The Pharmacokinetics and Pharmacodynamics of Newer Inotropic Agents

Contents

Summary

Review Article

Clinical Pharmacokinetics 13: 91-109 (1987) 0312-5963/87/0008-0091/$09.50/0 © ADIS Press Limited All rights reserved.

The Pharmacokinetics and Pharmacodynamics of Newer Inotropic Agents

Mario L. Rocci Jr and Hugh Wilson Division of Clinical Pharmacology, Jefferson Medical College and Department of Pharmacy, Philadelphia College of Pharmacy and Science, Philadelphia

Summary ...... ... ... ............. ..... ..... .......... ... ......... .... ..... ........ .... ........... ..... .......... ....... .... ...... .. .. ....... ... 91 I. Amrinone ......... ......... ................ ....................... ... ......... .. ... .. .... .. ......................... ... ... ....... ... ...... 93

1.1 Absorption .. .. ............ .. .................. .. ....... ... .. ............. .. .... .. .... ...................................... .. ... ... 93 1.2 Distribution .................. ................ .... ............. .. ......... ... ................................... .............. ..... 93 1.3 Elimination ........................... ... ................................................ ............. ... .......................... 95 1.4 Relationship Between Haemodynamic Effects and Plasma Concentrations of

Amrinone ........... ... .... ... ............. .. ................ ... ............................ ............... ............... ..... ... ... 96 2. Milrinone ... .. ... ............. .. .. .......... .......................... ............................ ... .. .... ...................... ... ... ... 97

2.1 Absorption ................... .. .................................... ......... ... .................................. .. ........ .... .... 97 2.2 Distribution .................... .................. ............ .. .. ........... ...... , .. .......... .......... .... .. .. ..... .. ... ... .... 98 2.3 Elimination ... ........... .. .. .... ......................... .. ... .................................................................... 98 2.4 Relationship Between Haemodynamic Effects and Plasma Concentrations of

Milrinone .. ... .......... .. ... ................................ ... .............. .. ................ ....... ... .... ............ .. ....... 1 00 3. Enoximone ..................... .. ..... ............... .. .............................................................. ................ .. 101

3.1 Absorption ................. ............................................................................... ... .... ........ ... .. ... 101 3.2 Distribution ............. .. .................................... .. ............................................................. ... 102 3.3 Elimination .. ............. ................ ................ .. ................ ... .. ..................... ........ ....... ... ..... .... 102

4. Piroximone .................................................. .. ....................... .............. .. ..... ... .... ........ .. ............ 1 04 5. Dobutamine .. ................................................................................... .. ................. .. ......... ... .. ... 104 6. Ibopamine ......................... ... ........... ............... .. .... .. ........................ ........................................ 106 7. The Future ................ .. ............................................. .. ..... ........... .......................................... .. 107

In the past few years an intense effort has been directed toward the development of new inotropic agents for the treatment of chronic cardiac failure. Traditionally, therapy of this disease has included treatment with digitalis glycosides, diuretics, sodium restriction and vasodilators. While digitalis has proven to be an effective inotropic agent, it possesses a low therapeutic index and many patients remain symptomatic or 'refractory' despite its inotropic effects. This review focuses on the pharmacokinetiCS and pharmacodynamics of newer inotropic agents that have been developed or which are currently undergoing investigation.

Amrinone and milrinone are two bipyridine derivatives which have been shown to be effective in the short term treatment of cardiac failure. Milrinone is currently being evaluated for its long term efficacy. The mechanism of action of amrinone and milrinone appears to be unrelated to the cardiac glycosides and sympathomimetic agents, and they are rapidly and well absorbed following oral administration. The bioavailability of mil-

The Pharmacokinetics and Pharmacodynamics of Newer Inotropic Agents 92

rinone appears to be somewhat reduced in patients with chronic cardiac failure. The distribution of these drugs to extravascular tissues is very rapid; the volume of distribution suggests that they are not extensively bound to tissues. While the volume of distribution of amrinone appears to be unaffected by the presence of heart failure. that of milrinone appears to be somewhat enhanced. The major route of elimination of both drugs appears to be excretion into urine as unchanged drug. A substantial fraction of the amrinone dose. however. undergoes hepatic metabolism to many metabolites. including an N-acetyl derivative. Clearance of amrinone and milrinone is dramatically reduced in patients with chronic cardiac failure compared with normal volunteers. resulting in proportionate increases in the serum half-lives of these drugs. Studies examining the acute and chronic disposition of these agents in cardiac failure patients have not demonstrated changes in their pharmacokinetics secondary to improvements in cardiocirculatory jUnction. Both drugs show strong correlations between mean improvements in haemodynamics and drug serum concentrations. although considerable intrapatient variability may exist. It is currently unclear as to whether the site for the pharmacological action of amrinone is pharmacokinetically distinguishable from plasma.

Enoximone and its sulphoxide metabolite. piroximone. are two compounds currently undergoing investigation for the treatment of chronic cardiac failure. Like the bipyridine derivatives. the mechanism of action of these compounds appears to be unrelated to sodium-potassium ATPase inhibition or sympathomimetic activity. Following oral administration of enoximone a substantial fraction of the dose is converted to piroximone on the first pass through the liver. The volumes of distribution of enoximone and piroximone do not suggest extensive tissue distribution of these drugs. The major pathway for elimination of enoximone is conversion to piroximone with subsequent renal excretion. Discrepancies exist in the literature concerning the half-life of these drugs. This discrepancy may be explained by the existence of terminal phases of disposition which have only recently been recognised. Any relationships between the haemodynamic effects of these drugs and their serum concentrations remain to be determined.

Dobutamine. a synthetic catecholamine. was the first inotropic agent to become available for therapeutic use after the advent of digoxin. The limited data examining dobutamine pharmacokinetics suggest that it possesses an extremely high clearance. a limited volume of distribution. and a very short half-life. Strong relationships exist between changes in mean haemodynamic parameters and mean plasma dobutamine concentrations.

Ibopamine. the 3.4-di-isobutyryl ester derivative of deoxyadrenaline (deoxyepinephrine; epinine) is an orally active. positive inotropic drug with dopaminergic vasodilatory activity. Upon oral administration. deoxyadrenaline exists primarily in the conjugated state in plasma. Elimination of this drug is primarily through metabolism; homovanillic acid is the primary urinary metabolite. The time course of haemodynamic effects of ibopamine greatly exceed the plasma persistence of free deoxyadrenaline. The site of action of ibopamine may be in a physiological compartment which is pharmacokinetically distinguishable from plasma.

The development and investigation of newer inotropic agents in the treatment of chronic cardiac failure is evolving. Many more studies are needed to jUlly elucidate the pharmacokinetics of these and future compounds. as well as the relationships between the pharmacokinetics of these drugs and their effects in patients.

The treatment of heart failure has undergone considerable change in recent years, with many new therapeutic agents being investigated and employed in its management. The main goals of treatment after the correction and reversal of the under-

lying pathophysiological cause still remain the augmentation of cardiac contractility and reduction of left ventricular filling pressure. Traditional therapy of congestive heart failure has included digitalis glycosides, diuretics and sodium restric-


tion, along with the recent addition of vasodilators. However, despite these therapeutic modalities, many patients still remain symptomatic or 'refractory', which has spurred interest in newer more potent therapies, especially in the area of cardiac inotropes.

Since the tum of the century, digitalis has proven to be an effective inotropic agent, albeit relatively weak. Because of its low therapeutic-toxic ratio, and the fact that many patients remain symptomatic despite therapeutic concentrations of the drug, intense efforts have focused on the development of new inotropic agents. This paper will review the pharmacokinetics and pharmacodynamics of these agents.

1. Amrinone

Amrinone (5-amino-3,4'-bipyridine-6[ 1 H]-one), a bipyridine derivative, was the first non-glycosidic, non-sympathomimetic inotropic agent marketed for the treatment of chronic cardiac failure. It is currently available for intravenous use in the USA, and intravenously and orally in other parts of the world. Amrinone possesses both positive inotropic and vasodi1atory properties, and is effective in improving cardiac performance (Goldstein 1986; Likoff et al. 1984).

1.1 Absorption

Amrinone absorption following oral administration to normal volunteers appears to be both rapid and complete. Mean ± SD maximum concentrations of amrinone following a 75mg dose were achieved at 61 ± 33 minutes; absolute bioavailability ofamrinone was 93 ± 12% (Park et al. 1983). While the aforementioned study is the only one to date assessing amrinone bioavailability, several studies performed in both healthy volunteers and cardiac failure patients have demonstrated similar times to peak amrinone serum concentrations, with values ranging from 0.5 to 3 hours (Benotti et al. 1982; Edelson et al. 1983; Kullberg et al. 1981; Wilson et al. 1982). In a study designed to assess the dose proportionality in the pharmacokinetics of

amrinone following oral doses of 75, 150, and 225mg to 18 healthy subjects, Edelson et al. (1983) demonstrated a less than proportionate increase in the peak amrinone serum concentration with mean ± SE values being 1.03 ± 0.07, 1.74 ± 0.15, and 2.53 ± 0.26 mg/L, respectively. This disproportionality in peak concentrations with dose does not appear to be due to decreased bioavailability of amrinone at higher doses, since the area under the plasma concentration-time curves were proportional to dose (4.00 ± 0.46 vs 8.18 ± 0.63 vs 12.35 ± 1.33 mg/L· h).

1.2 Distribution

Following the intravenous administration of amrinone, distribution of the drug to extravascular tissues is extremely rapid, with a mean distribution half-life in patients of 1.4 minutes (Edelson et al. 1981). Estimates of the apparent volume of distribution of amrinone obtained in healthy volunteers and in patients with various degrees of congestive heart failure are presented in table I. Many of the volume of distribution estimates presented in the literature have not been true estimates of amrinone distribution; they were derived following oral administration of the drug and are thus confounded by uncertainties in the bioavailability of the drug in the subjects studied. In addition, estimation of the volume of distribution following oral administration of the drug is typically accomplished by the computation of an area-based volume, which can be sensitive to changes or differences in drug elimination (Jusko & Gibaldi 1972). The apparent volume of distribution of amrinone in healthy volunteers is approximately 1.3 to 2 L/ kg, indicating a lack of extensive tissue distribution (Edelson et al. 1983; Kullberg et al. 1981; Park et al. 1983). Studies in patients with chronic cardiac failure have yielded similar estimates, ranging from 1.2 to 1.6 L/kg (Rocci et al. 1983; Wilson et al. 1982). Thus, the presence or severity of chronic cardiac failure does not appear to have an effect on the volume of distribution of amrinone, although further studies are needed to definitively assess this issue.

Table I. Mean ± SD pharmacokinetic parameters for amrinone

Reference Study sample n Dose Vdss CL (L/kg) (L/h/kg)

Edelson et al. (1983)· Healthy volunteers 18 75-225mg orally 129 ± 65b,d 23.0 ± 14.2b•d

(1.8 ± 0.9)" (0.33 ± 0.20)"

Kullberg et al. (1981) Healthy volunteers 15 0.8-2.2 mg/kg IV bolus

Kullberg et al. (1981)· Healthy volunteers 14 25-250mg orally 1.5 ± 0.4 0.42 ± 0.26

Park et al. (1983)· Healthy volunteers 14 75mg IV bolus 94 ± 25d 19.8 ± 7.0d

(1.3 ± 0.36)" (0.28 ± 0.10)"

Park et al. (1983)· Healthy volunteers 14 75mg orally 141 ± 30b,d 23.5 ± 12.0b,d (2.0 ± 0.43)- (0.34 ± 0.17)-

Benotti et al. (1982) NYHA III 6 100mg orally 0.19 ± 0.11f

Edelson et al. (1981) NYHA III and IV 11 150-300mg orally

Rocci et al. (1983) NYHA II (n = 8) 9 75-150mg orally 1.3 ± 0.5b .g 0.18 ± 0.07b

NYHA III (n = 1)

Rocci et al. (1983) NYHA II (n = 8) 9 75-150mg q8h orally, 1.6 ± 0.8b .g 0.17 ± 0.08b

NYHA III (n = 1) steady-state assessment

Wilson et al. (1982) NYHA II (n = 1) 15 100mg orally 1.2 ± O.4b .g 8.64 ± 5.2i NYHA III (n = 13) (0.12 ± 0.07)-NYHA IV (n = 1)

a Computed from data presented in the manuscript: CL = Dose/AUCo_oo; Vd.r_. = Dose/(AUCo.oo • K); tv, = 0.693/K. b Not corrected for bioavailability. c n = 10; data reflects urinary recovery from 0 to 24h (and in one instance 25.1 h) after drug administration. d Not corrected for bodyweight. e Normalised to a 70kg person. f Value is mean ± SE. 9 Vd.r_ ••

h Range of renal clearance values presented. % of dose excreted over a dosing interval. Clearance expressed as L/h/m2.

t'h CLR % Excreted (h) (L/h) unchanged

into urine

4.3 ± 1.3

2.6 ± 1.4 26 ± 9C

3.7 ± 2.1

4.1 ± 1.7

4.9 ± 1.6

5.1 ± 0.6f

8.3 ± 1.1 f

5.5 ± 2.4h 0.26-6.2h (0.004-0.09)-

7.3 ± 4.6h 0.32-12.7h 30 ± 20;

(0.004-0.18)-

4.8 ± 3.0

Abbreviations: n = number of study subjects; Vdss = volume of distribution at steady state; CL = systemic clearance; tv, = elimination half-life; CLR = renal clearance; NYHA = New York Heart Association classification of heart failure severity; AUCo.oo = total area under the plasma concentration vs time curve; K = elimination rate constant.

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Larijani et al. (1984) examined the protein binding of amrinone in healthy volunteers and in patients with chronic cardiac failure. Amrinone was added to serum obtained from 4 healthy volunteers in concentrations ranging from 0.2 to 20 mg/L. Amrinone binding was also assessed in 4 chronic cardiac failure patients following steady-state administration of the drug (IOOmg every 8 hours). The latter samples contained amrinone in concentrations of 0.2 to 3.2 mg/L. Amrinone binding in both groups was linear over the ranges studied, with a mean ± SD percentage bound of 32.4 ± 3.6% and 43.3 ± 8.6%, respectively, this difference being statistically significant. This variation may be related to differences in serum concentrations of c¥)

acid glycoprotein demonstrated between these study groups. The precise serum constituents to which amrinone binds, however, requires further investigation.

1.3 Elimination

The routes of elimination for amrinone in humans have not been completely characterised. Studies conducted in rats, dogs, and monkeys have shown urinary excretion of unchanged amrinone to be the major route of elimination of the drug. In addition, glucuronidation of amrinone at potentially two sites, formation of a 2-S-cysteinyl metabolite, and N-acetylation of amrinone with subsequent oxidation to the N-glycolate have been reported (Baker et al. 1982). In humans, the formation of an N-acetyl metabolite of amrinone has been demonstrated in healthy volunteers (Kullberg et al. 1981) and in patients with chronic cardiac failure (Rocci et al. 1983; Wilson et al. 1982). In each of these studies, the plasma concentrations of the N-acetyl metabolite were low relative to amrinone. Less than 6% of the amrinone dose can be accounted for as the N-acetyl metabolite in the urine of healthy volunteers and patients (Edelson et al. 1983; Rocci et al. 1983).

The clearance, half-life and characteristics of the urinary elimination of amrinone are outlined in table I. The elimination of unchanged amrinone into urine in healthy volunteers and in patients

ranges from 26 to 30%, suggesting significant metabolism of the drug in humans (table I). The renal clearance appears to have substantial inter- and intrapatient variability (Rocci et al. 1983). A proportion of this variability may be due to the lack of consideration of amrinone excretion as glucuronides. The magnitude of the renal clearance and protein binding suggests that glomerular filtration, tubular reabsorption and active tubular secretion may all be involved in the renal handling of the drug.

The total apparent clearance of amrinone established in healthy volunteers ranges from approximately 0.28 to 0.42 L/h/kg (table I). These estimates are confounded in several instances by the unknown bioavailability of amrinone in the volunteers studied. Following an intravenous dose, Park et al. (1983) estimated the total clearance of amrinone to be 19.8 ± 7.0 L/h which equates to 0.28 ± 0.1 L/h/kg for a 70kg person. In a study designed to assess the linearity of amrinone pharmacokinetics following 75, 150 and 225mg doses, Edelson et al. (1983) observed dose-dependent increases in the area under the plasma concentrationtime curve and a less than proportionate increase in the peak amrinone plasma concentration. Reanalysis of this data has yielded no dose-related changes (75mg vs 150mg vs 225mg) in the mean ± SD apparent clearance (23.0 ± 14.2 vs 20.6 ± 7.5 vs 25.5 ± 21 L/h) or area-based volume of distribution (117 ± 42 vs 127 ± 58 vs 142 ± 87L) for amrinone. A statistically significant, but clinically insignificant change in amrinone half-life could be detected with increasing dose (4.0 ± 1.4 vs 4.4 ± 1.2 vs 4.5 ± l.4h). Despite the observed minor non-linearity in amrinone peak concentrations and half-life, the apparent clearance and volume of distribution of amrinone are independent of dose.

The total apparent clearance of amrinone in chronic cardiac failure patients, appears to be lower than in volunteers, with estimates ranging from 0.12 to 0.18 L/h/kg (Rocci et al. 1983; Wilson et al. 1982). It is unclear whether this decrease in the apparent clearance is secondary to diminished renal function, reduced hepatic function, or both. The half-life for amrinone in healthy volunteers ranges


from 2.6 to 4.9 hours, with more prolonged halflives being observed in patients with chronic cardiac failure (4.8 to 8.3 hours; table I). This prolongation in half-life is probably due to the decrease in clearance discussed above. In a study designed to assess whether amrinone-induced improvements in cardiac performance might alter the pharmacokinetics, Rocci et a1. (1983) examined the pharmacokinetics in 9 patients after oral doses ranging from 75 to 150mg every 8 hours. Patients were studied following their first dose, and at steadystate (4 to 6 weeks into therapy). No changes in the mean apparent clearance (0.18 vs 0.17 L/h/kg) or volume of distribution (1.3 vs 1.6 L/kg) were observed, with relatively little intrapatient variability. Thus, amrinone distribution and clearance appear to be relatively insensitive to the improvements in cardiocirculatory function which accompanies amrinone therapy.

1.4 Relationship Between Haemodynamic

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Effects and Plasma Concentrations of Amrinone plasma concentration (mg/L)

Amrinone

Studies performed to examine the relationship between amrinone plasma concentrations and its haemodynamic effects have correlated improvements in cardiac index with amrinone plasma concentrations. To date, no correlations between reductions in pulmonary capillary wedge pressure or right atrial pressure and amrinone plasma concentration have appeared in the literature.

Strong and highly significant relationships (r > 0.9; p < 0.025) between cardiac index corrected for baseline and amrinone plasma concentration existed in 5 of the 15 individuals with chronic cardiac failure of diverse aetiology examined by Wilson et a1. (1982). In the remaining patients, either no relationship appeared to exist or insufficient data were available for analysis. The relationship between the 2 parameters for the pooled data is depicted in figure 1. A modest but significant relationship (r = 0.67; p < 0.01) existed between improvement in cardiac index and amrinone plasma concentration when samples were examined in the post-absorptive, post-distributive phase. No differences in the

Fig. 1. Relationship between cardiac index corrected for baseline and amrinone plasma concentrations in 13 of the study

patients. The solid line is the perpendicular least squares

regreSSion line characterising the data excluding the atypical

patient (with permission from Wilson et al. 1986). 0 = valvular

heart disease; • = idiopathic congestive cardiomyopathy; 0 = ischaemic heart disease; ... = valvular heart disease with atyp

ical response to amrinone vs remainder of group.

relationship appeared to exist as a function aetiology or functional aerobic capacity. The relationship between improvement in cardiac index and plasma concentration is consistent with data obtained by others (Benotti et a1. 1982; Edelson et a1. 1981). These investigators found strong and highly significant relationships (r > 0.80; p < 0.05) between the mean percentage increase in cardiac index and average amrinone plasma concentration. Neither ofthese groups examined the nature of this relationship in individual patients.

Discrepancies exist in the literature as to whether the sites of pharmacological actions of amrinone


are pharmacokinetically distinguishable from the central compartment. Wilson et al. (1982) demonstrated, following a l00mg oral dose of amrinone, that a counterclockwise hysteresis exists when cardiac index corrected for baseline is plotted as a function of amrinone plasma concentration (fig. 2). These data suggest that the site for amrinone action is pharmacokinetically distinguishable from the central compartment. In contrast, other investigators have shown generally good concordance between the time courses of change in cardiac index and plasma concentration of amrinone (Edelson et al. 1981). Despite this disparity, all studies generally demonstrate significant relationships between mean improvements in cardiac index and mean amrinone plasma concentrations when measurements in the postabsorptive, postdistri-

1.6

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Amrinone concentration (mg/L)

Fig.2. Relationship between the mean ± SO cardiac index corrected for baseline and the mean ± SO amrinone plasma con

centration in the study patients. The closed triangular arrows

denote the progression of time relative to the administration of the dose. The asterisks in the figure denote that the mean value was obtained in 14 rather than 15 patients.

butive phase of amrinone disposition are employed.

It is unclear whether any of the metabolites of amrinone exert pharmacological effects, although two studies have demonstrated the presence of an N-acetyl metabolite in patients (Rocci et al. 1983; Wilson et al. 1982). As was previously stated, the plasma concentrations of the N-acetyl metabolite following therapeutic doses are low and very close to the sensitivity of the assay, making correlations of metabolite concentrations with improvements in cardiac function impractical.

2. Milrinone

Milrinone (1 ,6-dihydro-2-methyl-6-oxo[3,4'-bipyridine]-5-carbonitrile) is currently undergoing investigation for the treatment of chronic cardiac failure (LeJemtel et al. 1986; Likoff et al. 1985). It is structurally related to amrinone and is 30 times more potent as a positive inotrope in guinea-pig papillary muscles (Alousi et al. 1983).

2.1 Absorption

The rate and extent of milrinone absorption in healthy volunteers is both rapid and complete. Stroshane et al. (19~4b) examined the time course of milrinone plasma concentrations following either oral or intravenous administration to 39 healthy men, and estimated the mean absolute bioavailability to be 92%. This estimate was based on the comparison of two patallel groups of volunteers receiving either oral or intravenous milrinone. Nonetheless, measurement of the 24-hour urinary recovery of milrinone revealed that 79.9 ± 10.7% of the dose was excreted into the urine following oral administration. Peak plasma concentrations occurred 1.1 ± 0.6 hours following drug administration. This agrees well with data obtained by Larsson et al. (1986), who evaluated a 5mg oral dose of milrinone in healthy subjects, which produced peak milrinone plasma concentrations at 0.64 ± 0.43 hours postdose.

The rate and extent of milrinone absorption in patients with chronic cardiac failure may be slightly


reduced. Wilson et a1. (1984) demonstrated the occurrence of peak milrinone plasma concentrations at 1.7 ± 1.5 hours following the administration of a 5mg dose. Peak concentrations of milrinone following this dose appeared to be higher (218 ± 130 mg/L) than in healthy volunteers (162 ± 142 mg/ L) [Larsson et a1. 1986; Wilson et a1. 1984], despite a reduced mean ± SD bioavailability of 75.6 ± 22.7% in the heart failure patients. These differences in the maximum plasma concentrations attained following similar doses of milrinone may reflect reduced elimination of the drug in heart failure patients (see section 2.3).

2.2 Distribution

Following intravenous doses, milrinone exhibits 2-compartmental, pharmacokinetic behaviour. Distribution of the drug to extravascular tissues is very rapid, with a mean half-life of 5 minutes (Stroshane et a1. 1984a). The volume of distribution at steady-state for milrinone calculated after a single intravenous bolus of the drug to healthy volunteers is 0.25 ± 0.06 to 0.32 ± 0.08 L/kg (Stroshane et a1. 1984a). The volume of distribution is not dramatically altered by the presence of mild heart failure (Wilson et a1. 1984; table II). The distribution of milrinone in patients with more severe heart failure [New York Heart Association (NYHA) Classes III and IV] may be somewhat enhanced. Distribution volumes following intravenous administration of this drug have yielded parameters ranging from 0.33 to 0.47 L/kg (Benotti et a1. 1985; Edelson et a1. 1986; Stroshane et a1. 1984b; Wilson et a1. 1984; table II). The volume of distribution of milrinone does not suggest extensive tissue binding of the drug. No statistically significant alterations in the volume of distribution of milrinone occur with dose (Edelson et a1. 1986).

2.3 Elimination

The major pathway for milrinone elimination is excretion of unchanged drug into the urine. Studies performed in healthy volunteers have sug-

gested that 79.9 to 84.5% of the dose is excreted unchanged within 24 hours (Larsson et a1. 1986; Stroshane et a1. 1984a; table II). The magnitude of the renal clearance values obtained in healthy volunteers suggests that active tubular secretion is a major process in the renal elimination of the drug (table II). The systemic clearance of milrinone following intravenous bolus doses is 25.9 ± 5.7 L/h (approximately 0.37 L/hfkg), and is markedly lower in patients with chronic cardiac failure (0.11 to 0.16 L/h/kg). This reduced clearance of milrinone may be the result of reduced renal function. In the NYHA class III and IV patients studied by Edelson et a1. (1986), creatinine clearance values were approximately half those obtained in healthy volunteers (52 vs 119 ml/min). No alterations in the clearance of milrinone have been detected as a function of milrinone dose (Edelson et a1. 1986).

The reduction in the systemic clearance of milrinone in patients produces a longer elimination half-life. Studies conducted in healthy volunteers have demonstrated half-lives for milrinone ranging from 0.88 to 0.97 hours (Larsson et a1. 1986; Stroshane et a1. 1984a). In contrast, Wilson et a1. (1984) observed a mean ± SD milrinone half-life in a group of NYHA class II and III patients which was approximately 50% longer (1.5 ± 0.6 hours). In patients with more severe forms of heart failure, milrinone half-life appears to be further prolonged, with estimates for patients with class III and IV failure ranging from 1.7 to 2.7 hours (Benotti et a1. 1985; Edelson et al. 1986).

The general improvement in cardiac function which accompanies therapy with inotropic agents could potentially alter pharmacokinetic parameters with continued therapy. Edelson et a1. (1986) investigated this concept in patients with chronic cardiac failure. The results contrast with what might be expected: no changes in the systemic clearance, half-life, or volume of distribution of milrinone occurred following one month oftherapy. Creatinine clearance also remained unchanged over the study period, suggesting that although cardiac function is improved with inotropic therapy, there may not be

Table II. Mean ± SE pharmacokinetic parameters for milrinone

Reference Study sample

Larsson et al. Healthy volunteers (1986)

Stroshane et al. Healthy volunteers (1984a)

Stroshane et al. Healthy volunteers (1984a)

Benotti et al. NYHA III (n = 2) (1985) NYHA IV (n = 11)

Edelson et al. NYHA III & IV (1986)



Stroshane et al. NYHA III & IV (1984b)



Wilson et al. NYHA II (n = 9) (1984) NYHA III (n = 2)

a Value is mean ± SO.

b CL is expressed as L/h.

c Normalised for a 70kg person.

d Not corrected for bioavailabilily. e Vd~.

f Vdar •••

Abbreviations: see table I.

n Dose Vdss

(L/kg)

7 5mg orally

21 10-125 I'g/kg IV bolus 0.25 ± 0.06a

18 1-12.5mg orally

13 12.5-75I'g/kg IV bolus 0.35 ± 0.02·

26 12.5-125I'g/kg IV bolus 0.38 ± 0.01f

26 0.2-0.7 I'g/kg/min IV 0.47 ± 0.03f

for 18h

21 2.5-15mg orally 0.56 ± 0.02".1

6 12.5-75 I'g/kg IV bolus 0.33 ± 0.03

8 0.2-0.7 I'g/kg/min IV 0.47 ± 0.05f

for 18h

10 2.5-10mg orally 0.52 ± 0.05"·f

11 12.5-75 I'g/kg IV bolus 0.30 ± 0.12··f

CL t'h (L/h/kg) (h)

0.94 ± 0.12

25.9 ± 5.7a.b 0.88 ± 0.34 (0.37 ± 0.08)C

29.7 ± 6.7a.M 0.97 ± 0.26 (0.42 ± 0.1)C

0.15 ± 0.03 1.7 ± 0.3

0.13 ± 0.01 2.3 ± 0.1

0.14 ± 0.01 2.6 ± 0.2

0.16 ± 0.005" 2.7 ± 0.1

0.11 ± 0.01

0.16 ± 0.02

0.16 ± 0.01"

0.15 ± 0.06a 1.5 ± 0.6a

CLR % Excreted

(L/h) unchanged into urine

17.3 ± 4.0 82.7 ± 7

21.1 ± 2.9 84.5 ± 10.1

23.8 ± 6.4 79.9 ± 10.7

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Fig. 3. The relationship between the renal clearance of milrinone and creatinine clearance in individuals with normal cardiac function and varying degrees of renal insufficiency. Unear regression analysis yields: y = 2.54x- 16.7. r = 0.91; p < 0.001 (with permission from Larsson et at 1986).

an accompanying increase in renal perfusion (Cody et al. 1984).

Larsson et al. (1986) found that plasma milrinone half-life ranged from 0.94 hours in healthy subjects (creatinine clearance ,., 114 ml/min/ l.73m2) to 3.24 hours in patients with severe renal insufficiency (creatinine clearance ,., 14 ml/min/ I. 73m2). This prolongation in half-life in severe renal insufficiency was due to reductions in the renal clearance of milrinone. A strong and highly significant relationship was observed between milrinone clearance and creatinine clearance (r = 0.91; p < 0.001), shown in figure 3. The decrease in the elimination of milrinone in severe renal insufficiency may be of clinical importance, but further

studies are required to determine whether doses need to be adjusted in this patient population.

2.4 Relationship Between Haemodynamic Effects and Plasma Concentrations of Milrinone

A number of investigators have examined the relationship of mean milrinone plasma concentration to changes in mean cardiac index, pulmonary capillary wedge pressure and blood pressure (Benotti et al. 1984; Cody et aI. 1984; Larsson et al. 1986). However, relationships between pharmacological effect and plasma concentration within given individuals have not been reported. The relationship between the mean change in cardiac index and the mean peak milrinone plasma concentration in 10 patients with NYHA class III and IV chronic cardiac failure is shown in figure 4. A strong relationship exists between these mean parameters (Cody et aI. 1984). The maximum percent change

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Maximum milrinone plasma concentration {Jtg/L)

Fig. 4. Relationship of maximum milrinone plasma concentration and maximal percent increase in cardiac index (CI) from 10 patients with NYHA class III or IV chronic cardiac failure (with permission from Cody et at 1984).


in cardiac index ranges from 22.5% at the 2.5mg milrinone dose to approximately 48% at a dose of 10mg.

A somewhat weaker, but significant relationship appears to exist between peak reductions in pulmonary capillary wedge pressure and milrinone plasma concentration (fig. 5). Benotti et al. (1985) examined the relationship between individual maximal cardiac output and milrinone plasma concentration in a group of patients receiving various single doses of milrinone, but were unable to demonstrate such a relationship. This may be related to the severity of the heart failure in the patients studied, the potential dose-related predominance of putative mechanisms of action and/ or interpatient variability in the response to the drug.

In addition to the positive inotropic effect of milrinone, it possesses a direct vasodilatory effect, and has been shown to significantly lower blood pressure in animals (Alousi et al. 1984). Larsson et al. (1986) examined the effects of milrinone on blood pressure and its relationship to plasma concentration. Reductions in both systolic and diastolic blood pressure following a single 5mg oral dose were observed in healthy volunteers (from 118/71 to 107/56mm Hg) and patients with renal insufficiency (from 159/95 to 136/79mm Hg), but were not related to milrinone serum concentrations. The therapeutic use of milrinone as an antihypertensive agent requires further evaluation.

3. Enoximone

Enoximone (MDL 17043: 1,3-dihydro-4-methyl-5-[ 4-(methylthio )-benzoyl]-2H-imidazol-2-one) is a cardiotonic agent currently undergoing investigation for the treatment of chronic cardiac failure. Like amrinone and milrinone, this drug possesses both positive inotropic and vasodilating properties, and does not appear to share mechanisms of action similar to either the cardiac glycosides or sympathomimetic agents (Roebel et aI. 1982). While the exact mechanism by which enoximone acts is not completely understood, it has been shown to be a potent phosphodiesterase inhibitor ex vivo

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Fig. 5. Relationship between mean maximum change in pulmonary capillary wedge pressure (PCWP) and milrinone plasma concentration obtained at the time that the maximum reduction in PCWP was observed. These data were obtained from 11 patients with NYHA class III or IV chronic cardiac failure (with permission from Benotti et al. 1984).

(Kariya et al. 1982). Only limited information is currently available describing the pharmacokinetics of this compound.

3.1 Absorption

Following an oral dose of 3 mg/kg of enoximone peak concentrations occur within 10 to 30 minutes, and disappear rapidly with the drug generally being undetectable after 7 hours. A substantial fraction of enoximone is converted on first-pass through the liver to the corresponding sulphoxide metabolite, which has also been demonstrated to have pharmacological activity. Sulphoxide plasma concentrations are higher and persist longer than those of enoximone, following both oral and intravenous administration (AIken et al. 1984). Peak


concentrations of this metabolite occur about 30 minutes after peak concentrations of enoximone are achieved.

A bioavailability study of enoximone conducted in 6 healthy volunteers yielded estimates ranging from 44 to 69%, with a mean value of 55% using plasma data and 58% using urinary recovery data. Uretsky et al. (1985) examined the pharmacokinetics of enoximone in 20 patients (NYHA class III or IV heart failure) following oral doses of 3 to 6 mg/kg, and observed peak concentrations of enoximone at 1.6 ± 1.2 hours following drug administration. Peak concentrations of the sulphoxide metabolite in these patients occurred at 2.5 ± 1.6 hours (Uretsky et al. 1985). This delay in the attainment of peak concentrations of the metabolite in cardiac failure patients might be due to delayed absorption, or attenuation of the first-pass metabolism of enoximone secondary to hepatic congestion. As with healthy volunteers, peak concentrations of the metabolite were substantially higher than those of the parent compound.

3.2 Distribution

The volume of distribution at steady-state for enoximone following a 1 mg/kg intravenous infusion of the drug over 5 minutes was evaluated in 6 healthy volunteers, and ranged from 0.9 to 2.9 L/kg with a mean ± SD of 1.8 ± 0.68 L/kg (table III; AIken et al. 1984). Computation of a volume of distribution for this same panel of volunteers following oral doses yielded a higher value. This finding is probably due to the incomplete systemic availability of enoximone, which artificially elevates the volume of distribution value. No data exist to date examining the volume of distribution of enoximone or its sulphoxide metabolite In

patients with chronic cardiac failure.

3.3 Elimination

The total clearance, half-life, and selected parameters describing enoximone and its sui ph oxide metabolite's renal elimination are presented in table III. Excretion of unchanged enoximone into the

urine is a minor pathway of elimination accounting for less than 0.5% of the administered dose. The major route of elimination of enoximone is through the formation and subsequent excretion of the sulphoxide metabolite into the urine. Following intravenous and oral dosing, 75.7 and 64.3% of the enoximone dose, respectively, is eliminated as the sulphoxide metabolite (AIken et al. 1984).

The half-life of enoximone in healthy volunteers is extremely short, with estimates of 1 and 1.3 hours observed following intravenous and oral administration of the drug. Corresponding half-life estimates for the sui ph oxide metabolite were 2.2 and 2.3 hours. These estimates are greatly different from those obtained in patients with chronic cardiac failure. Uretsky et al. (1985) showed the halflife of enoximone and its sulphoxide metabolite to be 20 and 25.6 hours, respectively, following a single oral dose of the drug, and 10.2 and 13.1 hours at steady-state. The great differences in half-life between chronic cardiac failure patients and healthy volunteers may be due to disease-induced alterations in the pharmacokinetics of enoximone and its metabolite. A recent study, however, has revealed the existence of a prolonged terminal elimination phase which may not have been detected in the studies conducted in volunteers, potentially explaining this discrepancy in half-life (personal communication).

The reason for the shorter half-lives of enoximone and its sulphoxide metabolite following long term therapy compared with acute dosing is currently unclear. Future studies are needed to assess the effects of improved cardiocirculatory function on the pharmacokinetics of enoximone and its sulphoxide metabolite.

The renal clearance of enoximone measured in healthy volunteers is extremely small, indicating that glomerular filtration and tubular reabsorption are the primary modes of renal handling of unchanged drug (table III). In contrast, the renal clearance of the sulphoxide metabolite greatly exceeds glomerular filtration rate suggesting tubular secretion as a predominant renal mechanism (table III). Studies examining the pharmacokinetics and

Table III. Mean ± SO pharmacokinetic parameters for other investigational inotropic agents

Reference Study sample

Enoximone Aiken et al. (1984) Healthy volunteers

Aiken et al. (1984) Healthy volunteers

Uretsky et al. NYHA III (n = 5) (1985) NYHA IV (n = 15)

Uretsky et al. Patients (1985)

Piroximone Okerholm et al. (1983)

a Sulphoxide metabolite. b Normalised to a 70kg person. Abbreviations: See table I.

n

6

6

20

6

Dose Vd •• CL (L/kg) (L/h/kg)

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3 mg/kg orally (n = 10) 6 mg/kg orally (n = 10)

Same as above (steady-state evaluation)

1 mg/kg IV Mean'" 2 0.6 and 1 mg/kg orally

t1/2 CLR

(h) (L/h)

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1.3 ± 0.4 0.34 ± 0.16 (0.005 ± 0.002)b

2.3 ± 0.4" 23.2 ± 7.0" (0.33 ± 0.10)"·b

20.0 ± 5.8

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% Excreted unchanged into urine

< 0.5

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< 0.5

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pharmacodynamics of enoximone, and more importantly, its sulphoxide metabolite in patients with varying degrees of renal insufficiency are warranted.

Uretsky et al. (1985) demonstrated a plateau in plasma concentrations following oral administration of enoximone at two different dose levels (3 and 6 mg/kg), such that plasma concentrations following the 6 mg/kg dose were in the same general range as those following the lower dose. This plateau was accompanied by an apparent plateau in the time course of haemodynamic effects. An explanation for these findings is currently unavailable.

4. Piroximone

Piroximone (MDL 19205), the sulphoxide metabolite of enoximone, is a new, orally active agent possessing inotropic and vasodilatory properties. Limited data exist evaluating the pharmacokinetics of piroximone following its administration in humans. Preliminary studies (table III) following 1 mg/kg intravenous doses and oral doses of 0.6 and 1 mg/kg indicate a mean volume of distribution at steady-state of about 2 L/kg and a mean clearance of about 0.69 L/h/kg (Okerholm et al. 1983). Approximately 50% of the administered dose is excreted unchanged into the urine. Okerholm et al. (1983) reported a mean half-life for piroximone of approximately 1 hour. This half-life estimate is probably much shorter than the terminal half-life of the drug owing to a recently detected prolonged terminal phase (personal communication). Studies examining the relationship between the haemodynamic effects of piroximone and piroximone serum concentrations in patients with chronic cardiac failure are currently lacking.

5. Dobutamine

Dobutamine, a synthetic catecholamine, was the first inotropic agent to become available for therapeutic use since the advent of digoxin. This drug is structurally related to dopamine and has been shown in animal models to have potent positive

inotropic acttvity with mild vasodilatory effects (Tuttle & Mills 1975). The primary mechanism of action of dobutamine is tJ,-receptor stimulation, resulting in direct enhancement of myocardial contractility (Leier & Unverferth 1983). Unlike dopamine, none of the effects of dobutamine appear to be mediated through noradrenaline (norepinephrine) release and dobutamine does not possess the renal vasodilatory effects observed with dopamine (Ozaki et al. 1982). Dobutamine is only effective following intravenous administration, and is only approved for short term use in patients with acute cardiac decompensation.

Limited data exist examining the pharmacokinetics of dobutamine. Studies conducted in patients with severe cardiac failure (Kates & Leier 1978; Leier et al. 1979) during infusions of 2.5, 5, 7.5, and 10 ~g/kg/min have indicated a strong and highly significant linear correlation (r = 0.93; p < 0.01) between the dobutamine infusion rate and plasma dobutamine concentrations. The mean systemic clearance, volume of distribution, and halflife of dobutamine are 2.33 ± 0.33 L/min/m2, 0.2 ± 0.028 L/kg and 2.37 ± 0.23 minutes, respectively (Kates & Leier 1978; Leier et al. 1979).

The relationships between changes in mean haemodynamic parameters and mean dobutamine plasma concentrations are presented in figure 6. Both cardiac output and stroke volume increased in a linear fashion with increasing plasma concentrations of dobutamine (r > 0.95; p < 0.01). The relationship between left ventricular stroke work index and plasma dobutamine concentrations was more variable (r = 0.8; p < 0.05; fig. 6), presumably due to the lack of a substantial effect of dobutamine on left ventricular stroke work index at the lowest dobutamine infusion rate. In addition to these parameters, decreases in pulmonary capillary wedge pressure were also linearly and strongly related to dobutamine plasma concentration (r = - 0.83; p < 0.05; fig. 6). No changes in either heart rate or mean arterial pressure occurred at any of the observed dobutamine plasma concentrations (fig. 6).

Strong correlations also exist between haemodynamic parameters describing left ventricular


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ations: LVSWI = left ventricular stroke work index; PCWP = pulmonary capillary wedge pressure; • p < 0.05 vs baseline value.


function measured non-invasively and dobutamine plasma concentration. Indices such as the mean ratio of the pre-ejection period to the left ventricular ejection time, mean percentage shortening of the minor axis of the left ventricle from diastole to systole, and the mean velocity of circumferential fibre shortening correlate well with the mean dobutamine plasma concentration (Leier et al. 1979). Based on the results of studies performed by Leier et al. (1979), therapeutic plasma concentrations of dobutamine for patients with low output cardiac failure appear to be between 40 and 190 mg/L with continual improvement in cardiac function as plasma concentrations increase through this range.

6. Ibopamine

Ibopamine, the 3,4-di-isobutyryl ester derivative of deoxyadrenaline (deoxyepinephrine; Nmethyldopamine; epinine) is an orally active, positive inotropic drug with dopaminergic vasodilatory activity currently being investigated for the treatment of chronic cardiac failure. Preliminary studies have demonstrated beneficial acute haemodynamic responses to ibopamine in patients with heart failure; long term efficacy of the drug is under investigation. Following oral administration, ibopamine is rapidly de-esterified to deoxyadrenaline (Nmethyldopamine), the therapeutically active moiety (Lodola et al. 1986). Studies performed in healthy volunteers examining the pharmacokinetics of the drug in plasma following a 100mg dose have demonstrated rapid absorption, with an absorption halflife in the range of 0.25 hours. Once absorbed, deoxyadrenaline exists in a free and conjugated state in plasma. Conjugated deoxyadrenaline appears to consist primarily of sulphuric esters with the 3-0-sulphate ester and a small amount of the 4-0-sulphate ester being detected in humans (Lodola et al. 1986). Peak plasma concentrations of total and free deoxyadrenaline are 3,313 and 35 nmol/L, respectively, with the time to these peak concentrations being 1.5 and 0.71 hours.

Deoxyadrenaline appears to be completely metabolised in vivo. Urinary concentrations could not be demonstrated following ibopamine doses of 50

to 200mg (Lodola et al. 1986). The major urinary metabolites appear to be sulphate conjugated forms of deoxyadrenaline, and several oxidised metabolites including homovanillic acid and dihydroxyphenylacetic acid. Cumulative excretion of these metabolites following 50, 100, and 200mg doses of ibopamine base is 68, 78, and 60% of the dose (Lodola et al. 1986), with homovanillic acid being the primary, and conjugated deoxyadrenaline the least prevalent, metabolite. The mean elimination halflife for ibopamine in healthy volunteers is 1.54 hours (Lodola et al. 1986).

DeVita et al. (1986) studied the acute haemodynamic responses and pharmacokinetics of ibopamine in 11 patients with NYHA class III or IV chronic congestive heart failure following 200mg of ibopamine given orally. Mean peak total deoxyadrenaline concentrations were 4.575 ~mol/L,

which occurred 120 minutes after drug administration. The mean half-life of ibopamine in these patients was 2.73 hours and appeared to be more prolonged than that found in healthy volunteers (De Vita et al. 1986; Lodola et al. 1986). The administration of ibopamine in this study resulted in a 35% improvement in cardiac index, a comparable improvement in stroke volume, and a 48% enhancement of systolic work index. In addition, peripheral vascular resistance and pulmonary resistance were decreased approximately 27% (DeVita et al. 1986). The time course of haemodynamic effects of ibopamine greatly exceeded the plasma persistence of free deoxyadrenaline (fig. 7). Peak increases in cardiac index occurred at 90 minutes and were still present some 4 hours after drug administration. Systemic vascular resistance decreased significantly at 1.5 hours, with a duration of effect similar to that observed for the cardiac index. Plasma concentrations of deoxyadrenaline reached a peak 30 to 60 minutes after drug administration and were no longer detectable after about 2 hours. In contrast, the time course of the conjugated deoxyadrenaline plasma concentration appeared to be more concordant with that of the time course of pharmacological effects. However, both the 3-0- and 4-0-sulphate derivatives of deoxyadrenaline have been shown to be inactive by in


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Fig. 7. Time course of free (lower curve) and total (upper curve) deoxyadrenaline plasma concentrations in healthy subjects (n = 3, top) and in chronic cardiac failure patients (n = 8, middle), and the time-course of haemodynamic effects [bottom; upper curve: cardiac index (el); lower curve: systemic vascular resistance (SVR)] after ibopamine 200mg orally .• p < 0.05; •• P < 0.01; Tukey's test (with permission from DeVita et al. 1986).

vitro and in vivo pharmacological testing (Casagrande et al. 1986). It is thus conceivable that the site of action of ibopamine may be in a physiological compartment which is pharmacokinetically distinguishable from plasma.

Further studies are warranted to assess the existence and nature of relationships between improvement in haemodynamics and ibopamine concentrations in plasma and/or tissues.

7. The Future

The development and investigation of newer inotropic agents for the treatment of chronic cardiac failure is a relatively new area which is continually evolving. While many relevant aspects of the pharmacokinetics and pharmacodynamics of these drugs have been elucidated, much work remains to be done. Many of the compounds studied to date have been evaluated using dosage intervals which have far exceeded their half-lives. Research directed towards the development of sustained release formulations may facilitate the maintenance of drug serum concentrations necessary to produce sustained improvements in cardiac function.

Some of the drugs currently being investigated are administered orally and converted substantially to active metabolites on flrst pass through the liver. Research ~xamining the effects of hepatic disease on this metabolism and its pharmacodynamic consequences is warranted. With the exception of amrinone, no data exist in the literature describing the serum binding of these drugs in either healthy volunteers or patients with chronic cardiac failure. Further characterisation of the elimination of these compounds, particularly for those primarily metabolised is needed. The potential therapeutic or toxic effects of the metabolites also require evaluation. For compounds excreted primarily unchanged into urine, examination of the effects of varying degrees of renal impairment on the pharmacokinetics and pharmacodynamics of these drugs will aid in determining the necessity for dosage adjustment. Evaluation of the relationships between haemodynamic effects and drug serum concentrations within individual patients under both short


and long term dosing conditions is necessary to assess the nature of any inter- and intrapatient variability in response to these drugs. Finally, population-based studies designed to assess the average 'therapeutic ranges' of these drugs will provide information which will be useful in determining appropriate drug dosages, and also aid in the monitoring of cardiotonic therapy in patients with chronic cardiac failure.

References

AIken RG, Belz GG, Haegele KD, Meinicke T, Schechter PJ. Kinetics of fenoximone, a new cardiotonic, in healthy subjects. Clinical Pharmacology and Therapeutics 36: 209-216, 1984

Alousi AA, Canter JM, Cicero F, Fort DJ, Helstosky A, et al. Pharmacology of milrinone. In Braunwald et al. (Eds) Milrinone: investigation of new inotropic therapy for congestive heart failure, pp. 21-48, Raven Press, New York, 1984

Alousi AA, Stankus GP, Stuart JC, Walton LH. Characterization of the cardiotonic effects of milrinone, a new and potent cardiac bipyridine, on the isolated tissues from several animal species. Journal of Cardiovascular Pharmacology 5: 792-803, 1983

Baker JF, Chalecki BW, Benziger DP, O'Melia PE, Clemans SD, et al. Metabolism of amrinone in animals. Drug Metabolism and Disposition 10: 168-172, 1982

Benotti JR, Hood Jr WB. Dose ranging study of intravenous milrinone to determine efficacy and pharmacokinetics. In Braunwald et al. (Eds) Milrinone: investigation of new inotropic therapy for congestive heart failure, pp. 95-107, Raven Press, New York, 1984

Benotti JR, Lesko U, McCue JE. Acute pharmacodynamics and pharmacokinetics of oral amrinone. Journal of Clinical Pharmacology 22: 425-432, 1982

Benotti JR, Lesko U, McCue JE, Alpert JS. Pharmacokinetics and pharmacodynamics of milrinone in chronic congestive heart failure. American Journal of Cardiology 56: 685-689, 1985

Casagrande C, Santangelo F, Saini C, Doggi F, Gerli F, et al. Synthesis and chemical properties of ibopamine and of related esters of N-substituted dopamine: synthesis of ibopamine metabolites. Arzneimittel-Forschung 36: 291-303, 1986

Cody RJ, Chatterjee K, Kubo SH, Simonton C, Rutman H. Ascending dose-range study of oral milrinone in chronic congestive heart failure. In Braunwald et al. (Eds) Milrinone: investigation of new inotropic therapy for congestive heart failure, pp. 109-117, Raven Press, New York, 1984

DeVita C, Triulzi E, DeVizzi S, Colombo G, Palvarini M, et al. Evaluation of acute hemodynamic effects and pharmacokinetic behavior of ibopamine in patients with severe heart failure. Arzneimittel-Forschung 36: 349-354, 1986

Edelson J, LeJemtel TH, Alousi AA, Biddlecome CE, Maskin CS, et al. Relationship between amrinone plasma concentration and cardiac index. Clinical Pharmacology and Therapeutics 29: 723-728, 1981

Edelson J, Park GB, Angellotti J, Kershner RP, Ryan JJ, et al. Dose proportionality of amrinone. Clinical Pharmacology and Therapeutics 34: 190-194, 1983

Edelson J, Stroshane R, Benziger DP, Cody R, Benotti J, et al. Pharmacokinetics of the bipyridines, amrinone and milrinone. Circulation 73 (Suppl. III): 111-145, 1986

Goldstein RA. Clinical effects of intravenous amrinone in patients with congestive heart failure. Circulation 73 (Suppl. III): 191-194, 1986

Jusko WJ, Gibaldi M. Effect of change in elimination on various parameters of the two-compartment open model. Journal of Pharmaceutical Sciences 61: 1270-1273, 1972

Kariya T, Willie U, Dage RC. Biochemical studies on the mechanism of cardiotonic activity of MDL 17,043. Journal of Cardiovascular Pharmacology 4: 509-514, 1982

Kates RE, Leier CV. Dobutamine pharmacokinetics in severe heart failure. Clinical Pharmacology and Therapeutics 24: 537-541, 1978

Kullberg MP, Freeman GB, Biddlecome C, Alousi AA, Edelson J. Amrinone metabolism. Clinical Pharmacology and Therapeutics 29: 394-40 I, 1981

Larijani GE, Rocci Jr ML, Wilson H. Protein binding of amrinone in normal volunteers and in patients with chronic cardiac failure. Drug Intelligence and Clinical Pharmacy 18: 500, 1984

Larsson R, Liedholm H, Andersson KE, Keane MA, Henry G. Pharmacokinetics and effects on blood pressure of a single oral dose of milrinone in healthy subjects and in patients with renal impairment. European Journal of Clinical Pharmacology 29: 549-553, 1986

Leier CV, Unverferth DV, Kates RE. The relationship between plasma dobutamine concentrations and cardiovascular responses in cardiac failure. American Journal of Medicine 66: 238-242, 1979

Leier CV, Unverferth DV. Dobutamine. Annals of Internal Medicine 99: 490-496, 1983

LeJemtel TH, Gumbardo D, Chadwick B, Rutman HI, Sonnenblick EH. Milrinone for long term therapy of severe failure: clinical experience with special reference to maximal exercise tolerance. Circulation 73 (Suppl. III): 213-218, 1986

LikoffMJ, Weber KT, Andrews V, Janicki JS, Sutton MSJ, et al. Amrinone in the treatment of chronic cardiac failure. Journal of the American College of Cardiology 3: 1282-1290, 1984

Likoff MJ, Weber KT, Andrews V, Janicki JS, Wilson H, et al. Milrinone in the treatment of chronic cardiac failure: a controlled trial. Journal of the American College of Cardiology 110: 1035-1042, 1985

Lodola E, Borgia M, Longo A, Pocchiari F, Pataccini R, et al. Ibopamine kinetics after a single oral dose in healthy volunteers. Arzneimittel-Forschung 36: 345-348, 1986

Okerholm RA, Keeley FJ, Weiner DL, Spangenberg RB. The pharmacokinetics of a new cardiotonic agent, MDL 19,205,4-ethyl-I ,3-dihydro-5-( 4-pyridinyl)-2H-imidazol-2-one. Federation Proceedings 42: 1131, 1983

Ozaki N, Kawakita S, Toda N. Effects ofdobutamine on isolated canine cerebral, coronary, mesenteric, and renal arteries. Journal of Cardiovascular Pharmacology 4: 456-461, 1982

Park GB, Kershner RP, Angellotti J, Williams RL, Benet LZ, et al. Oral bioavailability and intravenous pharmacokinetics of amrinone in humans. Journal of Pharmaceutical Sciences 72: 817-819, 1983

Rocci Jr ML, Wilson H, Likoff M, Weber KT. Amrinone pharmacokinetics after single and steady-state doses in patients with chronic cardiac failure. Clinical Pharmacology and Therapeutics 33: 260, 1983

Roebel LE, Dage RC, Cheng HC, Woodward JK. Characterization of the cardiovascular activities ofa new cardiotonic agent, MDL 17,043 (I ,3-dihydro-4-methyl-5-[ 4-(methylthio )-benzoyl]-2H-imidazol-2-one). Journal of Cardiovascular Pharmacology 4: 721-729, 1982

Stroshane RM, Benziger DP, Edelson J. Pharmacokinetics of mil-


rinone in congestive heart failure patients. In Braunwald et al. (Eds) Milrinone: investigation of new inotropic therapy for congestive heart failure, pp. 119-131, Raven Press, New York, 1984a

Stroshane RM, Koss RF, Biddlecome CE, Luczkowec C, Edelson J. Oral and intravenous pharmacokinetics of milrinone in human volunteers. Journal of Pharmaceutical Sciences 73: 1438-1441, 1984b

Wilson H, Larijani GE, LikoffM, Weber KT, Rocci Jr ML. The pharmacokinetics of milrinone in patients with chronic cardiac failure . Clinical Pharmacology and Therapeutics 35: 283, 1984

Wilson H, Rocci Jr ML, Weber KT. Pharmacokinetics of oral amrinone in patients with chronic cardiac failure. Clinical Pharmacology and Therapeutics 31: 282, 1982

Tuttle RR, Mills J. Dobutamine: development of a new catecholamine to selectively increase cardiac contractility. Circulation Research 36: 185-196, 1975

Wilson H, Rocci Jr ML, 'Weber KT, Andrews V, Likoff M. Pharmacokinetics and hemodynamics of amrinone in patients with chronic cardiac failure of diverse etiology. Research Communications in Chemical Pathology and Pharmacology 56: 3, 1987

Uretsky BF, Generalovich T, Verbalis JG, Valdes AM, Reddy PS. MDL 17,043 therapy in severe congestive heart failure: characterization of the early and late hemodynamic, pharmacokinetic, hormonal and clinical response. Journal of the American College of Cardiology 5: 1414-1421, 1985

Authors' address: Dr Mario L. Rocci Jr, Head, Laboratory of Investigative Medicine, Clinical Pharmacology, Jefferson Medical College, 1100 Walnut St, Philadelphia, PA 19107 (USA).

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WrofeSSional Drug Intelligence ACOA~ 10 J9JC

The Pharmacokinetics and Pharmacodynamics of Newer Inotropic Agents

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Transcript of The Pharmacokinetics and Pharmacodynamics of Newer Inotropic Agents