Vincent F. Mauro

Meperidine-Related Seizures Associated with Patient-Controlled Analgesia Pumps

OBJECTIVE: To report three cases of meperidine-related seizures when meperidine was administered via patient-controlled analgesia pump (PCAP) and to review literature related to meperidine-associated seizures. DATA SOURCES: Case reports and review articles identified by a computerized search (MEDLINE) and manual search (Index Medicus). DATA SYNTHESIS: PCAPs are being used frequently to relieve the pain of sickle cell crisis as well as pain from many other etiologies. We report three cases of meperidine-related seizures associated with its administration via PCAP. Each of the patients received either relatively high doses, long-term therapy, or both. Meperidine has been associated with seizure activity when administered via traditional routes. Previously identified risk factors for the development of meperidine-related seizures include renal failure, high meperidine dosages, and coadministration of hepatic enzyme-inducing medications or phenothiazines. CONCLUSIONS: Meperidine administered via PCAP may be associated with seizures. Optimally, an alternative analgesic should be administered when this route is used.

Impact of ginkgo biloba on the pharmacokinetics of digoxin

Many medications are known to alter digoxin pharmacokinetics, including the herbal medication St. Johns 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 AUC0−∞ (digoxin alone: 21.0 ± 8.6 [ng/mL] × h; digoxin + GB: 25.6 ± 13.2 [ng/mL] × h). Additionally, no significant difference between therapies was observed with respect to Cmax, Tmax, or Clo. In six subjects, ke and t1/2 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.

New Recommendations from the 1999 American College of Cardiology/American Heart Association Acute Myocardial Infarction Guidelines

OBJECTIVE: To review literature relating to significant changes in drug therapy recommendations in the 1999 American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for treating patients with acute myocardial infarction (AMI). DATA SOURCES: 1999 ACC/AHA AMI guidelines, English-language clinical trials, reviews, and editorials researching the role of drug therapy and primary angioplasty for AMI that were referenced in the guidelines were included. Additional data published in 2000 or unpublished were also included if relevant to interpretation of the guidelines. STUDY SELECTION: The articles selected influence AMI treatment recommendations. DATA SYNTHESIS: Many clinicians and health systems use the ACC/AHA AMI guidelines to develop treatment plans for AMI patients. This review highlights important changes in AMI drug therapy recommendations by reviewing the results of recent clinical trials. Insights into evolving drug therapy strategies that may impact future guideline development are also described. CONCLUSIONS: Several changes in drug therapy recommendations were included in the 1999 AMI ACC/AHA guidelines. There is emphasis on administering fibrin-specific thrombolytics secondary to enhanced efficacy. Selection between fibrin-specific agents is unclear at this time. Low response rates to thrombolytics have been noted in the elderly, women, patients with heart failure, and those showing left bundle-branch block on the electrocardiogram. These patient groups should be targeted for improved utilization programs. The use of glycoprotein (GP) IIb/IIIa receptor inhibitors in non-ST—segment elevation MI was emphasized. Small trials combining reduced doses of thrombolytics with GP IIb/IIIa receptor inhibitors have shown promise by increasing reperfusion rates without increasing bleeding risk, but firm conclusions cannot be made until the results of larger trials are known. Primary percutaneous coronary intervention (PCI) trials suggest lower mortality rates for primary PCI when compared with thrombolysis alone. However, primary PCI, including coronary angioplasty, is only available at approximately 13% of US hospitals, making thrombolysis the preferred strategy for most patients. Clopidogrel has supplanted ticlopidine as the recommended antiplatelet agent for patients with aspirin allergy or intolerance following reports of a better safety profile. The recommended dose of unfractionated heparin is lower than previously recommended, necessitating a separate nomogram for patients with acute coronary syndromes. Routine use of warfarin, either alone or in combination with aspirin, is not supported by clinical trials; however, warfarin remains a choice for antithrombotic therapy in patients intolerant to aspirin. β -Adrenergic receptor blockers continue to be recommended, and emphasis is placed on improving rates of early administration (during hospitalization), even in patients with moderate left ventricular dysfunction. New recommendations for drug treatment of post-AMI patients with low high-density lipoprotein cholesterol and/or elevated triglycerides are included, with either niacin or gemfibrozil recommended as an option. Supplementary antioxidants are not recommended for either primary or secondary prevention of AMI, with new data demonstrating lack of efficacy for vitamin E in primary prevention. Estrogen replacement therapy or hormonal replacement therapy should not be initiated solely for prevention of cardiovascular disease, but can be continued in cardiovascular patients already taking long-term therapy for other reasons. Bupropion has been added as a new treatment option for smoking cessation. As drug therapy continues to evolve in treating AMI, more frequent updates of therapy guidelines will be necessary.

Digoxin–Macrolide Drug Interaction:

Macrolide antibiotics appear to be able to enhance the oral bioavailability of digoxin by altering the gastrointestinal flora that metabolize digoxin to less active dihydro metabolites, thus leading to increased serum digoxin concentrations and possible digoxin toxicity in select patients stabilized on digoxin therapy. This interaction may be of clinical importance in up to 10% of the population. Currently, the orally administered erythromycin, clarithromycin, and roxithromycin have been implicated. Although realistically this interaction may be encountered rarely, when it does occur, it can be of clinical significance. Addendum Following acceptance of this manuscript, two additional reports of a digoxin–clarithromycin drug interaction have been published. Nawarskas et al.28 described clarithromycin-induced digoxin toxicity (digoxin-induced ST segment changes, non-sustained ventricular tachycardia, and a digoxin concentration of 4.4 ng/mL) due to 3 days of clarithromycin 500 mg bid in a 78-year-old woman stabilized on oral digoxin 0.25 mg/d. Laberge and Martineau29 observed a clinical presentation suggestive of digoxin toxicity and an elevated digoxin concentration of 3.9 ng/mL in a 78-year-old man stabilized on digoxin 0.25 mg/d who had received 4 days of clarithromycin 250 mg bid.

Enhancement of phenytoin elimination by multiple-dose activated charcoal.

The effect of multiple-dose activated charcoal on the elimination of intravenously administered phenytoin was studied. Seven normal volunteers received phenytoin sodium 15 mg/kg IV with and without activated charcoal. During the charcoal phase, a total dose of 300 g was administered in repeated doses over 48 hours with sufficient sorbitol to produce one to two bowel movements per day. Serum phenytoin concentrations were determined from one to 72 hours after the infusions and were fitted to a one-compartment linear elimination model. The administration of multiple-dose activated charcoal reduced the phenytoin half-life from 44.5 to 22.3 hours. In addition, phenytoin area under the curve was decreased and the elimination rate was increased. Multiple-dose activated charcoal is effective in enhancing the elimination of phenytoin in normal volunteers. Although future studies are needed to determine its role in treating patients with phenytoin toxicity, multiple-dose activated charcoal may provide a readily available, inexpensive therapeutic intervention.

Misadventures with Activated Charcoal and Recommendations for Safe Use

OBJECTIVE: To review published reports of adverse effects associated with single- and multiple-dose activated charcoal therapy, and to formulate recommendations for safe use of activated charcoal therapy. DATA SOURCES: A manual search of Index Medicus from 1970 to December 1993 was conducted for English language articles; bibliographies of the resultant articles were also scanned. STUDY SELECTION: Cases were included if they were described in full detail, resulted in significant morbidity or mortality, and uniquely contributed to the formulation of recommendations for safe use of activated charcoal therapy. DATA SYNTHESIS: The major causes of morbidity and mortality secondary to activated charcoal therapy are aspiration of charcoal, gastrointestinal obstruction, and fluid and electrolyte abnormalities. Aspirations have occurred as a result of a number of circumstances that may be avoided. These include use in patients with unprotected airways, use of excessive charcoal dose, administration of inappropriately diluted charcoal, and administration of charcoal in the field. Gastrointestinal obstruction has occurred when multiple doses of activated charcoal have been administered without a cathartic and in cases in which a cathartic was administered if the patient had impaired peristalsis. Fluid and electrolyte abnormalities have occurred secondary to excessive cathartic administration. CONCLUSIONS: Activated charcoal therapy should be used judiciously so that related morbidity and mortality can be prevented. Adequate consideration for the patients airway protection capability is necessary. Judicious dosing of charcoal and concomitant cathartic therapy, along with adequate monitoring of fluid and electrolyte status, abdominal physical assessment, and clinical condition are all vital to the safe use of activated charcoal therapy.

Simvastatin: A Review of its Pharmacology and Clinical Use

Simvastatin, a chemical derivative of lovastatin, is an antihyperlipidemic medication that inhibits hydroxymethylglutaryl coenzyme A reductase. Animal and clinical data suggest simvastatin is twice as potent as lovastatin. It lowers serum cholesterol by inhibiting hepatic synthesis of cholesterol and, more importantly, by increasing the number of low-density lipoprotein (LDL) receptors present on hepatic cellular membranes. Simvastatin, when used at doses of 40 mg/d in patients with heterozygous familial hypercholesterolemia, significantly reduces total cholesterol (>30 percent) and LDL cholesterol (35–45 percent) and tends to reduce triglycerides and raise high-density lipoprotein (HDL) cholesterol. The agent is also effective in patients with polygenic hypercholesterolemia, familial dysbetalipoproteinemia, and nephrotic syndrome. Addition of cholestyramine to simvastatin enhances the LDL cholesterol-lowering effect to approximately 55 percent. Common clinical adverse effects reported with simvastatin use include headaches and gastrointestinal complaints. Transient elevations in serum transaminases and creatine phosphokinase have also been seen. Based on data currently available, the drugs clinical activity and adverse-effect profile are similar to those of lovastatin. Therefore, there is no need for formularies to contain both medications. To choose between the two, one needs to consider the incidence of adverse effects and the daily cost of each product when used at equally effective doses. That information is now now available and, until it is, a clear recommendation cannot be made. Simvastatin, presently marketed in several countries, is investigational in the U.S. but is expected to be available soon.

Extrapyramidal symptoms associated with calcium-channel blockers

Flunarizine and cinnarizine have been well documented to cause EPS. Other CCBs, on rare occasions, also have been reported to cause EPS. Theoretical explanations for these events include the inhibition of calcium influx into striatal cells and direct dopaminergic antagonistic properties. In addition, the chemical structures of flunarizine and cinnarizine, which are related to neuroleptics, may explain the relatively greater incidence of EPS with these agents. Suggested risk factors for acquiring EPS with flunarizine or cinnarizine use appear to be age, although experience with using these agents in younger patients is limited, and a family history of tremors and/or Parkinsons disease. The onset and type of presentation is unpredictable and, in most instances, discontinuation of the medication relieves the symptoms within a few days to months. Pharmacologic management of EPS with continued use of the offending agent generally has not been of clinical benefit. In conclusion, patients receiving CCBs, particularly flunarizine and cinnarizine, should be monitored for EPS.

The Use of HMG-CoA Reductase Inhibitors to Prevent Accelerated Graft Atherosclerosis in Heart Transplant Patients:

Initial trials hint that HMG-CoA reductase inhibitors may have a role in preventing or retarding the progression of AGAS. Whether the potential of HMG-CoA reductase inhibitors to prevent AGAS is due to their lipid-lowering effect, immunomodulating properties, or a combination of both is also not completely known at present. Further study is needed to fully identify their mode of preventing AGAS and, more important, to determine their usefulness and role in preventing AGAS, especially since concurrent HMG-CoA reductase inhibitor use with cyclosporine is not innocuous. Potential for a pharmacokinetic drug interaction, which results in an elevation of HMG-CoA reductase inhibitor concentrations, exists when these two agents are used together, thus increasing the potential for the HMG-CoA reductase inhibitor to cause musculoskeletal complications. When such combination therapy is used, the likelihood of this interaction can be reduced by prescribing the HMG-CoA reductase inhibitor conservatively--using the smallest effective dose and increasing the daily dosage slowly. Although the risk of musculoskeletal toxicity exists at any HMG-CoA reductase inhibitor dosage, most patients should be able to tolerate daily dosages of up to 20 mg of lovastatin, 10 mg of simvastatin, and 40 mg of pravastatin. Patients also need to be made aware of and monitored for musculoskeletal symptoms suggestive of myositis and/or myalgias. In addition, the avoidance of elevated cyclosporine concentrations and when practical, monitoring of HMG-CoA reductase inhibitor concentrations are recommended.

Syncope: Pathophysiology, Diagnosis, and Pharmacotherapy

OBJECTIVE: To review the pathophysiology, diagnosis, and pharmacotherapy of syncope, with emphasis placed on neurocardiogenic syncope. DATA SOURCES: A MEDLINE search (1980–1995) using the term syncope and cross-referencing selected articles. STUDY SELECTION: Articles selected were those considered to assist in providing the reader with a basic introduction to the pathophysiology, diagnosis, and pharmacotherapy of syncope, with emphasis placed on neurocardiogenic syncope. DATA SYNTHESIS: Syncope is a common disorder with many different etiologies. The patients history and physical examination are extremely important in making the diagnosis. The recent availability of head-upright tilt testing and electrophysiologic studies of the myocardium have helped define the etiology in many patients in whom an etiology would not have been found in the past. When the cause of syncope has been diagnosed, the appropriate therapy to prevent future attacks will be defined in many instances. One form of syncope, known as neurocardiogenic syncope, can be difficult to treat. Recent trials have suggested the use of beta-blockers, fludrocortisone, disopyramide, or selective serotonin reuptake inhibitors may be helpful in some patients.