Drugs

, Volume 33, Issue 2, pp 123–155 | Cite as

Nitrendipine

A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Efficacy in the Treatment of Hypertension
  • Karen L. Goa
  • Eugene M. Sorkin
Drug Evaluation

Summary

Synopsis

Nitrendipine1is a calcium entry blocker shown to inhibit the movement of calcium through the ‘slow channel’ of cardiac and vascular smooth muscle, thus inducing peripheral vasodilation with consequent reductions in elevated blood pressure.

As evidenced by clinical trials, nitrendipine promptly lowers blood pressure in patients with mild to moderate hypertension, and sustains this effect during long term administration. Combining nitrendipine with other antihypertensive agents such as diuretics or β-blockers often results in successful treatment in patients unresponsive to nitrendipine monotherapy. Headache, oedema, flushing and palpitations commonly occurring during treatment with nitrendipine are generally mild, usually subsiding with continued therapy. Thus, although additional long term studies are required to properly assess the relative merits of the drug compared with other antihypertensives, by providing the clinician with an effective and safe alternative to traditional therapies, nitrendipine represents a step forward in the treatment of mild to moderate hypertension.

Pharmacodynamic Properties

As occurs with other calcium entry blockers, nitrendipine inhibits the ‘slow’ channel inward current of calcium into cardiac and vascular tissue. Furthermore, nitrendipine has been shown to possess a high degree of selectivity for vascular smooth muscle; hence, its main effect is to decrease peripheral vascular resistance with subsequent reduction of blood pressure. In vitro investigations in animal coronary artery and aorta demonstrate that nitrendipine blocks contractions induced by potassium, barium and calcium chloride, and the calcium agonist Bay K 8644 to a similar extent as nicardipine, nisoldipine and nimodipine, and more strongly than nifedipine, verapamil and diltiazem. However, unlike the latter 3 drugs, nitrendipine does not alter conduction through the sinus or atrioventricular nodes.

In patients with mild to moderate hypertension, a single 20mg oral dose of nitrendipine has been shown to lower systolic and diastolic pressure by about 15 to 20% within 1 to 2 hours after administration. During longer term administration of nitrendipine, usually 20 to 40 mg/day, this effect is sustained. The effects of nitrendipine on resting blood pressure appear to be greater than its effects on blood pressures elevated during submaximal exercise. Although most pharmacodynamic studies have employed nitrendipine in twice daily dosage regimens, once daily dosing has also been shown to effectively maintain reductions in blood pressure.

Elderly patients and those with low baseline plasma renin activities tend to respond better to nitrendipine than their younger counterparts and those with high plasma renin activities. However, a close correlation between high pretreatment blood pressure and the degree of response to the drug has not been convincingly demonstrated. In normotensive subjects blood pressure remains the same or may decrease after nitrendipine. Conversely, nitrendipine initially increases heart rate in both normotensive and hypertensive subjects, but this effect diminishes with continued treatment.

Although nitrendipine produces significant reductions in systemic vascular resistance, alterations in cardiac output and decreases in left ventricular filling pressure have not been consistently observed. Furthermore, while cardiac output and left ventricular ejection time have increased in some short term studies, these effects are probably not significant in the long term. Some hypertensive patients have experienced diminution in left ventricular hypertrophy during nitrendipine therapy, but no correlation has been demonstrated between these reductions and decreases in blood pressure in humans as yet. In a single study, nitrendipine reduced cardiac workload during exercise and prolonged time to onset of angina pectoris.

Studies in hypertensive patients investigating the effects of nitrendipine on the peripheral vascular circulation have shown that the drug produces a significant dilatation of small and large arteries resulting in decreases of total peripheral vascular resistance of about 20%.

The renal effects of nitrendipine have not been fully elucidated, but it has been observed that the drug does not produce consistent changes in animal renal perfusion or in renal blood flow, renovascular resistance or glomerular filtration rate in humans. Diuresis seen following acute doses of nitrendipine has not persisted with long term use. Significant potassium loss is unlikely with nitrendipine, but urinary excretion of aldosterone was shown to increase during a 6-month study. Furthermore, most evidence indicates that the drug initially increases plasma renin activity, but this effect may diminish with prolonged treatment.

In animal models, nitrendipine dilates cerebral blood vessels as do some other dihydropyridine derivatives, and reduces pulmonary artery vasoconstriction with subsequent decreases in pulmonary artery pressure. A single study in patients with pulmonary hypertension demonstrated similar effects. Further studies of the effect of nitrendipine in pulmonary hypertension are needed.

In addition to its relaxant effects on vascular smooth muscle, nitrendipine inhibits tracheobronchial and uterine contractions in animal models in vitro; however, the clinical implications of these findings are uncertain. No changes have occurred in fasting blood glucose or plasma lipids in patients receiving nitrendipine.

Pharmacokinetic Properties

After an oral dose of nitrendipine 20mg, peak plasma concentrations (which vary widely from 5 to 40 µg/L) are achieved within 1 to 2 hours. Proportional increases in AUC after 10, 20 and 40mg oral doses of the drug indicate that nitrendipine kinetics are linear within this dosage range; furthermore, nitrendipine does not accumulate after multiple dosing.

Nitrendipine is about 98% bound to plasma proteins; its 4 more polar inactive metabolites are bound less extensively (70 to 80%). The volume of distribution of the drug is 2 to 6 L/kg at steady-state.

Nitrendipine undergoes extensive hepatic biotransformation. Less than 0.1% of an oral dose appears as unchanged drug in the urine, while about 80% of a dose is recoverable during the first 96 hours as inactive polar metabolites.

The half-life of nitrendipine, while variable, is about 12 to 24 hours as measured by recently developed sensitive assays. Since the drug is effective as a once daily dosage regimen, it has been suggested that release from deep tissue compartments prolongs its activity. As might be expected with such an extensively metabolised compound, hepatic but not renal disease prolongs the elimination half-life and increases its bioavailability, possibly because of decreases in the ‘first-pass’ effect. Consequently, dosage modifications may be required in patients with hepatic disease. Elderly subjects in apparent good health have also demonstrated increased plasma concentrations of nitrendipine.

Therapeutic Trials

Open trials of 1 to 12 months’ duration have shown that nitrendipine (usually 10 to 40mg daily) reduces systolic and diastolic pressures to within normal limits in 45 to 86% of patients with mild to moderate hypertension. These response rates can be further increased by the addition of a β-blocker or a diuretic. Results from a few comparative trials indicate that nitrendipine enables significantly more patients to achieve goal blood pressures than does placebo, and is as effective as hydralazine, hydrochlorothiazide, β-blockers (atenolol, oxprenolol, acebutolol and propranolol) and nifedipine.

In addition, when nitrendipine is combined with β-blockers, a diuretic or captopril, target antihypertensive response is often attained in patients previously unresponsive to nitrendipine monotherapy. While recent evidence indicates that the antihypertensive effect of nitrendipine persists during prolonged treatment, further long term studies are needed to adequately assess the potential, if any, for development of tolerance to the drug.

Side Effects

The most commonly reported side effects of nitrendipine — headache, flushing, oedema and palpitations — arise from the vasodilating properties of the drug. Despite their relatively frequent occurrence, these adverse reactions are generally mild and usually disappear with continued treatment, and necessitate withdrawal from therapy in only about 5% of patients. However, some patients may require supplementary analgesics, diuretics or a β-blocker if initial headache, oedema or tachycardia persists.

Drug Interactions

Plasma concentrations of digoxin have either increased or remained unchanged during concomitant administration of nitrendipine; hence, whether downward adjustment of the digoxin dose may be required is uncertain. Plasma concentrations of nitrendipine have not been affected by the simultaneous administration of ranitidine, cimetidine, digoxin or digitoxin.

Dosage and Administration

Therapy with nitrendipine should be initiated at a dose of 10mg given once daily, and the dose titrated to individual patient responses over several weeks to a maximum of 40 mg/day in 1 or 2 doses. Elderly patients may respond to lower daily doses (5 to 10mg/day). Dosage adjustments may be necessary in the presence of hepatic but not renal insufficiency.

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References

  1. Aboul-Khair M, Wicker P, Tarazi RC. Differences between the effects of hydralazine and a calcium antagonist (Bay e 5009) on cerebral, renal and coronary blood flow. Clinical Research 29: 704A, 1981Google Scholar
  2. Altura BM, Altura BT, Gebrewold A. Selective cerebral vasodilator actions of new dihydropyridine derivatives: novel calcium antagonists. Stroke 15: 186, 1984Google Scholar
  3. Anderson CL, Scriabine A, Janis RA. Effects of a Ca2+ channel agonist (Bay K 8644) and antagonists (nitrendipine, nisoldipine, verapamil and diltiazem) on Ca2+ uptake by rabbit aortic rings. Federation Proceedings 43: 1550, 1984Google Scholar
  4. Anderson CL, Scriabine A, Maurer SC, Janis RA. Effect of nitrendipine on rat uterine smooth muscle: inhibition of contraction and ligand binding studies. Federation Proceedings 42: 367, 1983Google Scholar
  5. Andrén L, Hannson L, Orö L, Ryman T. Experience with nitrendipine — a new calcium antagonist — in hypertension. Journal of Cardiovascular Pharmacology 4(Suppl. 3): S387–S391, 1982PubMedGoogle Scholar
  6. Aoki K, Kawaguchi Y, Sato K, Kondo S, Yamamoto M. Clinical and pharmacological properties of calcium antagonists in essential hypertension in humans and spontaneously hypertensive rats. Journal of Cardiovascular Pharmacology 4(Suppl. 3): S298–S302, 1982PubMedGoogle Scholar
  7. Armstrong JM, Lefournier C. Calcium entry blocking agents: comparative potency using rat aorta and taenia caecum preparation in vitro. British Journal of Pharmacology 84 (Suppl.): 173P, 1985Google Scholar
  8. Aronoff GR. Pharmacokinetics of nitrendipine in patients with renal failure: comparison to normal subjects. Journal of Cardiovascular Pharmacology 6(Suppl. 7): S974–S976, 1984PubMedGoogle Scholar
  9. Aronoff GR, Sloan RS. Nitrendipine kinetics in normal and impaired renal function. Clinical Pharmacology and Therapeutics 38: 212–218, 1985PubMedGoogle Scholar
  10. Aronoff GR, Sloan RS, Pottratz ST, Luft FC. Elimination half-life of nitrendipine in patients with renal insufficiency. Clinical Pharmacology and Therapeutics 35: 226, 1984Google Scholar
  11. Barnes PJ. Calcium-channel blockers and asthma. Thorax 38: 481–485, 1983PubMedGoogle Scholar
  12. Batra S. Characterisation of [3H]-nitrendipine binding to uterine smooth muscle plasma membrane and its relevance to the inhibition of calcium entry. British Journal of Pharmacology 85: 767–774, 1985PubMedGoogle Scholar
  13. Bean BP, Sturek M, Puga A, Hermsmeyer K. Calcium channels in muscle cells isolated from rat mesenteric arteries: modulation by dihydropyridine drugs. Circulation Research, in press, 1986Google Scholar
  14. Black HR, Vlachakis N. Once and twice daily nitrendipine therapy in essential hypertension. In Scriabine et al. (Eds) Nitrendipine, pp. 509–518, Urban and Schwarzenberg, Baltimore, 1984Google Scholar
  15. Bolger GT, Gengo P, Klockowski E, Luchowski E, Siegel H, et al. Characterization of binding of the Ca++ channel antagonist, [3H] nitrendipine, to guinea-pig ileal smooth muscle. Journal of Pharmacology and Experimental Therapeutics 225: 291–309, 1983PubMedGoogle Scholar
  16. Brouwer RM, Bolli P, Erné P, Conen D, Kiowski W, et al. Antihypertensive treatment using calcium antagonists in combination with captopril rather than diuretics. Journal of Cardiovascular Pharmacology 7(Suppl. 1): S88–S91, 1985PubMedGoogle Scholar
  17. Brügmann U, Blasini R, Reiniger G, Rudolph W. Antihypertensive und antiischämische Wirkung von Nitrendipin. Herz 10: 53–57, 1985PubMedGoogle Scholar
  18. Bühler FR. Calcium antagonists, new partners for betablockers for treatment of high blood pressure UPHAR 9th International Congress of Pharmacology, London 1984. Abstract no. S15-5.Google Scholar
  19. Burka JF. Effects of calcium channel blockers and a calmodulin antagonist on contractions of guinea pig airways. European Journal of Pharmacology 99: 257–268, 1984PubMedGoogle Scholar
  20. Burris JF, Notargiacomo AV, Papademetriou V, Freis ED. Acute and short-term effects of a new calcium antagonist in hypertension. Hypertension 4(Suppl. 2): II–32–II–35, 1982Google Scholar
  21. Chaffman M, Brogden RN. Diltiazem: a review of its pharmacological properties and therapeutic efficacy. Drugs 29: 387–454, 1985PubMedGoogle Scholar
  22. Chatelain P, Demol D, Roba J. Comparison of [3H] nitrendipine binding to heart membranes of normotensive and spontaneously hypertensive rats. Journal of Cardiovascular Pharmacology 6: 220–223, 1984PubMedGoogle Scholar
  23. Cheng JB, Bewtra A, Townley RG. Identification of calcium antagonist receptor binding sites using (3H) nitrendipine in bovine tracheal smooth muscle membranes. Experientia 40: 267–269, 1984PubMedGoogle Scholar
  24. Christensen RL, McDonald JM. Inhibition of glucose transport in adipocytes by organic calcium channel antagonists. Federation Proceedings 44: 1429, 1985Google Scholar
  25. Cohen CJ, Janis RA, Taylor DG, Scriabine A. Where do calcium antagonists act? In Opie LH (Ed.) Calcium antagonists and cardiovascular disease, pp. 151–163, Raven Press, 1984Google Scholar
  26. Cornett LE, Ball DW, Norris JS. Calcium channel blockers do not interact with α1adrenergic receptors of a smooth muscle cell line. Federation Proceedings 42: 383, 1983Google Scholar
  27. Cosmi F, Mollaioli M, Aimi M, Conti G, Corbacelli C, et al. La nitrendipina, un nuovo calcio-antagonista, nella terapia dell’ipertensione arteriosa. Progressi in Terapia 76: 1983–1990, 1985Google Scholar
  28. Crook JE, Mroczkowski PJ. Increased red cell Na-K ATPase activity following exposure to a new calcium entry blocker — nitrendipine. International symposium on calcium entry blockers and tissue protection, Rome, Mar 15–16, 1984. Abstract no. H6, p. 121, 1984Google Scholar
  29. Debbas NM, Jackson SH, Turner P. A comparison of the haemodynamic effects of nifedipine, nisoldipine and nitrendipine in man. British Journal of Clinical Pharmacology 18: 295P, 1984Google Scholar
  30. Debbas NM, Jackson SH, Turner P. A comparison of the haemodynamic effects of nifedipine, nisoldipine and nitrendipine in man. European Journal of Clinical Pharmacology 30: 393–397, 1986PubMedGoogle Scholar
  31. de Divitiis O, Petitto M, DiSomma S, Galderisi M, Villari B, et al. Nitrendipine and atenolol: comparison and combination in the treatment of arterial hypertension. Arzneimittel-Forschung 35: 727–729, 1985PubMedGoogle Scholar
  32. Drayer JI, Gardin JM, Weber MA, Brewer DD. Cardiac muscle mass reduction during calcium channel blocker therapy: importance of age. Clinical Pharmacology and Therapeutics 35: 236, 1984Google Scholar
  33. Dube GP, Baik YR, Vaghy PL, Schwartz A. Nitrendipine potentiales Bay K 8644 — induced contraction of isolated porcine coronary artery: evidence for functionally distinct dihydropyridine receptor subtypes. Biochemical and Biophysical Research Communications 128: 1295–1302, 1985PubMedGoogle Scholar
  34. Duncan PG, Douglas JS. Sensitivity and responsiveness of tracheal and bronchial tissues from young and old guinea pigs: effect of calcium antagonists. Journal of Pharmacology and Experimental Therapeutics 228: 612–619, 1984PubMedGoogle Scholar
  35. Dunn FG, Ventura HO, Sesoko S, Oigman W, Messerli FH, et al. Acute systemic and regional hemodynamic effects of nitrendipine. Studies in patients with essential hypertension and in the spontaneously hypertensive rat. In Scriabine et al. (eds). Nitrendipine, pp. 451–462, Urban and Schwarzenberg, Baltimore, 1984Google Scholar
  36. Ehlert FJ, Itoga E, Roeske WR, Yamamura HI. The interaction of [3H] nitrendipine with receptors for calcium antagonists in the cerebral cortex and heart of rats. Biochemical and Biophysical Research Communications 104: 937–943, 1982PubMedGoogle Scholar
  37. Ene MD, Williamson PJ, Roberts CJ, Waddell G. The natriuresis following oral administration of the calcium antagonists — nifedipine and nitrendipine. British Journal of Clinical Pharmacology 19: 423–427, 1985PubMedGoogle Scholar
  38. Erne P, Kiowski W, Bolli P, Bürgisser E, Bühler FR. Reduction of elevated intracellular free calcium in platelets and blood pressure in essential hypertension by chronic treatment with calcium antagonists. Journal of Hypertension 2: 102–103, 1984Google Scholar
  39. Escourrou PJ, Teisseive BP, Hérigault RA, Valiez MO, Dupeyrat AJ. Effects of nitrendipine on pulmonary vasoconstriction and gas exchange during hypoxia in piglets. American Review of Respiratory Disease 129(Suppl. 2): A343, 1984Google Scholar
  40. Esper RJ, Esper RC, Cassola D, Spiritoso RA, Mosca H, et al. Effectiveness of nitrendipine in the treatment of essential hypertension: a multi-center trial. In Scriabine et al. (Eds) Nitrendipine, pp. 477–489, Urban and Schwarzenberg, Baltimore, 1984aGoogle Scholar
  41. Esper RJ, Esper RC, Baglivotl P, Castro JM, Rohwedder RW, et al. Long-term effectiveness of Bay e 5009 — Nitrendipine in the treatment of mild and moderate arterial hypertension. Journal of Cardiovascular Pharmacology 6(Suppl. 7): S1096–S1099, 1984bPubMedGoogle Scholar
  42. Fagan TC, Sternleib C, Vlachakis N, Deedwania PC, Mehta JL. Efficacy and safety comparison of nitrendipine and hydralazine as antihypertensive monotherapy. Journal of Cardiovascular Pharmacology 6(Suppl. 7): S1109–S1113, 1984PubMedGoogle Scholar
  43. Fagan TC, Nelson EB, Lasseter KC, Crook J, Marledge J, et al. Once- and twice-daily nitrendipine in patients with hypertension and noninsulin-dependent diabetes. Pharmacotherapy 6: 128–136, 1986PubMedGoogle Scholar
  44. Fanta CH, Drazen JM. Calcium blockers and bronchoconstriction. American Review of Respiratory Disease 127: 673–674, 1983PubMedGoogle Scholar
  45. Ferrara LA, Soro S, Fasano ML. Effects of nitrendipine on glucose and lipid serum concentrations. Current Therapeutic Research 37: 614–618, 1985aGoogle Scholar
  46. Ferrara LA, Fasano ML, de Simone G, Soro S, Gagliardi R. Antihypertensive and cardiovascular effects of nitrendipine: a controlled study vs placebo. Clinical Pharmacology and Therapeutics 38: 434–438, 1985bPubMedGoogle Scholar
  47. Heckenstein A, Tritthart H, Döring HJ, Byon KY. Bay a 1040-ein hockaktiver Ca++ — antagonistscher Inhibitor der elektromechanischen Koppelungsprozesse im Warmblütermyokard. Arzneimittel-Forschung 22: 22–23, 1972Google Scholar
  48. Fouad FM, Pedrinelli R, Abi-Samra F, Textor SC, Bravo EL, et al. Systemic and renal hemodynamics during treatment with nitrendipine (N) a new calcium entry blocker (CEB). Circulation 66: 11–107, 1982Google Scholar
  49. Fouad FM, Pedrinelli R, Bravo EL, Abi-Samra F, Textor SC, et al. Clinical and systemic hemodynamic effects of nitrendipine. Clinical Pharmacology and Therapeutics 35: 768–775, 1984PubMedGoogle Scholar
  50. Franz I-W, Wiewel D. Antihypertensive effects on blood pressure at rest and during exercise of calcium antagonists, β-receptor blockers, and their combination in hypertensive patients. Journal of Cardiovascular Pharmacology 6(Suppl. 7): S1037–S1042, 1984PubMedGoogle Scholar
  51. Fritschka E, Distler A, Gotzen R, Thiede H-M, Philipp T. Crossover comparison of nitrendipine with propranolol in patients with essential hypertension. Journal of Cardiovascular Pharmacology 6(Suppl. 7): S110–S1104, 1984Google Scholar
  52. Frohlich ED. Hemodynamic effects of calcium entry-blocking agents in normal and hypertensive rats and man. American Journal of Cardiology 56: 21H–27H, 1985PubMedGoogle Scholar
  53. Fronek K. Effect of nitrendipine on endothelial relaxing factor (EDRF). Federation Proceedings 44: 808, 1985Google Scholar
  54. Garthoff B, Kazda S, Knorr A, Thomas G. Factors involved in the antihypertensive action of calcium antagonists. Hypertension 5(Suppl II): II34–II38, 1983PubMedGoogle Scholar
  55. Garthoff B, Knorr A, Thomas G, Kazda S. Nitrendipine increases sodium excretion in acutely saline-loaded rats. Biochemical Pharmacology 31: 3015–3016, 1982PubMedGoogle Scholar
  56. Glossman H, Ferry DR, Lubbecke F, Mewes K, Hofmann F. Calcium channels: direct identification with radioligand binding studies. Trends in Pharmacological Sciences 3: 431–437, 1982Google Scholar
  57. Glossman H, Ferry DR, Goll A, Striessnig J, Zernig G. Calcium channels and calcium channel drugs: recent biochemical and biophysical findings. Arzneimittel-Forschung/Drug Research 35: 1917–1935, 1985Google Scholar
  58. Golichowski AM, Tzeng DY. Binding of the calcium antagonist [3H] nitrendipine to human myometrial plasmalemma. Biology of Reproduction 33: 1102–1112, 1985Google Scholar
  59. Grover AK, Kwan C-Y, Luchowski E, Daniel EE, Triggle DJ. Subcellular distribution of [3H] nitrendipine binding in smooth muscle. Journal of Biological Chemistry 259: 2223–2226, 1984PubMedGoogle Scholar
  60. Grover AK, Oakes P. Nitrendipine binding and pharmacology in rat myometrium. Federation Proceedings 44: 1641, 1985Google Scholar
  61. Häberle DA, Kawata T, Davis JM. The site of action of nitrendipine in the rat kidney. Presented at the International Workshop on the Renal Effects of Dihydropyridine Type Calcium Antagonists, Cascais, Jun 27, 1986Google Scholar
  62. Hall CE, Hungerford S. Control of spontaneous and DOC-salt hypertension and polyuria by nitrendipine pellets. Canadian Journal of Physiology and Pharmacolgy 62: 436–440, 1984Google Scholar
  63. Hamann SR, Blouin RA, McAllister Jr RG. Clinical pharmacokinetics of verapamil. Clinical Pharmacokinetics 9: 26–41, 1984PubMedGoogle Scholar
  64. Hansson L, Andrén L, Orö L, Ryman T. The antihypertensive effects of nitrendipine in patients with essential hypertension. In Scriabine et al. (Eds) Nitrendipine, pp. 423–433, Urban and Schwarzenberg, Baltimore, 1984Google Scholar
  65. Herbette L, Colvin R, Ashavaid T, Katz AM, LaCroce L, et al. Ultrastructure and drug-receptor binding of purified cardiac sarcolemmal membranes. Circulation 66(Suppl. 2): II–72, 1982Google Scholar
  66. Hermsmeyer K, Kuthe C. Calcium antagonists and excitation of vascular muscle membrane. Journal of Cardiovascular Pharmacology 6(Suppl. 7): S933–S936, 1984PubMedGoogle Scholar
  67. Hottenstein OD, Mitzner WA, Sylvester JT. Calcium dependence of isometric contractile forces during acute hypoxia in isolated rat main pulmonary arteries. Federation Proceedings 43: 923, 1984Google Scholar
  68. Ishii K, Kano T, Ando J, Yoshida H. Binding of [3H] nitrendipine to cardiac and cerebral membranes from normotensive and renal, deoxycorticosterone/NaCl and spontaneously hypertensive rats. European Journal of Pharmacology 123: 271–278, 1986PubMedGoogle Scholar
  69. Jain AK, McMahon FG, Ryan JR, Maronde R, Vlachakis N, et al. Efficacy and safety of nitrendipine in patients with severe hypertension: a multiclinic study. Journal of Cardiovascular Pharmacology 6(Suppl. 7): S1053–S1059, 1984PubMedGoogle Scholar
  70. Janis RA, Sarmiento JG, Maurer SC, Bolger GT, Toggle DJ. Characteristics of the binding of [3H] nitrendipine to rabbit ventricular membranes: modification by other Ca++ channel antagonists and by the Ca++ channel agonist Bay K 8644. Journal of Pharmacology and Experimental Therapeutics 231: 8–15, 1984PubMedGoogle Scholar
  71. Janis RA, Scriabine A. Sites of action of Ca2+ channel inhibitors. Biochemical Pharmacology 32: 3499–3507, 1983PubMedGoogle Scholar
  72. Janis RA, Triggle DJ. 1,4-dihydropyridine Ca2+ channel agonists and activators: a comparison of binding characteristics with pharmacology. Drug Development Research 4: 257–274, 1984Google Scholar
  73. Johns EJ, Manitius J. The renal actions of nitrendipine and its influence on the neural regulation of calcium and sodium reabsorption in the rat. Presented at the International Workshop on the Renal Effects of Dihydropyridine Type Calcium Antagonists, Cascais, Jun 27, 1986Google Scholar
  74. Johnson BF, Romero L, Marwaha R. Hemodynamic and metabolic effects of the calcium channel blocking agent nitrendipine. Clinical Pharmacology and Therapeutics 39: 389–394, 1986PubMedGoogle Scholar
  75. Jones CA, Brown JK. Differential effects of nifedipine and verapamil on 1,4-dihydropyridine binding sites in airway smooth muscle. American Review of Respiratory Diseases 129: A233, 1984Google Scholar
  76. Kann J, Krol GJ, Raemsch KD, Burkholder DE, Levitt MJ. Bioequivalence and metabolism of nitrendipine administered orally to healthy volunteers. Journal of Cardiovascular Pharmacology 6(Suppl. 7): S969–S972, 1984Google Scholar
  77. Katz AM, Hager WD, Messineo FC, Pappano J. Cellular actions and pharmacology of the calcium channel blocking drugs. American Journal of Medicine 77: 2–10, 1984PubMedGoogle Scholar
  78. Kiowski W, Bühler FR, Fadayomi MO, Erne P, Müller FB, et al. Age, race, blood pressure and renin: predictors for antihypertensive treatment with calcium antagonists. American Journal of Cardiology 56: 81H–85H, 1985PubMedGoogle Scholar
  79. Kirch W, Hutt HJ, Heidemann H, Rämsch K, Janisch HD, et al. Drug interactions with nitrendipine. Journal of Cardiovascular Pharmacology 6(Suppl. 7): S982–S985, 1984PubMedGoogle Scholar
  80. Kirch W, Dylewicz P, Hutt HJ, Ohnhaus EE. Pharmacokinetics of nitrendipine in liver disease. Abstracts from the 14th Annual Meeting of the American College of Clinical Pharmacology. Journal of Clinical Pharmacology 25: 467, 1985Google Scholar
  81. Kirch W, Logemann C, Santos SR, Ohnhaus E. Nitrendipine increases digoxin plasma levels dose dependently. Journal of Clinical Pharmacology 26: 553, 1986Google Scholar
  82. Kito S, Itoga E, Yamamura HI. Calcium antagonist binding sites in the rat central nervous system. Japanese Journal of Medicine 22: 349, 1983Google Scholar
  83. Knight DR, Kirby DA, Vatner SF. Effects of a calcium channel blocker on cardiac output distribution in conscious hypertensive dogs. Hypertension 7: 380–385, 1985PubMedGoogle Scholar
  84. Krol GJ, Lettieri JT, Yeh SC, Burkholder DE, Birkett JP. Disposition and pharmacokinetics of 14C-nitrendipine in healthy volunteers. Presented at the Second International Nitrendipine Symposium, Lisbon, Apr 17–19, 1986aGoogle Scholar
  85. Krol GJ, Lettieri JT, Mazzu AL, Burkholde DE, Birkett JP, et al. Bioequivalence of Bayer and Miles nitrendipine dosage formulations. Presented at the Second International Nitrendipine Symposium, Lisbon, Apr 17–19, 1986bGoogle Scholar
  86. Lasseter KC, Shamblen EC, Murdoch AA, Burkholder DE, Krol GJ, et al. Steady-state pharmacokinetics of nitrendipine in hepatic insufficiency. Journal of Cardiovascular Pharmacology 6(Suppl. 7): S977–S981, 1984PubMedGoogle Scholar
  87. Lathrop DA, Di Salvo J, Dubé G, Schwartz A. Electromechanical effects of calcium channel inhibitors in isolated canine Purkinje strands and potassium contracted coronary vascular smooth muscle. In Scriabine et al. (Eds) Nitrendipine, pp. 185–197, Urban and Schwarzenberg, Baltimore, 1984Google Scholar
  88. Lee SM, Michael UF. The protective effect of nitrendipine on gentamicin acute renal failure in rats. Experimental and Molecular Pathology 43: 107–114, 1985PubMedGoogle Scholar
  89. Lee SM, Pattison ME, Michael VF. Nitrendipine protects against aminoglycoside nephrotoxicity in the rat. Presented at the International Workshop on the Renal Effects of Dihydropyridine Type Calcium Antagonists, Cascais, Jun 27, 1986Google Scholar
  90. Lehmann H-U, Hochrein H, Witt E, Mies H-W. Hemodynamic responses of nitrendipine in hypertensive patients. In Scriabine et al. (Eds) Nitrendipine, pp. 491–500, Urban and Schwarzenberg, Baltimore, 1984Google Scholar
  91. Lettieri J, Krol G, Yeh S, Ryan J, Jain A, et al. Pharmacokinetics of intrendipine in elderly and young healthy volunteers. Presented at the Second International Nitrendipine Symposium, Lisbon, Apr 17–19, 1986Google Scholar
  92. Levenson J, Simon AC, Safar ME, Bouthier J, Maarek BC. Large arteries in hypertension: acute effects of a new calcium entry blocker, nitrendipine. Journal of Cardiovascular Pharmacology 6(Suppl. 7): S1006–S1010, 1984PubMedGoogle Scholar
  93. Lopez LM, Mehta JL. Effects of hydralazine and nitrendipine on plasma lipids in hypertensive patients. Drug Intelligence and Clinical Pharmacy 18: 492–493, 1984Google Scholar
  94. Luft FC, Aronoff GR, Sloan RS, Fineberg NS, Weinberger MH. Calcium channel blockade with nitrendipine: effects on sodium homeostasis, the renin-angiotensin system, and the sympathetic nervous system in humans. Hypertension 7: 438–442, 1985PubMedGoogle Scholar
  95. Maltz MB, Davies DW, Lau CP, Creamer JE, Banim SO, et al. The effects of oral nitrendipine and propranolol, alone and in combination, on hypertensive patients with special reference to AV conduction. British Journal of Clinical Pharmacology 22: 463–467, 1986PubMedGoogle Scholar
  96. Marangos PJ, Patel J, Miller C, Martino AM. Specific calcium antagonist binding sites in brain. Life Sciences 31: 1575–1585, 1982PubMedGoogle Scholar
  97. Marsh JD, Loh E, Lachance D, Barry WH, Smith TW. Relationship of binding of a calcium channel blocker to inhibition of contraction in intact cultured embryonic chick ventricular cells. Circulation Research 53: 539–543, 1983PubMedGoogle Scholar
  98. M’Buyamba-Kabangu JR, Lepira B, Fagard R, Lijnen P, Ditu M, et al. Relative potency of a beta-blocking and a calcium entry blocking agent as antihypertensive drugs in black patients. European Journal of Clinical Pharmacology 29: 523–527, 1986PubMedGoogle Scholar
  99. McMahon FG, Brobyn R, Kann J, Levy B, Margolis R, et al. A double-blind comparative study of nitrendipine and propranolol in the treatment of hypertension. Presented at the Second International Nitrendipine Symposium, Lisbon, Apr 17–19,1986Google Scholar
  100. Meyer H, Scherling D, Karl W. Nitrendipine: identification and synthesis of main metabolites. Arzneimittel-Forschung 33:1528–1534, 1983PubMedGoogle Scholar
  101. Michael JR, Kennedy TP, Buescher P, Farrukh I, Lodato R, et al. Nitrendipine attenuates the pulmonary vascular remodelling and right ventricular hypoxia caused by intermittent hypoxia in rats. American Review of Respiratory Disease 133: 375–379, 1986PubMedGoogle Scholar
  102. Mikus G, Stauber M, Langen C, Zekorn C, Eichelbaum M. Pharmacokinetics, bioavailability, metabolism and hemodynamic effects of the calcium channel antagonist nitrendipine. Presented at the Second International Nitrendipine Symposium, Lisbon, Apr 17–19, 1986Google Scholar
  103. Miller WC, Moore Jr JB. High affinity binding sites for [3H]-nitrendipine in rabbit uterine smooth muscle. Life Sciences 34: 1717–1724, 1984PubMedGoogle Scholar
  104. Mioli V, Pacchiarotti P, Ragaiolo M, Bruni F, Nazzari M, et al. Short term evaluation of nitrendipine in essential and renal hypertension. Acta Therapeutica 12: 279–291, 1986Google Scholar
  105. Mols P, Naeije R, Hallemans R, Mélot C, Lejeune P, et al. Central and regional hemodynamic effects of nitrendipine in normotensive patients with chronic obstructive lung disease. Journal of Cardiovascular Pharmacology 8: 77–81, 1986PubMedGoogle Scholar
  106. Morledge J, Brown RD, Byyny R, Conradi E, Giles TD, et al. Comparative study of the effects of nitrendipine and hydrochlorothiazide in hypertensive patients. Presented at the Second International Nitrendipine Symposium, Lisbon, Apr 17–19, 1986Google Scholar
  107. Moser M, Lunn J, Nash DT, Burris JF, Winer N, et al. Nitrendipine in the treatment of mild to moderate hypertension. Journal of Cardiovascular Pharmacology 6(Suppl. 7): S1085–S1089, 1984PubMedGoogle Scholar
  108. Mroczek WJ, Burris JF, Yoder S. Effect of nitrendipine in severe hypertension. 10th Scientific Meeting of the International Society of Hypertension, Interlaken, Jun 17–21, 1984Google Scholar
  109. Müller FB, Bolli P, Erne P, Kiowski W, Bühler FR. Use of calcium antagonists as monotherapy in the management of hypertension. American Journal of Medicine 77: 11–15, 1984PubMedGoogle Scholar
  110. Muramatsu M, Fujita A, Tanaka M, Aihara H. Effect of neuraminidase on diltiazem-mediated alteration of nitrendipine binding in the hog coronary artery. Japanese Journal of Pharmacology 39: 217–223, 1985PubMedGoogle Scholar
  111. Nandiwada PA, Kadowitz PJ, Hyman AL. Vasodilator actions of two new calcium antagonists in the pulmonary vascular bed. Federation Proceedings 40: 590, 1981Google Scholar
  112. Nannan ME, Melin JA, Vanbutsele RJ, Lavenne F, Detry J-M. Acute and long-term effects of nitrendipine on resting and exercise hemodynamics in essential hypertension. Journal of Cardiovascular Pharmacology 6(Suppl 7): S1043–S1048, 1984PubMedGoogle Scholar
  113. Nayler WG. Calcium antagonists. Medical Journal of Australia 2: 506–512, 1983aPubMedGoogle Scholar
  114. Nayler WG. The heterogeneity of the slow channel blockers (calcium antagonists). International Journal of Cardiology 3: 391–400, 1983bPubMedGoogle Scholar
  115. Nayler WG, Horowitz JD. Calcium antagonists: a new class of drugs. Pharmacology and Therapeutics 20: 203–262, 1983PubMedGoogle Scholar
  116. Nickerson PA. A low dose of a calcium antagonist (nitrendipine) ameliorates cardiac and renal lesions induced by DOC in the rat. Experimental and Molecular Pathology 41: 309–320, 1984PubMedGoogle Scholar
  117. Olivari MT, Levine TB, Cohn JN. Acute hemodynamic effects of nitrendipine in chronic congestive heart failure. Journal of Cardiovascular Pharmacology 6(Suppl. 7): S1002–S1005, 1984PubMedGoogle Scholar
  118. Orö L, Ryman T. A long-term study of the combined antihypertensive action of nitrendipine and metoprolol. In Scriabine et al. (Eds) Nitrendipine, pp. 527–532, Urban and Schwarzenberg, Baltimore, 1984Google Scholar
  119. Pan M, Janis RA. Effect of calcium antagonists on Na+, K+-AT-Pase of smooth muscle. Biochemical Pharmacology 33: 787–791, 1984PubMedGoogle Scholar
  120. Pedrinelli R, Tarazi RC. Interference of calcium entry in vivo with pressor responses to α-adrenergic stimulation: effects of two unrelated blockers on responses to both exogenous and endogenously released norepinephrine. Circulation 69: 1171–1176, 1984PubMedGoogle Scholar
  121. Pedrinelli R, Tarazi RC. Calcium entry blockade by nitrendipine and alpha adrenergic responsiveness in vivo: comparison of systemic vs local effects. Journal of Pharmacology and Experimental Therapeutics 233: 643–649, 1985aPubMedGoogle Scholar
  122. Pedrinelli R, Tarazi RC. Calcium entry blockade by nitrendipine and alpha adrenergic responsiveness in vivo: comparison with noncalcium entry blocker vasodilators in absence and presence of phenoxybenzamine treatment. Journal of Pharmacology and Experimental Therapeutics 233: 636–642, 1985bPubMedGoogle Scholar
  123. Pedrinelli R, Fouad FM, Tarazi RC, Bravo EL, Textor SC. Nitrendipine, a calcium-entry blocker. Renal and humoral effects in human arterial hypertension. Archives of Internal Medicine 146: 62–65, 1986PubMedGoogle Scholar
  124. Pegram BL, Kobrin I, Sesoko S, Frohlich ED. Nitrendipine: hemodynamic effects in conscious normotensive and spontaneously hypertensive rats. Journal of Cardiovascular Pharmacology 6(Suppl. 7): S1011–1023, 1984Google Scholar
  125. Raemsch KD, Sommer J. Pharmacokinetics and metabolism of nitrendipine. In Scriabne et al. (Eds) Nitrendipine, pp. 409–420, Urban & Schwarzenberg, Baltimore, 1984Google Scholar
  126. Raemsch KD, Graefe KH, Scherling D, Sommer J, Ziegler R. Pharmacokinetics and metabolism of calcium blocking agents nifedipine, nitrendipine, and nimodipine. American Journal of Nephrology, in press, 1986Google Scholar
  127. Rogart RB, de Bruyn Kops A, Graham S, Dzau VJ. Differential effects of calcium channel blockers — possible roles of two channel subtypes shown by 3H-nitrendipine binding. Clinical Research 33: 221A, 1985Google Scholar
  128. Rose H, Philipson J, Puschett JB. Effect of nitrendipine in a rat model of ischemic acute renal failure. Presented at the International Workshop on the Renal Effects of Dihydropyridine Type Calcium Antagonists, Cascais, Jun 27, 1986Google Scholar
  129. Rosendorff C. Calcium channel blockers and hypertension. In Opie LH (Ed.) Calcium antagonists and cardiovascular disease, Raven Press, New York, 1984Google Scholar
  130. Rubin LJ, Moser K. Long-term effects of nitrendipine on hemodynamics and oxygen transport in patients with cor pulmonale. Chest 89: 141–145, 1986PubMedGoogle Scholar
  131. Rüddel H, Schmieder R, Langewitz W, Neus J, Wagner O, et al. Efficacy of nitrendipine as baseline antihypertensive therapy. Journal of Cardiovascular Pharmacology 6(Suppl. 7): S1049–S1052, 1984PubMedGoogle Scholar
  132. Rüddel H, Schmieder R, Neus J, Neus H, Otten H, et al. Biobehavioral effects of antihypertensive monotherapy: oxprenolol and nitrendipine. In Schmidt et al. (Eds). Biological Basis of Coronary Heart Disease, pp. 584–593, Springer-Verlag, Heidelberg, in press, 1986Google Scholar
  133. Rutsch W, Schmutzler H. Comparison of the acute hemodynamic effects of nifedipine with nitrendipine and a study of the electrophysiological effects of nitrendipine in man. Journal of Cardiovascular Pharmacology 6(Suppl 7): S1011–S1015, 1984PubMedGoogle Scholar
  134. Saad MH, Burka JF. Role of calcium in arachidonic acid-induced contractions of guinea pig airways. European Journal of Pharmacology 100: 13–20, 1984PubMedGoogle Scholar
  135. Sakamoto H, Huszar G. Pharmacologic levels of nitrendipine do not affect actin-myosin interaction in the human uterus and placenta. American Journal of Obstetrics and Gynecology 154: 402–407, 1986PubMedGoogle Scholar
  136. Saris SD, Porter RS, Lowenthal MD, Likoff CV. Effect of chronic vs acute dosing of nitrendipine in chronic liver disease. Clinical Pharmacology and Therapeutics 39: 226, 1986Google Scholar
  137. Schoenberger JA, Glasser SP, Ram CV, McMahon SG, Vanov SK, et al. Comparison of nitrendipine combined with low-dose hydrochlorothiazide to hydrochlorothiazide alone in mild to moderate essential hypertension. Journal of Cardiovascular Pharmacology 6(Suppl. 7): S1105–S1108, 1984PubMedGoogle Scholar
  138. Simon G, Snyder DK. Altered pressor responses in long-term nitrendipine treatment. Clinical Pharmacology and Therapeutics 36: 315–319, 1984PubMedGoogle Scholar
  139. Sorkin EM, Clissold SP, Brogden RN. Nifedipine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy, in ischaemic heart disease, hypertension and related cardiovascular disorders. Drugs 30: 182–274, 1985PubMedGoogle Scholar
  140. Stahlmann VJ, Varchmin G, Blanke R, Schnitker J. Nitrendipin in der Behandlung älterer Hypertoniker. Fortschritte der Medizin 104: 500–502, 1986Google Scholar
  141. Stanbrook HS, Morris KG. Nitrendipine reduces actue and chronic hypoxic pulmonary hypertension in rats. Journal of Cardiovascular Pharmacology 9 (Suppl.), in press, 1987Google Scholar
  142. Sterzel RB, McKenzie DE. Effects of nitrendipine on the course of experimental immunologic glomemlonephritis. Presented at the International Workshop on the Renal Effects of Dihydropyridine Type Calcium Antagonists, Cascais, June 27, 1986Google Scholar
  143. Stoepel K, Deck K, Corsing C, Ingram C, Vanov SK. Safety aspects of long-term nitrendipine therapy. Journal of Cardiovascular Pharmacology 6(Suppl. 7): S1063–S1066, 1984PubMedGoogle Scholar
  144. Takeo S, Elimban V, Dhalla NS. Effect of some Ca2+-antagonists on the heart. Sarcolemmal Na+-Ca2+ exchange activity. Federation Proceedings 44: 1640, 1985Google Scholar
  145. Takeshita A, Mark AL. Decreased Vasodilator capacity of forearm resistance vessels in borderline hypertension. Hypertension 2: 610–616, 1980PubMedGoogle Scholar
  146. Tammen A-T, Stoepel K, Vollmer H, Blümchen G. Efficacy and safety of nitrendipine in patients with essential hypertension associated with coronary heart disease. In Scriabine et al. (Eds) Nitrendipine, pp. 469–476, Urban and Schwarzenberg, Baltimore, 1984Google Scholar
  147. Thananopavarn C, Sambhi MP, Golub MS, Eggena P, Barrett JD. Saluretic and diuretic effects of nitrendipine during antihypertensive monotherapy. Clinical Pharmacology and Therapeutics 35: 279, 1984aGoogle Scholar
  148. Thananopavarn C, Golub MS, Eggena P, Barrett JD, Sambhi MP. Renal effects of nitrendipine monotherapy in essential hypertension. Journal of Cardiovascular Pharmacology 6(Suppl. 7): S1032–S1036, 1984bPubMedGoogle Scholar
  149. Tourkantonis A, Lasaridis A, Settas L. Clinical experience with long-term nitrendipine treatment in essential hypertension. Journal of Cardiovascular Pharmacology 6(Suppl. 7): S1090–S1095, 1984PubMedGoogle Scholar
  150. Towart R, Stoepel K. The vascular mechanism of action of Bay e 5009, a new calcium antagonist with a potent antihypertensive action. Naunyn-Schmiedeberg’s Archives of Pharmacology 308 (Suppl.): R18, 1979Google Scholar
  151. Towart R, Wehinger E. Stereoselective effects of nitrendipine (Bay e 5009) in isolated vascular smooth muscle. International symposium on calcium modulators, p. 100, Venice, Jun 17–18, 1982Google Scholar
  152. Trost BN, Weidmann P. Effects of nitrendipine and other calcium antagonists on glucose metabolism in man. Journal of Cardiovascular Pharmacology 6(Suppl. 7): S986–S995, 1984PubMedGoogle Scholar
  153. Vanov S, Burkholder D, Pun E. Hypertension: role of race, sex and page in the response to a calcium antagonist. Abstract no. 1701P. UPHAR 9th International Congress of Pharmacology, London, 1984.Google Scholar
  154. Ventura HO, Messerli FH, Oigman W, Dunn FG, Reisin E, et al. Immediate hemodynamic effects of a new calcium-channel blocking agent (nitrendipine) in essential hypertension. American Journal of Cardiology 51: 783–786, 1983PubMedGoogle Scholar
  155. Vitacolonna E, Guagnano MT, Capani F, Sensi S. Nitrendipine treatment of mild-to-moderate hypertension. Current Therapeutic Research 39: 414–420, 1986Google Scholar
  156. Vlachakis ND, Vanov SK, Taylor Jr RJ, Pun EF. Controlled comparison of nitrendipine and placebo in the treatment of hypertension. In Scriabine et al. (Eds) Nitrendipine, pp. 443–449, Urban and Schwarzenberg, Baltimore, 1984Google Scholar
  157. Wallia R, Greenberg A, Puschett JB. Renal hemodynamic and tubular transport effects of nitrendipine. Journal of Laboratory and Clinical Medicine 105: 498–503, 1985PubMedGoogle Scholar
  158. Wauquier A. Brain hypoxia and calcium entry blockers. International symposium on calcium entry blockers and tissue protection, Rome, Mar 15–16, 1984Google Scholar
  159. Weber MA, Drayer JI. The calcium channel blocker nitrendipine in single- and multiple-agent antihypertensive regimens: preliminary report of a multicenter study. Journal of Cardiovascular Pharmacology 6(Suppl. 7): S1077–S1084, 1984PubMedGoogle Scholar
  160. Weber MA. A one-year experience with the calcium-channel blocking agent nitrendipine in patients with essential hypertension: report of a multicenter study. Presented at the Second International Nitrendipine Symposium, Lisbon, Apr 17–19, 1986Google Scholar
  161. White WB, Smith V-E, McCabe EJ, Meeran MK. Effects of chronic nitrendipine on casual (office) and 24-hour ambulatory blood pressure. Clinical Pharmacology and Therapeutics 38: 60–64, 1985PubMedGoogle Scholar
  162. Williams LT, Tremble P. Binding of a calcium antagonist, [3H] nitrendipine, to high affinity sites in bovine aortic smooth muscle and canine cardiac membranes. Journal of Clinical Investigation 70: 209–212, 1982PubMedGoogle Scholar
  163. Ziegler R, Wingender W, Schmitz H, Rämsch K-D, Kuhlmann J. Study of pharmacokinetic interaction between nitrendipine and digoxin. Presented at the Second International Nitrendipine Symposium, Lisbon, Apr 17–19, 1986Google Scholar

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© ADIS Press Limited 1987

Authors and Affiliations

  • Karen L. Goa
    • 1
  • Eugene M. Sorkin
    • 1
  1. 1.ADIS Drug Information ServicesMairangi Bay, Auckland 10New Zealand

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