Verapamil activity

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. 

The side effects and toxic reactions to verapamil iaclude upper GI upset, constipation, di22iaess, headaches, flushing and burning, edema, hypotension, bradycardia, and various conduction disturbances. Verapamil has negative iaotropic activity and may precipitate heart failure ia patients having ventricular dysfunction (1,2). 

After po dosing, verapamil s absorption is rapid and almost complete (>90%). There is extensive first-pass hepatic metabolism and only 10—35% of the po dose is bioavahable. About 90% of the dmg is bound to plasma proteins. Peak plasma concentrations are achieved in 1—2 h, although effects on AV nodal conduction may be apparent in 30 min (1—2 min after iv adrninistration). Therapeutic plasma concentrations are 0.125—0.400 p.g/mL. Verapamil is metabolized in the liver and 12 metabolites have been identified. The principal metabolite, norverapamil, has about 20% of the antiarrhythmic activity of verapamil (3). The plasma half-life after iv infusion is 2—5 h whereas after repeated po doses it is 4.5—12 h. In patients with liver disease the elimination half-life may be increased to 13 h. Approximately 50% of a po dose is excreted as metabolites in the urine in 24 h and 70% within five days. About 16% is excreted in the feces and about 3—4% is excreted as unchanged dmg (1,2). 

Patients having high plasma renin activity (PRA) (>8 ng/(mLh)) respond best to an ACE inhibitor or a -adrenoceptor blocker those having low PRA (<1 ng/(mLh)) usually elderly and black, respond best to a calcium channel blocker or a diuretic (184). -Adrenoceptor blockers should not be used in patients who have diabetes, asthma, bradycardia, or peripheral vascular diseases. The thiazide-type diuretics (qv) should be used with caution in patients having diabetes. Likewise, -adrenoceptor blockers should not be combined with verapamil or diltiazem because these dmgs slow the atrioventricular nodal conduction in the heart. Calcium channel blockers are preferred in patients having coronary insufficiency diseases because of the cardioprotective effects of these dmgs. 

Diltiazem inhibits calcium influx via voltage-operated channels and therefore decreases intracellular calcium ion. This decreases smooth muscle tone. Diltiazem dilates both large and small arteries and also inhibits a-adrenoceptor activated calcium influx. It differs from verapamil and nifedipine by its use dependence. In order for the blockade to occur, the channels must be in the activated state. Diltiazem has no significant affinity for calmodulin. The side effects are headache, edema, and dizziness. 

Sulfinpyrazone may increase die anticoagulant activity of oral anticoagulants. There is an increased risk of hypoglycemia when sulfinpyrazone is administered with tolbutamide. Concurrent administration of sulfinpyrazone widi verapamil may decrease die effectiveness of verapamil. 

Frequent contacts with the manufacturer of verapamil, the Knoll company in Ludwigshafen, enabled an intense communication with Hugo Kubinyi, working at that time as a medicinal chemist for Knoll. As a consequence of frequent fruitful discussions with Hugo I included quantitative structure-activity relationship (QSAR) studies on verapamil congeners in my PhD work and continued working in the QSAR field till the present. 

International Verapamil-Trandolapril Study Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria study intrinsic sympathomimetic activity intravenous... 

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... 

A very simple technique is to use a radiolabeled ligand (usually a well-known substrate) of the specific transporter of interest. A recent suggestion for functional quantitation of the apparent affinities (fQ values) to P-gp using Caco-2 cells and the substrate taxol has been published [143], The method can be described simply as (1) determination of b —> a transport of3 H -taxol in normal, untreated Caco-2 cells and (2) determination of b —> a transport of 3H-taxol in the presence of verapamil (0.2 mM). The difference between these two components represents the active transport via P-gp. The two concentrations of the test compound are chosen as approximately 0.25 x K, and 4.0 x K, and for the inhibition of taxol transport, and in the study of Gao et al. [143], 16 pM and 250 pM of the test compound were used... 

Fig. 20.8. P -gp-ATPase activation profiles obtained by measurements of extracellular acidification rates in living cells by means of a cytosensor physiometer. (A) Cyclosporin A ( ), progesterone (0)> trifluoperazine (A) and verapamil ( ) in LLC-MDR1 cells (B) amitriptyline ( ), calcein-AM (A), diltiazem ( ) and vinblastine (T) in LLC-MDR1 cells.

G., Raschack, M., Cappelletto, B., Gigante, M., Boiocchi, M., Structure—activity relationship of verapamil analogs and reversal of multidrug resistance, Biochem. Pharmacol. 1995, 50, 1245-1255. 

Belehradek, J., Jr., Garrigos, M., Effects of steroids and verapamil on P-glycoprotein ATPase activity progesterone, desoxycorticosterone, corticosterone and verapamil are mutually non-exclusive modulators, Biochem. J. 1996, 337, 515-522. 

Cross-resistance to [Ru(r 6-bip)Cl(en)]PF6 in A2780ad fell from a factor of 38 to only threefold upon co-administration of verapamil, indicating that P-glycoprotein mediated active efflux of the anticancer drug was predominantly responsible for the observed cross-resistance and could be abrogated by addition of the competitive inhibitor. Such behavior is common for lipophilic positively charged drugs. 

Verapamil Verelan Calan, Isoptin Capsule 120, 180,240, 360 mg Film-coated tablet 40, 80, 120 mg Extended-release tablet 120, 180, 240 mg 80-480 mg/day combination with other drugs (e.g., carbamaze-pine, valproate, antipsy-chotics). L-type Ca+ channels Alters Ca+-Na+ (change Decreases 5-HT, DA, and endorphin activity... 

Garrigues et al. [49] characterized two different but partially overlapping P-gp pharmacophores. Initially, they determined affinities and mutual relationships from the changes in P-gp ATPase activity induced by a series of cyclic peptides, peptide-like compounds used alone or in combination. Because verapamil binding to P-gp... 

A more recent example of this technique has been the study on human absorption characteristics of fexofenadine [109], Fexofenadine has been shown to be a substrate for P-gp in the in vitro cell lines its disposition is altered in knockout mice lacking the gene for MDRla, and co-administration of P-gp inhibitors (e.g. ketoconazole and verapamil) was shown to increase the oral bioavailability of fexofenadine [110-113], Hence, it is suggested that the pharmacokinetics of fexofenadine appears to be determined by P-gp activity. In the human model, the intestinal permeability estimated on the basis of disappearance kinetics from the jejunal segment is low, and the fraction absorbed is estimated to be 2% [114], Co-administration of verapamil/ketoconazole did not affect the intestinal permeability estimates however, an increased extent of absorption (determined by de-convolution) was demonstrated. The increased absorption of fexofenadine was not directly related to inhibition of P-gp-mediated efflux at the apical membrane of intestinal cells as intestinal Peff was unchanged. Furthermore, the effect cannot be explained by inhibition of intestinal based metabolism, as fexofenadine is not metabolised to any major extent. It was suggested that this may reflect modulation of efflux transporters in hepatocyte cells, thereby reducing hepatobiliary extraction of fexofenadine. 

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