Blockers Blocking activity

All TCAs are either secondary- or tertiary-amines of a dibenzazepine nucleus (Fig. 20.3), and they all inhibit neuronal reuptake of noradrenaline and/or 5-HT but are much less potent as dopamine reuptake blockers. A common claim is that secondary amines (e.g. desipramine) are preferential inhibitors of noradrenaline uptake whereas the tertiary derivatives (e.g. imipramine, doxepin and amitryptyline) preferentially inhibit 5-HT uptake. However, when Richelson and Pfenning (1984) actually compared the effects of a wide range of antidepressants on the synaptosomal uptake of [ H]monoamines in vitro, and compared their A s, instead of merely ranking /C50S collected from different studies, they found that tertiary- and secondary-substituted compounds were equi-potent inhibitors of [ H]noradrenaline uptake. Moreover, all the TCAs turned out to be more potent inhibitors of [ H]noradrenaline than of [ H]5-HT uptake. Tertiary amines are even less convincing inhibitors of 5-HT reuptake in vivo, because any such action is diminished by their metabolism to secondary amines (e.g. imipramine to desipramine amitriptyline to nortriptyline). Only clomipramine retains any appreciable 5-HT uptake blocking activity in vivo with (an unimpressive) five-fold selectivity for 5-HT versus noradrenaline. 

Apart from possible clinical differences between the P-block-ers approved for HF, selection of a p-blocker may also be affected by pharmacologic differences. Carvedilol exhibits a more pronounced blood pressure lowering effect and thus causes more frequent dizziness and hypotension as a consequence of its ar receptor blocking activity. Therefore, in patients predisposed to symptomatic hypotension, such as those with advanced LV dysfunction (LVEF less than 20%) who normally exhibit low systolic blood pressures, metoprolol succinate may be the most desirable first-line P-blocker. In patients with uncontrolled hypertension, carvedilol may provide additional antihypertensive efficacy. 

Congestive heart failure treatment may be improved by cautiously adding a /3-blocker to conventional management with ACE-inhibitors and diuretics. Bisoprolol and carvedilol are the preferable /3-blockers, since their beneficial effect has been convincngly demonstrated in appropriate clinical trials. Bisoprolol is a highly selective /8i-blocker. Carvedilol has additional properties to its /8-receptor blocking activity, such as a weak vasodilator component and anti-oxidant activity. The beneficial effect is very likely to be caused by /8i-adrenoceptor blockade. 

Labetalol Normodyne, Trandate) possesses both p-blocking and a-blocking activity and is approximately one-third as potent as propranolol as a p-blocker and one-tenth as potent as phentolamine as an a-blocker. The ratio of p- to a-activity is about 3 1 when labetalol is administered orally and about 7 1 when it is administered intravenously. Thus the drug can be most conveniently thought of as a p-blocker with some a-blocking properties. 

Beta Blockers with Additional Alpha Blocking Activity... 

As might be expected, ganglionic blockers produce a multitude of side effects because of the inhibition of both sympathetic and parasympathetic responses. Some adverse effects include gastrointestinal discomfort (nausea, constipation), urinary retention, visual disturbances, and orthostatic hypotension. At higher doses, they may even exhibit some neuromuscular blocking activity. These and other side effects may be quite severe in some patients. Fortunately, ganglionic blockers are usually not used for extended periods because the patient is placed on other antihypertensive drugs when the hypertensive crisis is resolved. 

These results demonstrate that the RR and SR enantiomers are most responsible for the (3- and a-blocking activities, respectively. Hartley4 also showed that a 1 1 mixture of RR and SR enantiomers was twice as active a (3-blocker as labetalol and about 1.3 times as potent an ex-blocker. 

Several other therapeutic effects of sodium channel blockers have been suggested. Most of these stem from clinical activities of approved anticonvulsants and antiarrhythmics with sodium channel blocking activity. Beneficial effects of sodium channel blockers for the treatment of bipolar disease are suggested by clinical data with lamotrigine [63-67], phenytoin [68], topiramate [69], and carbamazepine [70,71]. In addition, clinical studies with lidocaine suggest efficacy in the treatment of tinnitus [72] and, as an inhaled formulation, in the suppression of cough [73,74]. 

Early studies from the Pfizer laboratories had revealed that compounds from a series of mzn.s-l-amino-4-phenyl-tetralins possessed potent norepinephrine (NE) uptake blocking activity. The activity was highly specific for the (1/ , 4S)-enantiomer and was confined to the trans derivatives. The corresponding (IS, 4/ )-enantiomer was much less active and the diastereomeric cis racemates were inactive at blocking NE uptake. It was subsequently shown that many compounds from the diastereomeric cis senes were unexpectedly potent and selective inhibitors of serotonin (5-HT) uptake, thus differentiating these compounds from the trans compounds. One of these compounds, sertraline (5), was originally discovered as a racemic mixture. Resolution showed that the (+)-enantiomer was several times more selective for 5-HT uptake blocking activity than the (-)-isomer. The (+)-enantiomer was subsequently shown to possess the in vivo behavioral effects expected of a potent and selective 5-HT blocker. Thus, as opposed to... 

Ketanserin appears to act principally to block serotonin vasoconstrictor (subtype 5-HTj) receptors but also has significant a-adrenoceptor blocking activity (its affinity ratio for the two receptors is 1 5). The latter explains its hypotensive action and use in Raynaud s disease. It is not available in many countries and offers no advantages over pure a-blockers such as doxazosin. 

ISA beta-blockers may have a role in patients who experiences severe bradycardia with non-ISA agents. When these agents are given to someone with a slow heart rate at rest, they may increase the heart rate. Conversely, ISA agents in someone with exercise-induced tachycardia may decrease the heart rate because the beta-blocking activity predominates. Avoid these agents in patients who are s/p Ml because the agonistic properties may be detrimental. 

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