Класс препаратов антагонисты кальция (АК), или блокаторы кальциевых каналов (БКК), объединяет в себе довольно разнородную группу лекарственных средств, обладающих общими вазодилатирующими свойствами за счет снижения тока кальция через гладкомышечные клетки сосудистой стенки и вместе с тем разной степенью влияния на сердечную мышцу, функцию синусового узла, атриовентрикулярную проводимость, тонус периферических сосудов и коронарное кровоснабжение. Появление лекарственных препаратов этого класса стало одним из великих достижений в области фармакологии в конце XX в. Особое место в гипертензиологии занимают БКК III поколения, обладающие высокой биодоступностью и тканевой селективностью. Современные пролонгированные АК широко применяются при артериальной гипертонии (АГ), особенно актуальны они у пациентов с сахарным диабетом, заболеваниями периферических артерий, хронической обструктивной болезнью легких и бронхиальной астмой, ишемической болезнью сердца, у больных пожилого возраста с систолической АГ. Эти препараты обладают не только выраженным антигипертензивным действием, органопротективными свойствами, но и способны улучшать прогноз у пациентов высокого и очень высокого кардиоваскулярного риска.
The class of drugs – calcium antagonists (CA), or calcium channel blockers (CCBs) is combined a quite heterogeneous drugs group possessing common vasodilatatory characteristics by disruption of the movement of calcium through the vascular smooth muscle cells and with different degree of impact on myocardium, the sinus node function, atrioventricular conduction, tonus of peripheral vessels and coronary blood flow. The existence of this class of drugs has become one of the great achievements in the field of pharmacology, at the end of the 20th century. Third Generation CCBs takes the special place in hypertensiology because of high bioavailability and tissue selectivity. Modern long-acting CA are widely used in case of arterial hypertension (AH), they can be used especially in patients with diabetes mellitus, peripheral artery disease, chronic obstructive pulmonary disease and bronchial asthma, ischemic heart disease and in elderly patients with systolic AH. These drugs show not only antihypertensive effect and organoprotective characteristics, but also can improve the prognosis in patients with high and very high cardiovascular risk.
1. Fleckenstein A, Tritthart H, Fleckenstein B et al. Eine neue Gruppe kompetitiver Ca2+-Antagonisten (Iproveratril, D6000, Prenylamin) mit starken Hemeffekten auf die elektromekanische Koppelung im Warmbluter-myocard. Pflugers Arch 1969; 307: R25.
2. Ringer S. A further contribution regarding the influence of the different constituents of the blood on the contraction of the heart. J Physiol Lond 1882; 4: 29–42.
3. Рациональная фармакотерапия сердечно-сосудистых заболеваний. Руководство для практикующих врачей. Под общ. ред. Е.И.Чазова, Ю.А.Карпова. 2-е изд. М.: Литтерра, 2014. / Ratsional'naia farmakoterapiia serdechno-sosudistykh zabolevanii. Rukovodstvo dlia praktikuiushchikh vrachei. Pod obshch. red. E.I.Chazova, Iu.A.Karpova. 2-e izd. M.: Litterra, 2014. [in Russian]
4. Echizen H, Eichelbaum M. Clinical pharmacokinetics of verapamil, nifedipine and diltiazem. Clin Pharmacokinetics 1986; 11: 425–49.
5. Hansson L. Randomized trial of old and new antihypertensive drugs in elderly patients: cardiovascular morbidity and mortality the Swedish Trial in Old Patients with Hypertension – II Study. Lancet 1999; 354: 1751–6.
6. The NORDIL Study group. The Nordic Diltiazem Study: An investigation study in hypertension comparing calcium antagonists base treatment with conventional therapy. 10th Meeting of the European Society on Hypertension, Goteborg, Sweden. Oral communication. Lancet 2000; 356: 359–65.
7. Furberg CD, Psaty BM, Meyer JV. Nifedipine. Dose-related increase in mortality in patients with coronary heart disease. Circulation 1995; 92 (5): 1326–31.
8. Brown MJ et al. INSIGHT: International Nifedipine GITS Study: intervention as a goal in hypertension treatment. 10th Meeting of the European Society on Hypertension, Goteborg, Sweden Oral communication. Lancet 2000; 356: 366–72.
9. Dahlof B, Sever PS, Poulter NR. For the ASCOT investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT–BPLA): a multicentre randomised controlled trial. Lancet 2005; 366: 895–906.
10. Bakris GL, Sarafidis PA, Weir MR et al. Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trial. Lancet 2010; 375 (9721): 1173–81.
11. Lindholm LH, Hansson L. Sweedish trial in old patients with hypertension 2 (STOP-Hypertension 2). Blood Press 1996; 5: 300–4.
12. Davis BR. Cutler JD, Gordon DJ et al. Rationale and design for the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Am J Hypertens 1996; 9: 342–60.
13. Julius S, Kjeldsen SE, Weber M et al. Outcomes in hypertensive patients at high cardiovascular risk treated with valsartan- or amlodipine-based regimens: VALUE, randomised trial. Lancet 2004; 363: 2022–31.
14. Nissen S. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT Study: a randomized controlled trial. JAMA 2004; 292 (18): 2217–25.
15. Estasio RO, Jeffers BW, Hiatt WR et al. The effect of nisoldipine as compared with noninsulin-dependent diabetes and hypertension. N Engl J Med 1998; 338: 645–52.
16. Packer M, Bristow MR, Cohn JN et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996; 334: 1349–55.
17. Zannad F et al. Double-blind, randomized, multicentre comparison of the effects of amlodipine and perindopril on 24h therapeutic coverage and beyond in patients with mild to moderate hypertension. General Physicians Investigators Group. J Hypretens 1999; 17 (1): 137–46.
18. Hansson L. Randomized trial of old and new antihypertensive drugs in elderly patients: cardiovascular morbidity and mortality the Swedish Trial in Old Patients with Hypertension – II Study. Lancet 1999; 354: 1751–6.
19. Карпов Ю.А. Применение антагонистов кальция у больных артериальной гипертонией и ишемической болезнью сердца: современное состояние вопроса. Кардиология. 2000; 10: 52–5. / Karpov Iu.A. Primenenie antagonistov kal'tsiia u bol'nykh arterial'noi gipertoniei i ishemicheskoi bolezn'iu serdtsa: sovremennoe sostoianie voprosa. Kardiologiia. 2000; 10: 52–5. [in Russian]
20. Esfasio R. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non insulin depended diabetes and hypertension. ABCD Study. N Engl J Med 1998; 338: 645–52.
21. Resnick LM. Ionic basis of hypertension, insulin resistance, vascular disease and related disorders. Am J Hypertens 1993; 6: (4): 123–4.
22. Rahn K. On behalf of the ELSA investigators. The European Lacidipin Study on Atherosclerosis (ELSA): prevalence of baseline carotid lesions and cо-relations with risk factors. J Hypertens 1998; 16: 31–3.
23. Mancini G. Post hoc analysis of coronary findings from the Prospective Randomized Evaluation of the Vascular Effects of the Norvasc Trial (PREVENT). Am Coll Cardiol 2002; 89: 1414–6.
24. Terpstra W. Effects of amlodipine and lisinopril on intima-media thickness imperviously untreated, elderly hypertensive patients (ELVERA trial). J Hypertens 2004; 22 (7): 1309–16.
25. Nissen S. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT Study: a randomized controlled trial. JAMA 2004; 292 (18): 2217–25.
26. Abernethy DR. The pharmacokinetic profile of amlodipine. Am Heart J 1989; 118 (5 Pt. 2): 1100–3.
27. Burges RA, Dodd MG, Gardiner DG. Pharmacologic profile of amlodipine. Am J Cardiol 1989; 64: 101–201.
28. Барышникова Г.А. Возможности изомера амлодипина в лечении артериальной гипертензии. Рус. мед. журн. 2009; 7 (17): 431–5. / Baryshnikova G.A. Vozmozhnosti izomera amlodipina v lechenii arterial'noi gipertenzii. Rus. med. zhurn. 2009; 7 (17): 431–5. [in Russian]
29. Kloner R et al. Sex-and age-related antihypertensive effects amlodipine. The Amlodipine Cardiovascular Community Trial Study Group. Am J Cardiol 1996; 77 (9): 713–22.
30 Liebson P. Comparison of five antihypertensive monotherapies and placebo for change in left ventricular mass in patients receiving nutritional-hygienic therapy in the Treatment of Mild Hypertension Study (TOMHS). Circulation 1995; 91: 698–706.
31. Марцевич С.Ю. Изучение терапевтической эквивалентности двух препаратов амлодипина (оригинального и воспроизведенного) у больных артериальной гипертонией. Результаты двойного слепого рандомизированного перекрестного исследования. Рос. кардиол. журн. 2004; 4 (48): 53–6. / Martsevich S.Iu. Izuchenie terapevticheskoi ekvivalentnosti dvukh preparatov amlodipina (original'nogo i vosproizvedennogo) u bol'nykh arterial'noi gipertoniei. Rezul'taty dvoinogo slepogo randomizirovannogo perekrestnogo issledovaniia. Ros. kardiol. zhurn. 2004; 4 (48): 53–6. [in Russian]
32. Frattola A et al. Prognostic value of 24-hour blood pressure variability. Hypertension 1993; 11(10): 1133–7.
33. Hansen TW. Prognostic value of reading-to-reading blood pressure variability over 24 hours in 8,938 subjects from 11 populations. Hypertension 2010; 55 (4): 1049–57.
34. Eguchi K. Night Time Blood Pressure variability Is a Strong Predictor for Cardiovascular Events in Patients With Type 2 Diabetes. Am J Hypertens 2009; 22 (1): 46–51.
35. Eguchi K. Visit-to-visit and ambulatory blood pressure variability as predictors of incident cardiovascular events in patients with hypertension. Am J Hypertens 2012; 25 (9): 962–8.
36. Webb A, Fischer U, Mehta Z, Rothwell PM. Effects of antihypertensive-drug class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta-analysis. Lancet 2010; 375: 906–15.
37. Mancia G. Short-and long-term blood pressure variability: present and future. Hypertension 2012; 60: 512–7.
38. Rothwell PM et al. Stroke 2011; 42: 2860–5.
39. Webb A, Fischer U, Mehta Z, Rothwell PM. Effects of antihypertensive-drug class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta-analysis. Lancet 2010; 375: 906–15.
40. Zhang Y, Agnoletti D, Blacher J, Safar ME. Effects of antihypertensive agents on blood pressure variability. Hypertension 2011; 58: 155–60.
41. Muntner P. Effect of chlorthalidone, amlodipine, and lisinopril on visit-to-visit variability of blood pressure: results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. J Clin Hypertens 2014; 16 (5): 323–30.
42. Wang JG, Yan P, Jeffers BW. Effects of amlodipine and other classes of antihypertensive drugs on long-term blood pressure variability: evidence from randomized controlled trials. J Am Soc Hypertens 2014; 8 (5): 340–9.
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1. Fleckenstein A, Tritthart H, Fleckenstein B et al. Eine neue Gruppe kompetitiver Ca2+-Antagonisten (Iproveratril, D6000, Prenylamin) mit starken Hemeffekten auf die elektromekanische Koppelung im Warmbluter-myocard. Pflugers Arch 1969; 307: R25.
2. Ringer S. A further contribution regarding the influence of the different constituents of the blood on the contraction of the heart. J Physiol Lond 1882; 4: 29–42.
3. Ratsional'naia farmakoterapiia serdechno-sosudistykh zabolevanii. Rukovodstvo dlia praktikuiushchikh vrachei. Pod obshch. red. E.I.Chazova, Iu.A.Karpova. 2-e izd. M.: Litterra, 2014. [in Russian]
4. Echizen H, Eichelbaum M. Clinical pharmacokinetics of verapamil, nifedipine and diltiazem. Clin Pharmacokinetics 1986; 11: 425–49.
5. Hansson L. Randomized trial of old and new antihypertensive drugs in elderly patients: cardiovascular morbidity and mortality the Swedish Trial in Old Patients with Hypertension – II Study. Lancet 1999; 354: 1751–6.
6. The NORDIL Study group. The Nordic Diltiazem Study: An investigation study in hypertension comparing calcium antagonists base treatment with conventional therapy. 10th Meeting of the European Society on Hypertension, Goteborg, Sweden. Oral communication. Lancet 2000; 356: 359–65.
7. Furberg CD, Psaty BM, Meyer JV. Nifedipine. Dose-related increase in mortality in patients with coronary heart disease. Circulation 1995; 92 (5): 1326–31.
8. Brown MJ et al. INSIGHT: International Nifedipine GITS Study: intervention as a goal in hypertension treatment. 10th Meeting of the European Society on Hypertension, Goteborg, Sweden Oral communication. Lancet 2000; 356: 366–72.
9. Dahlof B, Sever PS, Poulter NR. For the ASCOT investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT–BPLA): a multicentre randomised controlled trial. Lancet 2005; 366: 895–906.
10. Bakris GL, Sarafidis PA, Weir MR et al. Renal outcomes with different fixed-dose combination therapies in patients with hypertension at high risk for cardiovascular events (ACCOMPLISH): a prespecified secondary analysis of a randomised controlled trial. Lancet 2010; 375 (9721): 1173–81.
11. Lindholm LH, Hansson L. Sweedish trial in old patients with hypertension 2 (STOP-Hypertension 2). Blood Press 1996; 5: 300–4.
12. Davis BR. Cutler JD, Gordon DJ et al. Rationale and design for the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Am J Hypertens 1996; 9: 342–60.
13. Julius S, Kjeldsen SE, Weber M et al. Outcomes in hypertensive patients at high cardiovascular risk treated with valsartan- or amlodipine-based regimens: VALUE, randomised trial. Lancet 2004; 363: 2022–31.
14. Nissen S. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT Study: a randomized controlled trial. JAMA 2004; 292 (18): 2217–25.
15. Estasio RO, Jeffers BW, Hiatt WR et al. The effect of nisoldipine as compared with noninsulin-dependent diabetes and hypertension. N Engl J Med 1998; 338: 645–52.
16. Packer M, Bristow MR, Cohn JN et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996; 334: 1349–55.
17. Zannad F et al. Double-blind, randomized, multicentre comparison of the effects of amlodipine and perindopril on 24h therapeutic coverage and beyond in patients with mild to moderate hypertension. General Physicians Investigators Group. J Hypretens 1999; 17 (1): 137–46.
18. Hansson L. Randomized trial of old and new antihypertensive drugs in elderly patients: cardiovascular morbidity and mortality the Swedish Trial in Old Patients with Hypertension – II Study. Lancet 1999; 354: 1751–6.
19. Karpov Iu.A. Primenenie antagonistov kal'tsiia u bol'nykh arterial'noi gipertoniei i ishemicheskoi bolezn'iu serdtsa: sovremennoe sostoianie voprosa. Kardiologiia. 2000; 10: 52–5. [in Russian]
20. Esfasio R. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non insulin depended diabetes and hypertension. ABCD Study. N Engl J Med 1998; 338: 645–52.
21. Resnick LM. Ionic basis of hypertension, insulin resistance, vascular disease and related disorders. Am J Hypertens 1993; 6: (4): 123–4.
22. Rahn K. On behalf of the ELSA investigators. The European Lacidipin Study on Atherosclerosis (ELSA): prevalence of baseline carotid lesions and cо-relations with risk factors. J Hypertens 1998; 16: 31–3.
23. Mancini G. Post hoc analysis of coronary findings from the Prospective Randomized Evaluation of the Vascular Effects of the Norvasc Trial (PREVENT). Am Coll Cardiol 2002; 89: 1414–6.
24. Terpstra W. Effects of amlodipine and lisinopril on intima-media thickness imperviously untreated, elderly hypertensive patients (ELVERA trial). J Hypertens 2004; 22 (7): 1309–16.
25. Nissen S. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT Study: a randomized controlled trial. JAMA 2004; 292 (18): 2217–25.
26. Abernethy DR. The pharmacokinetic profile of amlodipine. Am Heart J 1989; 118 (5 Pt. 2): 1100–3.
27. Burges RA, Dodd MG, Gardiner DG. Pharmacologic profile of amlodipine. Am J Cardiol 1989; 64: 101–201.
28. Baryshnikova G.A. Vozmozhnosti izomera amlodipina v lechenii arterial'noi gipertenzii. Rus. med. zhurn. 2009; 7 (17): 431–5. [in Russian]
29. Kloner R et al. Sex-and age-related antihypertensive effects amlodipine. The Amlodipine Cardiovascular Community Trial Study Group. Am J Cardiol 1996; 77 (9): 713–22.
30 Liebson P. Comparison of five antihypertensive monotherapies and placebo for change in left ventricular mass in patients receiving nutritional-hygienic therapy in the Treatment of Mild Hypertension Study (TOMHS). Circulation 1995; 91: 698–706.
31. Martsevich S.Iu. Izuchenie terapevticheskoi ekvivalentnosti dvukh preparatov amlodipina (original'nogo i vosproizvedennogo) u bol'nykh arterial'noi gipertoniei. Rezul'taty dvoinogo slepogo randomizirovannogo perekrestnogo issledovaniia. Ros. kardiol. zhurn. 2004; 4 (48): 53–6. [in Russian]
32. Frattola A et al. Prognostic value of 24-hour blood pressure variability. Hypertension 1993; 11(10): 1133–7.
33. Hansen TW. Prognostic value of reading-to-reading blood pressure variability over 24 hours in 8,938 subjects from 11 populations. Hypertension 2010; 55 (4): 1049–57.
34. Eguchi K. Night Time Blood Pressure variability Is a Strong Predictor for Cardiovascular Events in Patients With Type 2 Diabetes. Am J Hypertens 2009; 22 (1): 46–51.
35. Eguchi K. Visit-to-visit and ambulatory blood pressure variability as predictors of incident cardiovascular events in patients with hypertension. Am J Hypertens 2012; 25 (9): 962–8.
36. Webb A, Fischer U, Mehta Z, Rothwell PM. Effects of antihypertensive-drug class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta-analysis. Lancet 2010; 375: 906–15.
37. Mancia G. Short-and long-term blood pressure variability: present and future. Hypertension 2012; 60: 512–7.
38. Rothwell PM et al. Stroke 2011; 42: 2860–5.
39. Webb A, Fischer U, Mehta Z, Rothwell PM. Effects of antihypertensive-drug class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta-analysis. Lancet 2010; 375: 906–15.
40. Zhang Y, Agnoletti D, Blacher J, Safar ME. Effects of antihypertensive agents on blood pressure variability. Hypertension 2011; 58: 155–60.
41. Muntner P. Effect of chlorthalidone, amlodipine, and lisinopril on visit-to-visit variability of blood pressure: results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. J Clin Hypertens 2014; 16 (5): 323–30.
42. Wang JG, Yan P, Jeffers BW. Effects of amlodipine and other classes of antihypertensive drugs on long-term blood pressure variability: evidence from randomized controlled trials. J Am Soc Hypertens 2014; 8 (5): 340–9.
Авторы
И.Е.Чазова, Ю.В.Жернакова*
Институт клинической кардиологии им. А.Л.Мясникова ФГБУ Российский кардиологический научно-производственный комплекс Минздрава России. 121552, Россия, Москва, ул. 3-я Черепковская, д. 15а
*juli001@mail.ru
________________________________________________
I.E.Chazova, Yu.V.Zhernakova*
A.L.Myasnikov Institute of Clinical Cardiology, Russian Cardiological Scientific-Industrial Complex of the Ministry of Health of the Russian Federation. 121552, Russian Federation, Moscow, ul. 3-ia Cherepkovskaia, d. 15a
*juli001@mail.ru