sustained-release verapamil formulations for treating hypertension

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  • J Clin Pharmacol 1992;32:455-462 455

    Sustained-Release Verapamil Formulationsfor Treating Hypertension

    William H. Frishman, MD, and Eliot J. Lazar, MD

    Verapamil, the first calcium-channel blocker to be introduced for clinical use, is a majordrug used for the treatment of systemic hypertension. During the past 10 years, the use ofverapamil for hypertension has produced a considerable clinical database to support theefficacy and safety of the agent in many patients. Because of its short half-life, verapamilwas originally administered 3 to 4 times daily. During the past decade, a sustained-re-lease formulation of verapamil has been marketed in the US. This product allows foronce-daily dosing up to 240 mg/d; however, when higher doses are needed, this sus-tained-release formulation should be administered twice daily. In addition, the medicineshould be taken with food to avoid the high peak blood levels of verapamil, whichappears to be related to the delivery system. A new pellet-filled capsule formulation ofverapamil (Verelan, Lederle, Wayne, NJ and Wyeth-Ayerst, Philadelphia, PA) is availableand provides controlled absorption, 24-hour blood pressure control, improved peak-to-trough plasma levels, and once-daily dosing regardless of dosage size. Prolonged-releaseverapamil can be taken without food.

    A lthough the goal of antihypertensive therapy isto reduce blood pressure, one also hopes to

    prevent major cardiovascular complications fromsystemic hypertension. In addition, the physicianstrives to accomplish these ends with the least possi-ble adverse effect on the patient or the quality of life.

    Verapamil, a papaverine derivative, was the firstcalcium-entry blocker used clinically. Verapamilhas been used many years in the treatment of pa-tients with various cardiovascular disorders. Thisarticle reviews the clinical experiences with tradi-tional and new prolonged-release verapamil formu-lations for antihypertensive therapy.

    MECHANISM OF ACTION

    Like other calcium-channel blockers, verapamil in-hibits the slow inward flux of calcium ions acrosscell membranes of cardiac and vascular smoothmuscle cells. This inhibition results in vasodilationof coronary and peripheral arteries. In addition,conduction in the atrioventricular and sinoatrial

    From the Department of Medicine, Albert Einstein College of Medicine,Hospital of The Albert Einstein College of Medicine/Montefiore Medi-cal Center, Bronx, New York. Address for reprints: William Frishman,MD, Department of Medicine, Hospital of the Albert Einstein College ofMedicine/Montefiore Medical Center, 1825 Eastchester Road, Bronx,NY 10461.

    nodes is slowed, and a slight negative inotropic ac-tion has been observed.1 These pharmacologic ac-tions are the foundation for the efficacy of calcium-channel blockers in the treatment of patients withhypertension, angina pectoris, and supraventriculararrhythmias (Table I),2HEMODYNAMIC EFFECTS

    Verapamil is an effective peripheral vasodilator andhas a direct negative chronotropic and inotropic ef-fect on the heart. The sum of these actions meansthat little change is seen in heart rate, cardiac out-put, or ejection fraction after verapamil administra-tion.3

    Oral verapamil administration has no effect onblood pressure in normal volunteers but consis-tently lowers systolic and diastolic blood pressuresin hypertensive patients.2-4 The antihypertensive ef-fect of verapamil in patients seems to be greater withhigher pretreatment blood pressures. The age of thepatient and the pretreatment renin status also influ-ence the antihypertensive response to verapamil;blood pressure reductions are directly correlatedwith age and inversely correlated with reninstatus.45

    PHARMACOKINETICS

    More than 90% of an oral dose of verapamil is ab-sorbed, and peak plasma levels are reached within I

  • FRISHMAN AND LAZAR

    456 #{149}J Clln Pharmacol 1992;32:455-462

    TABLE I

    Pharmacologic Effects of AvailableCalcium-Channel Blockers

    Effect Dlltlazem Verapamll Nifedlpine Nicardipine

    Heart rate4 4Myocardial

    contractility 4 44 4-Atrio-ventricular

    (AV) nodalconduction 4 44 -

    Peripheralvasodilation 4 4 44

    t-

    4-

    -

    l4

    The indicates decrease; f increases; and - no change.

    to 2 hours after a single dose. Since the drug is sub-ject to extensive first-pass hepatic extraction, thebioavailability of a single dose is approximately 10 to20% of the oral dose. Verapamil is approximately90% bound to plasma proteins.

    The plasma concentration, bioavailability, andhalf-life of oral verapamil increase when the drug isgiven long term. Maximum plasma verapamil con-centration may be up to 70% higher after repeateddosing than after a single dose. This effect may bedue to a reduction in first-pass hepatic metabolismsecondary to changes in hepatic blood flow, satura-tion of metabolic pathways, inhibition of the metab-olism of verapamil induced by the drug itself, or theexistence of a deep tissue compartment of drug dis-tribution that is not apparent after administration ofsingle doses.3

    The elimination of verapamil varies from one pa-tient to another-variations of up to 85% in oralclearance have been reported in patients receivinglong-term verapamil therapy.2 Verapamil clearancemay decrease significantly during chronic adminis-tration and when the drug is given to elderly pa-tients and to patients with hepatic dysfunction. Incontrast, dosage reductions do not appear necessaryin patients with chronic renal failure.3

    CLINICAL EXPERIENCE

    Calcium-channel blockers are one of the drugclasses considered appropriate for initial antihyper-tensive therapies.6 In addition to their usefulness asmonotherapy, these drugs may be used in combina-tion therapy since they act by mechanisms differentfrom those of other antihypertensive drugs.7

    Verapamil has a short half-life, and immediate-release formulations must be given in a thrice-dailyregimen. For antihypertensive therapy, doses of 240

    to 480 mg/d are prescribed. In elderly or small pa-tients, a starting dose of 120 mg/d (40 mg thricedaily) may be appropriate.

    The relationship of plasma verapamil levels toantihypertensive efficacy remains problematic; nosatisfactory plasma concentration guidelines havebeen defined.8 This is undoubtedly a function of themarked intersubject variability of verapamil plasmalevels after oral dosing. Therefore, monitoring of theefficacy of verapamil therapy is best done by clinicalobservation.9

    Placebo-Controlled Studies. Conventional verapamilformulations (160 to 480 mg/d) have consistentlyreduced systolic and diastolic blood pressures in hy-pertensive patients. In elderly patients (mean age: 75yr), smaller verapamil doses (80 to 240 mg/d) appearto produce greater reductions in blood pressure.2

    Long-term Efficacy of Verapamil. Documentation ofthe long-term efficacy of an antihypertensive agent(i.e., lack of development of tolerance) is essential,since therapy for hypertension must continuethroughout the life of the patient. A number of stud-ies in which verapamil was used have shown thatthe ability of verapamil to lower blood pressure inhypertensive patients is not impaired by long-term use.1#{176}

    Comparisons With Other Agents. Immediate-releaseverapamil formulations have been compared withnifedipine, nicardipine, and diltiazem in hyperten-sive patients. Verapamil produced blood pressurereductions comparable with those seen with theother calcium-channel blockers.2

    The antihypertensive effects of verapamil arecomparable with those of beta blockers, includingpropranolol, atenolol, pindolol, metoprolol, and la-betolol.1#{176}However, beta blockers may be less effec-tive in black patients, whereas no such differenceshave been observed with verapamil and other cal-cium-channel blockers.10

    The limited number of studies that compared di-uretics and verapamil have shown similar reduc-tions in systolic and diastolic blood pressures withboth types of drugs. Both verapamil and diureticsappear to be more effective than other agents inolder patients and individuals with low plasmarenin activity. Some investigators believe that vera-pamil may be an appropriate alternative to diureticsin these patients.2

    Only a few studies have been done that compareverapamil with ACE inhibitors. Blood pressure re-ductions observed in these studies were similar withboth drugs.14

  • SUSTAINED-RELEASE VERAPAMIL FOR HYPERTENSION

    HYPERTENSION 457

    Combination Therapy. When hypertension in a pa-tient is resistant to the range of drugs suitable for useas monotherapy, a combination of agents can oftenbe successful. Verapamil has been used successfullyin combination with diuretics, ACE inhibitors, pra-zosin, and methyldopa.2-4 The combination of vera-pamil and propranolol has been studied,2-5-7 but thiscombination should be approached with cautionsince these two classes of drugs have additive effectson myocardial contractility, heart rate, and atrio-ventricular conduction. In some patients, these ef-fects could lead to dangerous adverse cardiac ef-fects. 27

    SAFETY

    Target Organs and Co-existing Diseases. Antihyper-tensive doses of verapamil have no significant effectson renal plasma flow, glomerular filtration rate, so-dium or water excretion, plasma renin activity, cir-culating concentrations of the renin-angiotensin-al-dosterone system, glucose tolerance in diabetic ornondiabetic patients, or plasma lipid profiles in nor-molipidemic patients.15 Unlike beta blockers, vera-pamil administration is not contraindicated in asth-matic patients. Verapamil administration may slowthe progression of atherosclerosis, although moreclinical studies are needed on this topic.2-7 Regres-sion of left ventricular hypertrophy has been ob-served with verapamil therapy in elderly patients.16Verapami

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