Calcium channels, blocker

Arandipine NOj H OCH2COCH3 Nicardipine H NOj (CH2)2NCH2CgH5 Nifedipine NOj H OCH3 Nisoldipine H NO2 OCH2CH(CH3)2 

Fujitomo et describe the use of coupled achiral (anion exchange) and chiral (ovomucoid) columns to separate the enantiomers of methyl ( )-4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)thieno(2,3- )pyridine-5-carboxylate. The eluent was methanol-aq. potassium dihydrogen orthophosphate (50mmolL ) (45 4- 55 for the achiral column and 44 -f- 56 for the chiral one). Detection was at PGEs (Eli -I-O.IOV, E2 -1-0.50 V vs Pd). Sample preparation was by LLE into benzene. The inter-assay RSDs at 1 pgL were 9.1% and 12.7% for the 5 -(-f) and / -(-) isomers, respectively. 

SPE on octyl-modified silica columns, the analytes being eluted with 80% (v/v) methanol 

The dried residue was dissolved in chloroform and extracted on a silica cartridge 

The residue was dissolved in eluent and subjected to column switching with an ODS pre-column. 

---

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 electrophysiological effects of amiodarone may be a composite of several properties. In addition to prolonging action potential duration and refractory period in ad tissues of the heart, the compound is an effective sodium channel blocker (49), calcium channel blocker (50), and a weak noncompetitive -adrenoceptor blocking agent (51). Amiodarone slows the sinus rate, markedly prolongs the QT interval, and slightly prolongs the QRS duration (1,2). 

Verapamil. Verapamil hydrochloride is a pbenyl alkyl amine and is considered the prototype of the Class I calcium channel blockers. Verapamil is also a potent inhibitor of coronary artery spasm and is useful in Prinzmetal s angina and in unstable angina at rest. Verapamil produces negative chronotropic and inotropic effects. These two actions reduce myocardial oxygen consumption and probably account for the effectiveness of verapamil in chronic stable effort angina (98,99). Moreover, verapamil is an effective antihypertensive agent. 

ACE inhibitors can be administered with diuretics (qv), cardiac glycosides, -adrenoceptor blockers, and calcium channel blockers. Clinical trials indicate they are generally free from serious side effects. The effectiveness of enalapril, another ACE inhibitor, in preventing patient mortaUty in severe (Class IV) heart failure was investigated. In combination with conventional dmgs such as vasodilators and diuretics, a 40% reduction in mortaUty was observed after six months of treatment using 2.5—40 mg/d of enalapril (141). However, patients complain of cough, and occasionally rash and taste disturbances can occur. 

Calcium Channel Blockers. Because accumulation of calcium is one of the facets of the mote involved process leading to atherosclerosis, it would foUow that the antihypertensive calcium channel blockers might be effective in preventing atheroma. Both verapamil (Table 1) and nifedipine (Table 3) have been shown to stimulate the low density Upoprotein (LDL) receptor (159). This specific receptor-mediated pathway could theoretically improve Upid metaboUsm in the arterial wall, and thereby prove antiatherogenic. These effects have been proven in animals. 

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. 

Calcium channel blockers reduce arterial blood pressure by decreasing calcium influx, resulting in a decrease in intracellular calcium (236,237). The arterial smooth muscle tone decreases, thereby decreasing total peripheral resistance. The increase in vascular resistance in hypertension is found to depend much on calcium influx. Calcium channel blockers reduce blood pressure at rest and during exercise. They decrease the transmembranous calcium influx or entry that lead to a net decrease of intracellular calcium and therefore the vascular tone falls, as does blood pressure. 

In addition to the vascular effects, calcium channel blockers (Table 6) such as isradipine, nifedipine (Table 3), and nitrendipine, produce natriuretic... 

Calcium channel blockers normalize the blood pressure in about 80% of hypertensive patients older than 60 years of age, 50% of those between 40 and 60 years of age, and only 20% of patients under 40 years of age. Thus calcium channel blockers are best for patients who are elderly and have low PRA and mosdy ineffective in patients who have high PRA. This responsiveness profile is very similar to that of the diuretics. 

Calcium channel blockers cause more pronounced lowering of blood pressure in hypertensive patients than in normotensive individuals. Generally, all calcium channel blockers cause an immediate increase in PRA during acute treatment in patients having hypertension but PRA is normalized during chronic treatment despite the sustained decrease in blood pressure. These agents also do not generally produce sodium and water retention, unlike the conventional vasodilators. This is because they produce diuretic effects by direct actions on the kidney. 

The sales of oral diuretics are declining, and are forecast to continue their decline in constant dollars during the 1990s (119,120). Several possible explanations can be offered for these trends. The patents of market leaders are expiring, lea ding to the introduction of generic brands at ca 40% below the cost of the branded market leaders physicians are switching to newer treatments for hypertension, eg, calcium channel blockers and... 

Procardia XL. Procardia XL extended-release capsules, marketed by Pfizer Labs Division of Pfizer, Inc., contain nifedipine [21829-25-4] a calcium channel blocker of mol wt 346.3. The extended release tablet is formulated as a once-a-day controlled release capsule for oral adrninistration dehvering either 30, 60, or 90 mg nifedipine. Procardia XL is indicated for use in the management of vasospastic angina, chronic stable angina, and hypertension (see Cardiovascularagents). 

Heterocycles, calcium channels blockers, as auxiliary agents in resistant tumor therapy 97YZ455. 

The so-called calcium channel blockers constitute a class of cardiovascular agents that have gained prominence in the past few years. These drugs, which obtund contraction of arterial vessels by preventing the movement of calcium ions needed for those contractions, have proved especially useful in the treatment of angina and hypertension. Dihydropyridines such as nifedipine (30) are par-... 

The selectivity of another cellulose-based CSP, Chiralcel OJ, has also been examined in SFC [60]. Separations of racemic drugs such as benoxaprofen, temazepam, and mephobarbital were obtained. Acetonitrile proved to be a better modifier than methanol for some of the compounds investigated. The four optical isomers of a calcium channel blocker were resolved by Siret et al. on the Chiralcel OJ CSP [30]. In LC, two CSPs were required to perform the same separation. 

In the treatment of hypertension, ACE inhibitors are as effective as diuretics, (3-adrenoceptor antagonists, or calcium channel blockers in lowering blood pressure. However, increased survival rates have only been demonstrated for diuretics and (3-adrenoceptor antagonists. ACE inhibitors are approved for monotherapy as well as for combinational regimes. ACE inhibitors are the dtugs of choice for the treatment of hypertension with renal diseases, particularly diabetic nephropathy, because they prevent the progression of renal failure and improve proteinuria more efficiently than the other diugs. 

ACE inhibitors - AT antagonists - Alpha blockers - Beta blockers Isolated syslolic hypertension (older patienls) - Diuretics preferred (generally Thiazides) - Long-acting dihydropyridine calcium channel blocker... 

Pharmacological intervention NSAIDs, local anesthetics, opioid analgesics, sodium-channel blockers Opioid analgesics, NSAIDs, calcium-channel blockers ... 

The dihydropyridine-sensitive Cav1.2 calcium channel, that is essential for smooth muscle contration and the target for the calcium channel blocker/calcium antagonists. 

---