Sustained-Release Verapamil Formulations for Treating Hypertension

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<ul><li><p>J Clin Pharmacol 1992;32:455-462 455</p><p>Sustained-Release Verapamil Formulationsfor Treating Hypertension</p><p>William H. Frishman, MD, and Eliot J. Lazar, MD</p><p>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.</p><p>A lthough the goal of antihypertensive therapy isto reduce blood pressure, one also hopes to</p><p>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.</p><p>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.</p><p>MECHANISM OF ACTION</p><p>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</p><p>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.</p><p>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</p><p>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</p><p>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</p><p>PHARMACOKINETICS</p><p>More than 90% of an oral dose of verapamil is ab-sorbed, and peak plasma levels are reached within I</p></li><li><p>FRISHMAN AND LAZAR</p><p>456 #{149}J Clln Pharmacol 1992;32:455-462</p><p>TABLE I</p><p>Pharmacologic Effects of AvailableCalcium-Channel Blockers</p><p>Effect Dlltlazem Verapamll Nifedlpine Nicardipine</p><p>Heart rate4 4Myocardial</p><p>contractility 4 44 4-Atrio-ventricular</p><p>(AV) nodalconduction 4 44 -</p><p>Peripheralvasodilation 4 4 44</p><p>t-</p><p>4-</p><p>-</p><p>l4</p><p>The indicates decrease; f increases; and - no change.</p><p>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.</p><p>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</p><p>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</p><p>CLINICAL EXPERIENCE</p><p>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</p><p>Verapamil has a short half-life, and immediate-release formulations must be given in a thrice-dailyregimen. For antihypertensive therapy, doses of 240</p><p>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.</p><p>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</p><p>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</p><p>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}</p><p>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</p><p>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</p><p>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</p><p>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</p></li><li><p>SUSTAINED-RELEASE VERAPAMIL FOR HYPERTENSION</p><p>HYPERTENSION 457</p><p>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</p><p>SAFETY</p><p>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.16Verapamil has mild inhibitory effects on platelet ag-gregation, and it appears to preferentially inhibitepinephrine-induced aggregation.2-7</p><p>Drug Interactions. Since verapamil is metabolized bythe hepatic cytochrome P-450 enzyme system, in-teractions might be expected with drugs that alsouse this metabolic pathway. The potential hazards ofcombined verapamil/beta-blocker therapy havebeen described earlier. Verapamil administration in-creases the bioavailability of oral prazosin by about69%, whereas prazosin administration blocks thecompensatory reactions to vasodilatation producedby verapamil administration, When verapamil isgiven with antiarrhythmic drugs such as disopyra-mide or procainamide, additional cardiodepressionand conduction defects may be provoked. Combinedtreatment with verapamil and digoxin leads to in-creased plasma glycoside concentrations, possiblydue to decreased glycoside clearance. Concomitantverapamil administration will result in increasedplasma concentrations of theophylline, carbamaze-pine, doxorubicin, and cyclosporin. A clinicallysignificant interaction between verapamil and ri-fampin has also been documented, wherein oral ye-</p><p>rapamil bioavailability was decreased by simulta-neous dosing with rifampin. This was probably dueto induction of hepatic drug metabolism by ri-fampin.23</p><p>Adverse Experience Profile. The overall incidence ofadverse effects noted with verapamil administrationwas approximately 9% in one analysis of more than8000 patients; 1% of patients withdrew from treat-ment because of adverse reactions.2 Many of the ad-verse experiences reported with verapamil adminis-tration are extensions of the vasodilatory action andnegative inotropic properties of the drug; these ef-fects are less common after oral administration thanafter IV dosing. These effects include flushing, head-ache, peripheral edema, dizziness, and palpitations.The most common side effect of verapamil adminis-tration is constipation, which is a consequence ofdose-related relaxation of gastrointestinal smoothmuscle.2-3</p><p>SUSTAINED-RELEASE VERAPAMILFORMULATIONS</p><p>Rationale</p><p>Verapamil has a relatively short half-life (3-7 hr)and must therefore be given in divided dosesthroughout the day for effective control of bloodpressure over a 24-hour period. Even with thisschedule of administration, there will be constantfluctuations between peak and trough plasma levelsafter each dose. Under these conditions of adminis-tration, there is the possibility of alternately exceed-ing or falling below the plasma drug level needed fora therapeutic effect in a given patient. Another dif-ficulty is patient compliance with a dosing regimenthat requires taking a tablet several times a day. Pa-tient compliance is generally inversely related to thenumber of daily doses required. If a thrice-daily regi-men can be replaced by a once-daily dose, patientcompliance should be improved.</p><p>One way around these problems is to develop adrug formulation that releases a therapeuticallyequivalent amount of active agent slowly and con-tinuously over a sustained period. Such a formula-tion should reduce the high peak concentrations as-sociated with the immediate-release preparations,thereby avoiding dumping. Drug absorption willbe more uniform over time, and the peak-to-troughconcentration disparities will decrease. Ideally, thiswould result in maintenance of drug levels withinthe therapeutic concentration range for a prolongedperiod.</p></li><li><p>SUSTAINED-RELEASE VERAPAMIL FOR HYPERTENSION</p><p>458 #{149}J ClIn Pharmacol 1992;32:455-462</p><p>By inference, the therapeutic effect of the drugshould also be prolonged with sustained-releasepreparations. A by-product of the flattened peak-to-trough configuration should be a decreased chanceof toxic effects and a reduced incidence of intervalswhere plasma drug levels are subtherapeutic. Ide-ally, drug absorption from a sustained-release for-mulation should not be affected by gastric motility,pH, or the presence of food in the stomach.17</p><p>PREVIOUSLY AVAILABLE SUSTAINED-RELEASE VERAPAMIL PREPARATIONS</p><p>Until recently, a sustained-release formulation ofverapamil was marketed as two products in theUnited States: Calan SR (Searle, Chicago, IL) andIsoptin SR (Knoll, Whippany, NJ). A number of otherpreparations are available internationally.</p><p>These products have been evaluated in hyperten-sive patients using a variety of techniques, includingmanual blood pressure monitoring218 and 24-hourmonitoring by invasive19 and noninvasive2021methods. Although complete 24-hour blood pres-sure control with traditional sustained-release vera-pamil products has been debated,2-79 the 240-mgdose has been effective as a monotherapy in manyhypertensive patients.</p><p>Clinical studies comparing sustained-release for-mulations with conventional verapamil formula-tions in hypertensive patients have, in general,shown therapeutic equivalence between treatmentregimens incorporating identical total daily dosagesof verapamil (i.e., 80 mg immediate-release vera-pamil thrice daily or one 240-mg sustained-releaseverapamil dose).22224 However, some controlledstudies that used 24-hour monitoring showed thatblood pressure control waned before the end of the24-hour dosing interval with sustained-release prep-arations.2</p><p>The two traditional sustained-release verapamilproducts marketed in the United St...</p></li></ul>