Presynaptic adrenergic inhibitors

Drugs that inhibit the release of norepinephrine from the presynaptic terminals of peripheral adrenergic 

Drugs that inhibit the presynaptic synthesis and storage of norepinephrine are discussed in Chapter 20. The drugs in this category used to treat hypertension are listed in Table 21-4. These drugs are often used in conjunction with other agents in the stepped-care approach to hypertension (see Stepped-Care Approach to Hypertension ). 

Orthostatic hypotension is sometimes a problem with these agents. Other bothersome side effects include gastrointestinal disturbances such as nausea, vomiting, and diarrhea. 

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Table 4.3B Anti hypertensive Agents - Presynaptic Adrenergic Release Inhibitors ...

Mirtazapine is a piperazinoazepine and an analogue of mianserin. It is a presynaptic adrenergic a2-antagonist that increases central noradrenergic and serotonergic transmission. It is a potent inhibitor of histamine (Hj) receptors and this accounts for its sedative properties. It has little antimuscarinic activity. 

Noradrenaline transporters (NAT) are localized in the presynaptic plasma membrane of adrenergic nerve terminals. They belong to a family of proteins with 12 putative transmembrane proteins which are responsible for recycling of released neurotransmitters (noradrena-line/adrenaline, dopamine, serotonin, amino acid transmitters) back into the presynaptic nerve ending. Noradrenaline transporters can be blocked by a number of different antidepressant drags, including tricyclic antidepressants (e.g. desipramine) and selective noradrenaline reuptake inhibitors (e.g. reboxetine). 

Some failures will be due to the presence of variants in drug handling. Patients who are rapid acetylators of isoniazid have a slower antituberculous response than slow acetylators (Evans and Clarke, 1961). Asthmatics who do not respond well to (32-agonist bronchodilators may have fewer functioning p2-adrenergic receptors (Drysdale et al., 2000). Variations in the synthesis or structure of the serotonin transporter protein, which is involved in selective reuptake of serotonin by presynaptic neurons, may explain why some patients with depressive disorders respond to selective serotonin reuptake inhibitors and others do not (Steimer et al., 2001). 

Nefazodone is a weak inhibitor of both SERT and NET but is a potent antagonist of the postsynaptic 5-HT2A receptor, as are its metabolites. Trazodone is also a weak but selective inhibitor of SERT with little effect on NET. Its primary metabolite, m-cpp, is a potent 5-HT2 antagonist, and much of trazodone s benefits as an antidepressant might be attributed to this effect. Trazodone also has weak-to-moderate presynaptic -adrenergic blocking properties and is a modest antagonist of the Hi receptor. 

It was initially believed that the antidepressant effectiveness of MAOIs was the direct result of MAO inhibition. This acute effect decreases degradation of monoamines (e.g., norepinephrine, serotonin, or dopamine) stored in presynaptic neurons, thereby resulting in an increased amount of these neurotransmitters available at the synapse. More recent research indicates that this model does not fully explain the mechanism of MAOIs efficacy. For example, the positive (h-) stereoisomer of tranylcypromine is a poor antidepressant despite inhibiting MAO. The main pharmacologic difference between the negative (-) and + isomers of tranylcypromine is that the former has much weaker effects as a norepinephrine reuptake inhibitor in relation to its potency as an MAOI. The other MAOIs may also block the reuptake of selected neurotransmitters. However, like the non-MAOI uptake inhibitors, these acute effects often precede clinical antidepressant effects by weeks. More consistent with the 2- to 4-week lag in therapeutic effect, chronic treatment with a diverse number of MAOIs has been shown to reduce the number of a2- and P-adrenergic and serotonin (5-HT2) postsynaptic binding sites in the brain. 

When compared with the selective serotonin reuptake inhibitors (SSRIs), mirtazapine may show an earlier onset of action (although data are currently not well established). Mirtazapine has also been found to be efficacious in the treatment of elderly patients with depression. Mirtazapine has been shown to be effective in the treatment of panic disorder, social phobia, and post-traumatic stress disorder. In one study, mirtazapine combined with citalopram in obsessive-compulsive patients induced an earlier response when compared with citalopram plus placebo. It was suggested that antagonism of presynaptic a2-adrenergic receptors does not enhance serotonin neurotransmission directly, but rather disinhibits the norepinephrine activation of serotonergic neurons and thereby increases serotonergic neurotransmission by a mechanism that may not require a time-dependent desensitization of receptors. 

Although the mechanism of antidepressant action for bupropion is unclear, in vitro binding studies show bupropion to be a selective inhibitor of dopamine reuptake at the dopamine presynaptic neuronal membrane and minimal inhibition of NE and 5-HT reuptake (Table 21.2). Bupropion does not exhibit clinically significant anticholinergic, antihistaminic, ai-adrenergic blocking activity, or MAO inhibition. 

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