Formulary management of ACE inhibitors.

An increasing number of ACE inhibitors have become available in recent years. Because these agents are all similar, careful scrutiny is required in order to determine specific advantages of particular agents when making formulary decisions. Differences between agents with regard to structure and tissue specificity have been identified, but the clinical relevance of these differences is not clear. ACE inhibitors vary greatly with regard to bioconversion, distribution and elimination. Disease states such as congestive heart failure (CHF) and hepatic or renal insufficiency may affect the disposition of specific ACE inhibitors. These agents may differ substantially in duration of action, and ACE inhibitors that are given once daily may optimise patient compliance and decrease costs. ACE inhibitors have been extensively studied in patients with hypertension, CHF or nephropathy, and following myocardial infarction (MI). Differences in efficacy between agents are often a result of variations in study design, or because nonequipotent dosages were compared. It is likely that the benefits of ACE inhibitors are class effects, and it is probably reasonable to use an agent even if large scale clinical trials have not been performed with that particular drug. Few differences have been found between ACE inhibitors with regard to adverse effects or drug interactions, and these factors are of minor importance when making formulary decisions. Cost and availability may vary among agents, and will depend on geographical location and institution-specific purchasing contracts. ACE inhibitors have shown positive effects on quality of life when compared with agents of other classes. Quality-of-life studies that have directly compared ACE inhibitors have produced conflicting results. In the setting of hypertension, cost-effectiveness evaluations typically find that the newer, longer-acting ACE inhibitors provide the greatest financial benefit. Differences in cost effectiveness in the post-MI patient population are typically the result of variations in protocol design, including duration of treatment and nondrug costs. ACE inhibitors are fairly homogeneous and selection between agents can be difficult. Clinical efficacy, time course of action, and cost are the primary concerns in selecting agents for inclusion on a formulary.

Effect of simultaneous didanosine administration on itraconazole absorption in healthy volunteers.

STUDY OBJECTIVE: To investigate the effect of simultaneously administered didanosine (ddI) on the absorption of a single dose of itraconazole. DESIGN: Randomized, crossover, unblinded single-dose pharmacokinetic study in healthy volunteers. Comparisons of itraconazole alone and itraconazole with simultaneous ddI were performed on days 1 and 15. SETTING: A university medical center. PATIENTS: Seven healthy men and women. Six subjects (86%) completed the study; one was removed due to the development of a rash. INTERVENTIONS: Volunteers received a single 200-mg oral dose of itraconazole or itraconazole with concomitant oral ddI 300 mg (two 150-mg tablets) dispersed in 240 ml water. Each regimen was separated by a 2-week washout period. Serum samples were obtained frequently for 12 hours after the dose. MEASUREMENTS AND MAIN RESULTS: Concentrations of itraconazole were determined using a microbiologic assay. Individual concentrations in serum versus time data were evaluated by linear regression analysis. Peak serum concentration and time to peak were determined by visual inspection of each individual's serum concentration-time curve. A mean +/- SD peak serum itraconazole concentration of 0.90 +/- 0.30 micrograms/ml was observed at 3.0 +/- 0.7 hours when itraconazole was administered alone, compared with undetectable levels in all patients during therapy with ddI. CONCLUSIONS: Simultaneous oral administration of ddI significantly decreases absorption of itraconazole. These drugs should not be administered concurrently.

Use of calcium channel antagonists for cardiovascular disease.

Until recently, only three calcium channel antagonists--verapamil, diltiazem and nifedipine--were available for managing cardiovascular disorders such as hypertension and ischemic heart disease. In the past few years, however, several dihydropyridine calcium channel antagonists, including nicardipine, isradipine, felodipine, nimodipine, and amlodipine, have been marketed. Others are currently awaiting FDA approval. In addition, bepridil, which belongs to a new class of calcium channel antagonists, has recently been marketed for refractory angina pectoris. Clinical uses of calcium channel antagonists have been expanded since the 1970s to include management of cardiovascular disorders such as supraventricular arrhythmias, CHF secondary to diastolic dysfunction, and myocardial reinfarction in selected patients. Calcium channel antagonists are also being investigated for prevention of atherosclerosis. Calcium channel antagonists are a heterogeneous group of pharmacologic agents. Differences in tissue selectivity are largely responsible for the variations in hemodynamic and electrophysiologic properties of these agents. Thus, their clinical uses and side effect profiles differ. These differences must be taken into consideration in the selection of the most appropriate agent for a specific indication. Potential advantages of some of the newer dihydropyridine calcium channel antagonists include less frequent dosing (amlodipine and isradipine) and little or no negative inotropic effect (nicardipine, felodipine, amlodipine, isradipine) compared with the prototype calcium channel antagonists. Additional clinical experience with these newer agents is required, however, before their role in the management of cardiovascular disorders can be fully delineated. The availability of sustained-release formulations of verapamil, diltiazem, nifedipine, felodipine, and nicardipine, as well as the recent marketing of calcium channel antagonists with relatively long half-lives (amlodipine and isradipine), makes once- or twice-daily dosing possible with most calcium channel blockers. However, selection of a particular agent will depend on several factors, including clinical efficacy, side effect profile, cost, and patient characteristics such as concomitant disease states and baseline hemodynamic status.

Formulary considerations in selection of beta-blockers.

Selection of beta-adrenergic blockers for formulary addition can be a difficult task, especially with the increasing availability of new beta-blockers, as well as the numerous differences in pharmacodynamic and pharmacokinetic properties of currently available agents. Nevertheless, appropriate evaluation of the important characteristics of beta-blockers should allow selection of the most cost-effective agents for formulary addition. Most importantly, differences in efficacy, product formulation and cost should be carefully considered when making formulary decisions. Notably, evidence from clinical trials indicates differences in efficacy among beta-blockers for post-myocardial infarction prophylaxis, situational anxiety, essential tremor, thyrotoxicosis, migraine prophylaxis and prevention of bleeding associated with oesophageal varices. For many clinical situations, it is also important to select an effective agent that is available in both an oral and intravenous formulation, especially for cardioprotection after acute myocardial infarction and for use in supraventricular arrhythmias. In addition, availability of sustained release products and generic formulations should be considered for their potential to increase compliance and decrease cost, respectively. Comparative drug costs, as well as costs associated with decreased compliance, should also be carefully evaluated. Differences in beta-receptor selectivity, duration of action and presence of intrinsic sympathomimetic activity (ISA) are also important considerations in the selection of beta-blockers for formulary consideration. Although degree of selectivity is relative, beta 1-selective agents may be less likely to induce bronchospasm in patients with chronic obstructive pulmonary disease (COPD) and may be less likely to affect glucose homeostasis in patients with diabetes mellitus. Duration of action of a beta-blocker is an important consideration for evaluation of efficacy throughout the recommended dosage interval. In addition, beta-blockers with a long duration of action can often be administered once or twice daily, potentially leading to increased compliance and thereby improved effectiveness and economic efficiency. The presence of ISA is an important consideration because certain beta-blockers with ISA may be less effective than those without ISA for certain indications. Factors considered to be less important when making formulary decisions of choice of beta-blockers include the route of elimination, lipophilicity and presence of membrane stabilising activity.

Heparin and warfarin therapy after acute myocardial infarction.

The roles of heparin and warfarin in reducing morbidity and mortality after acute myocardial infarction (AMI) are reviewed. Full-dose i.v. heparin, with or without thrombolytic therapy, is indicated for the prevention of reinfarction and thromboembolism after AMI. Heparin therapy consists of a bolus dose of 5,000-10,000 units, followed by a continuous infusion to maintain the activated partial thromboplastin time at 1.5-2.5 times the control value, and should be continued for 5-10 days in most patients. A longer course of heparin may be appropriate after non-Q-wave AMI. Patients being switched to warfarin should continue to receive heparin until a therapeutic International Normalized Ratio (INR) has been achieved. Warfarin is indicated for the prevention of thromboembolism in patients with anterior-wall AMI and should be given for three months in most cases. Longer-term warfarin therapy should be considered for patients with additional risk factors for thromboembolism. Patients with non-Q-wave infarction who are at high risk of reinfarction may also benefit from long-term warfarin therapy. Warfarin should be administered to maintain an INR of 2.0-3.0. Aspirin reduces mortality and reinfarction rates after AMI and should be given indefinitely to all patients who do not have contraindications. Some patients may benefit from the combination of aspirin and warfarin. Ongoing trials should more adequately define the safety and efficacy of heparin and warfarin, as well as aspirin, alone and in combination in post-AMI patients. New anti-thrombotic agents may also prove beneficial.

Polypharmacy in psychiatry: three case studies and methods for prevention.

OBJECTIVE: To illustrate problems of overprescribing in the elderly and to make practical suggestions for prevention of polypharmacy. DESIGN: Three cases of polypharmacy in psychiatric patients admitted to the hospital between January and March 1990 are described. Intervention to correct drug-related problems in these patients is described and methods of preventing polypharmacy are discussed. SETTING: Inpatient psychiatry service in a tertiary-care center. PATIENTS: Elderly psychiatry patients (n = 3) taking an excessive number of medications. This polypharmacy was believed to contribute to decreased cognitive and/or physical function. INTERVENTIONS: Medication regimens were reviewed by the physician and pharmacist. Those considered unnecessary or believed to be adversely affecting the patient were discontinued. RESULTS: All patients were discharged on a reduced number of medications, with improvement in cognitive and/or physical function. CONCLUSIONS: Polypharmacy contributes to an increased incidence of adverse reactions in the elderly. Implementation of practical methods for reducing polypharmacy can lead to a reduction in the number of drug-related adverse effects and improved care of the elderly patient.

Felodipine: a new dihydropyridine calcium-channel antagonist.

Felodipine, a dihydropyridine calcium-channel antagonist, significantly reduces systolic and diastolic blood pressure (BP) in patients with hypertension and has been associated with beneficial hemodynamic effects in patients with chronic stable angina pectoris or congestive heart failure (CHF). In hypertensive patients, felodipine does not appear to significantly affect glomerular filtration rate, creatinine clearance, glucose tolerance, or plasma lipoprotein concentrations. Studies comparing felodipine with other agents as monotherapy in mild to moderate hypertension have demonstrated felodipine to be at least as efficacious as hydrochlorothiazide (HCTZ) and HCTZ plus amiloride hydrochloride in combination. Comparisons of felodipine with other agents as adjuncts to beta-blocker or diuretic therapy have shown felodipine to be at least as effective as HCTZ, propranolol hydrochloride, prazosin hydrochloride, and nifedipine. Evaluations of patients with chronic stable angina are limited, and additional studies are needed before felodipine can be recommended for the routine management of angina pectoris. Similarly, additional studies are essential to delineate the role of felodipine, if any, in the management of CHF. In the management of hypertension, felodipine 5-40 mg/d significantly reduces systolic and diastolic BP. Although some patients may be controlled throughout the entire dosing interval when felodipine is administered bid, many patients will require more frequent dosing to obtain adequate BP control. Adverse effects associated with felodipine are similar to those of other dihydropyridine calcium-channel antagonists and include peripheral edema, headache, dizziness, flushing, and fatigue. A potentially clinically important drug interaction was observed when felodipine was administered concomitantly with theophylline aminopropanol; significant decreases in theophylline concentrations were noted. In summary, felodipine appears to be safe and effective for the management of hypertension when used alone or in combination with other antihypertensive agents. The efficacy of felodipine in the management of chronic stable angina pectoris and CHF requires further investigation.

Coordinate regulation of zinc metabolism and metallothionein gene expression in rats.

Regulation of zinc metabolism by dibutyryl cAMP, glucagon, and epinephrine was examined in rats fed adequate amounts of zinc. Dibutyryl cAMP, epinephrine, and glucagon each produced an increase in liver metallothionein levels by 10 h after they were first administered. The increase in liver metallothionein was inversely related to the serum zinc concentration. Treatment with dexamethasone, a glucocorticoid, accentuated these effects to some extent. Both metallothionein I and II were induced by dibutyryl cAMP and glucagon. Levels of metallothionein mRNA in total liver RNA extracts were measured by dot blot hybridization using a synthetic 21-base oligonucleotide complimentary to the 5' region of both the metallothionein I and II genes. Individual administration of dibutyryl cAMP, glucagon, and epinephrine increased the number of metallothionein mRNA molecules per cell by up to fourfold. The data suggest that glucagon and epinephrine are primary regulators of metallothionein gene expression acting at least in part via cAMP. In adrenalectomized rats, glucagon, dibutyryl cAMP, and epinephrine had a less potent effect in terms of metallothionein induction and depression of serum zinc concentrations. These effects were largely restored when dexamethasone was also given. Collectively these data suggest that changes in zinc metabolism associated with acute stress involve coordinate regulation mediated by many factors, including glucocorticoids and cAMP.