostasis in older persons can lead to important and common adverse drug effects the less robust homeostatic milieu may be stressed by drugs, causing adverse effects. Examples include orthostatic hypotension due to antihypertensives and other agents that cause a-adrenergic blockade (e.g. terazosin, doxazosin, tricyclic antidepressants and phenothiazines) in those with barorecep-tor dysfunction. Diuretics can cause hyponatraemia or hypokalaemia in older patients, whereas ACE inhibitors and NSAIDs can cause hyperkalaemia. 

Moreover, experimental studies are often inconclusive. Rarely does the antidepressant medication far exceed the placebo in effectiveness, and sometimes subjects in the control group actually report greater symptom relief Equally important, the newer classes of antidepressant medications (the SSRIs), hyped as the latest wonder drugs, are actually no more effective than categories of medications (for example, tricyclic antidepressants) that were discovered in the late I950s. Finally, these studies have no way to assess whether medications work better than positive life changes. The sociologist Allan Horwitz asks ... 

Medications with serotonergic activity may also have other monaminergic or sympathomimetic activity. Combining MAOIs with these medications may result in a complex side effect profile. For example, combining meperidine or dextromethorphan with MAOIs may result in respiratory depression, in addition to symptoms of serotonin excess. Furthermore, interactions between MAOIs and tricyclic antidepressants (TCAs) more commonly result in potentiating shared adverse events such as othostatic hypotension, as opposed to hyperadrenergic crises or the serotonin syndrome. 

If one of these enzymes is inhibited by another drug, then the plasma levels of the concurrently administered drugs that rely on the enzyme for metabolism increase. For example, 2D6 is essential for the usual metabolism of tricyclic antidepressants (TCAs), which are substrates for this enzyme. Paroxetine inhibits 2D6. If a patient is taking a TCA and paroxetine is added, or vice versa, plasma TCA levels increase, which may result in increased TCA-related side... 

Nuclei for tricyclic antidepressants and tranquilizers, for example clomacran (89) (64USP3131190), almost invariably contain the three rings fused in a linear array. An exception to this general rule is fantridone (90), an antidepressant obtained by alkylation of the anion of phenanthridone with 3-chloro-iV,iV-dimethylpropylamine (68BRP1135947). Similar activity is shown by a relatively simple quinoline derivative (91), which is derived from 2-chloroquinoline and piperazine (70GEP2006638). 

---