Clinical applications of slow channel blocking compounds

Ag, Ellrodt; Bn, Singh

doi:10.1016/0163-7258(83)90025-6

Cited by 36 publications

(6 citation statements)

References 219 publications

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“…The L-type VDCC is characterized by its sensitivity to a pharmacologically important group of drugs called calcium antagonists [5,6]. These drugs are widely used in the treatment of cardiovascular diseases such as coronary artery disease, supraventricular arrhythmia, and hypertension [7,8]. The skeletal muscle L-type VDCC has been extensively studied and its putative structure consists of 5 polypeptides, designated ~1, W, p, y, and S [9,10].…”

Section: Introductionmentioning

confidence: 99%

Evidence for the existence of a cardiac specific isoform of the α₁ subunit of the voltage dependent calcium channel

et al. 1989

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Biochemical, pharmacological and electrophysiological evidence implies the existence of tissue specific isoforms of the L-type VDCC. The a, and a, subunits of the skeletal muscle calcium channel have been previously cloned and their ammo acid sequence deduced. Here we report the isolation and sequencing of a partial cDNA that encodes a heart specific isoform of the a, subunit. The amino acid sequence deduced from this part cDNA clone shows 64.7% similarity with the skeletal muscle ar subunit. Northern analysis reveals 2 hybridizing bands, 8.5 and 13 kb, in contrast to one 6.5 kb band in the skeletal muscle. Selective inhibition of mRNA expression in Xenopus oocytes by complementary oligodeoxynucleotides derived from the heart clone provides further evidence that the cDNA corresponds to an essential component of the VDCC. These data further support the existence of tissue-specific isoforrns of the L-type VDCC.

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Section: Introductionmentioning

confidence: 99%

Evidence for the existence of a cardiac specific isoform of the α₁ subunit of the voltage dependent calcium channel

et al. 1989

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“…A large body of evidence has accumulated that suggests that calcium channel antagonists are valuable cardiovascular drugs with an as yet undefined limit of usefulness [Bou et al, 1983;Ellrodt and Singh, 1983;Naylor and Horowitz, 19831. Among the many pharmacological effects of these drugs is smooth muscle relaxation, a property shared by other drugs that do not block calcium entry into cells.…”

Section: Introductionmentioning

confidence: 99%

The activity of nifedipine, diltiazem, verapamil, and lidoflazine in isolated tissues: An approach to the determination of calcium channel blocking activity

Kenakin

Beek

1985

Drug Development Research

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Kenakin, T.P., D. Beek:The activity of nifedipine, diltiazern, veraparnil, and lidoflazine in isolated tissues: An approach to the determination of calcium channel blocking activity. Drug Dev. Res. 5:347-358, 1985. A characteristic profile of activity was obtained in six isolated tissues for the calcium channel antagonists nifedipine, diltiazern, veraparnil, and lidoflazine. All drugs produced relaxation of K+ depolarized guinea pig ileal longitudinal muscle strips and K+ depolarized canine coronary artery, depression of electrically stimulated basal contractions of guinea pig left atria, and depression of guinea pig right atrial rate. Also, all drugs produced parallel dextral displacement of concentration-response curves to calcium in guinea pig depolarized taenia caeci. The potency for this effect was quantified by Schild analysis yielding the following pA2 estimates: nifedipine 9.5, diltiazem 7.65, veraparnil 7.8, and lidoflazine 7.0.Nifedipine, diltiazem, and lidoflazine produced no relaxation of methoxamine-contracted rabbit aortae while weak effects were observed with veraparnil at concentrations 100 times greater than those required to reverse calcium effects in other tissues. In general, nifedipine and diltiazern displayed selectivity for smooth muscle over cardiac muscle while verapamil showed the least selectivity in this regard.

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“…Calcium antagonists exert their pharmacological effects (diminishing myocardial oxygen consumption resulting in a reduction in high-energy phosphate consumption; coronary and peripheral vasodilatation, slowing of the sinus node discharge; prolongation of sinus node recovery time; and lengthening of the atrioventricular conduction time) by inhibiting the calcium inward current through slow channels in these tissues (Antman et al 1980a;Fleckenstein 1983;Singh et al 1982;Zsoter & Church 1982). These properties constitute the pharmacological basis for the established therapeutic efficacy of calcium antagonists in the treatment of ischaemic heart disease, arterial hypertension, hypertrophic obstructive cardiomyopathy and certain cardiac arrhythmias (for review see Ellrodt & Singh 1983;Stone et al 1980). Several therapeutic trials have provided evidence that these drugs might also be of benefit for the treatment of pulmonary hypertension, congestive heart failure and cerebral as well as peripheral vasospastic disorders (Allen et al 1983;Camerini et al 1980;Polese et al 1979;Solomon et al 1983).…”

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confidence: 97%

Clinical Pharmacokinetics of Verapamil, Nifedipine and Diltiazem

Echizen

Eichelbaum

1986

Clinical Pharmacokinetics

181

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The calcium antagonists diltiazem, nifedipine and verapamil are widely used in the treatment of coronary heart disease, arterial hypertension, certain supraventricular tachyarrhythmias and obstructive hypertrophic cardiomyopathy. During recent years their pharmacokinetic properties and metabolism have been studied in more detail. Although these 3 calcium antagonists exhibit great diversity in chemical structure, they exhibit common pharmacokinetic properties. These drugs are extensively metabolised and only traces of unchanged drugs are eliminated in urine. Their systemic plasma clearances are high and dependent on liver blood flow. Therefore, their bioavailabilities (diltiazem 40 to 50%; nifedipine 40 to 50%; verapamil 10 to 30%) are low despite almost complete absorption following oral administration. During long term treatment, oral clearance decreases and bioavailability increases due to saturation of hepatic first-pass metabolism. Pronounced intra- and inter-individual variations in clearance and bioavailability are observed. In patients with liver cirrhosis the various pharmacokinetic parameters are grossly altered. Clearance decreases, elimination half-life is substantially prolonged, and bioavailability more than doubles. In addition, the volume of distribution increases. Whereas renal disease has no impact on the pharmacokinetics of diltiazem and verapamil, elimination half-life of nifedipine increases in relation to the degree of renal impairment due to an increase in volume of distribution. Systemic clearance, however, remains unchanged. The data so far available indicate that the plasma concentrations of these drugs correlate with both their electrophysiological and haemodynamic effects. However, no effective therapeutic plasma concentration range has been firmly established. As reliable clinical end-points are available for dose titration of calcium antagonists, it is doubtful whether therapeutic drug monitoring will be of great value. Calcium antagonists are often administered in combination with a variety of other drugs. Thus, the potential for both pharmacodynamic and pharmacokinetic drug interaction exists. The interaction between digoxin and these drugs is of clinical importance. Verapamil and diltiazem cause a significant increase in plasma digoxin concentrations. In contrast, nifedipine does not lead to a significant increase in the plasma digoxin concentration. The mechanism responsible for this interaction is inhibition of both renal and non-renal digoxin clearance.(ABSTRACT TRUNCATED AT 400 WORDS)

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Clinical applications of slow channel blocking compounds

Cited by 36 publications

References 219 publications

Evidence for the existence of a cardiac specific isoform of the α₁ subunit of the voltage dependent calcium channel

Evidence for the existence of a cardiac specific isoform of the α₁ subunit of the voltage dependent calcium channel

The activity of nifedipine, diltiazem, verapamil, and lidoflazine in isolated tissues: An approach to the determination of calcium channel blocking activity

Clinical Pharmacokinetics of Verapamil, Nifedipine and Diltiazem

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Clinical applications of slow channel blocking compounds

Cited by 36 publications

References 219 publications

Evidence for the existence of a cardiac specific isoform of the α1 subunit of the voltage dependent calcium channel

Evidence for the existence of a cardiac specific isoform of the α1 subunit of the voltage dependent calcium channel

The activity of nifedipine, diltiazem, verapamil, and lidoflazine in isolated tissues: An approach to the determination of calcium channel blocking activity

Clinical Pharmacokinetics of Verapamil, Nifedipine and Diltiazem

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Evidence for the existence of a cardiac specific isoform of the α₁ subunit of the voltage dependent calcium channel

Evidence for the existence of a cardiac specific isoform of the α₁ subunit of the voltage dependent calcium channel