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CIFENLINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Cifenline (formerly cibenzoline) is an imidazoline derivative, which is structurally unrelated to other antiarrhythmic agents, and possesses class Ia antiarrhythmic activity and also has some class III and class IV properties. The antiarrhythmic effects of cifenline lend themselves to several of the Vaughan Williams classifications, thus making the drug difficult to categorize. It is used in the management of ventricular and supraventricular dysrhythmias.

Specific Substances

    1) 2-(2,2-Diphenylcyclopropyl)2-imidazoline
    2) 2-(2,2-Diphenylcyclopropyl)2-imidazoline succinate
    3) 1H-Imidazole, 2-(2,2-diphenylcyclopropyl)-4,5-dihydro-
    4) Cibenzoline
    5) Cibenzoline succinate
    6) Cifenline succinate
    7) Ro 227796
    8) UP 33901
    9) Molecular formula: C18-H18-N2
    10) CAS 53267-01-9 (cifenline)
    11) CAS 100678-32-8 (cifenline succinate)

Available Forms Sources

    A) FORMS
    1) Cifenline is available as tablets for oral use and parenteral solution. Tablets are available as 130 mg and 160 mg (Massarella et al, 1991; Rothbart & Saksena, 1986).
    B) USES
    1) Cifenline is a Vaughan-Williams class Ia antiarrhythmic agent, also with class III and IV activity, used in the treatment of ventricular and supraventricular dysrhythmias (Humen et al, 1987; JEF Reynolds , 1999). It is primarily used in France (Similowski et al, 1997).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH POISONING/EXPOSURE
    1) Overdoses may result in intraventricular heart block and cardiogenic shock in severe cases. ECG changes have included prolongation of the PR and QRS intervals.
    2) Cifenline overdoses have resulted in reversible neuromuscular blockade and respiratory failure.
    3) Toxicity commonly results in nausea, vomiting, and blurred vision.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) ECG abnormalities including prolongation of the QRS, QT, and PR intervals, dose-related negative inotropic effects and severe hypotension may occur.
    2) Severe hypotension may occur following overdoses.
    0.2.6) RESPIRATORY
    A) WITH POISONING/EXPOSURE
    1) Respiratory failure and pulmonary edema may result following overdoses.
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) Serious toxicity has resulted in neuromuscular blockade (myasthenia-like syndrome) with respiratory failure.
    2) Overdoses may cause CNS depression.
    0.2.8) GASTROINTESTINAL
    A) WITH POISONING/EXPOSURE
    1) Nausea and vomiting are common overdose effects.
    0.2.11) ACID-BASE
    A) WITH POISONING/EXPOSURE
    1) Metabolic acidosis may develop in patients with hypotension.
    0.2.16) ENDOCRINE
    A) WITH THERAPEUTIC USE
    1) Severe hypoglycemia has been described as a toxic effect.
    0.2.20) REPRODUCTIVE
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.

Laboratory Monitoring

    A) Plasma cifenline levels greater than 400 ng/mL have been associated with toxicity.
    B) Obtain serial ECG's and institute continuous cardiac monitoring.
    C) Monitor vital signs and mental status.
    D) Monitor liver and renal function tests, CBC, and blood glucose following overdoses.
    E) Monitor blood gases in patients with respiratory depression, severe dysrhythmias, hypotension or pulmonary edema.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    B) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.
    1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.
    C) VENTRICULAR DYSRHYTHMIAS: Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Sodium bicarbonate is generally first line therapy for QRS widening and ventricular dysrhythmias, administer 1 to 2 mEq/kg, repeat as needed to maintain blood pH between 7.45 and 7.55. In patients unresponsive to bicarbonate, consider lidocaine.
    1) DO NOT USE quinidine, procainamide or disopyramide.
    D) LIDOCAINE: ADULT: LOADING DOSE: 1 to 1.5 milligram/kilogram via IV push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram. Only bolus therapy is recommended during cardiac arrest. INFUSION: Once circulation is restored begin an infusion of 1 to 4 mg/min. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute). PEDIATRIC: LOADING DOSE: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute. Monitor ECG continuously.
    E) TORSADES DE POINTES: Hemodynamically unstable patients require electrical cardioversion. Treat stable patients with magnesium (first-line agent) and/or atrial overdrive pacing. Correct electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia) and hypoxia, if present.
    1) MAGNESIUM SULFATE/DOSE: ADULT: 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes. An optimal dose has not been established. Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram/hour, if dysrhythmias recur. CHILDREN: 25 to 50 mg/kg diluted to 10 mg/mL; infuse IV over 5 to 15 minutes.
    2) OVERDRIVE PACING: Begin at 130 to 150 beats per minute, decrease as tolerated.
    3) Avoid class Ia (eg, quinidine, disopyramide, procainamide), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol).
    F) Initial treatment of bradycardia should include the use of atropine and isoproterenol.
    1) Refractory bradycardia or heart block that compromises blood pressure requires temporary pacemaker insertion. Markedly prolonged conduction, Mobitz II block, or third degree heart block should be considered indications for prophylactic pacemaker insertion.
    G) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    H) Theoretically, pure or predominant alpha agonists such as norepinephrine or metaraminol may be more effective than dopamine.
    I) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue).
    1) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    J) Treat hypoglycemia IV dextrose. when necessary.
    K) Hemoperfusion should be considered in severe toxicity.

Range Of Toxicity

    A) ADULT OVERDOSE - 3250 mg survived with supportive care; 3900 mg and 5200 mg were associated with rapidly fatal circulatory failure.

Clinical Effects

Summary Of Exposure

    A) WITH POISONING/EXPOSURE
    1) Overdoses may result in intraventricular heart block and cardiogenic shock in severe cases. ECG changes have included prolongation of the PR and QRS intervals.
    2) Cifenline overdoses have resulted in reversible neuromuscular blockade and respiratory failure.
    3) Toxicity commonly results in nausea, vomiting, and blurred vision.

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) Blurred vision is an anticholinergic effect and has rarely occurred following cifenline therapy but may occur in overdoses (acute or chronic) (Paelinck et al, 2001; Salerno, 1987) Zempol et al, 1987; (Brazzell et al, 1984).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) ECG abnormalities including prolongation of the QRS, QT, and PR intervals, dose-related negative inotropic effects and severe hypotension may occur.
    2) Severe hypotension may occur following overdoses.
    3.5.2) CLINICAL EFFECTS
    A) ELECTROCARDIOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) In an acute, single, IV dose study of the safety of cifenline in humans, a small and significant increase in heart rate and PR interval (sustained for about 20 minutes) was seen in some patients following a 1.2 mg/kg cifenline infusion (Humen et al, 1987).
    b) CASE REPORT - A 72-year-old woman presented to the hospital with first-degree AV block (280 ms) and left bundle-branch block with a wide QRS (200 ms) on ECG. She had chronically taken cifenline (260 mg/day for several years). Drug toxicity resulted from a progressive renal impairment, with prolongation of plasma elimination half-life and drug accumulation. Heart failure was reversible after treatment with repetitive infusions of Ringers lactate (250 mL infusions over 30 minutes times three infusions) and dobutamine (Paelinck et al, 2001).
    c) CASE REPORT - A 76-year-old woman, with a history of chronic renal insufficiency, developed severe hypotension, wide QRS tachycardia (QRS 182 ms, HR 123 bpm), and left bundle branch block after taking cibenzoline 130 mg twice daily for treatment of paroxysmal atrial fibrillation. The patient's blood cibenzoline concentration was 1497 ng/mL (therapeutic range 200 to 400 ng/mL). Following treatment with combined hemoperfusion and hemodialysis over an 8-hour period, she gradually recovered without sequelae (Meeus et al, 2008).
    2) WITH POISONING/EXPOSURE
    a) Overdoses may result in prolongation of the QRS, QT, and PR intervals. Development of bundle branch block and first-degree atrioventricular heart block has been reported (Takahashi et al, 2002; Hantson, 1999; Viallon et al, 1998; Humen et al, 1987; Kushner et al, 1984; Cocco et al, 1984; Rothbart & Saksena, 1986; Mohiuddin et al, 1987; Similowski et al, 1997).
    b) Hantson (1999) reported a PR interval of 200 msec, a QRS duration of 140 msec, and a QT/QTc of 480/330 msec in a 38-year-old woman following an overdose of 3250 mg cifenline (Hantson, 1999).
    c) Aoyama et al (1999) reported prolonged QRS (0.20 sec) and QTc (0.64 sec) intervals and pacing failure in an 80-year-old woman with cifenline poisoning (Aoyama et al, 1999).
    d) Viallon et al (1998) reported bradycardia and prolonged QRS complexes with cardiovascular collapse in 2 patients, which resulted in death, following overdoses of 5200 mg and 3900 mg, respectively (Viallon et al, 1998).
    B) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Dose related severe HYPOTENSION, CONGESTIVE HEART FAILURE, and dose-related NEGATIVE INOTROPIC effects have been reported with intravenous and oral cifenline, particularly in patients with preexisting evidence of left ventricular dysfunction and renal insufficiency (Takahashi et al, 2002; Paelinck et al, 2001; Kostis et al, 1989; Seals et al, 1987; Humen et al, 1987; Salerno, 1987; Klein et al, 1986; Rothbart & Saksena, 1986; Rothbart & Saksena, 1986; Kostis et al, 1984). Hypotension appears to be dose related.
    b) Cifenline can adversely affect hemodynamics in patients with borderline cardiac compensation secondary to negative inotropic effects (Kostis et al, 1984). The drug should be used with extreme caution in patients with left ventricular ejections fractions of less than 25% (Seals et al, 1987).
    c) Severe hypotension and depression of left ventricular function were reported in 3 patients during the first 3 days of oral cifenline therapy for nonsustained ventricular tachycardia (Seals et al, 1987). Left ventricular ejection fractions in these patients prior to cifenline ranged from 19% to 22%. All patients experienced acute, severe hypotension, and severe weakness, nausea, chest discomfort, or dyspnea; deterioration of renal function and a decrease in cardiac index was observed in 2 of the patients.
    1) Hemodynamic deterioration was associated with elevated peak plasma cifenline levels in 2 of the 3 patients (973 and 1362 ng/mL). All patients required aggressive treatment, including inotropic support, vasopressors, and/or intubation. Based upon baseline hemodynamic profiles, the data suggest that hemodynamic deterioration is more likely to occur with cifenline in the presence of: a resting and exercise pulmonary capillary wedge pressure of greater than 30 and 40 mmHg, respectively; peak exercise cardiac index of less than 2.5 L/minute/m(2); and a stroke volume index of less than 20 mL/minute even during exercise.
    d) Renal insufficiency may contribute to the development of toxicity (Inada et al, 2002; (Takahashi et al, 2002; Paelinck et al, 2001). It is recommended that cifenline be used only with great caution in patients with severely depressed left ventricular function (left ventricular ejection fraction of less than 25%).
    1) CASE REPORT - A 76-year-old woman, with a history of chronic renal insufficiency, developed severe hypotension (71/42 mmHg), wide QRS tachycardia, and left bundle branch block after taking cibenzoline 130 mg twice daily for treatment of paroxysmal atrial fibrillation. The patient's blood cibenzoline concentration was 1497 ng/mL (therapeutic range 200 to 400 ng/mL). Following treatment with combined hemoperfusion and hemodialysis over an 8-hour period, she gradually recovered without sequelae (Meeus et al, 2008).
    2) WITH POISONING/EXPOSURE
    a) Arterial systolic pressure of 75 mmHg was reported in a 38-year-old female following an overdose of 3250 mg cifenline (Hantson, 1999).
    b) Two fatal cases of massive overdoses resulted in circulatory failure which developed rapidly and was attributed to major atrioventricular and ventricular conduction disorders (Viallon et al, 1998).
    c) Cifenline poisoning resulted in shock in an 80-year-old, requiring sodium bicarbonate, dopamine, and norepinephrine (Aoyama et al, 1999).
    d) Decreased cardiac output (3.11 L/min) has been reported following an overdose (Hantson, 1999).
    C) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) PROARRHYTHMIC EFFECTS - Aggravation of dysrhythmias has been reported during cifenline therapy (Seals et al, 1987; Wasty et al, 1985; Kostis et al, 1989; Mohiuddin et al, 1989; Mohiuddin et al, 1987; Kostis et al, 1984; Kuhlkamp et al, 1990). The relatively small numbers of patients treated with the drug precluded an accurate assessment of the incidence of proarrhythmic effects (Mohiuddin et al, 1987; Mohiuddin et al, 1989).
    b) The presence of severe cardiovascular disease including impairment of left ventricular function represents a subset of patients more prone to developing proarrhythmic effects of cifenline (Kostis et al, 1989). In one study, involving 18 patients with nonsustained ventricular tachycardia and left ventricular dysfunction, oral cifenline proved effective in 14 patients, whereas first-episode sustained ventricular tachycardia or sudden death occurred in 4 (22%) (Seals et al, 1987). A further patient had a history of sustained ventricular tachycardia which recurred during cifenline therapy. Cifenline should be used with extreme caution in patients with left ventricular dysfunction and ventricular tachycardia.
    c) CASE REPORT - A 76-year-old woman, with a history of chronic renal insufficiency, developed severe hypotension, wide QRS tachycardia (QRS 182 ms, HR 123 bpm), and left bundle branch block after taking cibenzoline 130 mg twice daily for treatment of paroxysmal atrial fibrillation. The patient's blood cibenzoline concentration was 1497 ng/mL (therapeutic range 200 to 400 ng/mL). Following treatment with combined hemoperfusion and hemodialysis over an 8-hour period, she gradually recovered without sequelae (Meeus et al, 2008).
    2) WITH POISONING/EXPOSURE
    a) Vaillon et al (1998) reported the rapid development of circulatory failure due to major atrioventricular and ventricular conduction disorders following fatal doses in two patients (Viallon et al, 1998).

Respiratory

    3.6.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Respiratory failure and pulmonary edema may result following overdoses.
    3.6.2) CLINICAL EFFECTS
    A) ACUTE RESPIRATORY INSUFFICIENCY
    1) WITH POISONING/EXPOSURE
    a) Overdoses or high serum levels may result in neuromuscular blockade (myasthenia-like syndrome) leading to acute respiratory failure (Inada et al, 2002; Wakutani et al, 1998; Similowski et al, 1997) with profound hypoxemia and respiratory acidosis. In the event of a transient or an acute renal dysfunction, toxic serum concentrations of cifenline may result in acute respiratory failure.
    B) DYSPNEA
    1) WITH THERAPEUTIC USE
    a) Dyspnea has been observed in some patients as an adverse effect of cifenline treatment and as a result of toxicity (Paelinck et al, 2001; Seals et al, 1987).
    C) ACUTE LUNG INJURY
    1) WITH POISONING/EXPOSURE
    a) Pulmonary edema, secondary to compromised cardiac function, may theoretically occur following overdoses.

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Serious toxicity has resulted in neuromuscular blockade (myasthenia-like syndrome) with respiratory failure.
    2) Overdoses may cause CNS depression.
    3.7.2) CLINICAL EFFECTS
    A) MUSCLE WEAKNESS
    1) WITH POISONING/EXPOSURE
    a) Overdoses and high plasma levels of cifenline have resulted in neuromuscular blockade with a myasthenia-like syndrome and resultant acute respiratory failure (Kasuga et al, 1996; Similowski et al, 1997; Wakutani et al, 1998). Proximal muscle weakness, bilateral ptosis, difficulty in climbing stairs, fatigue, dysphagia, dysarthria, and intense and diffuse muscle fasciculations have been reported. Muscle weakness leading to acute respiratory failure requiring mechanical ventilation has occurred. Symptoms have resolved on dose reduction or discontinuation.
    B) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness, vertigo, and lightheadedness are relatively common adverse effects of cifenline, occurring in approximately 10% to 25% of patients treated (Seals et al, 1987; Kostis et al, 1989; Mohiuddin et al, 1989; Kuhlkamp et al, 1990; Mohiuddin et al, 1987). Dizziness develops 2 to 4 hours after administration of the drug and is unrelated to postural changes.
    C) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) Other adverse central nervous system effects have included weakness, asthenia, lethargy, headache, tremor, fatigue, and nervousness (Kostis et al, 1989; Klein et al, 1986; Seals et al, 1987) Nestico et al, 1988). It is unclear if some of these symptoms could be related to hypoglycemia, which has been associated with cifenline therapy (Gachot et al, 1988; Hilleman et al, 1987).
    2) WITH POISONING/EXPOSURE
    a) Clouding of consciousness with Glasgow Coma Scale 13 was reported following cifenline poisoning in an 80-year-old (Aoyama et al, 1999).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Nausea and vomiting are common overdose effects.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Adverse gastrointestinal effects have occurred in 1% to 4% of cifenline-treated patients, and include nausea, vomiting, epigastric pain, diarrhea, dry mouth, and altered taste (Mohiuddin et al, 1987; Kostis et al, 1984; Brazzell et al, 1984) Nestico et al, 1988; (Seals et al, 1987; Kostis et al, 1989; Rothbart & Saksena, 1986).
    2) WITH POISONING/EXPOSURE
    a) Nausea and vomiting are signs of cifenline toxicity (Kushner et al, 1984; Humen et al, 1987; JEF Reynolds , 1999).
    B) APTYALISM
    1) WITH THERAPEUTIC USE
    a) Dry mouth is a common adverse effect of cifenline (Zempol et al, 1987).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Evidence of potential hepatotoxic effects have been reported during oral cifenline therapy, as evidenced by elevations in serum transaminases, alkaline phosphatase, and lactic dehydrogenase (LDH) (Wasty et al, 1985; Miura et al, 1985; Klein et al, 1986; Salerno, 1987). Liver function tests have returned to normal following withdrawal of the drug. In 1 study, liver enzyme elevations recurred within 4 days after rechallenge with the drug (Klein et al, 1986).
    B) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) Ischemic hepatitis resulting in hepatic failure has been reported as an adverse effect of cifenline therapy. This is an indirect drug effect, with diminishing cardiac output resulting in an ischemic hepatitis (Gutknecht et al, 1991).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL RENAL FUNCTION
    1) WITH THERAPEUTIC USE
    a) Deterioration of renal function has been reported in patients developing hypotension and depression of left ventricular function during oral cifenline therapy for nonsustained ventricular tachycardia (Seals et al, 1987).
    B) RETENTION OF URINE
    1) WITH POISONING/EXPOSURE
    a) Although not reported following overdoses, urinary retention may occur following a massive overdose due to its minor anticholinergic properties (Miura et al, 1985; Hilleman et al, 1987).

Acid-Base

    3.11.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Metabolic acidosis may develop in patients with hypotension.
    3.11.2) CLINICAL EFFECTS
    A) LACTIC ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) Cifenline poisoning may result in lactic acidosis secondary to hypoperfusion. Hantson (1999) reported a patient with metabolic acidosis (arterial pH 7.24 and arterial blood lactate concentration of 5.1 mmol/L) and significant widening of QRS complexes and prolonged QT and PR interval. Following large doses of sodium lactate the patient recovered (Hantson, 1999).
    b) Metabolic acidosis (pH 7.344, PCO2 34.5 mmHg, PO2 95.3 mmHg, HCO3 18.8 mmol/L) was reported in an 80-year-old with cifenline poisoning (Aoyama et al, 1999).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) Leukopenia has been described rarely during cifenline therapy (Klein et al, 1986).

Endocrine

    3.16.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Severe hypoglycemia has been described as a toxic effect.
    3.16.2) CLINICAL EFFECTS
    A) HYPOGLYCEMIA
    1) WITH THERAPEUTIC USE
    a) Severe hypoglycemia is a common clinical effect of cifenline toxicity (Takahashi et al, 2002; Sakane et al, 1998; Similowski et al, 1997; Noury & Delvaux, 1989) Jeandell et al, 1988; (Gachot et al, 1988; Lefort et al, 1988; Hilleman et al, 1987) with recurrence of hypoglycemia on re-challenge (Hilleman et al, 1987; Mohiuddin et al, 1987). Symptoms associated with the hypoglycemia have included central nervous system depression, electrocardiographic abnormalities, hyperkalemia, and respiratory distress (Hilleman et al, 1987).
    1) Cifenline is thought to stimulate insulin secretion since serum insulin levels are inappropriately elevated.
    3.16.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPOGLYCEMIA
    a) RATS - Cifenline was shown to have a direct concentration-dependent stimulatory effect on insulin release in rats with a resultant hypoglycemia. The authors speculated a direct action on pancreatic B cells was effected by cifenline (Bertrand et al, 1992).

Reproductive

    3.20.1) SUMMARY
    A) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy or lactation.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma cifenline levels greater than 400 ng/mL have been associated with toxicity.
    B) Obtain serial ECG's and institute continuous cardiac monitoring.
    C) Monitor vital signs and mental status.
    D) Monitor liver and renal function tests, CBC, and blood glucose following overdoses.
    E) Monitor blood gases in patients with respiratory depression, severe dysrhythmias, hypotension or pulmonary edema.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Liver and renal function tests, complete blood counts, and blood glucose should be monitored following cifenline overdoses.
    2) Plasma levels of greater than 400 ng/mL have been associated with toxicity in some patients (Kostis et al, 1989; Brazzell et al, 1984).
    4.1.3) URINE
    A) OTHER
    1) DRUG-LAB MODIFICATIONS -
    a) URINE PROTEIN TEST - False-positive results for proteinuria, ranging from trace to 3-plus, occurred in 23 of 53 patients receiving cifenline when bromphenol reagent strips were used. This reaction is thought to occur because cifenline forms a complex with the indicator tetrabromphenol blue, altering its pKa profile and mimicking the effect of proteins on it (Kovacs et al, 1984).
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Obtain serial ECG's and institute continuous cardiac monitoring following overdoses. ECG should be monitored for cardiac dysrhythmias, including torsades de pointes, QRS widening, QT prolongation, and AV dissociation.
    2) MONITORING
    a) Monitor vital signs, especially blood pressure and heart rate.
    b) Monitor blood gases in patients with respiratory depression, severe dysrhythmias, hypotension or pulmonary edema.
    3) OXYGEN SATURATION
    a) Monitor oxygen saturation and respiratory function in all cifenline overdose cases. Severe overdoses may result in muscle weakness with respiratory failure (Wakutani et al, 1998; Similowski et al, 1997).

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Chest x-ray should be obtained in any patient with significant toxicity or pulmonary symptoms.

Methods

    A) CHROMATOGRAPHY
    1) A high performance liquid chromatography (HPLC) method is described for the determination of plasma and urine cifenline (Massarella et al, 1986c) Brazzell et al, 1984; (Hackman et al, 1983).
    2) A gas chromatography-mass spectrometry (GC/MS) method was reported in a pharmacokinetic study, with a limit of sensitivity of 1 ng/mL (Aronoff et al, 1991).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) All patients with a history of cifenline ingestion should have a baseline electrocardiogram and be monitored for a minimum of 6 hours.
    1) If the patient remains symptom-free, and there are no signs of nausea, vomiting, or cardiovascular toxicity, the patient may be referred for psychiatric evaluation.
    2) All symptomatic patients should be hospitalized and monitored until symptom-free and the ECG has normalized.

Monitoring

    A) Plasma cifenline levels greater than 400 ng/mL have been associated with toxicity.
    B) Obtain serial ECG's and institute continuous cardiac monitoring.
    C) Monitor vital signs and mental status.
    D) Monitor liver and renal function tests, CBC, and blood glucose following overdoses.
    E) Monitor blood gases in patients with respiratory depression, severe dysrhythmias, hypotension or pulmonary edema.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    B) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor blood pressure, renal function (i.e., urine output, BUN, serum creatinine), and liver function. Obtain serial ECG's and institute continuous cardiac monitoring. Central venous or pulmonary artery pressure monitoring may be useful in patients with hypotension.
    2) Monitor serum electrolyte concentrations and correct, if necessary.
    3) Monitor cifenline plasma levels and serum potassium. If refractory dysrhythmia develops, assess calcium and magnesium levels.
    4) Monitor for neuromuscular blockade (myasthenia-like syndrome) and respiratory failure. Mechanical ventilation may be required (Similowski et al, 1997).
    B) VENTRICULAR ARRHYTHMIA
    1) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Sodium bicarbonate is generally first line therapy for QRS widening and ventricular dysrhythmias, administer 1 to 2 mEq/kg, repeat as needed to maintain blood pH between 7.45 and 7.55. In patients unresponsive to bicarbonate, consider lidocaine. DO NOT use procainamide, quinidine, or disopyramide as their effects may be additive.
    2) SERUM ALKALINIZATION
    a) Administer sodium bicarbonate. A reasonable starting dose is 1 to 2 mEq/kg by intravenous bolus, repeated as needed. Maintain arterial pH between 7.45 and 7.55. Monitor serial ECGs and arterial blood gases frequently.
    3) LIDOCAINE
    a) LIDOCAINE/INDICATIONS
    1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010; Vanden Hoek et al, 2010).
    b) LIDOCAINE/DOSE
    1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010). Only bolus therapy is recommended during cardiac arrest.
    a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010).
    2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).
    c) LIDOCAINE/MAJOR ADVERSE REACTIONS
    1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010).
    d) LIDOCAINE/MONITORING PARAMETERS
    1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).
    C) TORSADES DE POINTES
    1) SUMMARY
    a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
    b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
    2) MAGNESIUM SULFATE
    a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
    b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
    c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
    d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
    3) OVERDRIVE PACING
    a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).
    4) POTASSIUM REPLETION
    a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
    5) ISOPROTERENOL
    a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
    c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    6) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    7) AVOID
    a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.
    D) BRADYCARDIA
    1) ATROPINE
    a) ATROPINE/DOSE
    1) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
    2) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.
    a) There is no minimum dose (de Caen et al, 2015).
    b) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).
    2) ISOPROTERENOL
    a) ISOPROTERENOL INDICATIONS
    1) Used for temporary control of hemodynamically significant bradycardia in a patient with a pulse; generally other modalities (atropine, dopamine, epinephrine, dobutamine, pacing) should be used first because of the tendency to develop ischemia and dysrhythmias with isoproterenol (Neumar et al, 2010).
    2) ADULT DOSE: Infuse 2 micrograms per minute, gradually titrating to 10 micrograms per minute as needed to desired response (Neumar et al, 2010).
    3) CAUTION: Decrease infusion rate or discontinue infusion if ventricular dysrhythmias develop(Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    4) PEDIATRIC DOSE: Not well studied. Initial infusion of 0.1 mcg/kg/min titrated as needed, usual range is 0.1 mcg/kg/min to 1 mcg/kg/min (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    3) Refractory bradycardia or heart block that compromises blood pressure requires temporary pacemaker insertion. Markedly prolonged conduction, Mobitz II block, or third degree heart block should be considered indications for prophylactic pacemaker insertion.
    E) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) Pure or predominant alpha agonists may be more effective in managing hypotension. These include norepinephrine or metaraminol. However, isoproterenol, a pure beta agonist, was effective in maintaining blood pressure in a patient who ingested 20 grams of disopyramide (Holt et al, 1980).
    a) NOREPINEPHRINE
    1) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    2) DOSE
    a) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    b) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    c) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    4) PHENYLEPHRINE
    a) MILD OR MODERATE HYPOTENSION
    1) INTRAVENOUS: ADULT: Usual dose: 0.2 mg; range: 0.1 mg to 0.5 mg. Maximum initial dose is 0.5 mg. A 0.5 mg IV dose can elevate the blood pressure for approximately 15 min (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011). PEDIATRIC: Usual bolus dose: 5 to 20 mcg/kg IV repeated every 10 to 15 min as needed (Taketomo et al, 1997).
    b) CONTINUOUS INFUSION
    1) PREPARATION: Add 10 mg (1 mL of a 1% solution) to 500 mL of normal saline or dextrose 5% in water to produce a final concentration of 0.2 mg/mL.
    2) ADULT DOSE: To raise blood pressure rapidly; start an initial infusion of 100 to 180 mcg/min until blood pressure stabilizes; then reduce infusion to 40 to 60 mcg/min titrated to desired effect. If necessary, additional doses in increments of 10 mg or more may be added to the infusion solution and the rate of flow titrated to the desired effect (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011).
    3) PEDIATRIC DOSE: Intravenous infusion should begin at 0.1 to 0.5 mcg/kg/min; titrate to the desired effect (Taketomo et al, 1997).
    c) ADVERSE EFFECTS
    1) Headache, reflex bradycardia, excitability, restlessness and rarely dysrhythmias may develop (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011).
    5) DOBUTAMINE
    a) DOSE: ADULT: Infuse at 5 to 10 micrograms/kilogram/minute IV. PEDIATRIC: Infuse at 2 to 20 micrograms/kilogram/minute IV or intraosseous, titrated to desired effect (Peberdy et al, 2010; Kleinman et al, 2010).
    b) CAUTION: Decrease infusion rate if ventricular ectopy develops (Prod Info dobutamine HCl 5% dextrose intravenous injection, 2012).
    6) If conventional therapies are unsuccessful, extra-corporeal cardiocirculatory assistance should be considered.
    F) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    G) HYPOGLYCEMIA
    1) DEXTROSE
    a) Treat patients who develop laboratory evidence of hypoglycemia (blood glucose less than 60 milligrams/deciliter) or significant clinical effects (altered mental status, seizures) with IV dextrose.
    b) DOSE
    1) ADULT
    a) BOLUS - The administration of 25 grams glucose solution will correct the majority of acute hypoglycemic states. This dose may need to be repeated in patients with profound hypoglycemia.
    b) INFUSION - Initiation of a continuous 10% to 20% dextrose intravenous infusion is recommended in patients who become hypoglycemic, as relapses of hypoglycemia may occur after overdose (Jeandel et al, 1988).
    1) Do not stop the IV dextrose infusion abruptly. Slowly decrease the rate of dextrose infusion with hourly monitoring of blood glucose after blood glucose levels have been stable for 6 to 8 hours.
    2) PEDIATRIC
    a) BOLUS - 0.5 to 1 gram/kilogram intravenously, usually administered as D25W (2 to 4 milliliters/kilogram/dose) given over 1 to 2 minutes.
    1) D50W (1 to 2 milliliters/kilogram/dose) may be used for children greater than 5 years and D10W for preterm infants.
    2) INFUSION - Initiation of a continuous 10% to 20% dextrose in 0.2 percent normal saline intravenous infusion is recommended in patients who become hypoglycemic. Titrate to maintain blood glucose above 100 milligrams/deciliter.
    a) Do not stop the IV dextrose infusion abruptly. Intravenous dextrose may need to be prolonged or repeated. Slowly decrease the rate of dextrose infusion with hourly monitoring of blood glucose after blood glucose levels have been stable for 6 to 8 hours.
    H) EXTRACORPOREAL CIRCULATION PROCEDURE
    1) In severe, refractory cases of toxicity, extracorporeal cardiocirculatory assistance may be advisable when conventional therapy fails.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis and peritoneal dialysis are not expected to be effective in the removal of cifenline. Wakutani et al (1998) attempted hemodialysis on a chronic renal failure patient for elimination of cifenline from serum, which was not effective following 3 sessions. The same patient had been on continuous ambulatory peritoneal dialysis (CAPD) which also did not decrease the cifenline serum level (Wakutani et al, 1998).
    2) Aronoff et al (1991) reported only 13% drug clearance following hemodialysis in chronic renal failure patients (Aronoff et al, 1991).
    B) HEMOPERFUSION
    1) Although the role of hemoperfusion is yet to be established, it should be considered in overdose patients manifesting serious toxicity.
    2) CASE REPORT - Aoyama et al (1999) reported the use of charcoal hemoperfusion in an 80-year-old patient with an initial cifenline plasma level of 2581 ng/mL. Prior to hemoperfusion, the cifenline t1/2 was 92.4 hours. On day 4 charcoal hemoperfusion was started. During the procedure, t1/2 was 9.82 hours, and the mean dialyzer clearance of cifenline was 117.6 mL/min. Rapid reduction of plasma cifenline levels was associated with significant clinical improvement in this case (Aoyama et al, 1999).
    3) CASE REPORT - Takahashi et al (2002) used a charcoal hemoperfusion method described by Aoyama et al (1999) in which plasma cifenline concentrations dropped to within the therapeutic range about a week later. Toxicity symptoms resolved simultaneously (Takahashi et al, 2002).
    C) COMBINED HEMOPERFUSION-HEMODIALYSIS
    1) CASE REPORT - Combined hemoperfusion-hemodialysis was performed in a 76-year-old woman, with a history of chronic renal insufficiency, who developed severe hypotension, wide QRS tachycardia, and left bundle branch block after taking cibenzoline 130 mg twice daily for treatment of paroxysmal atrial fibrillation. Her plasma cibenzoline concentration, obtained at ICU admission, was 1497 ng/mL (therapeutic range 200 to 400 ng/mL) and the total body pool of cibenzoline was 447.2 to 806.6 mg. Combined hemoperfusion-hemodialysis was initiated 16 hours after ICU admission (approximately 20 hours after patient's last cibenzoline dose) and was continued for 8 hours. After 8 hours, hemoperfusion and hemodialysis clearances were 45.96 and 65.93 mL/min, respectively. The total amount of cibenzoline removed from the patient during the 8-hour period was 28.98 mg; however, her plasma cibenzoline concentration rapidly normalized and the patient recovered uneventfully (Meeus et al, 2008).
    D) HEMOFILTRATION
    1) Wakutani et al (1998) reported successful reduction of cifenline serum levels (from 1890 ng/mL to 1450 ng/mL) following the first hemodiafiltration (HDF) in a chronic renal failure patient. After the sixth HDF the patient was able to resume full activities (Wakutani et al, 1998).

Range Of Toxicity

Summary

    A) ADULT OVERDOSE - 3250 mg survived with supportive care; 3900 mg and 5200 mg were associated with rapidly fatal circulatory failure.

Therapeutic Dose

    7.2.1) ADULT
    A) ROUTE OF ADMINISTRATION
    1) INTRAVENOUS
    a) SUPRAVENTRICULAR DYSRHYTHMIAS -
    1) Intravenous cifenline in doses of 1 to 1.75 milligrams/kilogram has been effective in terminating dysrhythmias in patients with recurrent episodes of reentrant supraventricular tachycardia, atrial-nodal tachycardia, circus movement tachycardia involving an accessory pathway, or intra-atrial reentry during programmed stimulation (Waleffe et al, 1985).
    2) Doses of 1.5 milligram/kilogram intravenously have suppressed atrial fibrillation or flutter induced by programmed stimulation in patients with documented paroxysmal atrial fibrillation (Kuhlkamp et al, 1990a).
    b) VENTRICULAR DYSRHYTHMIAS -
    1) Intravenous cifenline 1.5 milligram/kilogram has been effective in preventing induction of ventricular tachycardia in some patients with drug-refractory sustained ventricular tachycardia (Kuhlkamp et al, 1990).
    2) Researchers reported the efficacy of intravenous cifenline during ELECTROPHYSIOLOGIC TESTING in 33 patients with a history of ventricular tachycardia (Miura et al, 1985). Cifenline was administered by intermittent intravenous bolus infusions in initial doses of 10 milligrams every 5 minutes to a total of 1 milligram/kilogram; this was followed by increments of 1 milligram/kilogram to a maximum of 3 milligrams/kilogram if the lower doses failed to prevent ventricular tachycardia. With this regimen, cifenline provided protection against programmed electrical stimulation induction of sustained or non-sustained ventricular tachycardia in 16 of the patients; in 17 patients, tachycardia could be induced by programmed stimulation despite the use of incremental doses.
    c) INTRAVENOUS RATE OF ADMINISTRATION -
    1) Cifenline 1 to 1.5 milligram/kilogram has been given as an intravenous infusion over periods of 2 to 10 minutes (Waleffe et al, 1985; Humen et al, 1987).
    2) ORAL
    a) SUPRAVENTRICULAR DYSRHYTHMIAS -
    1) Oral cifenline in doses of 160 milligrams twice daily for 2 to 18 months (mean, 7 months) has been successful in the treatment of paroxysmal atrial fibrillation or flutter (Kuhlkamp et al, 1990a). In this study, prior prevention of atrial tachyarrhythmias induced by programmed stimulation with intravenous cifenline was predictive of the efficacy of oral therapy.
    b) VENTRICULAR DYSRHYTHMIAS -
    1) The optimal oral dose of cifenline for ventricular arrhythmias remains to be established. One group of investigators suggests that therapeutic benefits are achieved in most patients with oral doses of 3 to 4 milligrams/kilogram/day (Brazzell et al, 1984).
    2) Effective oral doses of cifenline are 130 to 160 milligrams twice daily (Mohiuddin et al, 1989; Kostis et al, 1989). Doses of 110 milligrams every 8 hours (Klein et al, 1986) and 80 milligrams every 6 hours (Mohiuddin et al, 1987) have also been used successfully for ventricular dysrhythmias.
    3) Although cifenline is effective during the first few months of treatment, long-term therapy of ventricular arrhythmias with oral cifenline has not been uniformly successful. Although some studies have reported that antidysrhythmic efficacy is maintained for up to 12 months of continuous treatment (Klein et al, 1986), others have described high failure rates with extended therapy (mean, 15 to 33 months) (Mohiuddin et al, 1987). It is recommended that long-term therapy be assessed objectively on a periodic basis to ensure continued efficacy (Mohiuddin et al, 1987).

Minimum Lethal Exposure

    A) ADULT
    1) Two cases of a massive suicidal overdose (5200 milligrams and 3900 milligrams) of cifenline resulting in a rapid onset of circulatory failure, due to major atrioventricular and ventricular conduction disorders, with bradycardia and prolonged QRS complexes, and unresponsive to conventional therapies have been reported. Both cases resulted in death (Vaillon et al, 1998).

Maximum Tolerated Exposure

    A) ADULT
    1) Following an intentional overdose of cifenline 3250 milligrams, flurazepam 685 milligrams, and lorazepam 25 milligrams, a 38-year-old female was found comatose 10 hours later. Heart rate was 42 beats/minute, arterial systolic pressure was 75 mmHg, and pulse oxygen saturation was 72%. ECG revealed wide QRS complexes (>200 msec) and prolonged QT interval (400 msec). The patient was in lactic acidosis. The patient recovered following symptomatic therapy (Hantson, 1999).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) GENERAL
    a) Plasma levels of 200 to 600 nanograms/milliliter, considered therapeutic, have been associated with a reduction in the frequency of premature ventricular contractions (Brazzell et al, 1984; Kostis et al, 1989; Wakutani et al, 1998; Hilleman et al, 1987).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) ADULT
    a) In some studies, plasma levels exceeding 400 nanograms/milliliter have been associated with toxicity (Kostis et al, 1989; Brazzell et al, 1984).
    b) Wakutani et al (1998) reported a cifenline serum level of 1890 nanograms/milliliter in a chronic renal failure patient treated with cifenline. Toxic effects of myasthenia-like syndrome and respiratory failure occurred (Wakutani et al, 1998).
    c) A toxic cifenline plasma concentration of 1800 nanograms/milliliter was reported in a patient with a severe hypoglycemic reaction due to cifenline (Hilleman et al, 1987).
    d) Toxic cifenline plasma levels in a 75-year-old end stage renal failure patient were reported to be 2.2 milligrams/liter (normal, 0.3 to 1 milligram/liter). Neuromuscular blockade with respiratory failure requiring mechanical ventilation occurred. Also reported were bradycardia, prolonged QRS complex and QT interval, and episodes of profound hypoglycemia (Similowski et al, 1997).
    e) Three adults treated with cifenline (300 milligrams/day) developed symptoms of toxicity (i.e., prolonged QTc, wide QRS, dysrhythmias, hypotension, hypoglycemia) after developing renal impairment. Plasma concentrations ranged between 1944 and 2580 micrograms/liter (Takahashi et al, 2002).
    f) A cibenzoline plasma concentration of 1497 ng/mL was reported in a 76-year-old woman, with chronic renal insufficiency, who was taking cibenzoline 130 mg twice daily for treatment of paroxysmal atrial fibrillation. The patient subsequently developed severe hypotension, wide QRS tachycardia, and left bundle branch block but recovered following treatment with combined hemoperfusion-hemodialysis (Meeus et al, 2008).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) CIFENLINE
    B) CIFENLINE SUCCINATE 1:1
    1) LD50- (ORAL)MOUSE:
    a) 180 mg/kg (RTECS, 2000)
    2) LD50- (SUBCUTANEOUS)MOUSE:
    a) 83300 mcg/kg (RTECS, 2000)
    3) LD50- (ORAL)RAT:
    a) 359 mg/kg (RTECS, 2000)
    4) LD50- (SUBCUTANEOUS)RAT:
    a) 156 mg/kg (RTECS, 2000)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) ANTIDYSRHYTHMIC - Cifenline is an imidazoline antidysrhythmic that is structurally unrelated to other antiarrhythmic agents (Salerno, 1987). The antidysrhythmic effects of cifenline lend themselves to several of the Vaughan Williams classifications, thus making the drug difficult to categorize. Cifenline has been demonstrated to reduce the height of the action potential and maximal rate of depolarization (Vaughan Williams Class 1), prolong the duration of action potential and its absolute refractory period (class 3), and exhibit calcium channel blocking effects (class 4) (Millar et al, 1982; (Humen et al, 1987). Cifenline is able to decrease rapid sodium inward current and slow inward current due to calcium and sodium ions.
    1) The drug primarily exhibits class 1 actions, with Vaughan William's class Ia, Ic, and III properties, and is commonly referred to as a class 1 antiarrhythmic (Kostis et al, 1989; Kostis et al, 1984; Mohiuddin et al, 1987; Waleffe et al, 1985) Massarella et al, 1991). Cifenline appears to have antiarrhythmic activity most similar to dipyridamole. It seems to lack some of the negative inotropic and anticholinergic side effects which typically characterize other type 1 drugs (Kushner et al, 1984).
    2) Brugada et al (1993) have shown that cifenline transforms random re-entry into ordered re-entry in the atria which is related to drug-induced depression of conduction (Brugada et al, 1993).
    B) ANTICHOLINERGIC - Cifenline's anticholinergic effects are approximately 1/15th those of disopyramide (Cazes et al, 1990) and its calcium channel blocking effect is approximately 1/50th that of verapamil (Anon, 1995).
    C) ELECTROPHYSIOLOGIC EFFECTS - Cifenline produces multiple electrophysiologic and electrocardiographic effects. The PR and QRS intervals are prolonged, whereas the QTc interval is either unchanged or increased (Salerno, 1987; Waleffe et al, 1985; Touboul et al, 1986). When observed, it appears that prolongation of the QTc interval is related to QRS prolongation. The QTc interval is not significantly prolonged (Salerno, 1987). Significant prolongations of the HV interval and ventricular refractory period have been reported with cifenline; AH interval is unchanged or prolonged (Salerno, 1987) Millar et al, 1982).
    1) Other effects have included an increase in sinus node recovery time in the absence of changes in sinus node rate, an increase in atrial effective refractory period, and prolongation of Vmax of phase 0 of the action potential (due to slowing of the sodium current) (Salerno, 1987) Millar et al, 1982). The action potential duration is only minimally prolonged but the amplitude of the action potential is reduced in Purkinje tissue; in ventricular tissue, increases in the action potential duration are observed (Salerno, 1987). The calcium channel current is decreased slightly with cifenline, and the drug has no beta-blocking effects (Salerno, 1987) Millar et al, 1982). Some electrophysiological effects of cifenline (ie, prolonged action potential duration) are similar to those of quinidine and procainamide (Mohiuddin et al, 1987).
    D) HEMODYNAMIC EFFECTS - Intravenous cifenline has been associated with an increase in systemic vascular resistance and a fall in cardiac index (Salerno, 1987). Blood pressure has been observed to increase or decrease with intravenous doses; however, in general, clinically significant changes in blood pressure are not seen with intravenous administration (Humen et al, 1987; Miura et al, 1985; Kuhlkamp et al, 1990). Severe hypotension has been observed occasionally (Humen et al, 1987).
    1) Heart rate has not been significantly affected with lower doses of the drug (0.25 to 0.75 mg/kg intravenously), but has been increased with higher doses (1.2 mg/kg) in association with a prolonged PR interval (Humen et al, 1987).
    2) Negative inotropic effects of cifenline have been reported, and these are dose-related (Salerno, 1987; Humen et al, 1987; van den Brand et al, 1984). Others reported dose-related negative inotropic effects with intravenous cifenline in patients undergoing diagnostic cardiac catheterization (Humen et al, 1987). Modest reductions in left ventricular ejection fraction (60% to 53%) were seen with lower doses of the drug (0.25, 0.5, or 0.75 mg/kg intravenously over 2 minutes), whereas more profound falls in ejection fraction (69% to 49%) occurred with higher doses of 1 or 1.2 mg/kg, which persisted for approximately 2 hours. This was associated with an increase in end diastolic volume index and end systolic volume index, and a fall in cardiac index; an increase in pulmonary capillary wedge pressure was also observed, with systemic pressure being maintained by a compensatory increase in systemic vascular resistance. In this study, intravenous cifenline 1 to 1.2 mg/kg (infused over 2 minutes) resulted in similar hemodynamic changes and a similar decline in left ventricular function as intravenous disopyramide at a dose of 2 mg/kg (infused over 15 minutes).

Toxicologic Mechanism

    A) HYPOGLYCEMIA - Following overdoses or high serum levels, interference with adenosine triphosphate-dependent potassium channels in pancreatic B cells occurs. This in turn results in elevation of intracellular calcium concentration and over-secretion of insulin leading to hypoglycemia (Wakutani et al, 1998; Bertrand et al, 1992; Ishida-Takahashi et al, 1996; Mukai et al, 1998).
    B) MYASTHENIA - High cifenline serum levels probably result in inhibition of muscular adenosine triphosphate-dependent potassium channels (K-ATPs) which may also affect calcium metabolism of muscle and functioning of neuromuscular junctions (Wakutani et al, 1998).
    C) PROARRHYTHMIC EFFECTS - Fujiki et al (1996) concluded that adverse proarrhythmic effects are primarily due to induction of unidirectional retrograde conduction of the manifest accessory pathway and the larger prolongation of the retrograde conduction time of the concealed accessory pathway than the refractory period (Fujiki et al, 1996).

Physicochemical

Physical Characteristics

    A) Cifenline is in the form of crystals from petroleum ether, with a melting point of 103 to 104 degrees (Budavari, 1996).
    B) Cifenline succinate is in the form of crystals from ethanol plus ether, with a melting point of 165 degrees (Budavari, 1996).

Molecular Weight

    A) 262.35 (Budavari, 1996)

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