Michael B. Bottorff

Pharmacokinetic Interactions with Calcium Channel Antagonists (Part II)

SummaryCalcium channel antagonists are a diverse class of drugs widely used in combination with other therapeutic agents. The potential exists for many clinically significant pharmacokinetic interactions between these and other concurrently administered drugs. The mechanisms of calcium channel antagonist-induced changes in drug metabolism include altered hepatic blood flow and impaired hepatic enzyme metabolising activity. Increases in serum concentrations and/or reductions in clearance have been reported for several drugs used with a number of calcium channel antagonists. A number of reports and studies of calcium channel antagonist interactions have yielded contradictory results and the clinical significance of pharmacokinetic changes seen with these agents is ill-defined. The first part of this article deals with interactions between calcium antagonists and marker compounds, theophylline, midazolam, lithium, doxorubicin, oral hypoglycaemics and cardiac drugs.

The role of cytochrome P450-mediated drug-drug interactions in determining the safety of statins.

The objectives of this review are to discuss the role of cytochrome P450 (CYP450) isoforms in drug metabolism, to explain differences in metabolism among the HMG-CoA reductase inhibitors (HMGs, statins), to review drug-drug and drug-food interaction studies dealing with the HMGs, to present case reports dealing with HMG-related myopathy, to discuss major clinical implications of these case reports and to express an opinion of use of HMGs in clinical practice.

Mechanisms of antiarrhythmic drug-induced changes in defibrillation threshold: Role of potassium and sodium channel conductance☆

OBJECTIVES We sought to determine which ion current predominantly affects defibrillation outcomes by using specific pharmacologic probes (lidocaine [a sodium channel blocking agent] and cesium [an outward potassium channel blocking agent]) in 26 swine. BACKGROUND The effect of a drug on sodium or potassium channel conductance, or both, may affect defibrillation threshold values. However, it is unknown which ion channel predominates. METHODS Each pig was randomly assigned to one of four treatment groups with two treatment phases: group 1 = placebo (D5W) in treatment phase I followed by placebo plus cesium in treatment phase II (n = 6); group 2 = lidocaine followed by lidocaine plus placebo (n = 7); group 3 = lidocaine followed by lidocaine plus cesium (n = 7); group 4 = placebo followed by placebo plus placebo (n = 6). Defibrillation threshold values and electrocardiographic measurements were obtained at baseline and at treatment phases I and II. RESULTS Lidocaine increased defibrillation threshold values from baseline by 71% in group 2 (p = 0.02) and by 92% in group 3 (p < 0.01). There were no changes in defibrillation threshold values from baseline to D5W in groups 1 and 4. When D5W was added to lidocaine in group 2 and D5W in group 4, there were no significant changes in defibrillation threshold values. However, when cesium was added to lidocaine in group 3, the elevated defibrillation threshold values (mean +/- SD) returned to baseline values (from 15.7 +/- 3.46 to 7.55 +/- 3.19 J, p < 0.01). Cesium added to D5W in group 1 also significantly reduced defibrillation threshold values from 7.10 +/- 1.27 to 4.14 +/- 1.75 J (p < 0.01). The effect of cesium on defibrillation threshold values was similar between groups 1 and 3, regardless of lidocaine, such that these values were reduced by 40 +/- 14% and 51 +/- 18%, respectively (p = 0.28). CONCLUSIONS Cesium, through potassium blockade, reverses lidocaine-induced elevation in defibrillation threshold values. The magnitude of defibrillation threshold reduction when cesium was added to lidocaine was similar to the defibrillation threshold reduction when cesium was added to placebo. Thus, inhibiting outward potassium conductance and prolonging repolarization decreases defibrillation threshold values independent of sodium channel blockade.

Antiplatelet therapy in patients with unstable angina and non-ST-segment-elevation myocardial infarction: findings from the CRUSADE national quality improvement initiative.

Evidence‐based clinical practice guidelines encapsulate current knowledge to guide health care professionals in the treatment of patients with unstable angina or non–ST‐segment‐elevation myocardial infarction (NSTEMI), yet adherence to guideline recommendations is suboptimal. Guideline adherence may be improved by quality improvement programs such as the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation?) National Quality Improvement Initiative of the American College of Cardiology–American Heart Association Guidelines. The CRUSADE data have been analyzed to demonstrate that overall guideline adherence is directly associated with mortality and that improvement in guideline adherence saves lives. Also, the CRUSADE data have determined that the real‐life mortality risk associated with unstable angina and NSTEMI is greater than suggested by clinical trials. The newer antiplatelet drugs recommended in early intervention and discharge treatment strategies are underused across many segments of the unstable angina–NSTEMI population. Glycoprotein IIb‐IIIa inhibitors are underused in high‐risk populations, and clopidogrel is markedly underused in patients who are medically managed rather than undergoing percutaneous coronary intervention or coronary artery bypass graft surgery. In addition, often the specialty of the treating physician and the status of the hospital influence the use of antiplatelet therapy. The reasons for underprescribing of antiplatelet drugs by physicians are not entirely clear but may be related to a lack of guideline familiarity and understanding, as well as factors such as drug novelty, safety, and cost. Continued education and data dissemination are therefore vital in promoting the prescription of guideline‐recommended drugs, both in the early hospitalization phase and as patients transition to community‐based care. The role of the pharmacist is pivotal in ensuring adherence to clinical guidelines by interacting with both the physician and patient.

Pharmacokinetics of Eprosartan in Healthy Subjects, Patients with Hypertension, and Special Populations

After oral administration of eprosartan to healthy volunteers, bioavailability is approximately 13%, with peak plasma concentrations occurring 1–2 hours after an oral dose in the fasted state. Food slows the rate of absorption and changes the overall extent by less than 25%, which is unlikely to be of clinical consequence. Plasma concentrations increase in a slightly less than dose‐proportional manner from 100–800 mg. There is no evidence of significant accumulation of eprosartan with long‐term therapy. The drugs terminal elimination half‐life is typically 5–9 hours after oral administration. The agent is highly protein bound (∼ 98%), with low plasma clearance (∼ 130 ml/minute) and small volume of distribution (∼ 13 L). It is primarily unmetabolized by the liver, with less than 2% of an oral dose recovered in the urine as a glucuronide. Biliary (primary) and renal excretion contribute to its elimination. No dosage adjustment is required in patients with mild to moderate renal impairment. Although an increase in systemic exposure to eprosartan was observed in the elderly, in patients with hepatic impairment, and in those with severe renal disease, this finding is unlikely to be of clinical consequence, based on the drugs excellent safety and tolerability profile (doses up to 1200 mg) in phase III clinical trials in hypertensive patients. Eprosartan can be safely administered to these special populations without an initial dosage adjustment, with subsequent dosing individualized based on tolerability and response.

Treating dyslipidemic patients with lipid-modifying and combination therapies.

Updated guidelines from the National Cholesterol Education Program give greater emphasis to lipoproteins other than low‐density lipoprotein cholesterol (LDL) than previous guidelines. Although statins remain first‐line therapy for most patients to lower LDL, combination therapy is the next logical step in achieving goals in patients with mixed dyslipidemia or elevated LDL despite statin therapy. As the prevalence of diabetes, metabolic syndrome, and atherogenic dyslipidemia rises, the importance of treating the total lipid profile becomes even more crucial. Niacin, fibrates, and bile acid sequestrants are effective in combination with statins in lowering LDL, triglycerides, and total cholesterol levels and increasing high‐density lipoprotein cholesterol (HDL). Although combination therapies may increase the risk of myopathy, both fibrate‐statin and niacin‐statin combinations are considered safe. In addition, niacin‐statin therapy reduces atherosclerotic progression and coronary events. New pharmacologic formulations exist that will further affect treatment: a single‐tablet combination of lovastatin and extended‐release niacin is available, as is ezetimibe, a cholesterol‐absorption inhibitor. In all, both HDL and triglyceride levels correlate with cardiovascular risk and should be considered secondary targets of therapy. Combination therapy can be safe and effective and can be constructed to affect all lipoprotein parameters.

‘Fire and forget?’ — pharmacological considerations in coronary care

The potential risk of drug-drug interactions is often overlooked during drug therapy selection. Multiple risk factors for drug-drug interactions exist in both the acute and chronic phases of acute coronary syndrome (ACS), including concomitant medications and underlying diseases. Some statins have been used for secondary prevention of coronary heart disease (CHD) in these patients and are not all equivalent in their susceptibility to drug-drug interactions. The lipophilic drugs lovastatin, simvastatin, atorvastatin, cerivastatin and fluvastatin are metabolized via the cytochrome P450 (CYP450) system in the liver and the gut, making them subject to potential interactions with concomitantly administered drugs that are competing for metabolism via this system. Clinically important interactions with simvastatin or lovastatin and drugs that inhibit the 3A4 isoenzyme (part of the CYP450 system) may result in myopathy and rhabdomyolysis, which can be fatal. However, pravastatin is water-soluble, it does not undergo metabolism via CYP450 to any significant extent (<1%), is excreted essentially unchanged and has not been shown to participate in any clinically relevant drug-drug interactions with CYP450 agents. When selecting drug therapy, knowledge of a drugs route of metabolism is important to predict and prevent life-threatening drug-drug interactions.

Pharmacokinetic Optimisation of the Treatment of Embolic Disorders

SummaryManagement of thromboembolic disease involves administration of anticoagulants, thrombolytics or antiplatelet agents to lyse or prevent thrombus extension. Despite widespread use and decades of experience with some of these agents, much is unknown about the effects of dose and plasma concentration on patient response.Unfractionated heparin (UFH) improves outcome in many thromboembolic disorders when administered to a target activated partial thromboplastin time (aPTT) or plasma heparin concentration. UFH exhibits dose-dependency both with absorption from subcutaneous sites and elimination. Doses based on bodyweight or estimated blood volume attain therapeutic aPTTs faster than fixed or standard doses. Low molecular weight heparins (LMWHs) were developed to increase the anti-factor Xa: anti-factor IIa activities. Several different LMWHs are as effective as UFH in treating deep venous thrombosis. Evidence fails to support a relationship between anti-factor Xa activity and either thrombosis evolution or bleeding. No comparisons have been made between bodyweight-based and anti-factor Xa activity-based doses.The dose of orally administered warfarin is adjusted to achieve a target International Normalised Ratio (INR). Maintenance doses are estimated on the basis of the patient’s INR during the first 3 days of therapy: the dose required to achieve an optimal INR decreases with age >50 years.The thrombolytic agents are administered in standard doses to achieve rapid thrombolysis with minimal alteration in systemic haemostasis. Accelerated intravenous alteplase may result in the highest rate of coronary artery reperfusion. Nevertheless, standard doses of streptokinase, anisoylated plasminogen streptokinase complex and alteplase result in similar 1-month mortality rates. The minimal advantage seen with alteplase is offset by higher rates of stroke. Future trials will focus on administration strategies achieving rapid thrombolysis, while minimising the risk of serious bleeding.With the antiplatelet agents, unpredictability in the pharmacokinetic parameters of different products has confounded interpretation of published reports. Optimal aspirin (acetylsalicylic acid) administration would include administration of an initial dose of 160 to 325mg after an acute vascular event, followed by maintenance dosages of approximately 75 mg/day for prophylaxis or treatment. Ticlopidine does not exhibit a relationship between either plasma concentration or dose and adverse effects, while pharmacodynamic effects may be dose-, but not plasma concentration-, dependent. The correlation between the concentration of dipyridamole and some of its antiplatelet effects may be the strongest amongst all the antiplatelet agents. However, unfortunately all clinical trials used standard doses and the current consensus is that dipyridamole alone is not an effective antiplatelet agent.

Use of diagnostic cluster methodology for therapeutic costing and drug surveillance of HMG-CoA reductase-inhibitor therapy

Diagnostic cluster methodology groups patients having similar medical conditions according to their International Classification of Diseases, 9th Revision codes. Episodes of care related to the diagnostic cluster can then be tracked from the claims data to determine the total charges associated with patient management. A retrospective claims analysis using an episode registry database was conducted to determine the 1-year (July 1, 1995, to June 30, 1996) covered charge for statin therapy, the overall cost of treating related cardiovascular (CV) disease, and the cost impact of coadministration of drugs that potentially compete for hepatic metabolism. The three statin treatment groups (lovastatin, pravastatin, and simvastatin) were similar with respect to age, gender, mean number of prescription refills, rate of refill compliance, and prevalence of the coadministration of potentially interacting agents. Before adjustment for severity of illness, there were no significant differences between groups in prescription drugs/services (statin Rx/Svc) or total CV charges. After adjustment for severity of illness, the pravastatin group had the lowest statin Rx/Svc and total CV charges. Within the group with the greatest severity of illness, statin Rx/Svc charges were significantly lower with pravastatin than with lovastatin and simvastatin. The statin Rx/Svc charges were not significantly different between lovastatin and simvastatin. Coadministration of a potentially interacting agent significantly increased both the statin Rx/Svc and total CV charges within the simvastatin-treated group but did not significantly influence costs in the lovastatin- or pravastatin-treated groups. The estimates of direct costs derived from this analysis are consistent with findings in the published literature and demonstrate that pravastatin has cost advantages compared with lovastatin and simvastatin. Diagnostic cluster methodology also generated valuable information regarding drug surveillance and the health care cost impact of potential drug-drug interactions with selected statins.

The Effects of Encainide versus Diltiazem on the Oxidative Metabolic Pathways of Antipyrine

The effects of diltiazem and encainide on the pharmacokinetics and metabolism of antipyrine were compared in nine healthy male volunteers. Diltiazem 90 mg every 8 hours for 5 days decreased the oral clearance of antipyrine from 2.34 to 1.86 L/hour (p < 0.05) and increased half‐life from 12.7 to 15.9 hours (p < 0.05). Diltiazem reduced the formation rate constants for 3‐hydroxymethylantipyrine by 27% (p < 0.05) and 4‐hydroxyantipyrine by 37% (p < 0.05). There was also a 21% reduction in the formation rate constant for norantipyrine (0.05 < p < 0.10). Encainide 25 mg every 8 hours for 5 days had no apparent effect on the oral clearance or half‐life of antipyrine, or on the formation rate constants for metabolites of antipyrine. In contrast to a previously published report in rats, encainide, unlike diltiazem, does not inhibit the oxidative metabolism of antipyrine in humans.