6-Adrenergic blocking potency

The net result is that low potency antipsychotics cause more histamine-blocking, acetylcholine-blocking, and a-1 adrenergic blocking side effects. The high potency antipsychotics are more likely to produce dopamine-blocking side effects. Now, let s take a brief look at each of the specific medications. 

Pharmacology Carvedilol, an antihypertensive agent, is a racemic mixture in which nonselective -adrenoreceptor blocking activity is present in the S(-) enantiomer and -adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency. Carvedilol has no intrinsic sympathomimetic activity. 

S)-Bufuralol is a nonselective (3-adrenergic antagonist. (3-Blocking potency of (5 )-bufuralol is approximately 100 times greater than that of the (/f)-enantiomer. In... 

It has been demonstrated that the / -selectivity is due to the para-substituents of /(-adrenoceptors. In contrast, (-)-erythro-isoetliarine, a bronchodilator. is 80 times more selective for ft -adrenergic receptors than for ft-receptors, lsoetharine contains ancr-alkyl substituent, thus producing four isomeric compounds. The (-)-erythro isomer is 100-1 old more active than the (-)-threo isomer and has more than 500 times the activity of either of the (+)-isomers and in blocking electrically stimulated spasms. In general, introduction of a-alkyl substituents on both /1-blockers and agonists provides diastereomers with increased ft-selectivity, but often with compromised potency. 

These very different sets of potencies indicated that two distinct adrenoceptor types are likely to be associated with each set of pharmacological effects. Set A effects could be blocked by adrenergic blockers available in 1948 (dibenamine, ergot alkaloids). These were named as a/p/ia-adrenoceptors Set B effects, where IPR was the most potent agonist, was then said to interact with era-adrenoceptors. In fact, IPR was found to be devoid of any a-agonist effects. Ahlquist s work also established that NE possessed primarily a-adrenoceptor activity, while EP acted on both types of receptors. 

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. 

For panic disorder, tricychc antidepressants and MAO inhibitors, as well as high-potency benzodiazepines (notably alprazolam, clonazepam, and lorazepam) (see Chapter 16), are effective in blocking the autonomic expression of panic itself, thereby facilitating a comprehensive rehabilitation program. Imipramine and phenelzine are well-studied antidepressants for panic disorder. SSRIs also may be effective, but /3 adrenergic receptor antagonists, buspirone, and low-potency benzodiazepines usually are not, and bupropion can worsen anxiety. 

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