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.

'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 drug's route of metabolism is important to predict and prevent life-threatening drug-drug interactions.

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 drug's terminal elimination half-life is typically 5-9 hours after oral administration. The agent is highly protein bound (approximately 98%), with low plasma clearance (approximately 130 ml/minute) and small volume of distribution (approximately 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 drug's 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.

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.

Aging effects on the organic base transporter and stereoselective renal clearance.

OBJECTIVE: The organic base transporter is responsible for stereoselective renal excretion. Changes in activity of this system secondary to aging may affect the disposition of an organic base in a stereoselective manner. METHODS: Eight young men (age range, 22 to 33 years) and seven elderly men (age range, 62 to 79 years) were given 10 mg pindolol twice daily, pindolol with 200 mg trimethoprim once daily (a known inhibitor of organic base secretion) and pindolol with 1.5 gm ammonium chloride (NH4Cl) four times daily for 3 days on three occasions. On day 4, urine and plasma were collected over 24 hours to determine renal clearance (CLR) values of pindolol isomers. RESULTS: R(+)-Pindolol CLR values in young versus elderly men were 203 +/- 82 versus 150 +/- 87 ml/min, 128 +/- 51 versus 113 +/- 35 ml/min, and 480 +/- 248 versus 247 +/- 59 ml/min during the control, trimethoprim, and NH4Cl study phases, respectively. S(-)-Pindolol CLR values in young versus elderly were 279 +/- 81 versus 207 +/- 105 ml/min, 178 +/- 70 versus 136 +/- 42 ml/min, and 593 +/- 294 versus 276 +/- 49 ml/min during control, trimethoprim, and NH4Cl phases, respectively. NH4Cl increased R(+)-pindolol CLR by 138% (p < 0.05 versus pindolol alone) in young men, which was significantly greater than that observed in elderly subjects (66%; p < 0.05 versus pindolol alone; p = 0.016 young versus old). NH4Cl affected S(-)-pindolol CLR in a similar manner. Trimethoprim decreased R(+)-pindolol CLR in the young subjects by 37% (p < 0.05 versus pindolol alone), which was similar to that observed in the elderly subjects (26%; p < 0.05 versus pindolol alone; p = 0.94 young versus elderly). Trimethoprim affected S(-)-pindolol CLR in a similar manner. Stereoselective renal excretion of pindolol was unaffected by NH4Cl and trimethoprim, where the R(+)/S(-)-pindolol CLR ratio was unchanged (p = NS) from control in the young and elderly subjects. Comparison of the pindolol CLR isomer ratio between young and elderly groups showed no significant differences. Changes in pindolol clearance values resulted in significant changes in beta-blocking activity, assessed by isoproterenol (INN, isoprenaline) testing. CONCLUSIONS: Trimethoprim and NH4Cl significantly affect pindolol renal and total clearance values. Aging does not alter renal excretion of pindolol except for the magnitude by which renal excretion can be stimulated.

Hypertonic saline does not reverse the sodium channel blocking actions of lidocaine: evidence from electrophysiologic and defibrillation studies.

Studies have shown that increasing extracellular sodium concentration can partially reverse sodium channel blockade. However, there is conflicting in vitro evidence in this regard for lidocaine. The effects of lidocaine on cardiac electrophysiology and defibrillation were studied in a basal and hypernatremic state to determine reversibility of sodium channel blockade. Electrophysiologic studies measured right ventricular effective refractory period at 350 ms pacing cycle length and QRS interval, JT interval, and monophasic action potential duration during sinus rhythm and right ventricular pacing (350 ms cycle length) in 14 pentobarbital-anesthetized swine (25-30 kg). Defibrillation threshold (DFT) was measured by quantitating successful conversion of sustained ventricular fibrillation to normal sinus rhythm. Each pig was randomly assigned to a treatment group with three study phases; group 1 = baseline, lidocaine (20 mg/kg/h), and lidocaine plus placebo (D5W; n = 7); and group 2 = baseline, lidocaine, and lidocaine plus hypertonic saline (2-3 mM/kg/h; n = 7). In groups 1 and 2, lidocaine infused alone significantly (p < 0.01) increased DFT values from baseline (9.8 +/- 3.9 to 15.7 +/- 5.8 J and 8.9 +/- 2.9 to 14.7 +/- 5.4 J, respectively) and increased QRS duration from baseline during right ventricular pacing (89 +/- 6 to 109 +/- 10 ms; p < 0.01; and 87 +/- 6 to 103 +/- 12 ms; p < 0.01). Lidocaine alone reduced right ventricular action potential duration (APD) in groups 1 and 2 (214 +/- 18 to 206 +/- 20 ms; p < 0.10; and 228 +/- 8 to 212 +/- 8 ms; p < 0.05), respectively, and it reduced paced JT interval in both groups (194 +/- 20 to 184 +/- 18 ms; p < 0.10; and 200 +/- 12 to 183 +/- 16 ms; p < 0.05), respectively. When hypertonic saline was added to lidocaine, DFT and QRS duration values were unaffected (14.7 +/- 5.4 to 16.1 +/- 3.7 J and 103 +/- 12 to 100 +/- 11 ms, respectively). However, APD and JT intervals returned to basal values when hypertonic saline was added to lidocaine (212 +/- 8 to 225 +/- 13; p < 0.05; and 183 +/- 16 to 192 +/- 18; p < 0.05, respectively). When D5W was added in the control group, no changes occurred in DFT or electrophysiologic values. Lidocaine slowed ventricular conduction velocity and reduced APD. The administration of hypertonic saline to increase extracellular sodium concentrations failed to reverse the effect of lidocaine on conduction-velocity slowing or elevated DFT values. Hypertonic saline did reverse the effects of lidocaine on repolarization parameters. These data suggest that shortening of repolarization is not a mechanism by which lidocaine makes it more difficult to defibrillate the heart.

Influence of hypertonic saline solution infusion on defibrillation efficacy.

Hypertonic saline solution may enhance cardiac conduction via the fast inward sodium channel and alter transmembrane Ca+2 conductance via the sodium-calcium exchanger. Evidence suggests that both Ca+2 conductance and myocardial conduction velocity may affect ventricular defibrillation. Since hypertonic saline solution solutions (ie, sodium bicarbonate) may be administered to patients who have conditions that often require ventricular defibrillation (ie, cardiac arrest or hypovolemic shock), we studied the effect of hypertonic saline solution on the defibrillation threshold (DFT) in 16 pentobarbital-anesthetized domestic farm swine (20 to 30 kg). Defibrillation was performed using two interfaced epicardial electrode patches. DFTs were determined at baseline and during treatment phase. Pigs were randomly assigned to treatment consisting of either hypertonic saline solution (6 mmol/kg load, 2.0 to 3.0 mmol/kg infusion) to maintain serum sodium concentrations 10 to 15 mmol/L above baseline or control (D5W given in equal volume). DFT values (joules) that predicted 50% success were modeled from a best-fit histogram. Hypertonic saline solution did not change DFT values from baseline values (10.2 +/- 4.3 vs 10.8 +/- 7.0, respectively). Likewise, placebo (D5W) did not change DFT values from baseline values (10.1 +/- 4.5 vs 11.3 +/- 4.3). During treatment phase, DFT values were 99 +/- 28% of baseline values in the hypertonic saline solution group and 116 +/- 23% of baseline values in the D5W groups (p = 0.21). The administration of hypertonic saline solution also did not affect ventricular conduction velocity, right ventricular action potential duration, or right ventricular effective refractory period. These data indicate that hypertonic saline solution does not appreciably affect defibrillation efficacy or electrical treatment of ventricular fibrillation.

Mechanism 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.

Urine acidification affects the activity of the organic base transporter in a nonstereoselective manner.

This investigation determined 1) the effect of urine acidification on renal clearance (Clrenal), total systemic clearance (Cltotal) and nonrenal clearance (Clnonrenal) of pindolol, 2) whether urine acidification affected the stereoselectivity of pindolol excretion and 3) the pharmacodynamic effects that may result from changes in the activity of the organic base transporter. The Clrenal, Cltotal and Clnonrenal values of pindolol isomers were determined during pindolol administration (10 mg twice daily; control phase) and during pindolol administration (10 mg twice daily) with NH4Cl, a systemic and urinary acidifier, (1.5 g every 6 hr). Eight healthy males (22-33 yr) randomly received this therapy for 3 days on two occasions. On day 4, urine and plasma were collected over 24 hr. R-(+) pindolol Clrenal values during control and NH4Cl were 203 +/- 82 and 480 +/- 248 ml/min, respectively (P = .03). S-(-) pindolol Clrenal values during control and NH4Cl were 279 +/- 81 and 593 +/- 294 ml/min, respectively (P = .005). NH4Cl increased R-(+) pindolol Clrenal by 173% +/- 136% (P = .003) and S-(-) pindolol Clrenal by 127% +/- 105% (P = .03). Stereoselective renal excretion of pindolol was unaffected by NH4Cl; the R(+)/S(-) pindolol Clrenal ratio was unchanged from control to NH4Cl (0.74 +/- 0.23 to 0.81 +/- 0.10, P = NS, respectively). NH4Cl, however, affected pindolol Clnonrenal in a stereoselective fashion; R-(+) pindolol Clnonrenal values increased (641 +/- 241 to 851 +/- 251 ml/min; P = .02), whereas S-(-) pindolol Clnonrenal values remained constant (354 +/- 116 vs. 370 +/- 213 ml/min). Changes in pindolol clearance values resulted in a significant reduction in beta-blocking activity assessed by isoproterenol testing. We conclude that increasing the urine proton gradient can increase the Clrenal value of organic bases by 2-fold in a manner that is not stereoselective. NH4Cl, however, did increase the Clnonrenal value of pindolol in a stereoselective manner. These data, therefore, indicate that the administration of a urine-acidifying agent can greatly enhance the elimination of organic bases and ultimately reduce the pharmacologic activity of the organic base.

Pharmacokinetic optimisation of the treatment of embolic disorders.

Management 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.

Management of heart failure. I. Pharmacologic treatment.

OBJECTIVE: This review of the pharmacologic treatment of heart failure due to left ventricular systolic dysfunction summarizes the recommendations of the expert panel for the Agency for Health Care Policy and Research Heart Failure Guideline. It provides specific advice to help guide practitioners through clinical decision making. DATA SOURCES: Data were obtained from English-language studies and referenced in MEDLINE or EMBASE between 1966 and 1993. We used the search terms heart failure, congestive; congestive heart failure; heart failure; cardiac failure; and dilated cardiomyopathy in conjunction with terms for the specific treatments. Where data were lacking, we relied on opinions of panel members and peer reviewers. STUDY SELECTION: Only large prospective trials were used to estimate treatment efficacy. Smaller trials, case series, and case reports were reviewed for the incidence of adverse effects. DATA EXTRACTION AND SYNTHESIS: Randomized clinical trials were reviewed for inclusion and exclusion criteria, patient outcomes, adverse effects, and eight categories of study quality using a defined list of study flaws. CONCLUSION: Angiotensin-converting enzyme (ACE) inhibitors should be given to all patients unless specific contraindications exist. Diuretics should be used judiciously early in treatment to prevent excessive diuresis that could prevent titration of ACE inhibitors to target doses. Digoxin has not been shown to affect the natural history of heart failure and should be reserved for patients who remain symptomatic after treatment with ACE inhibitors and diuretics. Isosorbide dinitrate and hydralazine hydrochloride should be tried in patients who cannot tolerate ACE inhibitors or who have refractory symptoms.

Accuracy of a first-order model for estimating initial heparin dosage.

The accuracy of a first-order pharmacokinetic model for determining initial heparin infusion rates was studied, and factors that could affect the accuracy of the method were investigated. Patients who received an i.v. infusion of heparin for at least 24 hours for treatment of deep-vein thrombosis, pulmonary embolism (PE), or myocardial infarction were identified by retrospective chart review. A therapeutic dosage of heparin was defined by an activated partial thromboplastin time of 45-75 seconds. Heparin dosages were calculated by using estimated blood volume as the heparin volume of distribution, a desired steady-state heparin concentration of 0.30 units/mL, and an elimination rate constant of 0.832 hr-1. The difference between the calculated dosage and the actual therapeutic dosage was calculated. The differences for various patient subgroups were compared, and the estimated dosages were regressed against the actual dosages to determine their predictive value. Data for 49 patients were analyzed. The mean +/- S.E. difference between the actual and calculated dosages was 29.2 +/- 37.1 units/hr. No significant differences were evident according to sex or indication for therapy. Smokers and nonsmokers differed, as did obese and lean patients. The equation appeared to be more accurate in nonsmokers than smokers. The addition of 200 units/hr to the calculated dosage for patients with PE resulted in minor improvement in the predictive capacity of the equation. Moderate agreement was observed between the actual and calculated heparin dosages in non-smokers of various body weights.

Pharmacokinetic interactions with calcium channel antagonists (Part II).

Since calcium channel antagonists are a diverse class of drugs frequently administered in combination with other agents, the potential for clinically significant pharmacokinetic drug interactions exists. These interactions occur most frequently via altered hepatic blood flow and impaired hepatic enzyme activity. Part I of the article, which appeared in the previous issue of the Journal, dealt with interactions between calcium antagonists and marker compounds, theophylline, midazolam, lithium, doxorubicin, oral hypoglycaemics and cardiac drugs. Part II examines interactions with cyclosporin, anaesthetics, carbamazepine and cardiovascular agents.

Pharmacokinetic interactions with calcium channel antagonists (Part I).

Calcium 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.