Depression 2 adrenoceptor antagonists

More then a dozen representatives of the above ring systems were introduced into the human therapy. Actisomide (2) and trequinsin (3) are used as antiarrhytmic and antihypertensive agents, respectively. Sunepitron (4), a a 2-adrenoceptor antagonist, is under clinical trials for the treatment of anxiety and depression. Representatives of the third generation of antibacterial quinolone-3-carboxylic acids the blockbluster ofloxacin (5), its levorotatory enantiomer, levofloxacin (6), and rufloxacin (7) have gained wide acceptance for the treatment of bacterial infections of the respiratory and urinary tracts, skin, and soft tissues, as well as sexually transmitted diseases, and pazufloxacin (8) is under development. Praziquantel (9) is widely applied for the treatment of schistosomes- and cestode-caused infection in both veterinary and human therapies (Scheme 4). 

Class II drugs are classical (3-adrenoceptor antagonists such as propranolol, atenolol, metoprolol or the short-acting substance esmolol. These drugs reduce sinus rate, exert negative inotropic effects and slow atrioventricular conduction. Automaticity, membrane responsiveness and effective refractory period of Purkinje fibres are also reduced. The typical extracardiac side effects are due to (3-adrenoceptor blockade in other organs and include bronchospasm, hypoglycemia, increase in peripheral vascular resistance, depressions, nausea and impotence. 

Beta-adrenoceptor antagonists, particularly propranolol, have been shown to be effective for anxiety symptoms particularly in situational anxiety and GAD. Buspirone, an azaspirodecanedione, is an agonist at 5-HTlA receptors and seems to have anxiolytic effects, though it is less potent than the BDZs and the effects take up to three weeks to become evident. There is high first pass metabolism and a considerable proportion of the effect is due to a metabolite (1-PP). The principal adverse effects of buspirone are nausea, gastrointestinal upset and headache. Antidepressant drugs, both the older tricyclic antidepressants and the newer drugs, have been demonstrated to have anxiolytic effects in mixed anxiety-depressive patients, GAD and panic disorder. 

On this basis, the potential antidepressant action of central ct2 adrenoceptor antagonists was predicted in 1978 (Langer 1978). However, as mentioned above, idazoxan, a selective antagonist on central (X2 adrenoceptors, does not possess antidepressant effects in monotherapy in unipolar depression. The antidepressant effects of idazoxan alone in bipolar depression remain to be confirmed by additional double blind studies against placebo. 

The beneficial effect of mirtazapine in the treatment of depression might be explained by its a2-adrenoceptor antagonistic property. Bupropion and desipramine might be also beneficial in depression because of their ability to increase extracellular NE levels (Femandez-Pastor et al., 2005 Li et al., 2002 Parini et al., 2005 Sacchetti et al., 1999). The beneficial effect of NE in depression can be explained by the excitatory effect of NE on 5-HT neurotransmission and by the direct involvement of NE transmission in anxiety, energy feeling and motivation (Guiard et al., 2008 Stahl, 2000). 

Q10 Beta-adrenoceptor antagonists are contraindicated in patients with asthma or respiratory obstructive diseases, bradycardia, heart block or heart failure. Adrenergic agonists are contraindicated in patients with closed-angle glaucoma and should be used cautiously in patients with hypertension or heart disease. Parasympathomimetics cause poor night vision and dimming of vision, because of development of miosis, headache and brow ache. Carbonic anhydrase inhibitors have a weak diuretic action and can induce depression, drowsiness, paraesthesia, electrolyte disturbance such as hypokalaemia, acidosis and lack of appetite. 

Since the introduction of propranolol, it has been recognized that patients with bronchial asthma treated with beta-adrenoceptor antagonists can develop severe airways obstruction (84), which can be fatal (85) or near fatal (86,87) this has even followed the use of eye-drops containing timolol (88). Beta-blockers upset the balance of bronchial smooth muscle tone by blocking the bronchial beta2-adrenoceptors responsible for bronchodilata-tion. They also promote degranulation of mast cells and depress central responsiveness to carbon dioxide (89,90). 

Clomethiazole, like the benzodiazepines, has an additive effect with other CNS depressants, and can cause profound bradycardia when combined with beta-adrenoceptor antagonists. 

Irrespective of the mechanism of action of tricyclic antidepressants, antagonists of a2 autoreceptors per se might have a beneficial effect in depressive illness, since they facilitate noradrenergic neurotransmission. Phenoxybenzamine, dihydroergotamine and yohimbine, but not the selective ai adrenoceptor antagonist prazosin, have been shown to be synergistic with several antidepressants in decreasing B-adrenoceptor density in rat cerebral cortex.Thus combined administration of an a2 adrenoceptor blocker with other antidepressants may provide a rapid onset therapy.RS 21361 produces a more rapid onset of B-adrenoceptor desensitization by itself than desipramine. 

Future Outlook for Antidepressants. Third-generation antidepressants are expected to combine superior efficacy and improved safety, but are unlikely to reduce the onset of therapeutic action in depressed patients (179). Many dmgs in clinical development as antidepressive agents focus on estabhshed properties such as inhibition of serotonin, dopamine, and/or noradrenaline reuptake, agonistic or antagonistic action at various serotonin receptor subtypes, presynaptic tt2-adrenoceptor antagonism, or specific monoamine—oxidase type A inhibition. Examples include buspirone (3) (only... 

The cardiac effects of the calcium antagonists, ie, slowed rate (negative chronotropy) and decreased contractile force (negative inotropy), are prominent in isolated cardiac preparations. However, in the intact circulation, these effects may be masked by reflex compensatory adjustments to the hypotension that these agents produce. The negative inotropic activity of the calcium antagonists may be a problem in patients having heart failure, where contractility is already depressed, or in patients on concomitant -adrenoceptor blockers where reflex compensatory mechanisms are reduced. 

HT2 antagonists like trazodone, nefazodone, clozapine and risperidone are used in the treatment of schizophrenia and depression. They block adrenoceptors and Hi-histamine-receptors as well. Hypotension, drowsiness and weight gain can occur. 

The TCA drugs have lost their place as first-line therapy for depression because of their bothersome side effects (Table 33.2) at therapeutic doses and lethal effects in toxic doses. In addition to their presynaptic effects on the neuronal uptake of norepinephrine and serotonin, they block several postsynaptic receptors. They are potent cholinergic muscarinic receptor antagonists, resulting in symptoms such as dry mouth, constipation, tachycardia, blurred vision and urinary retention. Blockade of histamine receptors (Hi) often results in sedation and weight gain. Antagonism of aj-adrenoceptors in the vasculature can cause orthostatic hypotension. 

Propranolol Nonselective competitive antagonist at adrenoceptors Decreased heart rate, cardiac output, and blood pressure decreases myocardial oxygen demand Prophylaxis of angina for other applications, see Chapters 10, 11, and 13 Oral and parenteral, 4-6 h duration of action Toxicity Asthma, atrioventricular block, acute heart failure, sedation Interactions Additive with all cardiac depressants... 

Depression and hypertension are both common conditions such that some co-morbidity is inevitable, and panic disorder is epidemiologically associated with hypertension. Co-prescription of an enzyme-inhibiting antidepressant with a P-adrenoceptor blocker (metoprolol, CYP 2D6) or with a calcium antagonist (diltiazem, amlodipine, CYP 3A4) may exaggerate antihypertensive effects. 

The introduction of this drug may represent a novel approach to the treatment of major depressive disorders since it appears to act as an antagonist at alpha -adrenoceptors in the CNS. 

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