Amitriptyline, structure

FIGURE 4.13 Structures of the CYP2D6 substrates, amitriptyline, codeine, haloperidol, and propranolol, and their metabolites. 

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. 

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... 

This chapter describes the structure and neurochemical function of TCAs, metabolism and significant interactions with other medications, side effects, and specific recommendations for monitoring of side effects in children and adolescents. Because of the recent concern regarding the sudden deaths of children stabilized on TCAs, particular attention will be paid to the potential cardiovascular effects of these medications. The chapter will focus on the five TCA medications that have been most widely used in children amitriptyline (AMI), nortriptyline (NT), imipramine (IMI), desipratnine (DMI), and clomipramine (CMI). 

The Division of Drug Experience of the US Department of Health and Welfare issued a note on five cases of the syndrome of inappropriate antidiuretic hormone secretion and drugs to which it has been attributed (1137). All involved drugs with a tricyclic structure one patient was taking imipramine, three carbamazepine, and the others the closely related muscle relaxant cyclobenz-aprine. The dosage of imipramine was 50 mg/day for 3 weeks and the patient was a 72-year-old woman. Other cases have been reported, involving amitriptyline (1137), imipramine, and protriptyline (SEDA-17,17). 

The chemical formula referred to in claim 1 is also known as amitriptyline, and its chemical structure is given in Figure 8.13, along with the chemical structure of imipramineused as an antidepressant and additional prior art compounds having central nervous system activity from which the method of claim 1 was deemed obvious. 

The CAFC upheld the USPTO s finding of a prima facie case of obviousness. In so doing, the court first noted the structural similarity between amitriptyline and... 

FIGURE 8.13 Structure of claimed compound (amitriptyline) and prior art compounds. 

Amitriptyline hydrochloride and imipramine hydrochloride are similar in structure, with the exception of the nitrogen in the center ring, and belong to the family of phenothiazine compounds. Finally, the two-carbon bridge linking the aromatic rings may be ethyl (-CH2CH2-) or ethylene (-CH=CH-). 

Molnar et al. [69] studied antibacterial effect and plasmid curing property of several phenothaizines and tried to correlate these functions with respect to their chemical structure. They observed that diethazine, amitriptyline, and impipramine showed bacteriostatic and bactericidal effect on different bacteria. Chlorpromazine sulfoxide and fluorescein were ineffective even at 1000 Ag/ml. The antibacterial compounds deleted at 40-70% frequency the F lac-t- plasmid of Escherichia coli K12 Le-140. Similar plasmid elimination potentiality by phenothiazines was reported by the same group of authors in 1982 [72],... 

Two cases of non-thrombocytopenic purpura occurred in patients taking tricyclic antidepressants. Both improved on withdrawal (107). True thrombocytopenia, with platelets counts as low as 120 x 1012/1, occurred in a 79-year-old woman taking doxepin. During later treatment with amitriptyline, thrombocytopenia recurred, but not when she took imipramine (108). Cross-sensitivity must be highly specific to chemical structure, doxepin and amitriptyline being more like each other than imipramine. 

With the phosphate buffer both components, basic amitriptyline and neutral toluene show poorer efficiency as the number of column volumes of mobile phase are passed through the column, indicating that the stationary-phase structure is becoming compromised (potential voids in the column). Moreover, if column voids are formed, it will effect the efficiency of all components... 

Melitracen is structurally and pharmacologically related to imipramine, with two methyl groups attached to the central ring. It has similar efficacy to amitriptyline, with a somewhat more rapid effect and similar adverse effects (1). 

Representative Chemicals Imipramine Amitriptyline Doxepin Desipramine Nortriptyline Chemical/Pharmaceutical/Other Class The tricyclic antidepressants are a group of drugs that have a three-ring molecular core and share a similar pharmacologic effect, inhibiting the reuptake of biogenic amines at central presynap-tic terminals Chemical Structures ... 

Cyclobenzaprine, a tricyclic amine structurally very similar to amitriptyline (see Figure 34-10), is used as a centrally acting skeletal muscle relaxant. Like amitriptyline, cyclobenzaprine causes sedation, produces central and peripheral muscarinic blockade, and potentiates adrenergic actions. In overdose, cyclobenzaprine may cause a typical anticholinergic toxidrome and cardiac arrhythmias, hypotension, and coma. However, cyclobenzaprine overdose is not as frequent nor as lethal as amitriptyline overdose. 

The selective inhibition of NA uptake by viloxazine, in the absence of effects on DA or 5-HT uptake, resided in the trans-S-isomer, paralleling the reserpine reversal effects.81 The anorectic drug mazindol was also a potent inhibitor of NA uptake,82 like its structural relative ciclazindol (22).83 In a double-blind trial, 2 was as effective as amitriptyline in ameliorating endogenous depression. Ciclazindol, which lacked significant anticholinergic or cardiotoxic effects, produced fewer side-effects than amitriptyline. Diverse structures included befuraline (DIV 154, 23) an... 

Amitriptyline resembled imipramine in its efficacy in the treatment of endogenous depression and its relative ineffectiveness in patients with neurotic (reactive) depressive symptoms (9). Some patients, who were unreactive to imipramine, responded to amitriptyline (9). Side effects were usually less severe (9, 34, 114) but there was a high incidence (18%) of somnolence (114). Some of the disadvantages inherent in imipramine were overcome, at least to some extent, by this structural variant ... 

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