Management of coronary heart disease risk factors and progression with calcium channel blockers.

The death rate from coronary heart disease (CHD) declined by 25% in the United States during 1987-1997, but the actual number of deaths fell by only 9%. Modifiable risk factors for CHD include hypertension, elevated low-density lipoprotein cholesterol, reduced high-density lipoprotein cholesterol, cigarette smoking, and diabetes. Several randomized clinical trials demonstrated that calcium channel blockers reduce the frequency of strokes in patients with hypertension, with particular benefit observed in patients with both hypertension and diabetes. Results of a meta-analysis suggest that calcium channel blockers are similar to beta-blockers in preventing death or myocardial infarction and in improving exercise tolerance among patients with established CHD. In addition, amlodipine, a long-acting dihydropyridine, was reported to reduce nonfatal vascular events and major vascular procedures in patients with angina. Ongoing clinical trials are comparing amlodipine with an angiotensin-converting enzyme inhibitor for slowing the onset and progression of coronary artery plaque and cardiovascular events.

Lack of gender differences and large intrasubject variability in cytochrome P450 activity measured by phenotyping with dextromethorphan.

Gender-based differences in cytochrome P450 (CYP) activity may occur due to endogenous hormonal fluctuations with the menstrual cycle, which are altered by oral contraceptives. This study assessed the average activity and within-subject variability in CYP3A4 and CYP2D6 in men, women taking Triphasil, and regularly menstruating women not receiving oral contraceptives. Thirty-three healthy volunteers participated in this 28-day pilot study (12 women receiving Triphasil) (OCs), 11 regularly menstruating women not on exogenous progesterone or estrogen (no OCs), and 10 men. CYP3A4 and CYP2D6 activities were phenotyped with dextromethorphan (DM) on study days 7, 14, 21, and 28 using urinary ratios of DM:3-methoxymorphinan (3MM) and DM:dextrorphan (DX), respectively. Serial blood concentrations of estrogen and progesterone and menstrual diaries were used to determine menstrual phase in both groups of women. Average urinary DM:3MM and DM:DX in the 28 extensive metabolizers of CYP2D6 did not differ between the three study populations (p = 0.86 and 0.93, respectively). Post hoc power analysis indicated that more than 1000 subjects would be needed for 80% power (alpha = 0.05) to detect a +/- 15% difference from the population mean in the urinary ratios of dextromethorphan and its metabolites 3MM and DX. Variability in CYP3A4 and CYP2D6 activity, characterized by intrasubject standard deviation, also did not differ. The varying doses of levonorgesterol and ethinyl estradiol in Triphasil, fluctuations in estrogen and progesterone, and menstrual phase did not influence CYP3A4 or CYP2D6 activity. It was concluded that CYP3A4 and CYP2D6 activity and intrasubject variability were not different in the three study populations, and thus a clinically important difference between men, women on Triphasil, and women not receiving oral contraceptives is unlikely. High inter- and intrasubject variability in DM:3MM and DM:DX were clearly demonstrated and limit the use of dextromethorphan to phenotype endogenous CYP3A4 and CYP2D6 activity.

Clinical pharmacokinetics of fluvastatin.

Fluvastatin, the first fully synthetic HMG-CoA reductase inhibitor, has been shown to reduce cholesterol in patients with hyperlipidaemia, to prevent subsequent coronary events in patients with established coronary heart disease, and to alter endothelial function and plaque stability in animal models. Fluvastatin is relatively hydrophilic, compared with the semisynthetic HMG-CoA reductase inhibitors, and, therefore, it is extensively absorbed from the gastrointestinal tract. After absorption, it is nearly completely extracted and metabolised in the liver to 2 hydroxylated metabolites and an N-desisopropyl metabolite, which are excreted in the bile. Approximately 95% of a dose is recovered in the faeces, with 60% of a dose recovered as the 3 metabolites. The 6-hydroxy and N-desisopropyl fluvastatin metabolites are exclusively generated by cytochrome P450 (CYP) 2C9 and do not accumulate in the blood. CYP2C9, CYP3A4, CYP2C8 and CYP2D6 form the 5-hydroxy fluvastatin metabolite. Because of its hydrophilic nature and extensive plasma protein binding, fluvastatin has a small volume of distribution with minimal concentrations in extrahepatic tissues. The pharmacokinetics of fluvastatin are not influenced by renal function, due to its extensive metabolism and biliary excretion; limited data in patients with cirrhosis suggest a 30% reduction in oral clearance. Age and gender do not appear to affect the disposition of fluvastatin. CYP3A4 inhibitors (erythromycin, ketoconazole and itraconazole) have no effect on fluvastatin pharmacokinetics, in contrast to other HMG-CoA reductase inhibitors which are primarily metabolised by CYP3A and are subject to potential drug interactions with CYP3A inhibitors. Coadministration of fluvastatin with gastrointestinal agents such as cholestyramine, and gastric acid regulating agents (H2 receptor antagonists and proton pump inhibitors), significantly alters fluvastatin disposition by decreasing and increasing bioavailability, respectively. The nonspecific CYP inducer rifampicin (rifampin) significantly increases fluvastatin oral clearance. In addition to being a CYP2C9 substrate, fluvastatin demonstrates inhibitory effects on this isoenzyme in vitro and in vivo. In human liver microsomes, fluvastatin significantly inhibits the hydroxylation of 2 CYP2C9 substrates, tolbutamide and diclofenac. The oral clearances of the CYP2C9 substrates diclofenac, tolbutamide, glibenclamide (glyburide) and losartan are reduced by 15 to 25% when coadministered with fluvastatin. These alterations have not been shown to be clinically significant. There are inadequate data evaluating the potential interaction of fluvastatin with warfarin and phenytoin, 2 CYP2C9 substrates with a narrow therapeutic index, and caution is recommended when using fluvastatin with these agents. Fluvastatin does not appear to have a significant effect on other CYP isoenzymes or P-glycoprotein-mediated transport in vivo.

Effect of fluoxetine on carvedilol pharmacokinetics, CYP2D6 activity, and autonomic balance in heart failure patients.

The objective of this study was to examine the pharmacokinetic and pharmacodynamic consequences of concomitant administration of fluoxetine and carvedilol in heart failure patients. Fluoxetine (20 mg) or matching placebo was administered in a randomized, double-blind, two-period crossover study to 10 patients previously identified as extensive metabolizers of CYP2D6 substrates. Patients were maintained on a carvedilol dose of 25 or 50 mg bid and given fluoxetine/placebo for a minimum of 28 days. Plasma was collected over the 12-hour carvedilol dosing interval, and the concentrations of the R(+) and S(-) enantiomers of carvedilol were measured. CYP2D6 phenotype was assessed during each study period using dextromethorphan (30 mg). Changes in autonomic modulation between study periods were measured by heart rate variability in the time and frequency domains using ambulatory electrocardiographic monitoring. Compared to placebo, fluoxetine coadministration resulted in a 77% increase in mean (+/- SD) R(+) enantiomer AUC0-12 (522 +/- 413 vs. 927 +/- 506 ng.h/mL, p = 0.01) and a nonsignificant increase in S(-) enantiomer AUC (244 +/- 185 vs. 330 +/- 179 ng.h/mL, p = 0.17). Mean apparent oral clearance for both enantiomers decreased significantly with fluoxetine administration (R(+): 10.3 +/- 7.2 vs. 4.5 +/- 2.2 mL/min/kg; S(-): 22.5 +/- 12.3 vs. 12.6 +/- 7.4 mL/min/kg; p = 0.004 and 0.03, respectively). No differences in adverse effects, blood pressure, or heart rate were noted between treatment groups, and there were no consistent changes in heart rate variability parameters. In conclusion, fluoxetine administration resulted in a stereospecific inhibition of carvedilol metabolism, with the R(+) enantiomer increasing to a greater extent than the S(-) enantiomer. However, this interaction was of little clinical significance in our sample population.

The effects of fluvastatin, a CYP2C9 inhibitor, on losartan pharmacokinetics in healthy volunteers.

Losartan is an angiotensin II receptor antagonist that is metabolized by CYP2C9 and CYP3A4 to a more potent antihypertensive metabolite, E3174. Interaction studies with inhibitors of CYP3A4 have not demonstrated significant changes in the pharmacokinetics of losartan or E3174. The authors assessed the steady-state pharmacokinetics of losartan and E3174 when administered alone and concomitantly with fluvastatin, a specific CYP2C9 inhibitor. A prospective, open-label, crossover study was conducted in 12 healthy volunteers with losartan alone and in combination with fluvastatin. The baseline phase was 7 days of losartan (50 mg QAM), and the inhibition phase was 14 total days of fluvastatin (40 mg QHS), with the final 7 days including losartan. The authors found that fluvastatin did not significantly change the steady-state AUC0-24 or half-life of losartan or E3174. Losartan apparent oral clearance was not affected by fluvastatin. Inhibition of losartan metabolism appears to require both CYP2C9 and CYP3A4 inhibition.

Optimal management of amiodarone therapy: efficacy and side effects.

OBJECTIVES: To review management and dosing guidelines for amiodarone therapy, and discuss the drug's adverse event profile. METHODS: Review of relevant studies and reports. RESULTS: Amiodarone is a highly effective antiarrhythmic drug, but is associated with adverse effects involving several organs. Amiodarone-induced arrhythmia is rare, with frequency of 0.3% in one study. Pulmonary toxicity is the most serious noncardiac side effect (2-17% of patients). Hypersensitivity pneumonitis can appear early in the course of therapy. Interstitial pneumonitis is a more common but insidious pulmonary reaction characterized by cough, low-grade fever, and dyspnea that occurs after months or years of therapy. Clinically important hypothyroidism and hyperthyroidism occur in 2-10% of patients. Optic neuritis or neuropathy in which patients experience decreased or blurred vision may progress to permanent blindness. Abnormalities in liver function tests, especially elevated aminotransferase and alkaline phosphatase levels, are seen in 4-25% of patients. Neurologic side effects were reported in 20-40% of patients, at times associated with tremor, ataxia, peripheral neuropathy, malaise or fatigue, sleep disturbances, dizziness, and headaches. Several types of dermatologic reactions have been reported, including allergic rash, photosensitivity, and blue-gray skin discoloration. The best strategy for early detection of pulmonary toxicity is vigilant clinical follow-up with monitoring of cardiac status and liver and thyroid function, and prescription of the lowest effective dosage. After an initial loading dose, 200 mg/day in many patients maintains arrhythmia control and minimizes the frequency of side effects. CONCLUSION: Amiodarone is a safe and efficacious antiarrhythmic agent when lower dosages are given to patients who are closely monitored and subject to careful follow-up.

Effects of erythromycin or rifampin on losartan pharmacokinetics in healthy volunteers.

BACKGROUND: Losartan is metabolized by CYP2C9 and CYP3A4 to an active metabolite, E3174, which has greater antihypertensive activity than the parent compound. Coadministered drugs that inhibit or induce metabolic processes may therefore alter the pharmacokinetics and pharmacologic response of losartan and E3174. OBJECTIVE AND METHODS: Ten healthy volunteers were studied to assess the effects of CYP3A4 inhibition and nonspecific P450 enzyme induction on the pharmacokinetics of losartan and E3174. Subjects completed three 1-week phases separated by 6 days: 50 mg losartan every morning, losartan plus 500 mg erythromycin four times a day, and losartan plus 300 mg rifampin (INN, rifampicin) twice a day. On the eighth day of each phase, serial plasma concentrations of losartan and E3174 were obtained over 32 hours and steady-state pharmacokinetics were determined. RESULTS: Rifampin decreased the area under the concentration-time curve from time zero to 24 hours after the dose (AUC[0-24]) of losartan by 35% (349 +/- 246 versus 225 +/- 130; p = 0.0001) and decreased the AUC(0-24) of E3174 by 40% (1336 +/- 445 versus 792 +/- 302; p < 0.005). Losartan oral clearance was increased by 44% (p = 0.0001). The half-life values of both compounds were decreased by 50% (p < 0.005). In contrast, erythromycin did not significantly affect the AUC(0-24) or half-life of either losartan or E3174. CONCLUSIONS: Rifampin is a potent inducer of losartan and E3174 elimination. Given the magnitude of the effect, this interaction is likely to be clinically significant. On the basis of the minimal inhibitory effects observed with erythromycin, CYP3A4 appears to play a minor role in the in vivo metabolism of losartan to E3174. Further studies are needed to define the contribution of other isozymes, particularly CYP2C9, to the pharmacokinetics of losartan and E3174.

Evolving role of calcium channel blockers in heart failure.

Calcium channel blockers are theoretically effective in the treatment of chronic systolic heart failure because of their actions as arteriolar dilators, antiischemic agents, and relaxants of diastolic left ventricular function, and because they may prevent progression of myocardial dysfunction. The first-generation calcium channel blockers nifedipine, verapamil, and diltiazem cause hemodynamic and clinical deterioration and may increase the frequency of cardiac events in postmyocardial infarction patients with heart failure. These drugs depress left ventricular contractility in the short term, and can activate neurohormonal systems due to their hypotensive effects. The second-generation calcium channel blocker felodipine does not activate the sympathetic nervous and renin-angiotensin systems, but has no effect on exercise capacity or mortality. Amlodipine increases exercise time and reduces symptoms and plasma norepinephrine concentration in heart failure. It also reduces morbidity and mortality in New York Heart Association class i.v. patients with nonischemic dilated cardiomyopathy, and appears to be effective as primary therapy for patients with dilated cardiomyopathy.

Absorption pharmacokinetics of atenolol in patients with the Marfan syndrome.

The negative inotropic and chronotropic effects of beta-blocker therapy have been reported to reduce morbidity and mortality in patients with Marfan syndrome; however, little is known about the pharmacokinetics of atenolol after oral administration of multiple doses to patients with the Marfan syndrome. We studied the pharmacokinetics of atenolol in 13 such patients aged 18.7 +/- 2.9 years who were receiving 1.78 +/- 0.58 mg/kg/day (70.1 +/- 20.3 mg/m2/day) of atenolol for 6 weeks or longer. Mean +/- SD percentage change in baseline heart rate after the administration of atenolol was -18.03 +/- 16.59% and mean +/- SD percentage change in exercise heart rate after atenolol was -33.22 +/- 14.75% (P < .01). Six to 8 atenolol serum concentrations were collected in each patient during a 12-hour dosing interval and were determined by high-performance liquid chromatography with ultraviolet detection. Serum atenolol concentrations at 0 (123 +/- 70 micrograms/L) and 12 (116 +/- 66 micrograms/L) hours were within 20% of each other and were thus assumed to be at steady-state. A one-compartment, steady-state pharmacokinetic model with first-order absorption and elimination was fitted to the concentration-time data for each patient using nonlinear regression. Maximal concentration was 343 +/- 120 micrograms/L, and the mean half-life was 4.72 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhaled verapamil-induced bronchoconstriction in mild asthma.

Methacholine challenges were performed in ten subjects with mild asthma at 2 h before and 20 min after placebo or 5, 10, 20, 40, 80, and 160 mg of inhaled verapamil given in a single-blind randomized crossover manner on different days. While verapamil did not have a bronchodilator effect, the 10-mg dose modestly increased the concentration of methacholine required to decrease FEV1 by 20 percent (PC20). The mean (+/- SEM) increase in PC20 from baseline was 2.1 +/- 0.2 times baseline after 10 mg of verapamil, compared to 1.1 +/- 0.1 times baseline after placebo (p less than 0.001). Unexpectedly, bronchoconstriction (greater than 10 percent decrease in FEV1) associated with cough or wheezing was observed in seven of ten subjects at doses of 20 mg or more. This adverse effect was not related to the osmolarity of the nebulized solutions. Thirty minutes before a standardized exercise challenge, 13 subjects inhaled placebo, 10 mg, or the highest dose of verapamil tolerated during the methacholine study (20 to 160 mg) in a double-blind randomized crossover manner. The exercise challenge was aborted in three subjects because of bronchospasm that occurred after administration of the higher dose. The mean (+/- SEM) maximum change in FEV1 after exercise in the ten subjects completing all three regimens of treatment was -17.1 +/- 4.0 percent after placebo, -12.7 +/- 4.3 percent after 10 mg (p less than 0.05), and -6.4 +/- 3.6 percent after the highest dose (p less than 0.05). We conclude that increasing the dose of verapamil above 10 mg did not provide greater benefit but, paradoxically, induced bronchoconstriction in most of the subjects. Because of this potential bronchoconstrictor effect, high doses of oral or intravenous verapamil should be used with caution in asthmatic subjects.

Electrophysiologic effects of verapamil metabolites in the isolated heart.

The electrophysiologic effects of the metabolites of verapamil are unknown and may contribute to the observed differences between intravenous and oral verapamil. We examined the electrophysiologic effects of verapamil and its metabolites (norverapamil, N-dealkylverapamil (D617), and N-dealkylnorverapamil (D620)) at estimated, free therapeutic concentrations, in the retrogradely perfused, isolated rabbit heart. Verapamil at 5 and 10 ng/ml significantly prolonged anterograde (11 and 27%, respectively) and retrograde (10 and 25%, respectively) atrioventricular (AV) nodal block cycle lengths. Anterograde and retrograde AV nodal conduction times and refractory periods were also prolonged. Norverapamil at 100 ng/ml had qualitatively similar effects equivalent to 20-50% that observed with verapamil at 10 ng/ml. D620 had small but statistically significant effects on some AV nodal parameters. D617 had no effect. The combination of verapamil plus its principal metabolite, norverapamil, had additive effects. None of the compounds had any measurable effect on atrial conduction, His-Purkinje conduction, or atrial refractoriness. Ventricular refractoriness was significantly prolonged only by norverapamil. In conclusion, some of the metabolites of verapamil have important electrophysiologic AV nodal effects and may contribute to the clinical effects observed during chronic oral verapamil dosing.

Lack of effect of atenolol and nadolol on the metabolism of theophylline.

The effects of 7 days of pretreatment with atenolol, 150 mg day-1, or nadolol, 80 mg day-1, on the pharmacokinetics and metabolism of theophylline were determined in six male smokers. Theophylline clearance, volume of distribution, half-life and the urinary excretion of theophylline and its metabolites were unchanged during either treatment compared with control.

Hepatic drug clearance in children: studies with indocyanine green as a model substrate.

For several drugs metabolized by the liver, higher dosages (mg/kg body weight) are required in children to attain serum concentrations comparable to those in adults. Indocyanine green (ICG), a commonly used model substrate for hepatic elimination of high intrinsic clearance drugs, has been extensively evaluated in adults but not in children. We evaluated the disposition of ICG in 115 children with leukemia and nine healthy adult volunteers. The mean (SD) ICG plasma clearance (CLp) for all 115 children (age 0.9-17.8 years) was significantly greater (p = 0.0006) than for adults [14.8 (7.8) versus 10.6 (2.4) mL/min/kg]. When clearances from only children less than 10 years of age (N = 85) were compared with those from adults, the difference was even greater [15.6 (7.3) versus 10.6 (2.4) mL/min/kg; p = 0.0001]. However, when ICG CLp was normalized to body surface area, values for children did not differ significantly from adults [378 (204) versus 422 (102) mL/min/m2]. These data provide insight as to why dosage (mg/kg) requirements of certain drugs are higher in children.

Lorazepam pharmacodynamics and pharmacokinetics in children.

We evaluated the effects of low doses of lorazepam on episodic versus long-term memory, attention, and somatic and affective symptoms, as well as its pharmacokinetics, in a group of 16 children aged 2.8 to 14.2 years. Psychologic assessments of each child were performed twice before intravenous administration of lorazepam (0.03 mg/kg), and 1 1/2 hours and 24 hours after lorazepam; there were no significant changes in long-term memory, attention, or somatic symptoms. There was a significant decrease in affective symptoms at 1 1/2 hours (p = 0.011), with a trend toward decreased anxiety at 1 1/2 and 24 hours after lorazepam (p = 0.026 and 0.028, respectively). There was also a selective anterograde amnestic effect in 5 of 16 children after lorazepam (p = 0.06). Mean (+/- SD) lorazepam systemic clearance was 1.3 +/- 0.4 ml/min/kg, with a terminal half-life of 10.5 +/- 2.9 hours and an unbound clearance of 15.9 +/- 5.2 ml/min/kg. A group of healthy adult volunteers who were given lorazepam had a mean systemic clearance of 1.0 +/- 0.4 ml/min/kg, somewhat less than that of the children (p = 0.069). There were no significant differences in any lorazepam pharmacokinetic parameter between those children who did versus those who did not have changes in affective symptoms or amnesia. These data should be helpful in establishing the dose of lorazepam in children, as the drug becomes more widely used as an antiemetic, premedicant, and anticonvulsant agent.

Altered protein binding of etoposide in patients with cancer.

Etoposide plasma protein binding (PB) is reported to be 94% based on in vitro studies using normal human serum albumin (SA). Etoposide PB in 17 patients with cancer receiving etoposide (50 to 100 mg/m2) and in plasma of 14 volunteers was determined by equilibrium dialysis with 3H-etoposide. The unbound fraction (Fu) in patients with cancer was 0.139 +/- 0.099 compared with 0.043 +/- 0.0036 in plasma from normal volunteers (p less than 0.0009; t test). Etoposide binding ratio (BR) was correlated directly with SA (r2 = 0.83; p less than 0.05). In the population with cancer Fu was significantly correlated with bilirubin (r2 = 0.837; p less than 0.05). In a multivariate analysis, SA and bilirubin were significant predictors of Fu (r2 = 0.93; p less than 0.05). This study corroborates previous reports of etoposide PB in normal human serum and demonstrates altered PB in patients with abnormal serum albumin or bilirubin levels.

Determination of verapamil and its primary metabolites in serum by ion-pair adsorption high-performance liquid chromatography.

A high-performance liquid chromatographic (HPLC) method for the simultaneous quantitation of verapamil, norverapamil, N-dealkylverapamil (D617) and N-dealkylnorverapamil (D620) concentrations in serum is developed. Analysis is performed on a microparticulate (10 microns) silica column using a counter-ion solvent system (0.6 mM NaBr in methanol). Column effluent is monitored by fluorescence detection at an excitation wavelength of 203 nm. The limit of sensitivity is less than 1 ng for all compounds in serum. No potential sources of interference are identified and a coefficient of variation of less than 10% is observed on replicate verapamil determinations. The method has the advantages of complete resolution of the metabolites of verapamil, low limits of detection, high degree of reproducibility, and short analysis time.

Nonlinear accumulation of propranolol enantiomers.

The accumulation of (+)- and (-)-propranolol was investigated in nine subjects who received 160 mg of racemic propranolol as a single dose and then once daily for 7 days. The serum concentrations of propranolol enantiomers were measured by h.p.l.c. using a novel chiral stationary phase allowing direct resolution of underivatized propranolol. The (+)-propranolol AUC increased from 412 +/- 223 ng ml-1 h after single doses (0-infinity) to 584 +/- 279 ng ml-1 h at steady-state (0-24 h) (P less than 0.05). Similarly, (-)-propranolol AUC increased from 609 +/- 304 to 777 +/- 370 ng ml-1 h (P less than 0.05). The AUC ratio (-)/(+) was 1.52 +/- 0.36 and 1.32 +/- 0.17 after single doses and steady-state, respectively (P greater than 0.05). Therefore, nonlinear accumulation occurs with both enantiomers although there is a trend for the (-)/(+) ratio to decrease at steady-state.