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Adrenergic Antagonists
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
It is an α-adrenoceptor nonselective antagonist which produces competitive antagonism. Phentolamine, a derivative of imidazoline has a similar/comparable cardiovascular activity to that of phenoxybenzamine. It causes vasodilation by competitively blocking both α1, α2 adrenoceptors with an abatement in PR and systemic BP (Majid et al., 1971; Russell et al., 1998; Juenemann et al., 1986). Activation of reflex sympathetic nerve elevates CO as outlined in Figure 4.3. It is utilized for managing short-term hypertension and bowel pseudo obstruction in pheochromocytoma patients. Moreover, it is utilized to counter anesthesia effect by antagonism of α receptor mediated vasoconstriction brought about by sympathomimetics usually administered along local anesthetics. A main adverse event observed is hypotension. Other effects include cardiac arrhythmia, ischemic cardiac events MI, and tachycardia. The drug administration is via parenteral route (Juenemann et al., 1986). Activity is instant on administration through intravenous route and about 15–20 min through intramuscular (IM) or subcutaneous (SC) route of administration. Its effect endures for about 10–15 min on intravenous administration and through intramuscular it takes 3–4 h. Biotransformation happens in the liver and elimination through urine (Brunton et al., 2011; Seideman, 1982).
Molecular Aspects of the Activity and Inhibition of the FAD-Containing Monoamine Oxidases
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
The one clear example of mixed inhibition that has been fully established is for the imidazoline compound 2-(2-benzofuranyl)-2-imidazoline (2-BFI). The 2-BFI binds in the entrance cavity of MAO B when the cavity is in a particular conformation that can be stabilized by tranylcypromine bound in the catalytic site (Bonivento et al., 2010; McDonald et al., 2010). The I2-type imidazoline compounds bind to a subset of MAO molecules with nanomolar affinity but inhibition of the bulk population of MAO requires micromolar concentrations (Jones et al., 2007; McDonald et al., 2010). The significance of imidazoline binding to MAO in the cell is not clear.
Evaluation of Autonomic Failure
Published in David Robertson, Italo Biaggioni, Disorders of the Autonomic Nervous System, 2019
A) Phentolamine is a 2-substituted imidazoline with α-adrenergic blocking activity. This drug produces competitive α-adrenergic blockade that is relatively transient. Phentolamine decreases blood pressure with an increase in venous capacity and decrease in peripheral resistance. The dilation is predominantly due to a direct action on vascular smooth muscle (Das and Parratt, 1971).
Pharmacological characterization of the α2A-adrenergic receptor inhibiting rat hippocampal CA3 epileptiform activity: comparison of ligand efficacy and potency
Published in Journal of Receptors and Signal Transduction, 2022
Joseph P. Biggane, Ke Xu, Brianna L. Goldenstein, Kylie L. Davis, Elizabeth J. Luger, Bethany A. Davis, Chris W.D. Jurgens, Dianne M. Perez, James E. Porter, Van A. Doze
Upon resolving the identity of the receptor subtype, we next assess the most suitable agonist for lead drug development. We also tested different classes of AR agonists (catecholamine, imidazoline, guanidine) to evaluate their performance at inhibiting epileptiform burst activities with respect to NE (Figure 4). From a therapeutic standpoint, agonist(s) possessing the highest potency and efficacy would be the most promising candidate. Although most catecholamine compounds are expected to be full agonists, the imidazoline/guanidine agonists have little structural resemblance to catecholamines and therefore may interact with the α2-ARs through completely different mechanisms [18–19]. However, unlike catecholamines, most imidazolines/guanidines can cross the blood–brain barrier, which is critical when considering their potential role in drug therapies. Rank order potency revealed that the imidazolines/guanidines possessed the highest pEC50 values (Figure 4(B)), as the most potent imidazoline, dexmedetomidnine, is over 30-fold more potent than EPI, the most potent catecholamine. However, all catecholamines were full agonists while only one non-catecholamine, UK-14304 (RE = 79.2), was a full agonist in this system (Figure 4(A)).
Pharmacotherapeutic strategies for treating hypertension in patients with obesity
Published in Expert Opinion on Pharmacotherapy, 2018
Revathy Carnagarin, Vance Matthews, Cynthia Gregory, Markus P. Schlaich
Given the important role of increased sympathetic outflow in the pathogenesis of OHT, it is perhaps surprising that central sympatholytic blockade with imidazoline I1-receptor agonists is not used more frequently in the management of OHT. Some misconceptions may exist relating to the adverse effects of older central sympatholytic agents such as clonidine or α-methyldopa, which were commonly associated with tiredness, sedation, and rebound hypertension when ceased (clonidine). The newer imidazoline I1-receptor agonists such as moxonidine and rilmenidine have been demonstrated to be well tolerated and effective in lowering BP. In contrast to clonidine which binds to central α2 receptors, the newer agents bind to the Imidazoline I1-receptor thereby largely avoiding the clonidine like side effects [66,67]. However, a dry mouth sensation can occur in up to 10% of patients on moxonidine due to its inhibitory effect on salivary flow [68]. From a metabolic perspective, moxonidine has been demonstrated to enhance insulin sensitivity, as shown with an insulin clamp technique in obese spontaneously hypertensive rats [69]. In addition to BP lowering, moxonidine treatment improves insulin sensitivity in patients with obesity hypertension [70]. The BP-lowering effect of moxonidine was comparable to amlodipine, but with additional effects such as the improvement of insulin resistance, reduction of plasma leptin levels and attenuation of sympathetic overdrive [71].
Xylazine poisoning: a systematic review
Published in Clinical Toxicology, 2022
Noah S. Ball, Brittany M. Knable, Taylor A. Relich, Allyson N. Smathers, Michael R. Gionfriddo, Branden D. Nemecek, Courtney A. Montepara, Anthony J. Guarascio, Jordan R. Covvey, David E. Zimmerman
Although not seen in this review, clinicians should obtain an ECG due to the potential for arrhythmias with xylazine. Two patients required a lidocaine infusion at a time when this was standard of practice for the development of premature ventricular contractions; however, this is no longer standard of practice. Administration of atropine is unlikely to have an effect with xylazine toxicity. Similar to clonidine and other imidazolines, xylazine results in alpha-2 agonism and potential agonist activity at the imidazoline receptors, I1 and I2, and not from cholinergic receptors [35–37]. It is still reasonable to administer atropine in presentations with bradycardia and an unknown cause.