Advertisement

Drugs

, Volume 40, Issue 4, pp 543–560 | Cite as

Cadralazine

A Review of its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Potential in the Treatment of Hypertension
  • Donna McTavish
  • Ronald A. Young
  • Stephen P. Clissold
Drug Evaluation

Summary

Synopsis

Cadralazine is a peripheral arteriolar vasodilator which, unlike hydralazine or dihydralazine, has a protected hydrazino group. In hypertensive patients the optimal effect, based on the antihypertensive efficacy to tolerability ratio, is seen after a 15mg dose when the drug is administered as monotherapy. When administered in combination with other antihypertensive agents, a 10mg daily dosage seems appropriate. Noncomparative trials have shown that, in patients who had failed to respond adequately to a β-blocker and/or diuretic, the addition of cadralazine 10 to 30mg once daily reduced systolic/diastolic blood pressure by 11 to 19%/13 to 22%. This antihypertensive effect becomes evident over a 2- to 6-week period of therapy and persists during longer term administration.

Comparative studies have shown that cadralazine is superior to placebo, and has a similar blood pressure lowering effect to hydralazine, dihydralazine and prazosin in patients not controlled by β-blocker and/or diuretic but who continued to receive these treatments. Similarly, cadralazine and chlorthalidone were equally effective in reducing blood pressure in resting hypertensive patients but cadralazine shows an advantage in reducing the pressor response in exercising patients.

Cadralazine is well tolerated when administered with a β-blocker or diuretic. Most adverse effects become less frequent and severe with continued use, occur more frequently at dosages of 20 mg/day or more, and do not generally require withdrawal of therapy. Manifestations of the drug’s vasodilating properties such as headache, asthenia, dizziness, palpitations and flushing are the most commonly reported symptoms during cadralazine monotherapy, but these may be reduced during combination therapy. The drug does not appear to induce a systemic lupus-like erythematosus syndrome, as may occur with hydralazine, but additional clinical experience is required to completely exclude this possibility.

In conclusion, because of its efficacy as a second- or third-line antihypertensive agent, its simple once daily dosage regimen and favourable risk: benefit ratio, cadralazine may have a useful role, particularly in those hypertensive patients who do not respond adequately to established antihypertensive treatments. However, the therapeutic potential of cadralazine cannot be clearly established until the present limited clinical base is expanded to include comparisons with other classes of vasodilating drugs (ACE inhibitors and calcium antagonists), and its utility in the management of other indications such as severe hypertension during pregnancy has been adequately explored.

Pharmacodynamic Properties

Cadralazine administered as a single oral 7.5 to 30mg dose reduces systolic and diastolic blood pressure in patients with essential hypertension by up to 20/25%, with a 15mg dose producing an optimum effect. Lowering of blood pressure is thought to be mediated via reduction of peripheral vascular resistance as a result of arterial smooth muscle relaxation; peripheral vascular resistance is reduced by 20 to 30% after a single cadralazine dose in hypertensive patients. Cadralazine produces reflex tachycardia which persists but tends to diminish during long term treatment, and it also increases cardiac output by about 16% in elderly hypertensive patients during long term therapy. The drug does not seem to cause significant sodium or water retention and, like other vasodilators, stimulates the renin-angiotensin system. Cadralazine appears to have a profound vasodilatory effect on renal blood vessels which enables renal blood flow and renal function to be maintained despite a marked fall in systemic blood pressure.

Pharmacokinetic Properties

Cadralazine is rapidly absorbed in healthy volunteers, and in patients with hypertension or chronic heart failure. Peak plasma concentrations of 130, 210 and 379 μg/L occurred after administration of 5, 10 and 20mg doses in healthy volunteers and similar concentrations were reported in hypertensive patients (224 and 568 ug/L following 15 and 30mg doses). After 12 hours, cadralazine is almost undetectable in plasma. Following absorption, cadralazine undergoes limited metabolism to at least 7 metabolites, one of which, the hydrazinopyridazine metabolite, has antihypertensive activity.

About 70 to 80% of an oral dose is recovered unchanged in urine within 24 hours. Faecal recovery represents about 5% of recovered drug. Elimination of cadralazine appears to be delayed in patients with hypertension or chronic heart failure compared with that reported in healthy volunteers; this may be due to impaired renal function in these patients.

Therapeutic Use

Cadralazine has not been studied in large numbers of patients and comparative studies are few. Nonetheless, encouraging results from noncomparative studies show that cadralazine administered as a 10 to 30 mg/day dosage reduced supine and standing blood pressures when given as a second- or third-line antihypertensive therapy in hypertensive patients who had previously failed to respond satisfactorily to 0-blockers and/or diuretics and who continued to receive this therapy. Blood pressure reductions of 11 to 19%/13 to 22% have been reported in such patients and at least 70%, and in some cases 100%, of patients achieved target blood pressure (diastolic blood pressure ⩽ 95mm Hg). The antihypertensive effects of cadralazine were apparent within 2 weeks of starting treatment, persisted during longer term administration and were significantly superior to placebo.

Combined treatment with a vasodilator plus a diuretic or 0-blocker is significantly more effective than β-blocker monotherapy. Cadralazine and chlorthalidone show a similar antihypertensive efficacy in resting hypertensive patients who were also receiving a β-blocker. Both drugs reduce blood pressure within 2 weeks and this effect is maintained during treatment of up to 6 months. However, during exercise testing cadralazine is clearly superior to chlorthalidone in reducing the pressor response.

In comparative clinical trials, cadralazine, hydralazine, dihydralazine and prazosin were similarly effective in hypertensive patients who had inadequate blood pressure control with previous diuretic or β-blocker therapy.

Adverse Effects

Cadralazine is well tolerated when administered with a diuretic and/or β-blocker with most adverse effects being mild to moderate in nature, occurring more frequently at higher dosages (⩾ 20 mg/day), becoming less frequent with prolonged treatment, and rarely requiring withdrawal of therapy.

The most common adverse effects are typical of a drug which produces peripheral vasodilation and include headache, asthenia, dizziness, oedema, palpitations and flushing; these generally may be less frequent and severe during combination therapy. Other less common symptoms are formication, dyspnoea, gastralgia, nausea and insomnia. Cadralazine appears to be better tolerated than dihydralazine and does not appear to produce a systemic lupus erythematosus-like syndrome in patients who had developed the syndrome under hydralazine treatment. However, more patients need to be treated with the drug before this possibility can be definitely excluded. Cadralazine has no clinically relevant effects on renal or thyroid function, routine laboratory tests, or ECG.

Dosage and Administration

As a second- or third-line antihypertensive agent the usual oral dosage of cadralazine is 10 to 20mg once daily.

Keywords

Hypertensive Patient Chronic Heart Failure Atenolol Essential Hypertension Prazosin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Amann FW, Bühler FR. Long-term antihypertensive therapy with a new vasodilator, ISF 2469, in combination with a beta-blocker and a diuretic. Clinica Europea 18: 1–7, 1979Google Scholar
  2. Andersson OK. Cadralazine did not produce the SLE-syndrome when hydralazine did. European Journal of Clinical Pharmacology 31: 741, 1987PubMedCrossRefGoogle Scholar
  3. Antonicelli R, Savonitto S, Tomassini PF, Gambini C, Sardina M, et al. Cadralazine in elderly hypertensives: a double-blind clinical haemodynamic study. Clinical and Experimental Hypertension, in press, 1990Google Scholar
  4. Bonardi G, Rossi E, Pellegatti M. [14 C]-Cadralazine: absorption, distribution and excretion in rat and dog. European Journal of Drug Metabolism and Pharmacokinetics 8(1): 25–33, 1983PubMedCrossRefGoogle Scholar
  5. Bouthier JD, De Luca N, Safar ME, Simon AC. Cardiac hypertrophy and arterial distensibility in essential hypertension. American Heart Journal 109: 1345–1352, 1985PubMedCrossRefGoogle Scholar
  6. Bouthier JD, Safar ME, Curien ND, London GM, Levenson JA, et al. Effect of cadralazine on brachial artery hemodynamics and forearm venous tone in essential hypertension. Clinical Pharmacology and Therapeutics 39: 82–88, 1986PubMedCrossRefGoogle Scholar
  7. Brundel P, Lecaillon J-B, Guyene TT, Imhof P, Ménard J. Influence of acetylator status on the haemodynamic effects and pharmacokinetics of cadralazine in healthy subjects. British Journal of Clinical Pharmacology 29: 503–509, 1990CrossRefGoogle Scholar
  8. Bühler FR. Antihypertensive treatment according to age, plasma renin and race. Drugs 35: 495–503, 1988PubMedCrossRefGoogle Scholar
  9. Buoninconti R, Motolese M. Antihypertensive activity of a new vasodilator, cadralazine, administered alone or in combination with a beta-blocker. International Journal of Clinical Pharmacology, Therapy and Toxicology 23: 613–616, 1985Google Scholar
  10. Caponnetto S, Valvo E, Mocarelli P, Alberti D, Savonitto S. Cadralazine versus prazosin as second-step treatment in β-blocked hypertensive patients: a randomized multicentre study. European Journal of Clinical Pharmacology, in press, 1990Google Scholar
  11. Carpi C, Dorigotti L, Semeraro C. Cadralazine and its identified metabolites: comparative effects on blood pressure and on arterial smooth muscle. British Journal of Pharmacology 72: 188–189, 1981Google Scholar
  12. Catalano M, Parini J, Libretti A. Cadralazine (ISF 2469 ): dose-related antihypertensive activity after single oral administration to patients. European Journal of Clinical Pharmacology 24: 157–161, 1983PubMedCrossRefGoogle Scholar
  13. Catalano M, Parini J, Romano M, Libretti A Controlled clinical trial of cadralazine as a second-step drug in the treatment of hypertension. European Journal of Clinical Pharmacology 28: 135–138, 1985PubMedCrossRefGoogle Scholar
  14. Corea L, Bentivoglio M, Beggi P, Motolese M. Haemodynamic response after single and repeated administration of cadralazine in hypertensives. Abstract 0254, 9th World Congress of Cardiology, Moscow, June 20–26, 1982Google Scholar
  15. Corea L, Camillo V, Bentivoglio M, Bichisao E, Fioroni E, et al. A dose-response study on the antihypertensive activity of once-daily cadralazine. Journal of Hypertension 1 (Suppl. 2): 362–364, 1983Google Scholar
  16. Costa FV, Borghi C, Mussi A, Ambrosioni E. Cadralazine and chlorthalidone as a second-step drug with atenolol in hypertensive patients: differences in blood pressure control during exercise. European Journal of Clinical Pharmacology 30: 145–150, 1986PubMedCrossRefGoogle Scholar
  17. Costa FV, Marata AM, Strocchi E, Ambrosioni E. Efficacy and tolerability of a long-acting vasodilator, cadralazine (ISF 2469), in hypertensive patients: results after one year of treatment. Current Therapeutic Research 34(4): 653–661, 1983Google Scholar
  18. Dorigotti L, Ferni G, Lombroso M, Semeraro C. Hemodynamic profile of the antihypertensive vasodilator cadralazine in conscious dogs. Arzneimittel-Forschung 34: 984–987, 1984PubMedGoogle Scholar
  19. Emilsson H. High-performance liquid Chromatographic determination of cadralazine in human plasma and urine. Journal of Chromatography 424: 119–128, 1988PubMedCrossRefGoogle Scholar
  20. Ferni G, Bonardi G, Lombroso M, Semeraro C, Dorigotti L. Renal function studies with cadralazine in conscious dogs: a comparison with hydralazine. Pharmacological Research 21(2): 211–222, 1989PubMedCrossRefGoogle Scholar
  21. Gibelin P, Lloret JL, Drici M, Leborgne L, Camous JP, et al. Treatment of severe chronic cardiac failure with cadralazine: short- and mid-term results. Archives des Maladies du Coeur et des Vaisseaux 80(2): 199–205, 1987PubMedGoogle Scholar
  22. Glorioso N, Motolese M, Dessi-Fulgheri P, Madeddu P, Oppes M, et al. A controlled study of once daily cadralazine in association with metoprolol slow-release in the treatment of mild to moderate hypertension. Abstract. 1st European Meeting of Hypertension, Milan, 29 May-1 June, 1983Google Scholar
  23. Glorioso N, Motolese M, Dessi-Fulgheri P, Madeddu P, Oppes M, et al. Long-term treatment of moderate/severe hypertension with a new vasodilator, cadralazine, combined with a beta-blocker and a diuretic. 1st National Congress of the Italian Society of Hypertension, Padova, September 28–29, 1984Google Scholar
  24. Haglund K, Dahlqvist R, Emilsson H, Englund G. Cadralazine pharmacokinetics — a pilot study. European Journal of Clinical Pharmacology 35: 571–572, 1988PubMedCrossRefGoogle Scholar
  25. Hauffe SA, Dubois JP. Determination of cadralazine in human plasma and urine by high-performance liquid chromatography. Journal of Chromatography 290: 223–230, 1984PubMedCrossRefGoogle Scholar
  26. Hauffe SA, Dubois JP, Imhof PR. Human pharmacokinetics of cadralazine: a new vasodilator. European Journal of Drug Metabolism and Pharmacokinetics 10(3): 217–223, 1985PubMedCrossRefGoogle Scholar
  27. Hedwall PR, Breitenfeld K, Gasser R, Thomann H. Preferential renal vasodilation following cadralazine. Abstract. Cardiovascular Pharmacotherapy International Symposium, Geneva, April 22–25, 1985Google Scholar
  28. Higashio T, Kuroda K. Effects of cadralazine on contractions induced by Ca2+ and norepinephrine in isolated rabbit aortic strips. Arzneimittel-Forschung 38: 346–349, 1988bPubMedGoogle Scholar
  29. Higashio T, Kuroda K. Effects of cadralazine on contractions induced by norepinephrine, serotonin, angiotensin II and K+ in rabbit aortic and renal strips. Arzneimittel-Forschung 38: 341–346, 1988aPubMedGoogle Scholar
  30. Higashio T, Tsuji Y, Nakao K, Sakaguchi S, Tanaka M. Hemodynamic effects of cadralazine in hexamethonium treated and non-treated anesthetized dogs. Arzneimittel-Forschung 38: 350–358, 1988PubMedGoogle Scholar
  31. Kokubu T, Hiwada K, Ikeda M, Yoshinaga K, Arakawa K, et al. Clinical evaluation of cadralazine on essential hypertension — multi-center double-blind study in comparison with hydralazine (combination therapy with antihypertensive diuretic thiazide). Rinsho Iyaku 4: 237–282, 1988Google Scholar
  32. Laurent S, Lacolley P, London G, Safar M. Haemodynamics of the carotid artery after vasodilation in essential hypertension. Hypertension 11: 134–140, 1988PubMedCrossRefGoogle Scholar
  33. Lavezzaro GC, Gastaldo D, Noussan P, Bensoni M, Parini J, et al. The effects of cadralazine (ISF 2469) on water-salt equilibrium and essential arterial hypertension. Abstract. Minerva Cardioangiologia 29: 527–534, 1981Google Scholar
  34. Leonetti G, Parini J, Visconti M, Gradnik R. Pharmacokinetics of cadralazine in hypertensive patients. European Journal of Drug Metabolism and Pharmacokinetics 13(4): 295–300, 1988PubMedCrossRefGoogle Scholar
  35. Libretti A, Catalano M, Romano M, Parini J. Comparison of cadralazine vs chlortalidone in hypertensive patients on chronic atenolol. Abstract. 10th Scientific Meeting of the International Society of Hypertension, Interlaken, June 17–21, 1984Google Scholar
  36. Mitsui M, Nakao K, Inukai T, Karaki H. Inhibitory effects of cadralazine and its metabolite, ISF-2405, on contractions and the level of cytosolic Ca2+ in vascular smooth muscle. European Journal of Pharmacology 178: 171–177, 1990PubMedCrossRefGoogle Scholar
  37. Motolese M, Magagna A, Abdel-Haq B, Lucarini S, Graziadei L, et al. Haemodynamic and humoral effects of a new vasodilator, cadralazine. Abstract. 9th World Congress of Cardiology, Moscow, June 20–26, 1982Google Scholar
  38. Muiesan G, Agabiti-Rosei E, Bentivoglio M, Corea L, Fioroni E, et al. Dose-related antihypertensive effect of a new long-acting vasodilator, cadralazine, in moderate hypertension. Abstract. 10th Scientific Meeting of the International Society of Hypertension, Interlaken, June 17–21, 1984Google Scholar
  39. Muiesan L, Romanelli G, Agabiti-Rosei E, Alicandri C, Beschi N, et al. Metabolic and hemodynamic changes after short term cadralazine treatment in essential hypertension. Abstract 0838. 9th World Congress of Cardiology, Moscow, June 20–26, 1982Google Scholar
  40. Mulder H. Conversion of drug-induced SLE-syndrome by the vasolidating agent cadralazine. Short communication. European Journal of Clinical Pharmacology 38: 303, 1990CrossRefGoogle Scholar
  41. Pålsson L, Weiner L, Englund G, Henning M, et al. Cadralazine challenge in patients with previous hydralazine-induced lupus: a 6-month study. Clinical Pharmacology and Therapeutics 46: 177–181, 1989PubMedCrossRefGoogle Scholar
  42. Persson B, Granerus G, Hedner T, Wysocki M, Andersson O. Systemic and renal hemodynamic effects of single oral doses of cadralazine and long term antihypertensive effects of cadralazine in patients receiving therapy with β-blockers and diuretics. Acta Medica Scandinavica (Suppl. 714): 177–182, 1986Google Scholar
  43. Pirrelli A, Nardecchia A, Pieri R, Motolese M. Cadralazine in the treatment of mild and moderate hypertension. Current Therapeutic Research 36(4): 712–718, 1984Google Scholar
  44. Rubegni M, Provvedi D, Francucci B, Motolese M. Antihypertensive activity of a new arterial vasodilator, cadralazine in association with a beta-blocker. Abstract. 1st European Meeting on Hypertension, Milan, 29 May–1 June, 1983Google Scholar
  45. Safar ME, London GM, Bouthier JA, Levenson JA, Laurent S. Brachial artery cross-sectional area and distensibility before and after arteriolar vasodilatation in men with sustained essential hypertension. Journal of Cardiovascular Pharmacology 9: 734–742, 1987PubMedCrossRefGoogle Scholar
  46. Salvadeo A, Villa G, Segagni S, Piazza V, Picardi L, et al. Cadralazine, a new vasodilator, in addition to a β-blocker for long term treatment of hypertension. Arzneimittel-Forschung 35(3): 623–625, 1985PubMedGoogle Scholar
  47. Schütz H, Faigle JW. Multiple inverse isotope dilution assay for cadralazine and four metabolites in biological fluids. Journal of Chromatography, 281: 273–280, 1983PubMedCrossRefGoogle Scholar
  48. Schütz H, Faigle JW, Küng W, Theobald W. Disposition and pharmacokinetics of cadralazine and individual metabolites in man. European Journal of Drug Metabolism and Pharmacokinetics 10: 147–153, 1985PubMedCrossRefGoogle Scholar
  49. Semeraro C, Dorigotti L, Banfi S, Carpi C. Pharmacological studies on cadralazine: a new antihypertensive vasodilator drug. Journal of Cardiovascular Pharmacology 3: 455–467, 1981PubMedCrossRefGoogle Scholar
  50. Semplicini A, Pessina AC, Caregaro L, Gatta A, Sama B, et al. Blood pressure, body fluids and renal tubular handling of sodium during cadralazine plus atenolol treatment in essential hypertension. Current Therapeutic Research 34(6): 1038–1043, 1983Google Scholar
  51. Stornello M, Valvo E, Scapellato L, Bichisao E, Motolese M. A new once-daily vasodilator, cadralazine, in association with slow-release metoprolol in the treatment of arterial hypertension. Current Therapeutic Research 40(3): 448–455, 1986Google Scholar
  52. Strocchi E, Costa FV, Caldari R, Malini PL, Marata AM, et al. Comparison of the antihypertensive activity of cadralazine (ISF 2469) and dihydralazine during chronic treatment. International Journal of Clinical Pharmacology, Therapy and Toxicology 21(10): 519–523, 1983Google Scholar
  53. Takeyama K, Ikeno A, Minato H, Fukuya F, et al. Antihypertensive activity of cadralazine in experimental hypertensive rats. Archives Internationales de Pharmacodynamie et de Thérapie 291: 163–174, 1988PubMedGoogle Scholar
  54. Terauchi Y, Watari S, Ishikawa S, Takeyama K, Sekine Y, et al. Pharmacokinetics of an active cadralazine metabolite in plasma and blood vessels of spontaneously hypertensive rats. Arzneimittel-Forschung 38: 237–239, 1988PubMedGoogle Scholar
  55. Valori C, Corea L, Bentivoglio M, Fioroni E, Francucci B, et al. A dose-response study on antihypertensive activity of once daily cadralazine. Abstract. 1st European Meeting on Hypertension, Milan, 28 May–1 June, 1983Google Scholar
  56. van Brummelen P, Bühler FR, Kiowski W, Bolli P, Bertel O. Antihypertensive efficacy of a new long acting hydralazine like vasodilator, ISF 2469 in combination with a betablocker and a diuretic. International Journal of Clinical Pharmacology and Biopharmacy 17(10): 380–385, 1979PubMedGoogle Scholar
  57. Yukimura T, Miura K, Tanaka M. Higashio T, Sakaguchi S, et al. Effects of cadralazine on systemic blood pressure, renal function and plasma renin activity in anesthetized dogs. Arzneimittel-Forschung 38: 25–28, 1988PubMedGoogle Scholar

Copyright information

© Adis International Limited 1990

Authors and Affiliations

  • Donna McTavish
    • 1
    • 2
  • Ronald A. Young
    • 1
  • Stephen P. Clissold
    • 1
  1. 1.Adis Drug Information ServicesAuckland
  2. 2.Arkansas Poison and Drug Information CenterUniversity of Arkansas for Medical SciencesLittle RockUSA

Personalised recommendations