First-generation antidepressants

Treatment of Major Depression. Dmgs commonly used for the treatment of depressive disorders can be classified heuristicaHy iato two main categories first-generation antidepressants with the tricycHc antidepressants (TCAs) and the irreversible, nonselective monoamine—oxidase (MAO) inhibitors, and second-generation antidepressants with the atypical antidepressants, the reversible inhibitors of monoamine—oxidase A (RIMAs), and the selective serotonin reuptake inhibitors (SSRIs). Table 4 fists the available antidepressants. 

Second-Generation Antidepressants. The frequency of adverse effects associated with first-generation antidepressants and the lack of patient compliance arising from such adverse effects led to the development of a number of second-generation antidepressants. 

The second-generation antidepressants, particularly RIMAs and SSRJs, are much less toxic ia overdose than the older TCAs and irreversible MAO inhibitors. However, similar to first-generation antidepressants, the therapeutic effect only becomes manifest after several weeks. Up to one-third of depressed patients are nonresponders. Ideally, an antidepressant would combine a more rapid onset of action with greater clinical efficacy and a higher responder rate, as well as even better tolerability. 

Tricyclic antidepressants (TCAs) first-generation antidepressants... 

It is thus understandable why some earlier authors previously doubted the efficacy of antidepressants in general (Weiner et al.. 1980) or the advantages of newer antidepressants compared with classical products (Song et al., 1993). However, the great majority of doctors and scientific authors consider that the efficacy of first-generation antidepressants (imipramine, amitriptyline, nortriptyline) has been proved beyond any reasonable doubt, and that efficacy also has been demonstrated for newer products such as trazodone, the selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake... 

The first-generation antidepressants demonstrate varying degrees of selectivity for the reuptake pumps for norepinephrine and serotonin (Table 30-3). They also have numerous autonomic actions, as described below under Adverse Effects. 

Tricyclic antidepressants (TCAs) - first-generation antidepressants Examples - tertiary amine type imipramine, amitriptyline, dothiepin, clomipramine... 

NE secretion can be effectively decreased by administration of reseipine, an alkaloid isolated from a small woody perennial found in India (Rauwolfia), which has a high affinity for the vesicular monoamine h ansporter-2 (VMAT-2) and as such prevents NE storage. Alternatively, NE secretion can be increased by administration of tyramine (decarboxylated tyrosine), which is a constituent of a variety of foods including red wine, pickled herring and cheese. Amphetamine has a similar effect, which is most prominently manifested in the CNS. The termination of NE effects can be circumvented by the administration of cocaine, which blocks NE transport into presynaptic nerve endings (NET) an effect, which is also shared by some of the first generation antidepressants, such as imipramine. 

Tricyclic first generation antidepressants as for example imipramine and dothiepin (fig. 2) not only inhibit 5-HT and NE reuptake but also act as antagonists on histamine-1, cholinergic muscarine, adrenergic alpha and 5-HT2 receptors [26-28]. 

Outline the neurochemical modes of action of two named antidepressant drugs from different classes (e.g., first-generation TAD, MAO inhibitor, SSRI). 

Tricyclic antidepressant A family of first-generation (typical) antidepressants with a three-ringed structure that inhibit the action of monoamine transporters. 

The first second-generation antidepressant an alpha-2 adrenoceptor antagonist with some affinity for S-HT a/ 5-HT2a arid 5-HT3, alpha-1 adrenoceptors and HI receptors... 

Mianserin was the first of the second-generation antidepressants to be developed. It lacked the amine reuptake inhibitory and MAOI actions of the first-generation drugs and also lacked the cardiotoxicity and anticholinergic activity of the TCAs. However, it was sedative (antihistaminic), caused postural hypotension (alpha-1 blockade) and also caused blood dyscrasias and agranulocytosis in a small number of patients. This has limited the use of mianserin in recent years. 

The enzyme, monoamine oxidase, exists in two forms MAO-A (intestinal mucosa and intraneuronally in the brain) and MAO-B (platelets and mainly extraneuronally in the brain). Serotonin is preferentially metabolised by MAO-A and noradrenaline (NA norepinephrine), and dopamine and lyramine by both forms. The first generation MAOI antidepressants (phenelzine, tranylcypromine, and isocarboxazid) inhibit both MAO-A and MAO-B and are thought to work by increasing the availability of 5-HT and NA in the synapse—with longer-term adaptive effects occurring as for the TCAs. These MAOls are irreversible, i.e. they permanently inactivate MAO. Thus, recovery of activity occurs slowly, over days, as new MAO molecules are synthesised. 

The first generation of antidepressants, MAO (monoamine oxidase) inhibitors, inhibited neurotransmitter degradation by inhibiting monoamine deoxidase, a flavin containing enzyme, found in the mitochondria of neurons and other cell types, that oxidatively deaminates naturally occurring sympathomimetic monoamines, such as norepinephrine, dopamine, and serotonin within the presynapse. In 1952, isoniazid and its isopropyl derivative, iproniazid (1), were developed for the treatment of tuberculosis, where it was subsequently found that these agents had a mood enhancing effect on... 

The precise mechanism by which the first-generation tricyclic antidepressants, monoamine oxidase inhibitors, and the newer-generation antidepressants exert their effects is uncertain. However, it is clear that antidepressants exert their effects at both pre- and postsynaptic receptor sites (Figure 43.3 and Figure 43.4). 

The first-generation tricyclic antidepressants, the monoamine oxidase inhibitors, and the newer agents can cause sedation, insomnia, orthostatic hypotension, or nausea. Because of their anticholinergic properties, they may also produce cardiac toxicides (Table 43.2). 

The safety of antidepressants should be the first priority for the elderly. For this reason, the second-generation antidepressants, or the atypical tricyclic antidepressant lofepramine, should be the drugs of choice. Undoubtedly the SSRI antidepressants have a major role to play and of these, citalopram and fluvoxamine have been extensively studied in the elderly depressed patient. 

The potentiation of sedative effects from benzodiazepines when combined with centrally acting drugs with antihistamine properties (for example first-generation antihistamines, tricyclic antidepressants, and neuroleptic drugs) can pose problems (143). Antihistamines that do not have central actions do not interact with benzodiazepines as in the case of mizolastine and lorazepam (144), ebastine and diazepam (145), and terfenadine and diazepam (143). 

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