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MILRINONE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Milrinone is a phosphodiesterase inhibitor with positive inotropic and vasodilator activity.

Specific Substances

    1) Milrinone lactate
    2) 1,6-Dihydro-2-methyl-6-oxo[3,4'-bipyridine]-5-carbonitrile
    3) Win-47203-2
    4) Molecular formula: C12-H9-N3-O
    5) CAS 78415-72-2
    1.2.1) MOLECULAR FORMULA
    1) C12-H9-N3-O (Sweetman, 2007)

Available Forms Sources

    A) FORMS
    1) Milrinone is available as 1 mg/mL intravenous solution of milrinone (Prod Info milrinone lactate in 5% dextrose intravenous injection solution, 2014).
    B) USES
    1) Milrinone is used for the short-term (less than 48 hours) intravenous treatment of patients with acute decompensated heart failure (Prod Info milrinone lactate in 5% dextrose intravenous injection solution, 2014).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Milrinone is used for the short-term (less than 48 hours) treatment of patients with acute decompensated heart failure.
    B) PHARMACOLOGY: Milrinone lactate along with amrinone belongs to the bipyridine inotropic/vasodilator class of medications. It exerts its vasodilatory action by selectively inhibiting cyclic adenosine monophosphate (AMP)-specific phosphodiesterase III isoenzyme in cardiac and smooth vascular muscle. The increase in vascular muscle AMP facilitates calcium uptake by the sarcoplasmic reticulum, thereby reducing calcium stores available for myofibril contraction, with subsequent reduction of vascular tone.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Adverse effects reported with therapy include ventricular and supraventricular dysrhythmias, hypotension, angina/chest pain, headache, bronchospasm, anaphylactic shock, elevated liver enzymes, rash, hypokalemia, tremor, and thrombocytopenia. Torsades de pointes is a rare occurrence with milrinone therapy.
    E) WITH POISONING/EXPOSURE
    1) Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. Clinical effects in overdose include hypotension because of its vasodilator effect.
    0.2.20) REPRODUCTIVE
    A) Milrinone is classified as FDA pregnancy category C.

Laboratory Monitoring

    A) Monitor vital signs and serum electrolytes.
    B) Obtain an ECG and institute continuous cardiac monitoring.
    C) Monitor CBC with platelet count following a significant overdose.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Vasopressin has been effective in patients not responding to fluids and other pressors. Monitor CVP to help guide therapy. Treat ventricular dysrhythmias using ACLS protocols. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. Monitor serial CBC with platelets; thrombocytopenia has been reported. Consider transfusions in patients with severe thrombocytopenia, bleeding.
    C) DECONTAMINATION
    1) Gastrointestinal decontamination is not recommended; administered via the parenteral route.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with life-threatening cardiac dysrhythmias, hemodynamic instability, or severe allergic reactions.
    E) ANTIDOTE
    1) None.
    F) TACHYCARDIA
    1) If hemodynamic compromise develops secondary to tachycardia, consider esmolol or metoprolol.
    G) TORSADE DE POINTES
    1) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Hemodynamically unstable patients require electrical cardioversion. Treat stable patients with magnesium and/or atrial overdrive pacing. Correct electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia).
    H) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no role for home management.
    2) OBSERVATION CRITERIA: Patients with a significant overdose should be sent to a healthcare facility for evaluation.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (ie, hypotension, dysrhythmias), or in whom the diagnosis in not clear.
    I) PITFALLS
    1) When managing a suspected overdose of milrinone, the possibility of multidrug involvement should be considered. A typical patient receiving milrinone is usually receiving digoxin and diuretics.
    J) PHARMACOKINETICS
    1) Protein binding: Approximately 70%. Vd: 0.33 to 0.47 L/kg. Excretion: Following intravenous administration, 85% of the dose is excreted unchanged in the urine within 24 hours. Elimination half-life: Approximately 2.4 hours in patients with congestive heart failure.
    K) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause hypotension (eg, vasodilators, beta blockers, calcium channel blockers) or dysrhythmias.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. Therapeutic doses of milrinone may cause hypotension because of its vasodilator effect.
    B) THERAPEUTIC DOSING: ADULT: Loading dose: 50 mcg/kg IV given slowly over 10 minutes. Maintenance dose: 0.375 to 0.75 mcg/kg/min IV as a continuous infusion. Total daily dose: 0.59 to 1.13 mg/kg.

Clinical Effects

Summary Of Exposure

    A) USES: Milrinone is used for the short-term (less than 48 hours) treatment of patients with acute decompensated heart failure.
    B) PHARMACOLOGY: Milrinone lactate along with amrinone belongs to the bipyridine inotropic/vasodilator class of medications. It exerts its vasodilatory action by selectively inhibiting cyclic adenosine monophosphate (AMP)-specific phosphodiesterase III isoenzyme in cardiac and smooth vascular muscle. The increase in vascular muscle AMP facilitates calcium uptake by the sarcoplasmic reticulum, thereby reducing calcium stores available for myofibril contraction, with subsequent reduction of vascular tone.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Adverse effects reported with therapy include ventricular and supraventricular dysrhythmias, hypotension, angina/chest pain, headache, bronchospasm, anaphylactic shock, elevated liver enzymes, rash, hypokalemia, tremor, and thrombocytopenia. Torsades de pointes is a rare occurrence with milrinone therapy.
    E) WITH POISONING/EXPOSURE
    1) Overdose effects are anticipated to be an extension of adverse effects following therapeutic doses. Clinical effects in overdose include hypotension because of its vasodilator effect.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) In Phase II and III clinical trials, 12.1% of patients receiving milrinone lactate injection experienced ventricular dysrhythmias, including ventricular ectopic activity, 8.5%; nonsustained ventricular tachycardia, 2.8%; sustained ventricular tachycardia, 1%, and ventricular fibrillation, 0.2% (two patients had more than one type of dysrhythmia). In Holter monitoring recordings, dysrhythmias were rarely life-threatening, and did not appear to be related to the dose of milrinone or to the plasma level (Prod Info milrinone lactate in 5% dextrose intravenous injection solution, 2014).
    b) Four of 19 patients, who received chronic milrinone therapy, died suddenly after a mean treatment duration of 4.8 months. It is unclear whether the potential arrhythmogenic effects or some other effects of milrinone may have contributed to the fatalities. All patients had severe underlying coronary artery disease (Baim et al, 1983a). These investigators recommend caution when prescribing to patients with advanced coronary artery disease.
    B) VENTRICULAR PREMATURE BEATS
    1) WITH THERAPEUTIC USE
    a) Increased ectopic activity was observed with intravenous infusions of milrinone in 12 patients with chronic heart failure (Anderson et al, 1986). Although no patient had a history of cardiac arrest or sustained ventricular tachyarrhythmia, 9 patients had primary idiopathic dilated cardiomyopathy, and 3 patients had coronary artery disease. Milrinone was administered as a loading dose of 53 mcg/kg/10 min (range, 37.5 to 75), followed by a 48-hour maintenance infusion of 0.53 mcg/kg/min (range, 0.25 to 0.75). The frequency of premature ventricular complexes (PVCs) increased from 87 PVCs/h to 141 PVCs/h. Additionally, the mean frequency of couplets increased from 6/h to 14.3/h during the infusion. The frequency of runs of PVCs was 0.9 +/- 0.8 per hour before the infusion, as compared to 2.7 +/- 2.4 per hour during the infusion. Two patients experienced proarrhythmias (an increase in PVCs of greater than 4 times that of baseline and/or repetitive forms of greater than 10 times baseline). However, neither patient required reduction in dose of milrinone or additional antiarrhythmic therapy. Four additional patients had a twofold increase in PVCs. The authors recommend continuous electrocardiogram monitoring when intravenous milrinone is prescribed (Anderson et al, 1986).
    b) Milrinone therapy, 7.5 to 12.5 mg orally every 6 hours for 2 to 4 weeks, was associated with the development of PVC complexity and a significant increase in the density of complex premature ventricular contractions (PVC) in patients with severe congestive heart failure, despite hemodynamic improvements. A greater than tenfold increase in simple premature ventricular complex density, a greater than tenfold increase in complex PVC form density, or an increase from 0 to greater than 5 episodes per 24 hours of any complex PVC was observed in 7 of 20 patients (35%) treated with milrinone. A greater than tenfold reduction in simple PVC density was observed in 1 of 20 (5%) patients, with 12 (60%) additional patients having no change in ventricular arrhythmia profile while receiving the drug. Prior to treatment, all patients had PVCs, and 10 of the patients had a mean PVC density of greater than 10 PVCs per 1,000 total beats. The authors suggest that hemodynamic improvement with milrinone may be associated with an increase in ventricular arrhythmias in congestive heart failure patients (Holmes et al, 1985). (NOTE: The oral form of milrinone was withdrawn in 1990).
    C) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) Beta blockers successfully managed tachycardia induced by milrinone without compromising its inotropic support. Intravenous milrinone was given to improve the cardiac index (CI) and blood pressure in a 74-year-old postsurgical patient who was in sinus rhythm with a rate of 140 beats per minute, but whose systolic blood pressure had fallen to 90 mmHg, accompanied by decreased CI and low urine output. Intravenous milrinone improved blood pressure, but heart rate increased, which was treated with intravenous esmolol. When milrinone was resumed, heart rate increased again, and was treated with intravenous metoprolol. Target CI with no increase in HR was then achieved by an infusion of both milrinone and metoprolol (Alhashemi & Hooper, 1998).
    D) ANGINA
    1) WITH THERAPEUTIC USE
    a) In Phase II and III clinical trials, angina/chest pain was reported in 1.2% of patients receiving milrinone injection (Prod Info milrinone lactate in 5% dextrose intravenous injection solution, 2014).
    b) Several patients have experienced an increase in angina symptoms following the institution of milrinone therapy. This response necessitated adjustments in concurrent antianginal therapy (Baim et al, 1983a).
    E) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) In Phase II and III clinical trials, hypotension was reported in 2.9% of patients receiving milrinone injection (Prod Info milrinone lactate in 5% dextrose intravenous injection solution, 2014).
    b) Three patients with congestive heart failure and superimposed sepsis developed clinically significant hypotension after initiation of milrinone therapy. The cause was attributed to excessive arterial dilatation. These investigators noted that these 3 patients had low systemic vascular resistance index (SVRI) at baseline while other patients who did not develop hypotension had elevated SVRI at baseline (Varriale & Ramaprasad, 1997).
    c) An acute hypotensive episode occurred in a pediatric patient with renal failure administered milrinone (50 mcg/kg, then 0.5 mcg/kg/minute) for nonhyperdynamic septic shock. The patient's systemic vascular resistance index suddenly dropped from 688 to 320 dyne-sec/cm(5)/m(2) (Lindsay et al, 1998a).
    2) WITH POISONING/EXPOSURE
    a) Clinical effects in overdose include hypotension because of its vasodilator effect (Prod Info milrinone lactate in 5% dextrose intravenous injection solution, 2014).
    F) TORSADES DE POINTES
    1) WITH THERAPEUTIC USE
    a) Rare cases of torsades de pointes have been reported with milrinone therapy in post-marketing experience (Prod Info milrinone lactate in 5% dextrose intravenous injection solution, 2014).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) BRONCHOSPASM
    1) WITH THERAPEUTIC USE
    a) Rare cases of bronchospasm and anaphylactic shock have been reported with the use of milrinone in worldwide post-marketing experience (Prod Info milrinone lactate in 5% dextrose intravenous injection solution, 2014).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) In Phase II and III clinical trials, headaches were reported in 2.9% of patients receiving milrinone (Prod Info milrinone lactate in 5% dextrose intravenous injection solution, 2014).
    b) Headache occurred in 1 of 19 patients who received long-term oral milrinone therapy. The headache responded to withdrawal of the drug (Baim et al, 1983a).
    B) TREMOR
    1) WITH THERAPEUTIC USE
    a) Tremor has been rarely reported (0.4%) with milrinone therapy; however, a causal relationship has not been definitively established (Prod Info milrinone lactate in 5% dextrose intravenous injection solution, 2014).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Liver function test abnormalities have been reported with use of milrinone in worldwide post-marketing experience (Prod Info milrinone lactate in 5% dextrose intravenous injection solution, 2014).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) TOXIC NEPHROPATHY
    1) WITH THERAPEUTIC USE
    a) Mild elevations in serum creatinine and renal failure have been reported in patients receiving milrinone. In one case report, following treatment with intravenous milrinone (0.25 mcg/kg/min), a patient with cardiac amyloidosis developed acute oligoanuric renal failure requiring peritoneal dialysis secondary to milrinone-induced hypotension. The patient had also been receiving an ACE inhibitor which may have contributed to the hypotension and renal failure. The patient responded well to treatment with vasopressin (0.05 units/minute); urine output improved and dialysis was discontinued (Saab et al, 2002).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) In Phase II and III clinical trials, thrombocytopenia was reported in 0.4% of patients receiving milrinone injection (Prod Info milrinone lactate in 5% dextrose intravenous injection solution, 2014).
    b) Thrombocytopenia was the primary adverse effect of milrinone given after open heart surgery to 19 infants and children; a platelet count of 100,000 per mm(3) developed in 58%, but only 2 patients required transfusions (Ramamoorthy et al, 1998b).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERUPTION
    1) WITH THERAPEUTIC USE
    a) Rare cases of skin rash have been reported with the use of milrinone in worldwide post-marketing experience (Prod Info milrinone lactate in 5% dextrose intravenous injection solution, 2014).
    B) INJECTION SITE REACTION
    1) WITH THERAPEUTIC USE
    a) Infusion site reactions were reported with the use of milrinone in worldwide post-marketing experience (Prod Info milrinone lactate in 5% dextrose intravenous injection solution, 2014).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLAXIS
    1) WITH THERAPEUTIC USE
    a) Rare cases of bronchospasm and anaphylactic shock have been reported with the use of milrinone in worldwide post-marketing experience (Prod Info milrinone lactate in 5% dextrose intravenous injection solution, 2014).

Reproductive

    3.20.1) SUMMARY
    A) Milrinone is classified as FDA pregnancy category C.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) LACK OF EFFECT - There was no evidence of teratogenicity in rats and rabbits following oral maternal administration of milrinone at doses up to 40 mg/kg/day and 12 mg/kg/day, respectively. There was also no evidence of teratogenicity following intravenous administration of milrinone to pregnant rats and rabbits at doses up to 3 mg/kg/day (approximately 2.5 times the maximum recommended clinical intravenous dose) and 12 mg/kg/day, respectively (Prod Info PRIMACOR(R) injection, 2007).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) The manufacturer has classified milrinone as FDA pregnancy category C (Prod Info PRIMACOR(R) injection, 2007).
    B) ANIMAL STUDIES
    1) RABBITS - An increased resorption rate occurred following intravenous milrinone administration to pregnant rabbits at doses of 8 mg/kg/day and 12 mg/kg/day (Prod Info PRIMACOR(R) injection, 2007).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is unknown whether milrinone is excreted in human milk (Prod Info PRIMACOR(R) injection, 2007).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) LACK OF EFFECT - There was no effect on the fertility of male and female rats following oral milrinone administration at doses up to 32 mg/kg/day (Prod Info PRIMACOR(R) injection, 2007).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS78415-72-2 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) There was no evidence of carcinogenicity in mice who were given milrinone orally at doses up to 40 mg/kg/day (approximately 50 times the human oral therapeutic dose in a 50 kg patient) for 24 months. There was also no evidence of carcinogenicity in rats who were given milrinone orally at doses up to 5 mg/kg/day (approximately 6 times the human oral therapeutic dose) for 24 months or at doses of 25 mg/kg/day (approximately 30 times the human oral therapeutic dose) for up to 18 months in male rats and 20 months in female rats (Prod Info PRIMACOR(R) injection, 2007).

Genotoxicity

    A) There was no evidence of mutagenicity with the Ames Test, the Mouse Lymphoma Assay, the Micronucleus Test, and the in vivo Rat Bone Marrow Metaphase Analysis; however, the Chinese Hamster Ovary Chromosome Aberration Assay was positive in the presence of a metabolic activation system (Prod Info PRIMACOR(R) injection, 2007).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and serum electrolytes.
    B) Obtain an ECG and institute continuous cardiac monitoring.
    C) Monitor CBC with platelet count following a significant overdose.

Methods

    A) CHROMATOGRAPHY
    1) High performance liquid chromatography has been used for the determination of milrinone in human plasma. With this method, the lower limit of quantitation was 10 ng/mL based on 100 mcL of plasma (Brocks et al, 2005).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients who remain symptomatic despite treatment should be admitted.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no role for home management.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (ie, hypotension, dysrhythmias), or in whom the diagnosis in not clear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Patients with a significant overdose should be sent to a healthcare facility for evaluation.

Monitoring

    A) Monitor vital signs and serum electrolytes.
    B) Obtain an ECG and institute continuous cardiac monitoring.
    C) Monitor CBC with platelet count following a significant overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not recommended; administered via the parenteral route.

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. Therapeutic doses of milrinone may cause hypotension because of its vasodilator effect.
    B) THERAPEUTIC DOSING: ADULT: Loading dose: 50 mcg/kg IV given slowly over 10 minutes. Maintenance dose: 0.375 to 0.75 mcg/kg/min IV as a continuous infusion. Total daily dose: 0.59 to 1.13 mg/kg.

Therapeutic Dose

    7.2.1) ADULT
    A) ACUTE CONGESTIVE HEART FAILURE
    1) INITIAL: Loading dose, 50 mcg/kg IV over 10 minutes (Prod Info milrinone lactate in 5% dextrose intravenous injection solution, 2014)
    2) MAINTENANCE: 0.375 to 0.75 mcg/kg/min continuous IV infusion (Prod Info milrinone lactate in 5% dextrose intravenous injection solution, 2014)
    7.2.2) PEDIATRIC
    A) ACUTE CONGESTIVE HEART FAILURE
    1) Safety and efficacy have not been established in pediatric patients . However, the following dosing has been used in studies.
    B) CHRONIC HEART FAILURE, ADVANCED
    1) Maintenance infusions of 0.25 to 1 mcg/kg/minute are used for outpatient therapy in children with advanced chronic heart failure (Berg et al, 2007; Price et al, 2006).
    C) INOTROPIC SUPPORT, LOW CARDIAC OUTPUT
    1) LOADING DOSE: 50 to 75 mcg/kg IV/IO over 10 to 60 minutes, immediately followed by a maintenance infusion (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Khazin et al, 2004; Barton et al, 1996).
    2) MAINTENANCE INFUSION: 0.5 to 0.75 mcg/kg/minute continuous IV infusion (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Duggal et al, 2005; Barton et al, 1996). Infusion doses as low as 0.3 mcg/kg/minute have been used for infants with low cardiac output syndrome following cardiac surgery (Duggal et al, 2005). May also be given by IO infusion if IV access unavailable (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    D) LOW CARDIAC OUTPUT SYNDROME; POSTOPERATIVE PREVENTION
    1) LOADING DOSE: 75 mcg/kg IV over 60 minutes, immediately followed by a maintenance infusion (Hoffman et al, 2003).
    2) MAINTENANCE INFUSION: 0.75 mcg/kg/minute continuous infusion for 35 hours postoperatively (Hoffman et al, 2003).
    E) POSTOPERATIVE PULMONARY HYPERTENSION; ADJUNCT WITH NITRIC OXIDE
    1) LOADING DOSE: 50 mcg/kg IV followed by a maintenance infusion (Khazin et al, 2004).
    2) MAINTENANCE INFUSION: 0.5 mcg/kg/minute continuous infusion (Cai et al, 2008; Cai et al, 2008a; Khazin et al, 2004).
    F) Milrinone has been used in children following open heart surgery. One dosing regimen was a 25 mcg/kg bolus over 5 minutes followed by an infusion of 0.25 mcg/kg/min, with a second bolus of 25 mcg/kg 30 minutes after the first bolus with a subsequent increase in the infusion rate to 0.5 mcg/kg/min. Another regimen was a 50 mcg/kg bolus over 10 minutes followed by an infusion of 0.5 mcg/kg/min, with a second bolus of 25 mcg/kg 30 minutes after the 1st bolus, with a subsequent increase in the rate of infusion of 0.75 mcg/kg/min (Ramamoorthy et al, 1998).

Maximum Tolerated Exposure

    A) A specific toxic dose has not been established. The vasodilator effect of milrinone may result in hypotension in the event of an overdose (Prod Info milrinone lactate in 5% dextrose intravenous injection solution, 2014).

Workplace Standards

    A) ACGIH TLV Values for CAS78415-72-2 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS78415-72-2 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS78415-72-2 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS78415-72-2 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)MOUSE:
    1) 137 mg/kg (RTECS, 2006)
    B) LD50- (SUBCUTANEOUS)MOUSE:
    1) 62 mg/kg (RTECS, 2006)
    C) LD50- (ORAL)RAT:
    1) 91 mg/kg (RTECS, 2006)
    D) LD50- (SUBCUTANEOUS)RAT:
    1) 58 mg/kg (RTECS, 2006)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Milrinone exerts its vasodilatory action by selectively inhibiting cyclic adenosine monophosphate (AMP)-specific phosphodiesterase III isoenzyme in cardiac and smooth vascular muscle. The increase in vascular muscle AMP facilitates calcium uptake by the sarcoplasmic reticulum, thereby reducing calcium stores available for myofibril contraction, with subsequent reduction of vascular tone (Arakawa et al, 2001).
    1) Milrinone is a bipyridine inotropic agent with a similar chemical structure to amrinone. The chemical name of milrinone is 1,6-dihydro-2-methyl-6-oxo-(3,4-bipyridine)-5-carbonitrile (Baim et al, 1983). The inotropic potency of milrinone is approximately 20 times that of amrinone on a weight basis (Alousi et al, 1981). Milrinone has been well tolerated, intravenously, in phase I and phase II studies, and appears to lack the side effects seen with inamrinone (fever, thrombocytopenia) (Baim et al, 1983; Maskin et al, 1983). Milrinone possesses inotropic, lusitropic, and vasodilator properties (Huwer & Pickworth, 1993; Rocci & Wilson, 1987; Cody et al, 1986). These properties are clinically advantageous in congestive heart failure; they allow maximal improvement in hemodynamic performance without excessively increasing myocardial oxygen demand (Baim et al, 1983; Siegel et al, 1981). The primary mechanism of action of milrinone appears to be related, at least in part, to phosphodiesterase inhibition and resultant increases in intracellular cyclic AMP, which improves calcium handling (Colucci, 1991; Monrad et al, 1985; Earl et al, 1984; Harrison et al, 1986; Binah et al, 1986; Endoh et al, 1986; Scholz & Meyer, 1986). Additional direct effects on transmembrane calcium fluxes may also occur (Monrad et al, 1985; Rapundalo et al, 1986; Sutko et al, 1986; Alousi & Johnson, 1986). The drug has produced stimulatory effects on calcium ATP-ase (Monrad et al, 1985; Alousi & Johnson, 1986).

Physicochemical

Physical Characteristics

    A) Milrinone is a white to tan, hygroscopic, crystalline solid that is freely soluble in dimethyl sulfoxide and practically insoluble in water, chloroform, and methyl alcohol (Sweetman, 2007).

Molecular Weight

    A) 211.2 (Sweetman, 2007)

References

General Bibliography

    1) 40 CFR 372.28: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Lower thresholds for chemicals of special concern. National Archives and Records Administration (NARA) and the Government Printing Office (GPO). Washington, DC. Final rules current as of Apr 3, 2006.
    2) 40 CFR 372.65: Environmental Protection Agency - Toxic Chemical Release Reporting, Community Right-To-Know, Chemicals and Chemical Categories to which this part applies. National Archives and Records Association (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Apr 3, 2006.
    3) 49 CFR 172.101 - App. B: Department of Transportation - Table of Hazardous Materials, Appendix B: List of Marine Pollutants. National Archives and Records Administration (NARA) and the Government Printing Office (GPO), Washington, DC. Final rules current as of Aug 29, 2005.
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