Effect of Tiapamil and Nifedepine During Critical Coronary Stenosis and in the Presence of Adrenergic β-Receptor Blockade in Anesthetized Dogs

Rk, Saini; Ie, Fulmor; Mj, Antonaccio

doi:10.1097/00005344-198209000-00012

Cited by 15 publications

(3 citation statements)

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“…In this model of limited cardiac reserve (critical stenosis), tiapamil (2 mg/kg i.v.) elicited a 15% increase in myocardial contractility, slight bradycardia (-7%), a more pronounced fall in blood pressure (-23%), and a marked increase in CAF (+58%) (51). These findings support the notion that by increasing flow to ischemic regions of the myocardium coronary vasodilation contributes significantly to the beneficial effects of tiapamil.…”

Section: Antiischemic Effectssupporting

confidence: 73%

Tiapamil

Hoick

Osterrieder

1987

Cardiovascular Drug Reviews

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Tiapamil is a Ca2+ entry blocker that is under development for the treatment of mild to moderate hypertension and angina pectoris. It also possesses antiarrhythmic properties. This review focuses on the pharmacological, toxicological, and clinical properties of tiapamil. A comparison is made of the effects of tiapamil with the effects of some other Ca2+ entry blockers. CHEMISTRYTiapamil (Ro 1 1-178 1 , Larocord) is the hydrochloride monohydrate of N-(3,4-dimethoxyphenethy1)-2-(3,4-dimethoxyphenyl)-N-methyl-rn-dithiane-2-propylamine 1,1,3,3-tetraoxide; it was synthesized by Ramuz (47,48) ( Fig. 1). With a molecular weight of 610.18, it is an odorless white crystalline powder with a bitter taste. It is moderately soluble in water (-1.7% at 25°C) and is a weak base with a pKa of 8.35 at 25°C. Tiapamil lacks an asymmetrical carbon atom; it is thus a single chemical entity. In this respect tiapamil differs from other phenylalkylamine derivatives, which are available only as racemic mixtures. PHARMACOLOGYTiapamil inhibits depolarization-induced transmembrane Ca2+ influx and interferes with excitation-contraction coupling in the heart and vascular smooth muscle (15,27). Inhibitory effects of tiapamil have been demonstrated in isolated vascularpreparations, including rabbit main pulmonary artery, dog coronary artery, and rat mesenteric and renal arteries (15,27,29). Tiapamil was most effective in relaxing high K+ (150 mM) induced contractures of isolated dog coronary artery strips, with a potency (ICSO 0.22 FM) only slightly lower than that of verapamil (ICSO 0.17 p~) . Both compounds also inhibited 45Ca influx induced by K+ depolarization in rabbit main pulmonary artery at concentrations similar to those required for relaxation of contracture. In isolated, depolarized renal arteries of the rat, tiapamil 77

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Section: Antiischemic Effectssupporting

confidence: 73%

Tiapamil

Hoick

Osterrieder

1987

Cardiovascular Drug Reviews

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“…In clinical studies, verapamil has also been shown to be more negatively inotropic than the other calcium antagonists [24,25] and that this detrimental effect is very marked in patients with bad left ventricular function and can lead to severe collapse [11]. In contrast, therapeutic doses of tiapamil do not decrease myocardial contractility of dogs [27,28], monkeys [29] and pigs [30] with myocardial ischaemia. Intravenous tiapamil improves clearly the haemodynamic status of patients with acute myocardial infarcts [31] or with chronic coronary artery disease [23],…”

Section: Discussionmentioning

confidence: 99%

Haemodynamic Effects of Tiapamil and Verapamil in Conscious Rats following Chronic Myocardial Infarction

Clozel

1988

Cardiology

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The haemodynamic effects of the two calcium antagonists, tiapamil and verapamil, were compared in conscious rats with or without myocardial infarction. In control rats without myocardial infarction, verapamil was about 20 times more potent than tiapamil to reduce arterial blood pressure. However, if equihypotensive doses of tiapamil and verapamil were compared, verapamil produced a 2-fold larger decrease of dp/dt_max+ (p < 0.01). Three weeks after myocardial infarction, the negative inotropic effect of both tiapamil and verapamil were potentiated to the same extent. However, if equihypotensive doses of tiapamil and verapamil were compared, tiapamil was still less negative inotropic than verapamil.

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“…The negative inotropic ef fects resulting from calcium-entry antago nists and beta-blockers given together has been documented in both animal studies [Hamann et al. 1985;Saini et al, 1982] and clinical reports [Krikler, 1974;Wayne et al, 1982;Robson cl al., 1982]. Various features of such drug interactions were observed in a clinical study [Packer ct al., 1982] in which progressive negative inotropic effects re sulted from the addition of increasing doses of the prototype phcnylalkylaminc calciumentry antagonist, verapamil, to stable dosing regimens of propranolol which produced plasma levels of the latter drug in a 'thera peutic' range.…”

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confidence: 99%

Hemodynamic and Pharmacokinetic Aspects of the Interactions between Verapamil and Pindolol

Hamann

Kaltenborn²

1987

Pharmacology

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Combined administration of verapamil, a phenylalkylamine calcium-entry antagonist, with a pure beta-adrenoceptor blocker, propranolol, produces profound cardiovascular depression associated with decreased hepatic clearance of both drugs. We have therefore studied the combination of verapamil and pindolol, a beta-adrenoceptor blocker with intrinsic sympathomimetic activity (ISA), to evaluate whether or not the property of ISA will confer protection from the usual toxic effects observed with verapamil and a beta-adrenoceptor blocking agent. In an anesthetized dog model, dosing regimens which produced stable plasma concentrations of either verapamil and/or pindolol resulted in drug effects which were closely related to the plasma levels of the individual agents. When pindolol was combined with verapamil, profound depression of cardiac pump function occurred, similar to that previously found with propranolol. Further, plasma concentrations of verapamil promptly increased into a toxic range during combined administration with pindolol. In summary, since the cardiovascular depression resulting from verapamil and pindolol in combination is similar to that which occurs with verapamil and propranolol, ISA does not appear to obviate the toxic effects of verapamil and a beta-adrenoceptor agent in combination.

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Effect of Tiapamil and Nifedepine During Critical Coronary Stenosis and in the Presence of Adrenergic β-Receptor Blockade in Anesthetized Dogs

Cited by 15 publications

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Tiapamil

Tiapamil

Haemodynamic Effects of Tiapamil and Verapamil in Conscious Rats following Chronic Myocardial Infarction

Hemodynamic and Pharmacokinetic Aspects of the Interactions between Verapamil and Pindolol

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