The Physical Compatibility of Clinically Used Concentrations of Diltiazem Hydrochloride With Heparin Sodium.

Background: Acute treatment of atrial fibrillation often requires concomitant intravenous (IV) continuous infusions of unfractionated heparin and diltiazem. Concomitantly infusing these medications through the same IV line minimizes multiple IV sites. Diltiazem and heparin visual compatibility have been previously investigated but with limited drug dwell times and differing drug concentrations leading to inconsistent published results. Objective: To investigate the physical compatibility of diltiazem hydrochloride at concentrations of 5 and 1 mg/mL combined with an equal volume of heparin sodium 100 units/mL. Methods: Using a 0.22-µm filter, 15 mL of heparin sodium were placed into a polyvinyl chloride infusion bag followed by 15 mL of either diltiazem hydrochloride 5 or 1 mg/mL. Admixtures were prepared in triplicate. Each admixture was investigated for visual precipitation, spectrophotometric absorbance, and pH change at baseline and 1, 5, 8, and 24 hours after mixing. Physical incompatibility was determined by visual observation, increased spectrophotometric absorbance, and demonstrative pH changes. Results: Each diltiazem 5 mg/mL admixture exhibited a slight haze and enhanced absorbance readings indicating turbidity while none revealed a demonstrative pH change. None of the diltiazem 1 mg/mL assessments revealed visual precipitation or suggested turbidity. Only one pH reading at 5 hours revealed a demonstrative change from baseline. Conclusions: Our findings indicate that infusing diltiazem hydrochloride 5 mg/mL with heparin sodium 100 units/mL in the same IV line cannot be advocated. In contrast, our findings suggest that heparin sodium 100 units/mL infused with diltiazem hydrochloride 1 mg/mL is physically compatible but chemical stability was not assessed.

Role of the Funny Current Inhibitor Ivabradine in Cardiac Pharmacotherapy: A Systematic Review.

The pharmacology, pharmacokinetics, efficacy and safety of ivabradine are reviewed. Ivabradine is an oral medication that directly and selectively inhibits the hyperpolarization-activated cyclic-nucleotide gated funny (If) current in the sinoatrial node resulting in heart rate reduction. It has a plasma elimination half-life of 6 hours and is administered twice daily. Ivabradine is extensively metabolized by cytochrome P450 3A4, and its metabolism is affected by inducers and inhibitors of the 3A4 enzyme. Studies in patients with heart failure indicate that ivabradine improves surrogate markers such as exercise tolerance. The results of (1) phase III trial demonstrated ivabradine significantly reduced heart failure hospitalizations but had no effect on mortality. Ivabradine has been extensively evaluated for coronary artery disease wherein (2) large trials was shown to have no mortality benefit. Ivabradine has been associated with improved symptoms in stable chronic angina pectoris. Ivabradine has been evaluated for other cardiovascular conditions including tachycardias of various natures, arrhythmia prevention postcardiac surgery, in acute coronary syndrome, and for heart rate control during coronary computed tomography angiogram. The most common adverse events reported in clinical trials were bradycardia, new-onset atrial fibrillation, and phosphenes. Ivabradine, a novel cardiac medication, has been studied in numerous cardiac conditions. It is only currently approved in the United States to reduce hospitalizations for systolic heart failure. The role of this medication in other conditions has not been fully elucidated.

Illicit narcotic injection masquerading as acute pulmonary embolism.

A 23-year-old male presented from a nursing home with hypotension, tachycardia, diaphoresis and electrocardiographic evidence of right ventricular strain that was confirmed by echocardiography. His differential diagnosis included sepsis and pulmonary embolism. A high-resolution computed tomography scan demonstrated no pulmonary emboli but did demonstrate multiple bilateral pulmonary nodules. Upon questioning he admitted to injecting a long-acting narcotic that had been manually macerated, dissolved in saline, and injected through an indwelling intravenous line. Lung biopsy findings were consistent with cellulose-induced perivascular granulomatosis. Cellulose granulomatosis can be seen in patients who inject medications designed for oral use and should be considered in patients who present with acute pulmonary hypertension.

Practical considerations for the pharmacotherapy of pulmonary arterial hypertension.

Pulmonary arterial hypertension is a devastating disease. Before the 1990s, when pharmacologic treatment was finally approved, only supportive therapy was available, consisting of anticoagulation, digoxin, diuretics, and supplemental oxygen. Calcium channel blocker therapy was also an option, but only a small percentage of patients respond to it. However, starting with epoprostenol in 1996, the number of drugs approved to treat pulmonary arterial hypertension increased. Three distinct classes of drugs were developed based on the pathophysiology of the disease: the prostanoids, endothelin-1 receptor antagonists, and phosphodiesterase type 5 inhibitors. The prostanoids are administered either parenterally or by inhalation to replace the lack of prostacyclin within the pulmonary arterial vasculature. The endothelin-1 receptor antagonists were the first class of oral drugs to be developed, but drug interactions and adverse effects are prominent with this class. The phosphodiesterase type 5 inhibitors increase the second messenger cyclic guanosine monophosphate (GMP) that is induced by nitric oxide stimulation. All of the drugs within these three classes are distinct in and of themselves, and their clinical use requires in-depth knowledge of pulmonary arterial hypertension and its pathophysiology. Because these drugs have different mechanisms of action, combination therapy has shown promise in patients with severe disease, although data are still lacking. This article should serve as a practical guide for clinicians who encounter patients with pulmonary arterial hypertension and the drugs used for the treatment of this devastating disease.

Incidence of bleeding in renally impaired patients receiving incorrectly dosed eptifibatide or bivalirudin while undergoing percutaneous coronary intervention.

BACKGROUND: Limited data are available regarding adverse bleeding events associated with antithrombotic agents incorrectly dosed based on renal function in patients receiving percutaneous coronary intervention (PCI). OBJECTIVE: To compare the incidence of bleeding during their hospital stay in patients with reduced renal function receiving incorrect doses of bivalirudin or eptifibatide to the incidence of correct doses, based on manufacturer recommendations; secondary objectives were to determine the incidence of correct dosing based on manufacturer recommendations and the incidence of TIMI (Thrombolysis in Myocardial Infarction) major bleeding. METHODS: A chart review over a 32-month period showed that patients with reduced renal function who received either eptifibatide or bivalirudin during PCI were evaluated for correct dosing based on manufacturer recommendations, bleeding incidence according to the TIMI criteria, and extent of bleeding according to the TIMI and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) criteria. RESULTS: One hundred ninety patients met inclusion criteria, 56 who received eptifibatide and 134 who received bivalirudin. Eptifibatide was dosed incorrectly in 64% of the patients. Patients receiving incorrectly dosed compared to correctly dosed eptifibatide experienced significantly more bleeding (64% vs 35%, respectively, p = 0.04), a greater extent of bleeding based on the TIMI and GUSTO criteria (p = 0.03 and p = 0.009, respectively), and had more TIMI major bleeding (19% vs 5%, respectively). Bivalirudin was dosed incorrectly in 28% of the patients. Patients receiving incorrectly dosed compared to correctly dosed bivalirudin experienced a significantly greater extent of bleeding based on the GUSTO criteria (p = 0.01). There was no significant difference between the incidence of bleeding (37% vs 21%, respectively; p = 0.06), extent of bleeding based on the TIMI criteria (p = 0.058), or incidence of TIMI major bleeding (5% vs 3%). CONCLUSIONS: Patients receiving incorrectly dosed eptifibatide and bivalirudin are susceptible to adverse bleeding events. The occurrence of incorrect dosing offers an opportunity for pharmacist-driven institutional improvement.

Community pharmacists and Colleges of Pharmacy: the Ohio partnership.

OBJECTIVE: To develop pharmacist practice standards, pharmacy preceptor standards, and objectives for students completing advanced practice community pharmacy rotations. SETTING: Ohio. PRACTICE DESCRIPTION: Pharmacy schools and community pharmacies that serve as advanced practice rotation sites. PRACTICE INNOVATION: Developed standards for preceptors and objectives for student experiences. INTERVENTIONS: Focus groups that included both community pharmacists and pharmacy faculty collaborated on defining key standards for advanced community pharmacy rotations. MAIN OUTCOME MEASURE: Not applicable. RESULTS: Three main documents were produced in this initiative, and these are provided as appendices to this article. Professional and patient care guidelines for preceptors define minimum standards for these role models. Expectations of pharmacists as preceptors provide insights for managing this student-teacher relationship, which is fundamentally different from the more common employer-employee and coworker relationships found in pharmacies of all types. Objectives for student experiences during advanced practice community pharmacy rotations present core expectations in clinical, dispensing, patient education, wellness, and drug information areas. CONCLUSION: Through this collaboration, Ohio colleges of pharmacy developed a partnership with practitioners in community settings that should enhance the Ohio experiential educational program for student pharmacists. Use of the established guidelines will help educators and practitioners achieve their shared vision for advanced practice community pharmacy rotations and promote high-quality patient care.

Coronary event secondary prevention with statins irrespective of LDL-cholesterol.

OBJECTIVE: To review the evidence for statin secondary prevention of coronary artery disease in patients with near-optimal or optimal low-density lipoprotein cholesterol (LDL-C). DATA SOURCES: A MEDLINE search (1966-October 2003) was conducted using the search terms HMG-CoA reductase inhibitor, statins, coronary disease, post-myocardial infarction, and average cholesterol. DATA SYNTHESIS: Secondary prevention trials enrolling subjects with near-optimal (<130 mg/dL) or optimal (<100 mg/dL) baseline LDL-C were included. Early statin secondary prevention studies suggested attenuated benefit, but more recent trials challenge this finding. CONCLUSIONS: Statin secondary prevention of coronary artery disease in patients near goal LDL-C is controversial, but recent trial results show promise.

Rate versus rhythm control in atrial fibrillation.

OBJECTIVE: To determine whether rate control is a viable initial treatment approach in persistent atrial fibrillation (AF) through the evaluation of recently completed trials comparing rate and rhythm control. DATA SOURCES: Biomedical literature was obtained through MEDLINE (1966-December 2003) and the Iowa database. STUDY SELECTION AND DATA EXTRACTION: Articles identified from the biomedical literature search were reviewed and included if deemed relevant. DATA SYNTHESIS: Currently available data suggest that rate control is not inferior to rhythm control in patients with persistent AF with respect to mortality. Rate control also reduces hospitalizations and the occurrence of proarrhythmias. No significant difference was observed between treatments with respect to thromboembolism and strokes. CONCLUSIONS: Due to the increased incidence of hospitalizations and antiarrhythmic adverse effects associated with rhythm control, rate control is a reasonable first-line strategy in the treatment of recurrent AF, especially in elderly patients who are asymptomatic or mildly symptomatic. Further studies are needed to clearly define the role of rate control in younger patients.

Impact of ginkgo biloba on the pharmacokinetics of digoxin.

Many medications are known to alter digoxin pharmacokinetics, including the herbal medication St. John's wort. An open-labeled, randomized, crossover trial was conducted in eight healthy human volunteers to determine if ginkgo biloba (GB) also alters the pharmacokinetics of digoxin. On two occasions separated by 2 weeks, subjects ingested digoxin, 0.5 mg. One week prior to each study phase, half of the volunteers were randomly initiated on GB therapy, 80 mg three times daily, that continued until the end of the study phase. Immediately prior to and for 36 hours following digoxin ingestion, multiple blood samples were collected for digoxin plasma concentration determination. No significant difference between treatments was observed with respect to AUC(0- infinity ) (digoxin alone: 21.0 +/- 8.6 [ng/mL] x h; digoxin + GB: 25.6 +/- 13.2 [ng/mL] x h). Additionally, no significant difference between therapies was observed with respect to C(max), T(max), or Cl(o). In six subjects, k(e) and t(1/2) were able to be determined. These parameters also did not differ significantly between treatments. In conclusion, within the context of the specific GB product used during this investigation, the concomitant use of GB and digoxin did not appear to have any significant effect on the pharmacokinetics of orally administered digoxin in healthy volunteers.

Ezetimibe for management of hypercholesterolemia.

OBJECTIVE: To review the primary literature describing the pharmacology of ezetimibe and clinical trials investigating its use in the management of hypercholesterolemia. DATA SOURCES: A MEDLINE search (1966-December 2002) was performed using SCH 48461, SCH 58235, ezetimibe, and 2-azetidinone as key words. English-language articles were identified and the references of these articles were used to further identify pertinent articles and abstracts. Given the paucity of published articles available on ezetimibe, many of the references cited are abstracts. STUDY SELECTION: All acquired articles that discussed the pharmacology, pharmacokinetics, chemistry, and clinical efficacy of ezetimibe were reviewed. DATA EXTRACTION: Articles were selected based on content regarding the medicinal chemistry, pharmacology, and clinical use of ezetimibe. DATA SYNTHESIS: Ezetimibe, approved for use in October 2002, belongs to a new class of antihyperlipidemic agents that uniquely inhibit the absorption of cholesterol by inhibiting the cholesterol transport system located within intestinal cell walls. In humans, ezetimibe reduced cholesterol absorption by >50%. In clinical trials, ezetimibe 10 mg/d reduced low-density lipoprotein cholesterol (LDL-C) by approximately 18% and further enhanced the LDL-C-lowering effect of statin medications by an additional 15-20%. In addition, ezetimibe lowered triglycerides about 5% and increased high-density lipoprotein cholesterol (HDL-C) approximately 3%. Ezetimibe is well tolerated. At present, no serious adverse effects have been directly attributable to ezetimibe. CONCLUSIONS: Based on the data currently available, it appears that ezetimibe has a potential role in the treatment of primary hypercholesterolemia; however further data are needed to determine its long-term tolerability and efficacy. The potential roles for ezetimibe include its concurrent use with a statin to further enhance the lowering of LDL-C. Other possible roles for ezetimibe include its concurrent use with a statin to permit a lowering of statin dosage to avoid statin-related complications or its use as monotherapy to treat hypercholesterolemia when statin use cannot be tolerated or is contraindicated. Outcome data demonstrating that cardiovascular morbidity and/or mortality are reduced by ezetimibe therapy have yet to be generated.

Pharmacology and clinical use of bivalirudin.

OBJECTIVE: To review the primary literature describing the pharmacology and clinical uses of bivalirudin. DATA SOURCES: A MEDLINE search (January 1966-May 2001) was conducted that used bivalirudin, hirulog, and direct thrombin inhibitor as key words. References from retrieved articles and unpublished information acquired from the manufacturer and the Internet were also used. STUDY SELECTION: All acquired articles that discussed the pharmacology, pharmacokinetics, and clinical efficacy of bivalirudin were reviewed. DATA EXTRACTION: Articles were selected based on content regarding the pharmacology and clinical use of bivalirudin. Given the paucity of data pertaining to the clinical use of bivalirudin, most articles were used, including abstracts and communications with the manufacturer. DATA SYNTHESIS: Bivalirudin is a direct thrombin inhibitor that inactivates both unbound and fibrin-bound thrombin. Bivalirudin rapidly induces anticoagulation and has a relatively short duration of action. Bivalirudin displays linear kinetics and is primarily eliminated renally. Bivalirudin was proven effective in preventing postprocedural ischemic complications in patients with unstable or postinfarction angina who received percutaneous transluminal coronary angioplasty (PTCA). Yet, further investigations that include less critically ill patients and use the current clinical practice of administering glycoprotein IIb/IIIa antagonists and/or inserting intracoronary stents are needed to fully evaluate its efficacy. Bivalirudin has also induced early patency in patients with myocardial infarction in combination with streptokinase, but its use with newer thrombolytics needs to be studied. Bivalirudin has been used in patients with immunologically mediated, heparin-induced thrombocytopenia (HIT) without complications. Bleeding is the major adverse effect and occurs more commonly in patients with renal dysfunction. CONCLUSIONS: At present, bivalirudin is worthy of consideration in patients requiring PTCA who have HIT. Advocating the routine use of bivalirudin in patients experiencing an acute coronary syndrome or HIT is premature.

Effect of Single Dose Fluoxetine on Theophylline Serum Concentrations.

Fluoxetine has been previously reported to elevate plasma concentrations of several hepatically metabolized medications. Eight healthy male volunteers received intravenous aminophylline (approximately 6 mg kg(minus sign1)) on two occasions separated by 2 weeks. A 40-mg dose of oral fluoxetine was administered 8 h prior to the second administration of fluoxetine. Blood samples were collected and assayed for theophylline. Fluoxetine administration was not associated with any significant differences with respect to peak theophylline serum concentration, total body clearance, or half-life. Possible explanations include the fact that only a single dose of fluoxetine was administered and low fluoxetine serum concentrations were present at the time of aminophylline administration. The most likely explanation, however, is the fact that fluoxetine inhibits cytochrome P450 2D6 activity, whereas theophylline is predominately metabolized by cytochrome P450 1A2. In summary, a single 40-mg dose of fluoxetine failed to alter the plasma concentrations of theophylline when administered intravenously as aminophylline.