Robert L. Talbert

Drug Dosing in Renal Insufficiency

Drug dosing in renal insufficiency needs to be individualized whenever possible to optimize therapeutic outcomes and to minimize toxicity. Although a number of published tables that provide dosing guidelines and nomograms exist to assist in dose modification, individualization of therapy should be based on pharmacokinetic principles whenever possible. The basis equations to estimate the pharmacokinetic parameters of clearance, volume of distribution, and half‐life for intravenous drug administration of drugs with first‐order kinetics are not difficult to understand and apply. Their use should be encouraged in patient care.

Safety issues with statin therapy

OBJECTIVEnTo describe the most important potential adverse effects related to statin therapy, discuss mechanisms of toxicity and drug interactions, and suggest approaches for enhancing safety with statin therapy.nnnDATA SOURCESnLarge-scale clinical trials, government databases and papers, and recent studies of statin safety.nnnSTUDY SELECTIONnBy the author.nnnDATA EXTRACTIONnBy the author.nnnDATA SYNTHESISnThe number of patients requiring intensive therapy with statins to achieve lipid goals is climbing, and as the number grows, so does the potential for adverse effects with these agents. The most detrimental adverse effects of statins are hepatotoxicity and myopathy. Liver dysfunction induced by statins is rare and usually mild, with asymptomatic transaminase elevation or acute cholecystitis. Progression to liver failure is exceedingly rare, and transaminase elevations is usually reversible with dose reduction. Statin-associated myopathy is generally a concern when patients have more than one risk factor for muscle syndromes, such as an elderly patient with poor renal function. Drug interactions represent an additional concern, especially for atorvastatin, lovastatin, and simvastatin, all of which are metabolized by the important 3A4 isoenzyme of the cytochrome P450 system of the liver.nnnCONCLUSIONnThe benefits of all available statins for the treatment or prevention of cardiovascular disease outweigh any potential risks of therapy. For patient groups most susceptible to adverse effects, such as the elderly and those on multiple medications, clinicians should consider the use of statins that are least likely to interact with other medications.

Cocaine Abuse and Its Treatment

Widespread use and abuse of cocaine have increased the frequency with which health professionals must manage acute and chronic intoxication and the complications stemming from drug ingestion. Acute intoxication from catecholamine excess progresses through three stages, affecting the cardiovascular, respiratory, and central nervous systems. Management is to support or return these systems to normal with sedation, ß blockade, and antiarrhythmics. Casual cocaine use is no longer considered benign, and numerous related medical complications are now recognized. Dopaminergic systems are the principal sites of reward and participate in abstinence symptomatology, putatively through depletion of dopamine and changes in receptor sensitivity and responsiveness. Long‐term treatment approaches have focused on psychologic strategies of behavior modification and supportive psychotherapy. Pharmacotherapy with desipramine, amantadine, and bromocriptine was shown in preliminary studies to minimize the symptoms of cocaine withdrawal when used adjunctively with psychotherapy. The response to treatment may depend on the patients premorbid psychiatric status.

Effect of fluvastatin and pravastatin, HMG-CoA reductase inhibitors, on fluconazole activity against Candida albicans

Synergy between fluvastatin, at clinically unachievable concentrations, and fluconazole against Candida albicans has been reported. The purpose of the present study was to evaluate the in-vitro activity of fluconazole alone and in combination with clinically achievable concentrations of pravastatin and fluvastatin against C. albicans. In-vitro susceptibility and synergy testing were performed against clinical isolates of C. albicans with fluconazole, pravastatin and fluvastatin. Both checkerboard method and time-kill studies were performed. MICs for fluconazole ranged from 0.5 (susceptible) to >256 mg/L (resistant) at 24 h. All isolates had MICs >2 mg/L for both statins. No synergy or antagonism was observed with fluconazole in combination with either agent against any isolate of C. albicans by the checkerboard assay or time-kill studies. Clinically achievable concentrations of pravastatin and fluvastatin did not affect the in-vitro activity of fluconazole against C. albicans.

Influence of hydroxypropyl methylcellulose polymer on in vitro and in vivo performance of controlled release tablets containing alprazolam

The purpose of this study was to investigate the influence of hydroxypropyl methylcellulose (HPMC) molecular weight on pharmacokinetic and pharmacodynamic parameters of controlled release formulations containing alprazolam. Tablet formulations contained alprazolam, excipients, and either HPMC K4MP or HPMC K100LVP. A ten patient in vivo clinical trial using a randomized, open-label, four-way crossover design was conducted in the fed and fasted states. Plasma alprazolam concentrations were determined for 72 h. The pharmacodynamic effects of alprazolam were monitored using subject rated sedation on visual analogue scale for wakefulness, observer rated sedation, and symbol digit modalities test (SDMT). Results indicated that the tablet formulations containing either HPMC K4MP or HPMC K100LVP had similar dissolution profiles, and the dissolution profiles did not change through 6 months at 40 degrees C/75% RH or 12 months at 25 degrees C/65% Relative Humidity (RH). The area under the plasma concentration-time curve, time to peak concentration, and peak plasma concentration were not significantly different between the two tablet formulations investigated in either the fed or fasted states. Pharmacodynamically, no significant differences in SDMT scores between the two formulations were found. In vitro dissolution results predicted in vivo pharmacokinetic and pharmacodynamic results irrespective of formulation or diet used in the controlled release tablet. The controlled release tablets were bioequivalent and pharmacodynamically equivalent irrespective of the tablet formulation.

A Review of Vasopeptidase Inhibitors: A New Modality in the Treatment of Hypertension and Chronic Heart Failure

Vasopeptidase inhibitors are a group of agents capable of inhibiting neutral endopeptidase and angiotensin‐converting enzymes, which leads to potentiation of natriuretic peptide actions and suppression of the renin‐angiotensin‐aldosterone system. With this distinctively characteristic mechanism, these agents have emerged as a new drug class for management of hypertension and heart failure. Several vasopeptidase inhibitors are under clinical investigation. Omapatrilat is the most studied agent in this class. Clinical studies of omapatrilat in hypertension have consistently shown the agents effectiveness in a variety of patient populations. In patients with heart failure, omapatrilat significantly improved neurohormonal and hemodynamic status. Long‐term effects of omapatrilat in patients with heart failure recently were compared with those of conventional therapy in a large phase II trial. Results of the study appear promising. Large clinical trials are ongoing, and additional information regarding safety and efficacy from these studies may help define the place in therapy for this agent.

Ibutilide: A new class III antiarrhythmic agent

Ibutilide fumarate is a new antiarrhythmic agent recently approved for the conversion of atrial flutter (AFl) and atrial fibrillation (AF) to normal sinus rhythm. A class III agent in the Vaughan Williams classification system, ibutilide prolongs cardiac repolarization by activating a slow inward, predominantly sodium current. An alternative or additive mechanism to prolong repolarization may be blockade of the outward delayed rectifier potassium rapid current. Ibutilide is administered intravenously, and approximately 40% of the drug in serum is protein bound. It is eliminated through hepatic metabolism by undefined enzyme systems, and it appears that none of the metabolites contributes significantly to antiarrhythmic activity. The elimination half‐life of ibutilide ranges from 2–12 hours. When administered by 10‐minute infusion, ibutilide 1 mg (approximately 0.015 mg/kg) resulted in conversion to sinus rhythm in 24–58% of patients with AFl and 20–32% with AF, compared with about 5% for placebo. Administering a second dose of 0.5–1 mg improved the overall response rates to approximately 75% and 45%, respectively. In randomized comparative trials, ibutilide was more effective than sotalol in converting AFl (70% vs 19%) and AF (44% vs 11%) and more effective than procainamide (76% vs 12% and 51% vs 20%, respectively). The time to conversion in most trials was usually 20–30 minutes. Nausea is the most common noncardiac adverse effect (< 2%). Nonsustained and sustained polymorphic ventricular tachycardia occurred in 2.7–6.7% and 1.7% of patients, respectively.

Pharmacokinetics and pharmacodynamics of beta blockers in heart failure

Although beta-blockers have been used for nearly three decades in the management of heart failure, only recent randomized clinical trials have demonstrated substantial benefit in reducing morbidity and mortality. Carvedilol, metoprolol succinate and bisprolol have evidence supporting their use in heart failure while other beta blockers either lack evidence supporting their use or have not been shown to be useful in heart failure. The only currently approved beta-blockers in the U.S. for heart failure are metoprolol succinate and carvedilol.Beta-blockers differ in their pharmacokinetic and pharmacodynamic properties. It should not be assumed that potential benefit in heart failure is a class effect since differences in the half-life, volume of distribution, protein binding, and route of elimination may give rise to differences in duration of beta blockade and potential drug interactions. Furthermore, pharmacodynamic differences exist because of selectivity for β1, β2 or α1 adrenoreceptor blockade among the beta-blockers. Receptor kinetics also differ among the beta-blockers and this may influence the extent and duration of beta and alpha blockade across the category.Carvedilol is an inherently long-acting beta-blocker while the duration of beta blockade for metoprolol is dependent on the salt and formulation, which is used. Metoprolol tartrate is a short-acting form of metoprolol while metoprolol succinate is a longer acting salt and the commercially available product is designed as a once daily formulation. A recently published trial, the Carvedilol or Metoprolol European Trial (COMET) tested carvedilol given twice daily versus metoprolol tartrate given twice daily in patients with chronic heart failure. Although carvedilol reduced all cause mortality when compared with metoprolol tartrate, extrapolation to similar findings with metoprolol succinate are not possible since the pharmacokinetic and pharmacodynamic effects of these two formulations are different. Furthermore, the dosing of metoprolol tartrate in COMET may have been inadequate based on prior studies. Additional studies are needed to compare carvedilol directly to metoprolol succinate before concluding inequivalency exists for these two beta-blockers in heart failure.

The Bleeding Time Effects of a Single Dose of Aspirin in Subjects Receiving Omega‐3 Fatty Acid Dietary Supplementation

Dietary supplementation with omega‐3 fatty acids reduces platelet aggregation in subjects who usually eat a diet low in these fatty acids. Aspirin also has an antiplatelet effect. The clinical effects of the concomitant administration of these agents were examined in this double‐blind controlled crossover trial. Twelve healthy adults were randomized to supplement their diet for 21 days with 8 g of omega‐3 fatty acids or identical‐looking olive oil capsules. At the end of each treatment period, bleeding times were obtained before and after the administration of one 325‐mg aspirin tablet. Overall, percent change in bleeding time after omega‐3 fatty acid supplementation was significantly prolonged compared with olive oil supplementation before aspirin administration but not after. Bleeding times were influenced significantly by the order of randomization in the two treatment groups. Changes in post‐aspirin bleeding time varied in subjects after they received olive oil. Post‐aspirin bleeding times after omega‐3 fatty acid supplementation were prolonged compared with baseline values but not significantly prolonged when compared with those after olive oil administration. The authors concluded that the concomitant administration of a single dose of aspirin does not prolong bleeding time in subjects who eat a diet enriched by omega‐3 fatty acids versus a diet enriched by olive oil.

Proton pump inhibitors and clopidogrel: Is it a significant drug interaction?

Importance of the field: Clopidogrel is indicated as part of a dual antiplatelet therapy (DAT) with aspirin for the prevention of cardiac related events in acute coronary syndromes particularly in patients undergoing percutaneous coronary intervention. Recently, there have been reports of a clinically significant drug interaction between clopidogrel and proton pump inhibitors (PPI), which are frequently co-prescribed to prevent DAT associated gastrointestinal (GI) bleeding. Areas covered in this review: This review evaluates the risk of GI bleeding associated with DAT and the rationale for the use of PPI. This review also describes the pharmacokinetic and pharmacodynamic basis for the interaction and evaluates its significance on clinical outcomes. An extensive literature search on PubMed from January 1980 to August 2009 was performed. Additionally, abstracts and presentations from key cardiology meetings and press releases were reviewed for relevant studies related to the interaction. What the reader will gain: At the end of the review, readers should have a complete understanding of the interaction and steps that can be taken to limit the interaction. Take home message: There is a mechanistic basis and pharmacodynamic data supporting an interaction between PPIs, particularly omeprazole and clopidogrel. The clinical significance of this interaction is, however, still a subject of intense debate and ongoing research.