Evolving Concepts in Chronotherapy with CCBs: Implications for Pharmacists

Behavioral Objectives

After completing this continuing education article, the pharmacist should be able to:

• Review the pathophysiology behind the circadian rhythm of cardiovascular events and focus on the role-modulating factors and onset of the event.
• Analyze chronotherapeutic strategies in the management of hypertension and chronic stable angina.
• Evaluate the current data on the use of novel chronotherapeutic agents in the management of hypertension and chronic stable angina.
• Provide appropriate patient counseling regarding the use of FDA-approved chronotherapeutic agents.
• Delineate the role of the pharmacist in optimizing patient care through the use of chronotherapy.

In pharmacy school, we are trained to focus on what specific therapeutic agent to recommend??what are its particular side effects, drug interactions, and contraindications; who exclusively should receive therapy; and how specifically should the therapy be monitored. As pharmacists, we are taught that our biology is maintained in a relatively constant state of homeostasis; therefore, we are not always concerned with when to administer a particular medication. Over the past decade, researchers have investigated the effects of timing drug administration to correspond to biologic rhythms for the management of certain disease states.^1-3 This movement has led to the development of new, innovative drugrelease technologies, allowing medications that are maximally effective at different points in our 24-hour circadian cycle to be used according to the body's specific physiologic needs. This new era of therapeutics has been termed chronopharmacology or chronotherapy. This review is designed to educate the pharmacist on the basic principles of chronotherapeutics, especially as it impacts cardiovascular disease.

Principles of Chronobiology

Chronobiology is defined as the scientific study of how biologic rhythms and their fundamental mechanisms impact both health and disease.^4,5 In other words, chronobiology teaches that human biologic and physiologic processes demonstrate a predictable-intime cyclic variability.⁴ Before understanding the principles of chronotherapy, it is useful to review the basic tenets of biologic rhythms. A biologic rhythm is a self-sustaining oscillation.⁴ It is defined by its period, amplitude, and stage. Period is "the duration of time required to complete a single cycle."⁶ A rhythm with a period ??24 hours is termed circadian.⁶ Amplitude is "a measure of predictable-in-time variability due specifically to rhythmicity."⁶ Examples of circadian rhythms that have relatively low amplitude are body temperature and heart rate, whereas plasma cortisol and norepinephrine exhibit a higher amplitude. The amplitude can differ in magnitude, depending on biologic variables, age, and concomitant morbidities.⁶ Stage, or phase, refers to "the timing of specific features, such as the peak and trough of rhythms, relative to the 24-hour day or the week, month, or year."⁶ For cortisol, the staging of its circadian rhythm is defined by a prominent morning peak and a trough that occurs during sleep.

Although the human circadian clock is perceived as exactly 24 hours, in most individuals it is slightly longer and sometimes shorter. Light/dark and other societal/environmental time cues train our dominant internal pacemaker clock, the anterior hypothalamus, to a 24-hour time structure and stage the peaks and troughs of circadian rhythms to support the diurnal activity-nocturnal sleep routine.^7-9 The timing of these peaks and troughs is quite predictable from 1 day to the next in the majority of people who adhere to a fairly regular sleep-activity schedule. The problem arises when the sleep-activity routine is abruptly altered, such as in workers who rotate between day and night shifts or travelers who rapidly move across different time zones.¹⁰ These situations require gradual restaging of the peaks and troughs of the body's circadian rhythms, which takes about 3 to 4 days. The therapeutic implications of this will be discussed later in the article.

The human circadian time structure can be represented as a clock-like diagram making reference to the sleepactivity cycle (Figure 1). Late at night or early in sleep, basal gastric acid secretion, white blood cell count, and atrial natriuretic peptides (which are potent vasodilators) begin to rise. Later in the sleep cycle, growth and thyroid-stimulating hormone, blood lymphocyte and eosinophil number, and plasma concentrations of melatonin and prolactin start to peak, as do adrenocorticotropic hormone, follicle-stimulating hormone, and luteinizing hormone. Plasma cortisol, renin, angiotensin, and aldosterone crest in the morning, as do arterial compliance, vascular resistance, platelet aggregation, and blood viscosity. Hemoglobin and insulin concentrations are greatest in the afternoon, whereas serum cholesterol and triglycerides are highest in early evening.^6,11-13 Clearly, these data are compelling that human biochemistry and physiology are not constant; rather, they vary in a predictable manner during the 24-hour time period.

It seems plausible that timing of certain medical conditions and life-threatening emergencies may parallel these physiochemical circadian variations. Osteoarthritis worsens during the course of daily activities, being most bothersome in the evening; heart failure worsens nocturnally; and depression can flare in the early morning hours (Figure 2).⁴ From large database analyses and epidemical studies, we know that acute myocardial infarction (MI), sudden cardiac death, thrombotic stroke, and angina occur several-fold more frequently in the initial early morning hours (ie, 6^AM-12^PM), compared with any other time of the day or night.^{14, 15} From a physiologic standpoint, why does this occur?

Chronobiology of Cardiovascular Conditions

Angina, Myocardial Infarction, Stroke, Sudden Death

Cardiovascular hemodynamics follow a circadian pattern. Heart rate (HR) and blood pressure (BP) are the lowest during sleep and rise toward the end of the sleep cycle (Figure 3).^16,17 Upon awakening, a change in posture is followed by systemic increases in catecholamines, cortisol, aldosterone, angiotensin, and plasma renin. Moreover, the body exhibits heightened sensitivity to such changes as evidenced by the lower concentration of epinephrine needed to induce platelet aggregation or vessel vasoconstriction.^18-20 All of these actions translate to increased HR, BP, coronary tone, and vessel caliber, which disrupts the equilibrium between myocardial oxygen demand and supply.^14,21 A method to evaluate this complex interaction between HR and systolic BP (SBP) is known as the rate-pressure product (RPP) [RPP = SBP x HR]. Sharp RPP elevations during the early morning hours have been associated with increased myocardial ischemic events particularly in patients with coronary artery disease. These findings are independent of the patient's BP. Clinically, this suggests that BP alone may not be an adequate indicator of myocardial oxygen demand and ischemia risk, but rather the RPP may be the better predictor.^22,23

The other key pathophysiologic process is possible rupture of vulnerable atherosclerotic plaques.^14,15 Mental or physical stress initiated by mechanical forces (eg, arterial pressure surges or vasoconstriction) promote shearing stress of sufficient magnitude to cause initial disruption of a stable atherosclerotic plaque. The exposure of naked intimal collagen and tissue factors in turn serve as foci for platelet aggregation, inflammatory mediators, and resultant thrombus formation around the disrupted plaque. Minor ruptures may elicit an asymptomatic mural thrombus or result in unstable angina or non-ST-segment elevation MI (ie, non-Q-wave MI). However, with the addition of other external stimuli (such as smoking) to the increased coagulability and vasoconstriction, a major rupture can culminate in a potentially fatal occlusive coronary thrombus.^14,15

Hypertension

Due to the neurohormonal changes discussed above, the typical circadian variation in BP for the majority of hypertensive patients follows a nadir occurring during the nighttime hours and a surge occurring during the early morning period when individuals typically rise for the day (Figure 4).¹⁷ These patients can be grouped into 2 subsets: "dippers"and "extreme dippers." The term "dippers"describes those patients whose nocturnal pressure is at least 10% to 20% lower than their daytime pressure. "Extreme dippers" have a nocturnal pressure that is > 20% lower than their daytime pressure.²⁴ In 10% to 30% of hypertensive patients, however, this characteristic pattern may be absent or blunted. These patients are known as "nondippers."^24-27 This subgroup of hypertensives are at greatest risk for end-organ damage (eg, left ventricular hypertrophy, cerebrovascular disease, microalbuminuria).²⁶ The causes of the nondipping BP pattern may involve autonomic dysfunction, diabetes, renal insufficiency, and drugs (eg, cyclosporine, high-dose corticosteroids).²⁸ For the extreme dippers, the risk for end-organ damage is also high (although not as high as with nondippers), although it remains unclear whether this risk is attributed to the rapid nocturnal BP decline, the low nocturnal BP itself, or the morning surge of BP on awakening. To answer this question, Kario and colleagues prospectively studied stroke prognosis in 519 older hypertensives in whom ambulatory BP monitoring (ABPM) was performed. The morning BP surge (MS) was defined as the difference between the mean systolic BP during the 2 hours after waking and arising minus the MS BP during the hour that included the lowest BP during sleep. Over the 41-month study period, 44 strokes occurred. Patients were divided into 2 groups: MS (??55 mm Hg) and non-MS (< 55 mm Hg). The investigators found that those in the MS group had a higher baseline prevalence of multiple cerebral infarcts (57% vs 33%, P=.001) and a higher incidence of stroke (19% vs 7.3%, P=.004), compared with the non-MS group, respectively. Moreover, the MS group was associated with stroke events independent of 24-hour BP, nocturnal BP dipping status, and baseline prevalence of silent infarcts (P=.008).²⁹

Overview of Chronotherapy

Chronotherapy is a method of optimizing safe and effective pharmacotherapy by proportioning drug concentration throughout the 24-hour time period in synchrony with biologic rhythms of disease processes. A chronotherapeutic approach may be chosen when the threat of dangerous medical events or the intensity and symptoms of a disease are known to vary predictably during the 24-hour time period.²⁸ Having patients take their prednisone once daily in the morning as opposed to multiple daily doses, so as to minimize the risk of hypothalamic-pituitary-adrenal suppression, or administering simvastatin in the evening, thereby taking advantage of evening increases of cholesterol synthesis, are examples of chronotherapy.

Chronotherapeutic Approaches with Conventional Antihypertensive/Antianginal Agents

How are these principles applied to improving patient care? In the cardiovascular patient, the focus of chronotherapy would be to optimally deliver the antihypertensive and/or antianginal agent in higher concentrations during the time of greatest need (ie, the early morning postawakening hours) and lower concentrations when the need is less (ie, the middle of the sleep cycle). This principle is extremely important for the dippers and extreme dippers. In these populations, higher nocturnal drug concentrations can correlate with a greater BP reduction and possible ischemic stroke and/or ischemia-induced neuropathy of the optic nerve.^30-33

One chronotherapeutic strategy would be to suggest that antihypertensive and/or antianginal agents be taken at bedtime. Although this seems obvious, the data at this point are insufficient to show whether altering the dosing time of a conventional agent can lead to the intended objective. Furthermore, only a few studies have assessed this strategy by administering conventional, once-daily antihypertensive agents in the morning versus in the evening.³⁴ Many of these studies demonstrated inconsistent findings, however, with some showing a change in circadian BP patterns and others suggesting no change. It is important to note that the majority of these studies are underpowered to demonstrate true equivalence of dosing effects. Until the issue is resolved, it is prudent to be cautious when administering conventional antihypertensive/antianginal medications at nighttime, especially for elderly patients and extreme dippers who may be more susceptible to drug-induced nocturnal hypotension.

FDA-Approved Chronotherapeutic Medications

Currently available once-daily, extended-release antihypertensive medications provide safe and effective BP reductions over a 24-hour dosing interval, but their static pattern of drug release may not be tailored to suit daily physiologic BP variations. The same can be said regarding once-daily antianginal medications. True chronotherapeutic agents impart a dynamic element to drug delivery by providing larger drug concentrations during the critical morning period and smaller amounts during the nighttime, thereby minimizing the risk of excessive nocturnal BP drops. Currently, 3 chronotherapeutic calcium channel blockers are available on the market for the management of certain cardiovascular diseases (Figure 5).^35-39 When administered at bedtime (2200), all 3 agents provide a peak effect coinciding with the rise in BP and HR in the critical time period of 6:00^AM to noon, and trough concentrations during sleep.^35-39

Approved by the FDA in 1996 for hypertension and angina, Covera-HS (verapamil HCl) was initially developed and marketed by Searle until Pfizer obtained the company in 2001. Covera-HS uses the controlled-onset, extended-release (COER) delivery system, which mirrors the gastrointestinal therapeutic system (GITS) used in extended-release Procardia XL (nifedipine). The tablet consists of multiple layers or coats. The outermost coat is composed of a semipermeable membrane that regulates the amount of water that can penetrate into the tablet. Water from the gastrointestinal (GI) tract will continue to saturate this layer at a fixed rate until the second coat is reached. This second coat will continue to absorb water but temporarily impedes any fluid from reaching the inner core of active drug. After 4 to 5 hours, fluid eventually penetrates to the third coat, which osmotically expands, pushing verapamil out of the tablet at a constant, fixed rate. This continued osmotic expansion allows the extended release of verapamil over the 24-hour time period.^13,37,40

Approved by the FDA in 1998 for hypertension, Verelan PM (verapamil HCl), marketed by Schwarz Pharma, uses the chronotherapeutic oral drug absorption system (CODAS) technology. This technology incorporates a 4-to 5-hour delay in drug delivery followed by extended drug release. Peak concentrations occur 11 hours after the drug is administered, with trough concentrations occurring approximately 4 hours post-dose. Each capsule contains pellets consisting of an inert core surrounded by active drug and rate-controlling membranes composed of water-soluble and water-insoluble polymers. Moving through the GI tract, the coated pellets are bathed in water, which in turn dissolves the water-soluble polymer, permitting the drug to diffuse through pores along the outer coating. The controlled release of the drug throughout the 24-hour time period is dependent on the water-insoluble polymers, which impede immediate dispersion of verapamil.^13,35,38

Approved by the FDA in 2003 for hypertension and angina, Cardizem LA (diltiazem HCl), marketed by Biovail, employs a unique graded extendedrelease tablet delivery system. Each tablet consists of polymer-coated, compressed beads. This particular polymer creates a lag time in tablet dissolution, allowing for detectable plasma concentrations within 3 to 4 hours and maximal concentrations within 11 to 18 hours post-dose.³⁹ Pharmacists frequently ask how the LA and CD formulations of Cardizem differ. First, as previously mentioned, bedtime dosing of Cardizem LA provides peak diltiazem concentrations within 11 to 18 hours, whereas bedtime dosing of Cardizem CD provides peak diltiazem within 10 to 14 hours (Figure 6).^41,42 To obtain possible chronotherapeutic benefits with Cardizem CD during the 6:00^AM to noon time period, the patient would have to administer the capsule at about 2:00^AM. Second, when dosed at bedtime, Cardizem LA demonstrates a 1-peak plasma concentration profile, as opposed to the CD formulation, which exhibits a 2-peak profile, with decreasing plasma concentrations during the early morning hours.^41,42 Finally, the polymer technology of the LA formulation allows for a longer diltiazem halflife of 6 to 9 hours, compared with 5 to 8 hours with the CD preparation.^39,43

Pivotal Data for Chronotherapeutic Agents in Hypertension and Angina

Hypertension

Because it was the first to receive approval, most of the available hypertension data are on Covera-HS. In comparison studies, Covera-HS (240 mg titrated to 360 mg at bedtime) exhibited significantly greater earlymorning BP reductions, compared with enalapril (10 mg titrated to 20 mg in the morning) and losartan (50 mg titrated to 100 mg in the morning) (-15/-10 mm Hg vs -9/-7 mm Hg vs -8/- 5 mm Hg, P <.01, P <.001, respectively). Covera-HS also led to a more significant decrease in morning HR (P <.001), rate-pressure product (P <.003), and rate of rise of BP (P <.05) compared with the other 2 groups. In terms of mean 24-hour, Covera-HS was similar to enalapril, but resulted in a greater reduction when compared with losartan (P <.01).42 Similar findings were observed when Covera-HS (180 mg titrated to 480 mg at bedtime) was compared with Procardia XL (30 mg titrated to 120 mg in the morning), although Procardia XL lowered nocturnal systolic BP to a greater extent than did Covera-HS (-11 mm Hg, vs -5.8 mm Hg; P <.001).44 As expected, Covera-HS also reduced nocturnal BP to a greater extent in hypertensive nondippers, compared with dippers (P <.0001).⁴⁵ Clinically, these last 2 studies highlight the safety of Covera-HS in high-risk hypertensive patients, compared with a long-acting dihydropyridine calcium channel blocker. Overall, the BP effects of Covera-HS are independent of body mass index, race, and age (??65 years).46-48 The recommended dose for hypertension is the same as that for angina.

Currently, no comparative trials with Verelan PM have been published, but studies show that in bedtime doses of 200 mg titrated to 400 mg/day, Verelan PM reduced diastolic BP to < 90 mm Hg and systolic BP to < 140 mm Hg in 85.3% and 76.9% of hypertensive patients, respectively.⁴⁹ Package labeling recommends beginning with 200 mg at bedtime, titrated to 300 mg, then to 400 mg.³⁸

Unlike the other chronotherapeutic agents, Cardizem LA can be dosed in the morning or in the evening, although higher diltiazem concentrations are obtained from 6:00^AM to noon when the product is dosed at bedtime (Figure 7).⁴¹ During this critical time, evening administration of Cardizem LA 360 mg correlated to an additional 3.3 mm Hg (P = .0004) diastolic BP reduction, compared with morning administration of 360 mg.50 In this 7-week randomized, placebo-controlled, dose-related trial, Cardizem LA showed greater reductions in leastsquare mean systolic BP with higher doses between 6 AM and noon (-12.2 mm Hg for 240 mg, -12.8 mm Hg for 360 mg, and -18.6 mm Hg for 540 mg). In a comparative study with ramipril, ramipril given in the evening (5 mg titrated to 10 mg to 20 mg) versus bedtime-administered Cardizem LA (240 mg titrated to 360 mg and to 540 mg), Cardizem LA significantly reduced early-morning systolic BP (-18 vs -13 mm Hg, P<.005); early-morning diastolic BP (-15 vs -8 mm Hg, P <.001); HR (-7.2 vs -1.1 beats per minute, P <.0001); and RPP (21% vs 12%, P <.001) to a greater extent, when compared with ramipril.⁵¹ The recommended dosing for hypertension is greater than that for angina; however, doses should be titrated every 2 weeks.³⁹ It is important to highlight that although effective antianginal treatment doses of diltiazem range from 180 mg/day to 360 mg/day, effective antihypertensive doses may require 360 mg/day or greater to achieve optimal BP reductions.⁵²

In a 12-week randomized, active-control study, Cardizem LA (360 mg titrated to 540 mg) significantly reduced diastolic BP during the first 4 hours after awakening and between 6^AM and noon by 3.5 mm Hg (P < .0049) and 3.2 mm Hg (P < .0019), respectively, compared with amlodipine (5 mg titrated to 10 mg) in African Americans with hypertension.

Cardizem LA also showed greater diastolic BP reduction between 6 AM and noon, compared with amlodipine (-12.0 mm Hg vs -8.8 mm Hg, respectively; P = .019). Although mean 24-hour diastolic BP and mean systolic BP reductions during the morning periods were comparable between treatment arms, amlodipine provided a significantly greater mean 24-hour systolic BP reduction (P < .002), whereas Cardizem LA exhibited a greater mean reduction in heart rate and rate-pressure product (P < .0008) at all time intervals.52

The highly anticipated CONVINCE trial (Controlled Onset Verapamil Investigation of Cardiovascular End Points) is the only study published evaluating the effect of chronotherapy on cardiovascular and cerebrovascular outcomes. This multicenter, double-blind randomized study attempted to determine whether Covera-HS (180 mg/ day), atenolol (50 mg/day), or hydro chlorothiazide (12.5 mg/day) could reduce first occurrence of stroke, MI, or cardiovascular disease -related deaths in 16,602 hypertensive patients with 1 or more risk factors for cardiovascular disease. This study was initially designed as a 5-year trial; it was prematurely terminated after 2 years for commercial reasons. At the study's termination and unblinding, no difference existed between groups for the composite primary end point, although patients receiving Covera-HS demonstrated a nonsignificant trend toward a lower incidence of acute MI, compared with both treatment groups.51 This was offset by a 15% (P = 26) higher risk of stroke and a statistically higher incidence of deaths or hospitalizations due to bleeding (P = .003) and heart failure (P = .05). At unblinding, less than a third of the planned number of events had been observed, thereby affecting the power of the study and limiting the applicability of the study end points.⁴⁴ Although these observations are important, because the study ended early the CONVINCE trial did not fully answer its primary question.

Chronic Stable Angina

Currently, only Covera-HS and Cardizem LA hold antianginal indications. In a dose-ranging study comparing bedtime-administered verapamil HCl 180 mg, 360 mg, 540 mg with placebo, all 3 doses significantly (P <.05) improved exercise duration and increased time to develop moderate-to-severe anginal symptoms, particularly with the higher doses.⁵³ Compared with other antianginal regimens, Covera-HS (240 mg titrated to 480 mg/day) was at least as effective as the combination of atenolol (50 mg/day) and amlodipine (5 -10 mg/day) or amlodipine monotherapy (5 -10 mg/day) at improving exercise tolerance and prolonging time to mild-to-moderate anginal symptoms. This study noted that Covera-HS monotherapy appeared to be more effective than amlodipine alone in decreasing ambulatory myocardial ischemia (P <.05), especially during the hours of 6:00^AM to noon. With all the studies, the most common side effect was constipation, which increased with large doses.⁵⁴

For Cardizem LA, evening doses of 180 mg, 360 mg, or 420 mg statistically improved exercise tolerance (P <.03), compared with morning doses of 360 mg or placebo. The greatest improvement occurred with the evening 360- mg dose??it had the largest impact of all evening doses during the critical time period of 7^AM to 11^AM (P <.0002). Although the 360-mg morning dose showed a trend toward improving exercise tolerance, it was not statistically significant (P = .06). For all evening doses, particularly during 7^AM to 11^AM, time to onset of angina and myocardial ischemia was significantly delayed (P <.03, respectively), compared with placebo. Overall, adverse events in all the Cardizem LA treatment groups were lower than those of placebo. A higher incidence of bradycardia was observed with the 420-mg dose; however, it is important to point out that these patients were also receiving concomitant atenolol.⁵⁵

Applying these data to practice, both chronotherapeutic technologies appear to be well tolerated, with an increasing number of side effects occurring at the higher dosing range. Covera-HS package labeling recommends a starting dose of 240 mg at bedtime and titrating to 360 mg, then to maximal dose of 480 mg.³⁷ Cardizem LA can be initiated either in the evening or in the morning at 180 mg and titrated to a maximal dose of 540 mg. Doses above 360 mg have not been shown to provide additional benefit in chronic stable angina, however.³⁹ To receive maximal effects, Cardizem LA should be administered in the evening.⁵⁵ Both medications can be titrated every 1 to 2 weeks. Please note that higher doses are required for optimal BP control in hypertension.

Implications for Pharmacists

Role of the Pharmacist

Chronotherapy can be confusing to comprehend for a patient. A patient who is being switched from a conventional long-acting antihypertensive or antianginal to a chronotherapeutic regimen may not fully understand the fundamentals behind the change. This in turn can lead to poor medication adherence, or, even worse, the patient may stop taking the medication. The pharmacist is in an excellent position to facilitate patient education regarding differences between conventional and chronotherapeutic technologies, the rationale for use, and pathophysiologic advantages of chronotherapy.

Informed pharmacists need to also instruct their fellow pharmacy colleagues in chronotherapeutic principles. A pharmacist may receive an order or prescription for a chronotherapeutic agent, only to realize that the agent is not stocked in the pharmacy, is not on formulary, and/or requires prior authorization. The pharmacist may try dispensing another long-acting formulation, believing that the conventional and chronotherapeutic agents are equivalent, but this is not the case. For a product to be considered bioequivalent and legally interchanged by the pharmacist, it must receive an AB rating by the FDA.⁵⁶ As seen in the Table, 5 brand-name extended-release diltiazem formulations are currently available: Cardizem CD, Cardizem SR, Tiazac, Dilacor XR, and Cardizem LA, none of which are AB-rated with each other. In the case of diltiazem, multiple AB-rated generics exist for Cardizem CD, Cardizem SR, Tiazac, and Dilacor XR, but not for Cardizem LA. The same holds true for sustained-release verapamil products and both Covera-HS and Verelan PM.⁵⁶

With the increased availability and acceptance of ABPM in the outpatient setting, pharmacists can accurately assist providers in identifying appropriate candidates for chronotherapy, as well as provide additional medication therapy management services such as dose adjustments and options for therapeutic alternatives. Despite achieving antianginal benefit at lower doses, patients will also need to be assessed for dose increases regarding BP control, which can be done by the pharmacist. Not all patients are candidates for chronotherapy. For example, nondippers warrant a more aggressive drug regimen that provides high drug concentrations over the entire 24-hour period. For patients who do shift work and are constantly flipping between night and day shifts, chronotherapy may be too complex and confusing to administer. Not all patients are candidates for verapamil or diltiazem. Pharmacists will need to diligently screen patients for systolic dysfunction, heart block, sick sinus syndrome, and/ or Wolf-Parkinson-White syndrome, because verapamil and diltiazem are contraindicated in these comorbidities. The charge for ABPM in the United States ranges from $100 to $350, and many third-party insurers have begun to pay for monitors. In addition, Medicare has announced plans to begin reimbursing for ABPM performed in patients with suspected white-coat hypertension. This policy change will likely lead to increased use of ABPM services, allowing pharmacists to become more involved with optimizing patients'pharmacotherapy.⁵⁷

Pharmacists should also be aware of the high potential for drug-drug interactions with diltiazem and verapamil.⁵⁸ Both agents are potent inhibitors of the cytochrome P450 3A4 isoenzyme (CYP3A4) and the efflux pump P-glycoprotein (P-gp). CYP3A4 is particularly clinically important because >60% of oxidized drugs undergo biotransformation through this enzyme system. Therefore, serum concentrations of CYP3A4 and P-gp substrates such as statins (eg, simvastatin, lovastatin), antiarrhythmics (eg, amiodarone, quinidine, dofetilide), positive inotropic agents (eg, digoxin), anticonvulsants (eg, phenytoin), immunosuppressants (eg, tacrolimus, cyclosporine), and benzodiazepines (eg, triazolam) can be increased when diltiazem or verapamil is added to a regimen.⁵⁸ Furthermore, the addition of negative inotropic/chronotropic medications (eg, betablockers, digoxin) to a verapamil-or diltiazem-containing regimen can promote increased bradycardia and heart block. The pharmacist is the ideal practitioner to provide pharmaceutical care , including identifying and intervening when potentially hazardous drug-drug interactions have been missed by the primary provider, suggesting dosage adjustments, and counseling patients on therapeutic options.

Patient Counseling

Patients should be educated on possible side effects such as bradycardia, constipation, dizziness, and lower extremity edema and told to immediately inform their pharmacist and provider if such symptoms should occur. If constipation occurs, patients may try increasing their fluid and fiber intake. Otherwise, the pharmacist can suggest to the provider that the dose be reduced, or if patients are taking verapamil, they might be switched to a diltiazem- containing agent if constipation becomes bothersome. If patients tolerate other nondihydropyridine calcium channel blockers, however, they should tolerate the chronotherapeutic counterparts.³⁴

Patients should also be reminded to keep appointments with the provider who is monitoring their therapy. Pharmacists should emphasize that office or pharmacy evaluation of BP during morning and early afternoon hours is essentially a measure of the drug's peak effect. The usual evaluation of trough effect, which sometimes might be needed to evaluate the appropriateness of any given dose, would be just prior to bedtime.

Patients should also be instructed to communicate with their pharmacist and provider if they receive any new prescription medications (such as for sleep, cholesterol, and heart problems) and/or begin taking any herbal therapies. Herbal agents, such as hawthorn, danshen, ginger, Panax ginseng, and valerian, can all lower BP and should be avoided in combination with diltiazem or verapamil.⁵⁹ St. John's wort is an inducer of both CYP3A4 and P-gp and can lower both verapamil and diltiazem concentrations, leading to therapeutic failure.⁶⁰ Other potential cardiotoxic herbal agents such as calamus, cereus, cola, coltsfoot, devil's claw, European mistletoe, fenugreek, fumitory, white horehound, mate, parsley, quassia, scotch broom flower, and shepherd's purse should all be avoided.⁵⁹

The pharmacist should also reinforce the proper dosing time of the regimen. In the case of Covera-HS and Verelan PM, the medication must be taken at bedtime. Cardizem LA can be administered either in the morning or at bedtime for both hypertension and angina. When Cardizem LA is taken at bedtime, however, additional antihypertensive and antianginal benefits are conferred. Furthermore, to achieve the true chronotherapeutic protection for hypertension, Cardizem LA should be taken prior to sleep. For patients who consistently work at night and sleep during the daytime, any of the 3 chronotherapeutic agents can be administered prior to sleeping regardless of environmental cues. Patients should try to take the medication at the same time every day. If a dose is missed, the dose should be taken as soon as the patient remembers, but if it is time for the next dose, the dose should be skipped.

All 3 agents can be administered independent of a meal, but Covera-HS and Verelan PM must be swallowed whole and not chewed, crushed, or split, as this may damage the drug delivery system and cause dose dumping. Although it is not scored, Cardizem LA can be split without damaging the integrity of the release system. This is an added benefit for patients who cannot swallow a large capsule or tablet. The drug cannot, however, be chewed or crushed. The pharmacist should warn patients receiving Covera-HS that they may see the drug "shell"in their stool. This is expected and does not mean that the drug is not working.

Robert Lee Page II, PharmD, BCPS: Assistant Professor of Clinical Pharmacy, UCHSC, School of Pharmacy; Clinical Specialist, Division of Cardiology/Heart Transplantation, University of Colorado Hospital

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(Based on the article starting on page 115.) Choose the 1 most correct answer.

1. The method of optimizing pharmacotherapy by allocating certain doses for certain times of the day is called..?

• Chronobiology
• Chronotherapy
• Chronotoxicity
• Chronokinetics

2. Cortisol's circadian rhythm exhibits a definitive morning peak, with a lower trough concentration occurring at bedtime. This is an example of which principle of chronobiology?

• Period
• Amplitude
• Biologic rhythm
• Phase

3. Aldosterone does not peak during the early morning hours.

• True
• False

4. Most acute episodes of angina, myocardial infarction, stroke, and sudden death occur during which part of the day?

• 6:00^AM-12:00^PM
• 12:00^PM-6:00^PM
• 6:00^PM-12:00^AM
• 12:00^AM-6:00^AM

Questions 5 and 6 involve the case below:

TJ is a patient who has been referred to your community pharmacy by his primary care physician for a pharmacotherapy consult. TJ has with him the latest results of his 24-hour ambulatory blood pressure monitor. He has a past medical history significant for type 2 diabetes, hypertension, severe chronic obstructive pulmonary disease, and renal insufficiency. He has no known drug allergies. You note that his nocturnal blood pressure is about 25% lower than his daytime blood pressure, but his early morning pressures are quite high. He is currently receiving hydrochlorothiazide 25 mg po daily, simvastatin 10 mg po hs, aspirin 325 mg po qd, ipratropium 2 puffs QID and albuterol 2 puffs QID, and glipizide 5 mg po daily. He has been receiving all of these medications for several years. TJ's physician wishes your opinion regarding TJ's antihypertensive regimen.

5. How would you classify TJ by his blood pressure?

• Dipper
• Extreme dipper
• Nondipper
• None of the above

6. Which of the following would be the best recommendation for TJ's provider?

• Consider adding Tropol XL (metoprolol) 100 mg po QHS
• Consider adding Cardizem LA (diltiazem) 180 mg po QHS
• Consider adding amlodipine 5mg po QHS
• Change nothing

7. Verelan PM (verapamil) 240 mg po QHS has been added to a patient's regimen for blood pressure control. The patient is currently receiving the following medications: aspirin 325 mg QHS, pravastatin 40 mg QHS, cyclosporine 100 mg BID, benazepril 20 mg daily, and warfarin 5 mg QHS. Which of the following medications should you be most concerned about interacting with the Verelan PM (verapamil)?

• Benazepril
• Warfarin
• Pravastatin
• Cyclosporine

8. Which of the following patient subgroups are at the highest risk for developing end-organ damage due to their hypertension?

• Dippers
• Nondippers
• Extreme dippers
• All of the above

9. Which of the following is true regarding the chronotherapeutic dosing of conventional antihypertensive agents?

• Dosing once-daily antihypertensive agents at bedtime is both safe and efficacious.
• Dosing once-daily antihypertensive agents at bedtime is hazardous and poorly controls blood pressure.
• Findings are inconsistent, which make the data hard to interpret.
• Higher drug concentrations in the nocturnal hours may be beneficial for extreme dippers.

10. Which of the following FDA-approved chronotherapeutic medications uses a unique graded extended-release tablet formulation?

• Verelan PM (verapamil)
• Cardizem CD (diltiazem)
• Cardizem LA (diltiazem)
• Covera-HS (verapamil)

11. Which of the following FDAapproved chronotherapeutic medications is approved only for hypertension?

• Verelan PM (verapamil)
• Cardizem CD (diltiazem)
• Cardizem LA (diltiazem)
• Covera-HS (verapamil)

12. CC is a 55-year-old African-American female who presents to your pharmacy with a new prescription for Covera-HS (verapamil). CC has been taking extended-release generic verapamil for several years and is concerned with the medication change. Which of the following points should you include in your consultation with CC?

• "Covera-HS will help lower your blood pressure during the early morning hours, when you are at highest risk for a stroke. However, there is no difference between your older verapamil medication and this new medication. I would recommend just taking your extendedrelease generic verapamil at bedtime."
• "Covera-HS will help lower your blood pressure during the early morning hours, when you are at highest risk for a stroke. However, it will cause more constipation than your extended-release generic verapamil."
• "Covera-HS will help lower your blood pressure during the early morning hours, when you are at highest risk for a stroke. Be aware that you may see the tablet shell within your stool."
• "Covera-HS will help lower your blood pressure during the early morning hours, when you are at highest risk for a stroke. However, if you have trouble swallowing the tablet, you can break it in half."

13. Which of the following is the best interpretation of the CONVINCE trial?

• Covera-HS was superior to atentolol and hydrochlorothiazide at reducing cardiovascular mortality.
• Atenolol and hydrochlorothiazide was superior to Covera-HS at reducing fatal and nonfatal stroke.
• Atentolol and hydrochlorothiazide had an increased risk for bleeding and bleeding hospitalizations.
• Data cannot be interpreted since the study was terminated early.

14. Which of the following patients with hypertension is not an ideal candidate for chronotherapy?

• TP, who is a 49-year-old white male who works nights at the shipyard and sleeps during the day.
• KL, who is a 35-year-old African-American emergency room physician who works nights 2 random weeks out of the month.
• TY, who is an 85-year-old Asian-American female whose nocturnal blood pressure drops about 15% lower than her daytime blood pressure.
• MR, who is a 55-year-old white female whose early-morning blood pressure is about 15% higher than her nocturnal blood pressure.

15. BB is a 58-year-old white man who is a nurse at a local hospital. He presents to your pharmacy with a new prescription for Verelan PM for his hypertension. After questioning BB, you note that he works only in the evenings and sleeps during the day. BB tells you that his physician told him to take 1 capsule once daily. He asks you for some clarification. What would you tell him?

• "Take 1 capsule just prior to going to work in the evening."
• "Take one capsule just prior to going to sleep in the morning."
• "Take 1 capsule either in the morning or evening, whichever works best for you."
• "Take 1 capsule just prior to eating lunch."

16. Which of the following is considered AB-rated with Cardizem LA (diltiazem)?

• Cardizem CD (diltiazem)
• Tiazac (diltiazem)
• Dilacor XR (diltiazem)
• None of the above (diltiazem)

17. ED is a 48-year-old Asian-American woman who is currently taking Covera-HS (verapamil), aspirin, and simvastatin. She presents to your pharmacy counter with 3 herbal products in her hand: hawthorn root, ginseng, and valerian root. She asks your opinion regarding any potential interactions with her current medications. What do you tell her?

• "The hawthorn root, ginseng, and valerian root all interact with your blood pressure medication. I don't recommend that you take these supplements."
• "The hawthorn root and valerian root can lower your blood pressure. However, the ginseng should be okay."
• "The ginseng can increase your blood pressure. However, the hawthorn and valerian root should be okay."
• "I have no problem with any of these supplements. In a few days, stop back by the pharmacy, and let me know how they are working for you."

18. An 85-year-old white female patient who has had hypertension for numerous years is switching from her sustained-release antihypertensive to one of the current FDA-approved chronotherapies. This patient has trouble swallowing pills and capsules. What can be done?

• Give the patient a prescription for Covera-HS (verapamil), and have her crush the tablet.
• Give the patient a prescription for Cardizem LA (diltiazem), and have her break the tablet in half.
• Give the patient a prescription for Covera-HS (verapamil), and have her break the tablet in half.
• Give the patient a prescription for Cardizem LA (diltiazem), and have her crush the tablet.

19. Which one of the following chronotherapeutic products has a delayed release of at least 11 hours?

• Verelan PM (verapamil)
• Cardizem LA (diltiazem)
• Covera-HS (verapamil)
• All of the above

20. RJ is a 47-year-old African-American man, with no known drug allergies, and a history of hypertension, systolic dysfunction, atrial fibrillation, and gastroesophageal reflux disease. RJ is currently taking enalapril, digoxin, aspirin, furosemide, metoprolol, and ranitidine; however, his provider wishes to add one of the available chronotherapeutic agents for additional hypertension coverage. Which of the following would you recommend to him?

• Verelan PM (verapamil)
• Cardizem LA (diltiazem)
• Covera-HS (verapamil)
• None of the above