- Email: [email protected]
Pharmacology of cardiovascular chronotherapeutic agents
AJH
2001; 14:296S–301S
Pharmacology of Cardiovascular Chronotherapeutic Agents David H. G. Smith Although sudden cardiac death, myocardial infarction, or stroke can occur at any time of day, event rates increase during the waking hours, particularly in the morning. In most people— both normotensive and hypertensive— blood pressure (BP) rises rapidly in the early morning hours, the time when most individuals wake and begin their day. This rise in BP corresponds to increased secretion of catecholamines and increased plasma renin activity. Thus, vascular tone and total peripheral resistance increase in the morning hours, and BP rises as a result. At the same time, heart rate increases. In the late morning or early afternoon, BP reaches its peak. After that, BP declines, falling 15 to 20 mm Hg between about 8 PM and 2 AM, the time when BP is usually lowest. These findings have led to an interest in chronotherapy for hypertension. A major objective of chronotherapy for hypertension is to deliver the drug in higher concentrations
A
during the early-morning post-awakening period, when BP is highest, and in lesser concentrations during the middle of a sleep cycle, when BP is low. Traditional sustainedrelease pharmacologic agents, which deliver a near-constant drug concentration, were not designed to complement the circadian pattern. There are currently two antihypertensive agents, Verelan PM (verapamil HCl) and Covera HS (verapamil HCl), that provide chronotherapy for hypertension. These drugs use novel delivery systems that provide 24-h BP control while maximizing drug concentrations in the morning and minimizing drug concentrations during sleep. Am J Hypertens 2001;14: 296S–301S © 2001 American Journal of Hypertension, Ltd. Key Words: Chronotherapy, hypertension, calcium channel antagonists, verapamil.
nalysis of large, population-based studies has shown that many cardiovascular events—including myocardial infarction (MI), stroke, and sudden cardiac death— cluster during the initial hours of morning activity, between 6 AM and 12 noon.1–3 In the Framingham Heart Study, the time of day of sudden cardiac death was analyzed among ⬎5,000 patients in the original cohort over a follow-up period of 38 years. The risk of sudden cardiac death was greatest between 6 AM and 12 noon, and was much higher during this period than other times during the day.1 Furthermore, a meta-analysis of 30 studies including ⬎66,000 patients demonstrated that the incidence of MI is highest between 6 AM and 12 noon (approximately 40% greater than at other times).2 Finally, a meta-analysis of 31 studies including almost 12,000 patients showed that stroke occurs in a very similar pattern, with a 49% increase during the hours between 6 AM and 12 noon.3 The pathophysiologic mechanisms behind these phenomena are not clearly understood, but are probably related to increased stress placed on the cardiovascular system by rapidly changing hemodynamic and hemostatic factors that occur during the early morning.4 It has long
been appreciated that there are marked circadian rhythms in blood pressure (BP), both in normotensive and hypertensive persons5 (Fig. 1). Generally, BP rises rapidly in the early morning hours, the time when most individuals wake and begin their day.5 This rise in BP corresponds to increased secretion of catecholamines and increased plasma renin activity.6 Thus, vascular tone and total peripheral resistance increase in the morning hours, and BP rises as a result. At the same time, heart rate increases.4 In the late morning or early afternoon, BP reaches its peak. After that, BP declines, falling 15 to 20 mm Hg between about 8 PM and 2 AM, the time when BP is usually lowest.5 A “dip” of 10% to 20% in BP also typically occurs during nighttime; however, this dip may vary or be absent with severe or secondary hypertension. The most recent guidelines from the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) acknowledge the importance of the enhanced vulnerability to cardiovascular events in the morning, and recommend use of longacting antihypertensive agents that provide 24-h efficacy.7 However, because of the ciradian variations in BP and the propensity for cardiovascular events in the morning, med-
Received April 3, 2001. Accepted May 8, 2001. From the Memorial Research Medical Clinic, Long Beach, CaliforniaOrange County Research Center, Orange, California.
Address correspondence and reprint requests to David H. G. Smith, MD, Orange County Research Center, 505 S. Main Street, Suite 1025, Orange, CA, 92868.
0895-7061/01/$20.00 PII S0895-7061(01)02176-8
© 2001 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.
AJH–September 2001–VOL. 14, NO. 9, PART 2
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FIG. 1. Circadian rhythm in blood pressure. Results of 24-h ambulatory blood pressure monitoring in five normotensive persons and 10 untreated hypertensive patients. Adapted with permission from Millar-Craig MW, et al: Circadian variation of blood pressure. Lancet 1978;1:795–797.5
ications that are formulated to ensure a near-constant drug concentration will not provide for periods of increased drug concentrations in attempts to control hypertension more optimally during these critical times of the 24-h period.4 One of the newest advances in antihypertensive therapy is chronotherapeutics, or the design of drugs according to chronobiological principles. Chronotherapeutic medications deliver drugs in concentrations that vary according to predictable changes in physiologic need.4,8 In hypertension, chronotherapeutic medications deliver the drug in highest concentrations during the morning post-awakening period, when the need is greatest, and in lesser concentrations at nighttime, when the need is lowest. Recently, verapamil has been marketed in two formulations that use novel delivery systems to provide chronotherapy: Verelan PM (Schwarz Pharma Inc, Milwaukee, WI) and Covera-HS (Pharmacia Corp, Peapack, NJ). This article discusses some of the potential pharmacokinetic and pharmacodynamic advantages of these chronotherapeutic antihypertensive agents.
Pharmacokinetics of Antihypertensive Therapies Fig. 2 compares the plasma concentrations of a shortacting, immediate-release antihypertensive agent requiring three doses daily, an extended-release antihypertensive agent given once daily, and a chronotherapeutic agent given once daily.9,10 As shown, the short-acting agent is associated with significant peaks and troughs in drug concentrations throughout a 24-h period that can cause wide fluctuations in BP control and enhance the chances of drug-level associated adverse events; therefore, shortacting agents are not recommended for treating high BP.7 For many patients, there is an additional shortcoming with short-acting agents: that is, the longest time between any
two doses is probably between the last dose in the evening and the next dose in the morning. Thus, drug concentrations would be lowest at the time of day when BP protection is most needed. The once-daily extended-release shows a sustained drug concentration over the 24-h dosing interval. Although this profile has been shown to result in safe and effective BP lowering, this static pattern of drug release is not tailored to suit daily physiologic variations. In contrast, true chronotherapeutic agents result in drug concentrations that synchronize with the daily variation in BP. Thus, chronotherapetic agents add a dynamic element to drug delivery and release greater amounts of drug during the critical morning period and lesser amounts of drug during the nighttime. This dynamic pattern of drug delivery maximizes BP control in the morning while minimizing the risk of excessive BP lowering during sleep. Maintaining adequate BP levels during sleep may be particularly important in elderly patients and in those with peripheral vascular disease; in such patients, traditional antihypertensive agents administered at bedtime may increase the risk of nighttime hypotension and subsequent ischemic stroke and ischemia-induced neuropathy of the optic nerve.11–15
Chronotherapeutic Delivery Systems Most calcium channel antagonists, including verapamil, are inherently short-acting compounds. These antihypertensive agents rely on a delivery system for sustained action and, in the case of Verelan-PM and Covera HS, to give them the dynamic chronotherapeutic element. Verelan PM uses Chronotherapeutic Oral Drug Absorption System (CODAS) technology, and Covera-HS uses the Controlled-Onset, Extended-Release (COER-24) Delivery System (Fig. 3). Both systems are designed for bedtime dosing, which results in maximum plasma concentrations
298S
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AJH–September 2001–VOL. 14, NO. 9, PART 2
FIG. 2. Effect of delivery system on steady-state plasma concentration of drug (From data on file, Schwarz Pharma, Pfizer Labs.9,10)
of verapamil in the morning, when BP typically surges, and in trough concentrations during sleep, when BP is normally lowest.
The CODAS delivery system incorporates a 4- to 5-h delay in drug delivery followed by an extended drug release with a peak concentration occurring approximately
FIG. 3. Delivery systems used in chronotherapeutic antihypertensive agents.
AJH–September 2001–VOL. 14, NO. 9, PART 2
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FIG. 4. Effect of CODAS-Verapamil 300 mg on blood pressure according to ambulatory blood pressure monitoring. A) Ambulatory systolic blood pressure (SBP) at baseline and the final study visit. B) Ambulatory diastolic blood pressure (DBP) at baseline and the final study visit. Data based on Smith DHG, et al.18
11 h after administration. Trough concentrations occur approximately 4 h after bedtime dosing. Each capsule
contains numerous pellets that consist of an inert core surrounded by active drug and rate-controlling membranes
FIG. 5. Response to therapy with CODAS-Verapamil. Diastolic blood pressure measured manually at time of trough concentration (approximately 11 h after CODAS-verapamil administration). Data based on Smith DHG, et al.18
300S
CARDIOVASCULAR CHRONOTHERAPEUTIC AGENTS
that combine water-soluble and water-insoluble polymers. As the pellets lie in the gastrointestinal tract, water washes over the polymer-coated pellets, slowly dissolving the water-soluble polymer and allowing the drug to diffuse through the resultant pores in the coating. The waterinsoluble polymer continues to provide a barrier and maintains the controlled release of the drug throughout the remainder of the 24-h dosing interval. The Covera-HS system is similar to the gastrointestinal therapeutic system used with extended-release nifedipine. The outermost component of the COER-24 delivery system is a semipermeable membrane that regulates absorption of water into the tablet. Water is absorbed from the gastrointestinal tract at a fixed rate, until a second layer is reached. The second layer, or delay coat, then absorbs water and temporarily prevents the passage of water into the inner core of the tablet, which contains verapamil. This process delays drug release for approximately 4 to 5 h. When sufficient moisture has been absorbed, a third layer expands by osmosis, pushing verapamil out of the tablet at a consistent rate. Continued absorption of water and ongoing osmotic expansion of the third layer provides for extended release of drug and 24-h control of BP.
Blood Pressure Control With Chronotherapeutic Agents Both Verelan PM (CODAS-verapamil) and Covera-HS (COER-verapamil) have been shown to be safe and effective antihypertensive agents.16 –18 In addition, 36-h ambulatory blood pressure monitoring (ABPM) has shown that these agents achieve optimal control during the morning period (6 AM to 12 noon) without excessive BP lowering during the nighttime hours. Smith et al18 evaluated CODAS-verapamil in a multicenter, placebo-controlled, double-blind study of 278 patients with mild to moderate essential hypertension. Patients were randomized to receive either placebo or verapamil in one of four daily doses (100, 200, 300, or 400 mg). Of the 278 patients who met the study eligibility criteria, 51 patients were randomized to placebo, 53 patients to CODAS-verapamil 100 mg, and 58 patients to each of the CODAS-verapamil 200 mg, 300 mg, and 400 mg groups. The ABPM was performed at the completion of each study phase (lead-in and randomization) in the 257 patients who completed adequate ABPM monitoring at the baseline and final study visits. CODAS-verapamil was effective in lowering diastolic blood pressure (DBP) versus placebo at all timepoints during the dosing interval. Systolic blood pressure (SBP) was also significantly reduced, except for at the time of trough concentration with the 200-mg dose. A dose-response was noted, with greater reductions in BP and heart rate occurring with higher doses.18 With all doses, BP and heart rate reductions were greatest during the morning (from 6 AM to 12 noon), when verapamil concentrations were highest. Fig. 4 shows the effect of CODAS-verapamil on SBP and DBP as assessed
AJH–September 2001–VOL. 14, NO. 9, PART 2
by ABPM. In addition, there was a lack of excessive BP lowering during the nighttime hours. With all CODASverapamil doses, there were significantly greater reductions in BP during the morning versus the nighttime hours and the 24-h mean reductions. Notably, CODAS-verapamil was also associated with excellent response rates; with doses of 300 mg and 400 mg daily, a decrease in DBP to ⬍90 mm Hg or ⬎10% was achieved in ⬎60% of patients18 (Fig. 5). Similar results were reported with COER-verapamil; BP was controlled throughout the dosing period, with greater reductions in the morning and smaller reductions in the evening.16,17 A subgroup analysis of COER-verapamil in “nondippers,” or patients who have a blunted or absent nocturnal decline in BP, showed that COER-verapamil had a greater effect on nighttime BP in this population.19 During the daytime, however, BP was similarly decreased in dippers and nondippers by COER-verapamil. This suggests that chronotherapy may help to normalize the circadian BP patterns in nondippers, a group at increased risk for target organ damage and cardiovascular events. In clinical studies of chronotherapeutic verapamil formulations, adverse events were primarily mild to moderate and comparable to those reported for other verapamil formulations. The most common adverse events were headache, infection, and constipation.16 –18
Morning Versus Evening Administration of Conventional Antihypertensive Agents Can the same effects be achieved by administering conventional antihypertensive agents at nighttime? In a small study of patients with moderate hypertension, Palatini20 demonstrated that nighttime administration of the angiotensin converting enzyme (ACE) inhibitor quinapril had a significantly greater effect on nocturnal BP versus morning administration (SBP 132 v 127 mm Hg, P ⬍ .01). Daytime pressures were similar with nighttime and morning administration. However, the results of studies with other antihypertensive agents given in the morning versus nighttime have been inconsistent; some show a change in the circadian BP patterns, whereas others suggest there is no change.16,20 Until the issue is resolved, it seems prudent to be cautious about administering conventional antihypertensive medications at nighttime— especially among elderly patients, who may be more susceptible to the adverse consequences of drug-induced nighttime hypotension.
Summary Statistical data continue to show that BP is poorly controlled in the United States. Thus, all strategies to lower and control BP more effectively need to be explored. Chronotherapeutic verapamil formulations provide effec-
AJH–September 2001–VOL. 14, NO. 9, PART 2
tive 24-h control of BP while mimicking normal circadian patterns. The delay in drug release avoids the problem of excessive BP lowering during sleep, whereas peak concentrations achieved in the morning protect against the hours of highest vulnerability. Data regarding the effect of chronotherapeutic agents on clinical outcomes will hopefully be available when the Controlled Onset Verapamil Investigation of Cardiovascular Endpoints (CONVINCE) Trial ends.21 This 5-year study began in 1996 and is scheduled for completion in 2002. The goal of CONVINCE is to determine whether a chronotherapeutic formulation of verapamil (COER-verapamil) will reduce the occurrence of cardiovascular endpoints (nonfatal myocardial infarction, stroke, or death due to cardiovascular disease) compared with a standard-care antihypertensive (a diuretic or -blocker). In this study, COER-verapamil will be dosed in the evening and the other agents will be dosed in the morning.21
References 1.
2.
3. 4.
5. 6.
7.
Willich SN, Levy D, Rocco MB, Tofler GH, Stone PH, Muller JE: Circadian variation in the incidence of sudden cardiac death in the Framingham Heart Study population. Am J Cardiol 1987;60: 801– 806. Cohen MC, Rohtla KM, Lavery CE, Muller JE, Mittleman MA: Meta-analysis of the morning excess of acute myocardial infarction and sudden cardiac death. Am J Cardiol 1997;79:1512–1515. Elliott WJ: Circadian variation in the timing of stroke onset. Stroke 1998;29:992–996. Smolensky MH, Portaluppi F: Chronopharmacology and chronotherapy of cardiovascular medications: relevance to prevention and treatment of coronary heart disease. Am Heart J 1999;137:S14–S24. Millar-Craig MW, Bishop CN, Raftery EB: Circadian variation of blood pressure. Lancet 1978;1:795–797. Tofler GH, Brezinski D, Schafer AI, Czeisler CA, Rutherford JD, Willich SN, Gleason RE, Williams GH, Muller JE: Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med 1987;316:1514– 1518. The Sixth Report of the Joint National Committee on Prevention Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med 1997;157:2413–2446.
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8. 9. 10. 11.
12.
13.
14.
15.
16.
17. 18.
19.
20.
21.
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Anwar YA, White WB: Chronotherapeutics for cardiovascular disease. Drugs 1998;55:631– 643. Data on file, Schwarz Pharma, Milwaukee, WI. Data on file, Pfizer Labs, New York, NY. Kario K, Matsuo T, Kobayashi J, Imiya M, Matsuo M, Shimada K: Nocturnal fall of blood pressure and silent cerebrovascular damage in elderly hypertensive patients. Hypertension 1996;27:130–135. White WB, Black HR, Weber MA, Elliott WJ, Bryzinski B, Fakouhi TD: Comparison of effects of controlled-onset extended-release verapamil at bedtime and nifedipine gastrointestinal therapeutic system on arising on early morning blood pressure, heart rate, and the heart-rate-blood pressure product. Am J Cardiol 1998;81:424– 431. Shimada K, Kario K: Altered circadian rhythm of blood pressure and cerebrovascular damage. J Ambul Blood Press Monit 1997;2: 333–338. Watanabe N, Imai Y, Nagai K, Tsuji I, Satoh H, Sakuma M, Sakuma H, Kato J, Onodera-Kikuchi N, Yamada M, Abe F, Hisamichi S, Abe K: Nocturnal blood pressure and silent cerebrovascular lesions in elderly Japanese. Stroke 1996;27:1319–1327. Hayreh SS, Zimmerman MB, Podhajsky P, Alward WLM: Nocturnal arterial hypotension and its role in optic nerve head and ocular ischemic disorders. Am J Ophthalmol 1994;117:603– 624. White WB, Anders RJ, MacIntyre JM, Black HR, Sica DA: Nocturnal dosing of a novel delivery system of verapamil for systemic hypertension. Verapamil Study Group. Am J Cardiol 1995;76:375– 380. White WB: A chronotherapeutic approach to the management of hypertension. Am J Hypertens 1996;9:29S–33S. Smith DHG, Neutel JM, Weber MA. A new chronotherapeutic oral drug absorption system for verapamil (CODAS-Verapamil) designed for once daily bedtime dosing optimizes blood pressure control in the morning. Am J Hypertens 2001;14:14 –19. White WB, Mehrotra DV, Black HR, Fakouhi TD: Effects of controlled-onset extended-release verapamil on nocturnal blood pressure (dippers versus nondippers). COER-Verapamil Study Group. Am J Cardiol 1997;80:469– 474. Palatini P: Can an angiotensin-converting enzyme inhibitor with a short half-life effectively lower blood pressure for 24 hours? Am Heart J 1992;123:1421–1425. Black HR, Elliott WJ, Neaton JD, Grandits G, Grambsch P, Grimm RH, Hansson L, Lacouciere Y, Muller J, Sleight P, Weber MA, White WB, Williams G, Wittes J, Zanchetti A, Fakouhi D: Rationale and design for the controlled onset verapamil investigation of cardiovascular endpoints (CONVINCE) trial. Control Clin Trials 1998; 19:370–390.
2001; 14:296S–301S
Pharmacology of Cardiovascular Chronotherapeutic Agents David H. G. Smith Although sudden cardiac death, myocardial infarction, or stroke can occur at any time of day, event rates increase during the waking hours, particularly in the morning. In most people— both normotensive and hypertensive— blood pressure (BP) rises rapidly in the early morning hours, the time when most individuals wake and begin their day. This rise in BP corresponds to increased secretion of catecholamines and increased plasma renin activity. Thus, vascular tone and total peripheral resistance increase in the morning hours, and BP rises as a result. At the same time, heart rate increases. In the late morning or early afternoon, BP reaches its peak. After that, BP declines, falling 15 to 20 mm Hg between about 8 PM and 2 AM, the time when BP is usually lowest. These findings have led to an interest in chronotherapy for hypertension. A major objective of chronotherapy for hypertension is to deliver the drug in higher concentrations
A
during the early-morning post-awakening period, when BP is highest, and in lesser concentrations during the middle of a sleep cycle, when BP is low. Traditional sustainedrelease pharmacologic agents, which deliver a near-constant drug concentration, were not designed to complement the circadian pattern. There are currently two antihypertensive agents, Verelan PM (verapamil HCl) and Covera HS (verapamil HCl), that provide chronotherapy for hypertension. These drugs use novel delivery systems that provide 24-h BP control while maximizing drug concentrations in the morning and minimizing drug concentrations during sleep. Am J Hypertens 2001;14: 296S–301S © 2001 American Journal of Hypertension, Ltd. Key Words: Chronotherapy, hypertension, calcium channel antagonists, verapamil.
nalysis of large, population-based studies has shown that many cardiovascular events—including myocardial infarction (MI), stroke, and sudden cardiac death— cluster during the initial hours of morning activity, between 6 AM and 12 noon.1–3 In the Framingham Heart Study, the time of day of sudden cardiac death was analyzed among ⬎5,000 patients in the original cohort over a follow-up period of 38 years. The risk of sudden cardiac death was greatest between 6 AM and 12 noon, and was much higher during this period than other times during the day.1 Furthermore, a meta-analysis of 30 studies including ⬎66,000 patients demonstrated that the incidence of MI is highest between 6 AM and 12 noon (approximately 40% greater than at other times).2 Finally, a meta-analysis of 31 studies including almost 12,000 patients showed that stroke occurs in a very similar pattern, with a 49% increase during the hours between 6 AM and 12 noon.3 The pathophysiologic mechanisms behind these phenomena are not clearly understood, but are probably related to increased stress placed on the cardiovascular system by rapidly changing hemodynamic and hemostatic factors that occur during the early morning.4 It has long
been appreciated that there are marked circadian rhythms in blood pressure (BP), both in normotensive and hypertensive persons5 (Fig. 1). Generally, BP rises rapidly in the early morning hours, the time when most individuals wake and begin their day.5 This rise in BP corresponds to increased secretion of catecholamines and increased plasma renin activity.6 Thus, vascular tone and total peripheral resistance increase in the morning hours, and BP rises as a result. At the same time, heart rate increases.4 In the late morning or early afternoon, BP reaches its peak. After that, BP declines, falling 15 to 20 mm Hg between about 8 PM and 2 AM, the time when BP is usually lowest.5 A “dip” of 10% to 20% in BP also typically occurs during nighttime; however, this dip may vary or be absent with severe or secondary hypertension. The most recent guidelines from the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) acknowledge the importance of the enhanced vulnerability to cardiovascular events in the morning, and recommend use of longacting antihypertensive agents that provide 24-h efficacy.7 However, because of the ciradian variations in BP and the propensity for cardiovascular events in the morning, med-
Received April 3, 2001. Accepted May 8, 2001. From the Memorial Research Medical Clinic, Long Beach, CaliforniaOrange County Research Center, Orange, California.
Address correspondence and reprint requests to David H. G. Smith, MD, Orange County Research Center, 505 S. Main Street, Suite 1025, Orange, CA, 92868.
0895-7061/01/$20.00 PII S0895-7061(01)02176-8
© 2001 by the American Journal of Hypertension, Ltd. Published by Elsevier Science Inc.
AJH–September 2001–VOL. 14, NO. 9, PART 2
CARDIOVASCULAR CHRONOTHERAPEUTIC AGENTS
297S
FIG. 1. Circadian rhythm in blood pressure. Results of 24-h ambulatory blood pressure monitoring in five normotensive persons and 10 untreated hypertensive patients. Adapted with permission from Millar-Craig MW, et al: Circadian variation of blood pressure. Lancet 1978;1:795–797.5
ications that are formulated to ensure a near-constant drug concentration will not provide for periods of increased drug concentrations in attempts to control hypertension more optimally during these critical times of the 24-h period.4 One of the newest advances in antihypertensive therapy is chronotherapeutics, or the design of drugs according to chronobiological principles. Chronotherapeutic medications deliver drugs in concentrations that vary according to predictable changes in physiologic need.4,8 In hypertension, chronotherapeutic medications deliver the drug in highest concentrations during the morning post-awakening period, when the need is greatest, and in lesser concentrations at nighttime, when the need is lowest. Recently, verapamil has been marketed in two formulations that use novel delivery systems to provide chronotherapy: Verelan PM (Schwarz Pharma Inc, Milwaukee, WI) and Covera-HS (Pharmacia Corp, Peapack, NJ). This article discusses some of the potential pharmacokinetic and pharmacodynamic advantages of these chronotherapeutic antihypertensive agents.
Pharmacokinetics of Antihypertensive Therapies Fig. 2 compares the plasma concentrations of a shortacting, immediate-release antihypertensive agent requiring three doses daily, an extended-release antihypertensive agent given once daily, and a chronotherapeutic agent given once daily.9,10 As shown, the short-acting agent is associated with significant peaks and troughs in drug concentrations throughout a 24-h period that can cause wide fluctuations in BP control and enhance the chances of drug-level associated adverse events; therefore, shortacting agents are not recommended for treating high BP.7 For many patients, there is an additional shortcoming with short-acting agents: that is, the longest time between any
two doses is probably between the last dose in the evening and the next dose in the morning. Thus, drug concentrations would be lowest at the time of day when BP protection is most needed. The once-daily extended-release shows a sustained drug concentration over the 24-h dosing interval. Although this profile has been shown to result in safe and effective BP lowering, this static pattern of drug release is not tailored to suit daily physiologic variations. In contrast, true chronotherapeutic agents result in drug concentrations that synchronize with the daily variation in BP. Thus, chronotherapetic agents add a dynamic element to drug delivery and release greater amounts of drug during the critical morning period and lesser amounts of drug during the nighttime. This dynamic pattern of drug delivery maximizes BP control in the morning while minimizing the risk of excessive BP lowering during sleep. Maintaining adequate BP levels during sleep may be particularly important in elderly patients and in those with peripheral vascular disease; in such patients, traditional antihypertensive agents administered at bedtime may increase the risk of nighttime hypotension and subsequent ischemic stroke and ischemia-induced neuropathy of the optic nerve.11–15
Chronotherapeutic Delivery Systems Most calcium channel antagonists, including verapamil, are inherently short-acting compounds. These antihypertensive agents rely on a delivery system for sustained action and, in the case of Verelan-PM and Covera HS, to give them the dynamic chronotherapeutic element. Verelan PM uses Chronotherapeutic Oral Drug Absorption System (CODAS) technology, and Covera-HS uses the Controlled-Onset, Extended-Release (COER-24) Delivery System (Fig. 3). Both systems are designed for bedtime dosing, which results in maximum plasma concentrations
298S
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AJH–September 2001–VOL. 14, NO. 9, PART 2
FIG. 2. Effect of delivery system on steady-state plasma concentration of drug (From data on file, Schwarz Pharma, Pfizer Labs.9,10)
of verapamil in the morning, when BP typically surges, and in trough concentrations during sleep, when BP is normally lowest.
The CODAS delivery system incorporates a 4- to 5-h delay in drug delivery followed by an extended drug release with a peak concentration occurring approximately
FIG. 3. Delivery systems used in chronotherapeutic antihypertensive agents.
AJH–September 2001–VOL. 14, NO. 9, PART 2
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FIG. 4. Effect of CODAS-Verapamil 300 mg on blood pressure according to ambulatory blood pressure monitoring. A) Ambulatory systolic blood pressure (SBP) at baseline and the final study visit. B) Ambulatory diastolic blood pressure (DBP) at baseline and the final study visit. Data based on Smith DHG, et al.18
11 h after administration. Trough concentrations occur approximately 4 h after bedtime dosing. Each capsule
contains numerous pellets that consist of an inert core surrounded by active drug and rate-controlling membranes
FIG. 5. Response to therapy with CODAS-Verapamil. Diastolic blood pressure measured manually at time of trough concentration (approximately 11 h after CODAS-verapamil administration). Data based on Smith DHG, et al.18
300S
CARDIOVASCULAR CHRONOTHERAPEUTIC AGENTS
that combine water-soluble and water-insoluble polymers. As the pellets lie in the gastrointestinal tract, water washes over the polymer-coated pellets, slowly dissolving the water-soluble polymer and allowing the drug to diffuse through the resultant pores in the coating. The waterinsoluble polymer continues to provide a barrier and maintains the controlled release of the drug throughout the remainder of the 24-h dosing interval. The Covera-HS system is similar to the gastrointestinal therapeutic system used with extended-release nifedipine. The outermost component of the COER-24 delivery system is a semipermeable membrane that regulates absorption of water into the tablet. Water is absorbed from the gastrointestinal tract at a fixed rate, until a second layer is reached. The second layer, or delay coat, then absorbs water and temporarily prevents the passage of water into the inner core of the tablet, which contains verapamil. This process delays drug release for approximately 4 to 5 h. When sufficient moisture has been absorbed, a third layer expands by osmosis, pushing verapamil out of the tablet at a consistent rate. Continued absorption of water and ongoing osmotic expansion of the third layer provides for extended release of drug and 24-h control of BP.
Blood Pressure Control With Chronotherapeutic Agents Both Verelan PM (CODAS-verapamil) and Covera-HS (COER-verapamil) have been shown to be safe and effective antihypertensive agents.16 –18 In addition, 36-h ambulatory blood pressure monitoring (ABPM) has shown that these agents achieve optimal control during the morning period (6 AM to 12 noon) without excessive BP lowering during the nighttime hours. Smith et al18 evaluated CODAS-verapamil in a multicenter, placebo-controlled, double-blind study of 278 patients with mild to moderate essential hypertension. Patients were randomized to receive either placebo or verapamil in one of four daily doses (100, 200, 300, or 400 mg). Of the 278 patients who met the study eligibility criteria, 51 patients were randomized to placebo, 53 patients to CODAS-verapamil 100 mg, and 58 patients to each of the CODAS-verapamil 200 mg, 300 mg, and 400 mg groups. The ABPM was performed at the completion of each study phase (lead-in and randomization) in the 257 patients who completed adequate ABPM monitoring at the baseline and final study visits. CODAS-verapamil was effective in lowering diastolic blood pressure (DBP) versus placebo at all timepoints during the dosing interval. Systolic blood pressure (SBP) was also significantly reduced, except for at the time of trough concentration with the 200-mg dose. A dose-response was noted, with greater reductions in BP and heart rate occurring with higher doses.18 With all doses, BP and heart rate reductions were greatest during the morning (from 6 AM to 12 noon), when verapamil concentrations were highest. Fig. 4 shows the effect of CODAS-verapamil on SBP and DBP as assessed
AJH–September 2001–VOL. 14, NO. 9, PART 2
by ABPM. In addition, there was a lack of excessive BP lowering during the nighttime hours. With all CODASverapamil doses, there were significantly greater reductions in BP during the morning versus the nighttime hours and the 24-h mean reductions. Notably, CODAS-verapamil was also associated with excellent response rates; with doses of 300 mg and 400 mg daily, a decrease in DBP to ⬍90 mm Hg or ⬎10% was achieved in ⬎60% of patients18 (Fig. 5). Similar results were reported with COER-verapamil; BP was controlled throughout the dosing period, with greater reductions in the morning and smaller reductions in the evening.16,17 A subgroup analysis of COER-verapamil in “nondippers,” or patients who have a blunted or absent nocturnal decline in BP, showed that COER-verapamil had a greater effect on nighttime BP in this population.19 During the daytime, however, BP was similarly decreased in dippers and nondippers by COER-verapamil. This suggests that chronotherapy may help to normalize the circadian BP patterns in nondippers, a group at increased risk for target organ damage and cardiovascular events. In clinical studies of chronotherapeutic verapamil formulations, adverse events were primarily mild to moderate and comparable to those reported for other verapamil formulations. The most common adverse events were headache, infection, and constipation.16 –18
Morning Versus Evening Administration of Conventional Antihypertensive Agents Can the same effects be achieved by administering conventional antihypertensive agents at nighttime? In a small study of patients with moderate hypertension, Palatini20 demonstrated that nighttime administration of the angiotensin converting enzyme (ACE) inhibitor quinapril had a significantly greater effect on nocturnal BP versus morning administration (SBP 132 v 127 mm Hg, P ⬍ .01). Daytime pressures were similar with nighttime and morning administration. However, the results of studies with other antihypertensive agents given in the morning versus nighttime have been inconsistent; some show a change in the circadian BP patterns, whereas others suggest there is no change.16,20 Until the issue is resolved, it seems prudent to be cautious about administering conventional antihypertensive medications at nighttime— especially among elderly patients, who may be more susceptible to the adverse consequences of drug-induced nighttime hypotension.
Summary Statistical data continue to show that BP is poorly controlled in the United States. Thus, all strategies to lower and control BP more effectively need to be explored. Chronotherapeutic verapamil formulations provide effec-
AJH–September 2001–VOL. 14, NO. 9, PART 2
tive 24-h control of BP while mimicking normal circadian patterns. The delay in drug release avoids the problem of excessive BP lowering during sleep, whereas peak concentrations achieved in the morning protect against the hours of highest vulnerability. Data regarding the effect of chronotherapeutic agents on clinical outcomes will hopefully be available when the Controlled Onset Verapamil Investigation of Cardiovascular Endpoints (CONVINCE) Trial ends.21 This 5-year study began in 1996 and is scheduled for completion in 2002. The goal of CONVINCE is to determine whether a chronotherapeutic formulation of verapamil (COER-verapamil) will reduce the occurrence of cardiovascular endpoints (nonfatal myocardial infarction, stroke, or death due to cardiovascular disease) compared with a standard-care antihypertensive (a diuretic or -blocker). In this study, COER-verapamil will be dosed in the evening and the other agents will be dosed in the morning.21
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