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Pharmacokinetic-Pharmacodynamic Relationships of Cardiovascular Drugs
Published in Hartmut Derendorf, Günther Hochhaus, Handbook of Pharmacokinetic/Pharmacodynamic Correlation, 2019
A more complex method was necessary to describe the biphasic antihypertensive effect of trimazosin. Meredith et al.46 reported an initial transient decrease in blood pressure within 1 h and a delayed maximum hypotensive effect 4 to 6 h after a single intravenous dose. This biphasic response could not be adequately described by trimazosin concentrations alone. The investigators proposed a model with an effect compartment for trimazosin and a separate effect compartment for its metabolite, 1-hydroxytrimazosin. Combined with a linear pharmacodynamic model and a two-compartment pharmacokinetic model, the results indicated that the initial hypotensive effect was associated with the parent compound while the greater delayed response was associated with the metabolite.
Adrenoceptor Antagonists
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
Trimazosin also displays α1-adrenoceptor selectivity with pharmacological properties and side-effects similar to prazosin. It exerts hypotensive effects by similar mechanisms but additionally has direct vasodilator activity. It has a slow onset of action, possibly because of conversion to the biologically active 1-hydroxy metabolite. The plasma half-life is equivalent to that of prazosin but it is regarded as having a longer duration of action similar to that of terazosin (Van Zwieten 1988).
Pharmaceuticals agents for preventing NSAID-induced gastric ulcers: a patent review
Published in Expert Review of Clinical Pharmacology, 2021
Daiane Franco Teixeira, Anamaria Mendonça Santos, Ana Maria Santos Oliveira, José Adão Carvalho Nascimento Júnior, Luiza Abrahão Frank, Marilia Trindade De Santana Souza, Enilton Aparecido Camargo, Mairim Russo Serafini
Crawford and colleagues’ discovery [48] showed that using piroxicam with other drugs (acetaminophen, doxepin, pirbuterol, diazepam, fanetizole, trimazosin, and pyridoxine) was effective in reducing the gastrointestinal effects of NSAIDs. Male Sprague rats were used in a piroxicam-induced ulcer model, with the treatment (disodium 5ʹ-guanylate) being administered simultaneously. Six hours later, the animals were sacrificed, and the number of lesions per animal was compared with the control (piroxicam only). The group analyzed the number of injuries per animal and compared it to the control (only piroxicam). A gastrointestinal protective effect of the drugs used was observed. These results showed the possibility of using piroxicam in association with NSAIDs in this type of treatment.
Antihypertensive effect and the underlying mechanisms of action of phytolaccagenin in rat models
Published in Clinical and Experimental Hypertension, 2022
Imran Ul Haq, Taseer Ahmad, Taous Khan, Abdul Jabbar Shah
Vascular smooth muscle also plays an important role in regulating vascular tone, and important antihypertensive drugs act on it, including calcium channel blockers, such as dihydropyridines (33,34). In addition, our in silico studies predicted phytolaccagenin as a calcium regulator (PASSonlie: Way to drug, Table S1). To see the effect of phytolaccagenin on vascular calcium channels, aortic rings were precontracted with phenylephrine and high K+. Interestingly, the cumulative addition of phytolaccagenin inhibited both contractions, with relatively more potency against phenylephrine. Contraction induced by phenylephrine, an alpha adrenoceptor agonist (35), is due to the influx of extracellular Ca2+ through receptor-operated calcium channels and partially due to Ca2+ release from the intracellular store (36). To evaluate the alpha-adrenergic receptor blocking effect of phytolaccagenin, in a separate set of experiments, using rat aortic preparations, CRCs of phenylephrine were constructed in the presence of different concentrations of phytolaccagenin and phentolamine. This pretreatment induced a non-parallel shift in the CRCs of phenylephrine, while phentolamine, an alpha blocker (37), induced a typical parallel shift. However, phytolaccagenin suppressed the fast component (fast phase of phenylephrine produced contraction) that is similar to some extent to the less potent trimazosin (38). This hypothesis was supported by in silico study via the generation of alpha-1-adrenergic receptor (AF_P35348) homologous model with binding energy −3.22 kcal/mol (Table S2). However, phytolaccagenin inhibited K+ (80 mM)-induced vascular smooth muscle contraction and significantly reduced the Ca2+-induced contraction in aortic rings at higher concentration, similar to verapamil. These findings suggest that phytolaccagenin also has an inhibitory effect on Ca2+ entry through voltage-dependent calcium channels (VDCs). To test this hypothesis, rat aortic rings were suspended in Ca2+-free/EDTA medium, and Ca2+ CRCs were obtained in duplicate. Pre-incubation of the aortic rings with different concentrations (10–100 μM) of phytolaccagenin induced a rightward shift with suppression of maximum response, and CaCl2 CRCs were obtained, similar to verapamil, indicating that phytolaccagenin also inhibits Ca2+ entry through VDCs at higher concentration.