Verapamil properties

Other agents are also used for the treatment of manic-depressive disorders based on preliminary clinical results (177). The antiepileptic carbamazepine [298-46-4] has been reported in some clinical studies to be therapeutically beneficial in mild-to-moderate manic depression. Carbamazepine treatment is used especially in bipolar patients intolerant to lithium or nonresponders. A majority of Hthium-resistant, rapidly cycling manic-depressive patients were reported in one study to improve on carbamazepine (178). Carbamazepine blocks noradrenaline reuptake and inhibits noradrenaline exocytosis. The main adverse events are those found commonly with antiepileptics, ie, vigilance problems, nystagmus, ataxia, and anemia, in addition to nausea, diarrhea, or constipation. Carbamazepine can be used in combination with lithium. Several clinical studies report that the calcium channel blocker verapamil [52-53-9] registered for angina pectoris and supraventricular arrhythmias, may also be effective in the treatment of acute mania. Its use as a mood stabilizer may be unrelated to its calcium-blocking properties. Verapamil also decreases the activity of several neurotransmitters. Severe manic depression is often treated with antipsychotics or benzodiazepine anxiolytics. 

Verapamil. Verapamil hydrochloride (see Table 1) is a synthetic papaverine [58-74-2] C2qH2 N04, derivative that was originally studied as a smooth muscle relaxant. It was later found to have properties of a new class of dmgs that inhibited transmembrane calcium movements. It is a (+),(—) racemic mixture. The (+)-isomer has local anesthetic properties and may exert effects on the fast sodium channel and slow phase 0 depolarization of the action potential. The (—)-isomer affects the slow calcium channel. Verapamil is an effective antiarrhythmic agent for supraventricular AV nodal reentrant arrhythmias (V1-2) and for controlling the ventricular response to atrial fibrillation (1,2,71—73). 

Waelbroeck M, Robberecht P, De Neef P, Christophe J. Effects of verapamil on the binding properties of rat heart muscarinic receptors evidence for an allosteric site. Biochem Biophys Res Commun 1984 121 340-345. 

It is difficult to prove that quaternary ammonium compounds can cross lipid bilayers using cell uptake experiments, since several mechanisms may be operative, and separating contributions from each may be very difficult [1]. It may be an advantage to use PAMPA to investigate transport properties of permanently ionized molecules. Of all the molecules whose permeabilities were measured under iso-pH conditions in 2% DOPC/dodecane, verapamil, propranolol, and especially quinine seem to partially violate the pH partition hypothesis, as shown in Figs. 7.47a-c. In Fig. 7.47c, the solid line with slope of +1 indicates the expected effective permeability if the pH partition hypothesis were strictly adhered to. As can be seen at pH 4... 

Compounds absorbed by active uptake mechanisms (e.g., glucose and Gly-Pro) and compounds known to be substrates for efflux transport (e.g., digoxin, verapamil) were also included in the list. The applied concentration (10-500 pM) only had minor effects on the permeability values. Thus, the choice of concentration was not critical for this set of compounds with respect to the relationship between permeability and fraction absorbed in humans. Changing the pH on the apical donor side had significant effects on the Papp values of several compounds, the effects being in agreement with the acid-base properties of the compounds. The... 

McTavish, D., Sorkin E. M., Verapamil an updated review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension, Drugs 1989, 38, 19-76. 

The latter type of compounds should preferably carry either one type I unit or at most two units (positioned as far apart as possible), and have an elongated structure (which does not fold as verapamil, for example) with a small cross-sectional area, Ad- The first type of compounds is expected to be transported slowly, whereas the second type may not be transported. Table 20.2 summarizes the drug properties relevant for transporter binding and lipid partitioning of a substrate (modulator or inhibitor) of P-gp. Inspection of the information contained in Table 20.2 shows that the synthesis and membrane incorporation of inhibitors with a low number of H-bond acceptor patterns should be simpler and more efficient than that of inhibitors with a large number of patterns. 

The absence of substituents with free radical scavenging properties in most of the (3-blockers makes doubtful their efficacy as powerful antioxidants. Arouma et al. [293] tested the antioxidative properties of several 3-blockers in reactions with superoxide, hydroxyl radicals, hydrogen peroxide, and hypochlorous acid. It was demonstrated that most of the compounds tested were inactive in these experiments. Nonetheless, propranolol, verapamil, and flunarizine effectively inhibited iron ascorbate-stimulated microsomal lipid peroxidation and all drugs (excluding flunarizine) were effective scavengers of hydroxyl radicals. Contrary to Janero et al. [292], these authors did not find the inhibition of xanthine oxidase by propranolol. It was concluded that 3-blockers are not the effective in vivo antioxidants. 

Verapamil and diltiazem cause less peripheral vasodilation than dihydro-pyridines such as nifedipine but greater decreases in AV node conduction. They must be used with caution in patients with preexisting conduction abnormalities or in patients taking other drugs with negative chronotropic properties. 

Nimodipine may be more effective than verapamil for rapid-cycling bipolar disorder because of its anticonvulsant properties, high lipid solubility, and good penetration into the brain. 

Mibefradil is a verapamil-like agent with a potentially attractive haemodynamic profile. It is a vasodilator, which also causes a reduction in heart rate, whereas it is devoid of negative inotropic activity. Some of its properties are attributed to its influence of calcium channels of the T- and N-types. Unfortunately, the compound has been withdrawn because of multiple interactions with various other drugs. 

By contrast, a number of studies have not found verapamil monotherapy to be effective for acute mania (Table 10-14). Several case reports in the literature have not supported verapamil s potential antimanic properties. For example. Barton and Gitlin ( 262) found that none of eight acutely manic or hypomanic patients treated openly improved on verapamil. By contrast, there are several case reports of hypomania (some monoamine oxidase inhibitor—induced) improving with verapamil. Dubovsky (255) notes that, in his experience with spontaneous mania, he has been unimpressed with verapamil in patients who had previously been unresponsive to lithium. 

The aim of the present study was to repeat the experiments of the previous study using a multiple-unit verapamil formulation instead of the single-unit tablet. The in vitro dissolution patterns of both formulations are approximately equal, thus allowing their biopharmaceutical properties to be compared. 

The pharmacokinetic properties of these drugs are set forth in Table 12-5. The choice of a particular calcium channel-blocking agent should be made with knowledge of its specific potential adverse effects as well as its pharmacologic properties. Nifedipine does not decrease atrioventricular conduction and therefore can be used more safely than verapamil or diltiazem in the presence of atrioventricular conduction abnormalities. A combination of verapamil or diltiazem with 3 blockers may produce atrioventricular block and depression of ventricular function. In the presence of overt heart failure, all calcium channel blockers can cause further worsening of heart failure as a result of their negative inotropic effect. Amlodipine, however, does not increase the mortality of patients with heart failure due to nonischemic left ventricular systolic dysfunction and can be used safely in these patients. 

Pancreatic cholesterol esterase (3.1.1.3.) aids in transporting cholesterol to the enterocyte. By utilizing a selective and potent cholesterol esterase inhibitor 6-chloro-3-(l-ethyl-2-cyclohexyl)-2-pyrone, the absorption of cholesterol in hamsters could be reduced [71]. Wadkins et al. [72] synthesized novel sulfonamide derivatives, which demonstrated greater than 200-fold selectivity for human intestinal carboxylesterase compared with the human liver carboxylesterase hCEl, and none of them was an inhibitor of human acetylcholinesterase or butyrylcholinester-ase. Maybe these agents can serve as lead compounds for the development of effective, selective carboxylesterase inhibitors for clinical applications. Also the potent P-gp inhibitor verapamil [73] as well as S,S,S-tributylphosphortrithionate (DEF) [74] may exhibit carboxylesterase inhibitory properties. Various other inhibitors of human esterases are listed in Table 5.6. 

Doppenschmitt S, Langguth P, Regardh CG, et al. Characterization of binding properties to human P-glycoprotein development of a [3H]verapamil radioligandbinding assay. J Pharmacol Exp Ther 1999 288(l) 348-357. 

Based on the specificity and affinity, low molecular mass efflux pump inhibitors are classified into three generations (Werle 2008a). First-generation P-gp inhibitors such as verapamil or cyclosporine are compounds that are in clinical use for other indications and exhibit additional inhibitory properties. 

Adverse effects Verapamil and diltiazem have negative inotropic properties and therefore may be contraindicated in patients with preexisting depressed cardiac function. Both drugs can also cause a decrease in blood pressure caused by peripheral vasodilation. 

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