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VASODILATORS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) These agents are vasodilators used in the management of hypertension and peripheral vascular disease. Minoxidil is also used topically in the treatment of hair loss.

Specific Substances

    A) BUFLOMEDIL (synonym)
    1) 2,4,6-Trimethoxy-4-(1-pyrrolidinyl)butyrophenone
    2) LL-1656
    3) CAS 55837-25-7 (Buflomedil)
    4) CAS 35543-24-9 (Buflomedil hydrochloride - synonym)
    CADRALAZINE (synonym)
    1) CGP-18684
    2) DC-826
    3) ISF-2469
    4) CGP-22639 (hydrazino metabolite)
    5) ISF-2405 (hydrazino metabolite)
    DIAZOXIDE (synonym)
    1) 7-chloro-3-methyl-2H-1,2,4-benzothiadiazine
    2) 1,1-dioxide
    3) SRG 95213
    4) CAS 364-98-7
    DIHYDRALAZINE
    1) Dihydralazine (synonym)
    FENOLDOPAM (synonym)
    1) SKF-82526-J
    2) CAS 67227-56-9 (fenoldopam)
    3) CAS 67227-57-0 (fenoldopam mesylate - synonym)
    HYDRALAZINE HYDROCHLORIDE (synonym)
    1) 1-Hydrazinophthalazine hydrochloride
    2) Apressinum
    3) Ciba 5968
    4) Cloridrato de hidralazina
    5) Hydralazini hydrochloridum
    6) CAS 86-54-4 (hydralazine)
    7) CAS 304-20-1 (hydralazine hydrochloride)
    ILOPROST (synonym)
    1) Ciloprost (synonym)
    2) Iloprosti
    3) CAS 73873-87-7
    4) Molecular Formula: C22-H32-O4
    ISOXSUPRINE (synonym)
    1) CAS 395-28-8 (isoxsuprine)
    2) CAS 579-56-6 (isoxsuprine hydrochloride - synonym)
    MINOXIDIL (synonym)
    1) 1-oxide
    2) 2,6-Diamino-4-piperidinopyrimidine
    3) Minoxidilum
    4) U-10858
    5) CAS 38304-91-5
    MOLSIDOMINE (synonym)
    1) CAS-276
    2) Molsidomin
    3) Molsidomina
    4) Molsidominum (synonym)
    5) Morsydomine
    6) Morsydominum
    7) Motazomin
    8) N-Ethoxycarbonyl-3-morpholinosydnonimine
    9) SIN-10
    10) Molecular Formula: C9-H14-N4-O4
    11) CAS 25717-80-0
    NICOTINYL ALCOHOL (synonym)
    1) 3-Hydroxymethylpyridine
    2) 3-Pyridinemethanol
    3) 3-Pyridylmethanol
    4) beta-Pyridylcarbinol
    5) Nicotinic alcohol
    6) Nicotinilico, alcohol
    7) NSC-526046
    8) NU-2121
    9) Ro-1-5155
    10) Molecular Formula: C6-H7-N-O
    11) CAS 100-55-0
    TODRALAZINE (synonym)
    1) Ecarazine
    2) BT-621
    3) CEPH
    4) CAS 14679-73-3 (todralazine)
    5) CAS 3778-76-5 (todralazine hydrochloride - synonym)

    1.2.1) MOLECULAR FORMULA
    1) HYDRALAZINE HYDROCHLORIDE: C8H8N4.HCl

Available Forms Sources

    A) FORMS
    1) HYDRALAZINE is available as Apresoline(R) and generic tablets 10, 25, 50 and 100 mg, and in combination products.
    2) DIAZOXIDE is available in 300 mg/20 mL ampule for injection and in 50 mg capsules and 50 mg/mL oral suspension.
    3) MINOXIDIL is available in 2.5 and 10 mg tablets. Minoxidil is available as a 2% topical solution.
    4) BUFLOMEDIL is available in Europe as 150, 300 and 600 mg tablets, 150 mg/mL oral drops, and 50 mg ampule.
    5) FENOLDOPAM is available as Corlopam(R) in 10 mg/mL ampules .

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: These agents are used for the treatment of hypertension, peripheral vascular disease and pulmonary hypertension. Minoxidil is also used to treat hair loss.
    B) PHARMACOLOGY: Hydralazine, diazoxide and minoxidil cause vasodilation by directly relaxing vascular smooth muscle. Iloprost is a prostacyclin PGI(2) analog that dilates pulmonary and systemic arteries. Fenoldopam is a D1 dopamine receptor agonist.
    C) TOXICOLOGY: Toxicity is generally an extension of the pharmacological effect, primarily hypotension. Hydralazine has an active metabolite that binds to cellular proteins and may trigger an autoimmune response.
    D) EPIDEMIOLOGY: Exposures are uncommon and deaths are extremely rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: All of these agents will cause a dose-related decrease in blood pressure.
    2) ADVERSE EFFECTS BY AGENT: Hydralazine: lupus-like syndrome, auto-immune dermal, liver and renal disease. Diazoxide: Hyperglycemia, hyperosmolar coma. Minoxidil: Hair growth. Fenoldopam: Tachycardia.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: All of these medications cause dose-related hypotension following overdose, often accompanied by tachycardia.
    2) SEVERE TOXICITY: Hydralazine: One case of electrocardiographic changes suggesting myocardial ischemia and acidosis without profound hypotension has been reported following hydralazine overdose. Diazoxide: A case of 2:1 heartblock has been reported following rapid IV injection. Minoxidil: Profound hypotension and myocardial ischemia have been reported following large overdoses. Fenoldopam: No reports of significant toxicity.
    0.2.5) CARDIOVASCULAR
    A) Hypotension, tachycardia, palpitations and cardiac dysrhythmias may occur. Severe hypotension may result in myocardial and cerebral ischemia, as well as other end-organ dysfunction.
    B) ECG abnormalities, ventricular fibrillation and cardiac arrest have been reported following buflomedil overdoses.
    0.2.6) RESPIRATORY
    A) Pulmonary edema has been reported following buflomedil overdoses.
    B) Respiratory depression may occur with buflomedil intoxication.
    0.2.7) NEUROLOGIC
    A) Headache, dizziness and sweating may occur with any of the vasodilators. Peripheral neuropathy has been reported following long term hydralazine therapy. Hyperglycemic, non-ketotic coma may occur with diazoxide.
    B) Seizures and coma may occur with buflomedil toxicity.
    0.2.8) GASTROINTESTINAL
    A) Nausea and vomiting are common following therapeutic administration of fenoldopam.
    0.2.10) GENITOURINARY
    A) Glomerulonephritis has been reported following chronic administration of hydralazine.
    0.2.12) FLUID-ELECTROLYTE
    A) Hypokalemia has been reported in buflomedil overdoses and with therapeutic administration of fenoldopam.
    0.2.19) IMMUNOLOGIC
    A) A lupus-like syndrome occurs in 10 to 20% of patients on chronic hydralazine therapy.
    0.2.20) REPRODUCTIVE
    A) While there are no adequate and well-controlled studies of diazoxide use in pregnant women, diazoxide has been shown to cross the placental barrier and appear in cord blood.
    B) Fenoldopam mesylate is classified as US Food and Drug Administration Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women, so the drug should be used by pregnant mothers only if clearly needed.
    C) Newborns of mothers taking hydralazine have been reported to have thrombocytopenia, fetal distress, and other effects. Data from a single patient indicate that hydralazine administration produces extremely low levels in breast milk, suggesting safety of the drug during the breastfeeding period.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) No specific lab work is needed in most patients.
    C) Drug concentration monitoring is not clinically useful or readily available.
    D) Institute continuous cardiac monitoring and obtain an ECG.
    E) Monitor for seizure activity and CNS depression, especially in buflomedil overdoses.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Administer IV fluids for hypotension.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Severe toxicity is rare following overdoses of these medications. Patients who remain hypotensive after fluid boluses should be treated with adrenergic vasopressors. Some authors suggest that phenylephrine may reverse hypotension without causing tachycardia. In cases of severe toxicity, consider coingestion or other medical conditions as a cause of the symptoms.
    C) DECONTAMINATION
    1) PREHOSPITAL: Decontamination is not recommended.
    2) HOSPITAL: Consider activated charcoal after large, recent ingestion.
    D) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be required following overdose.
    E) ANTIDOTE
    1) There is no antidote for poisoning from these medications.
    F) HYPOTENSION
    1) IV NS 10 to 20 mL/kg, dopamine or norepinephrine.
    G) WIDE QRS COMPLEX
    1) Dysrhythmias may respond to serum alkalinization, or lidocaine, bretylium, phenytoin.
    H) SEIZURE
    1) IV benzodiazepines or barbiturates.
    I) ENHANCED ELIMINATION
    1) Studies suggest that diazoxide and minoxidil clearance may be increased by dialysis, but there is no evidence suggesting that increased clearance improves outcomes and the vast majority of patients do well with supportive care.
    J) PATIENT DISPOSITION
    1) HOME CRITERIA: Children and adults can be managed at home if overdose was inadvertent, was less than 2 times the therapeutic dose for their weight, and no signs or symptoms are present.
    2) OBSERVATION CRITERIA: Symptomatic patients, those with deliberate ingestions or ingestions of more than twice the therapeutic dose for weight should be sent to a health care facility for 6 hours of observation.
    3) ADMISSION CRITERIA: Patients who develop persistent hypotension should be admitted until symptoms resolve.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in decision making whether or not admission is advisable, managing patients with severe toxicity, or in whom the diagnosis is not clear.
    K) PITFALLS
    1) Unusual complications of overdose must also be recognized and treated. Monitor and maintain adequate urine output (not forced diuresis). Peripheral neuropathies may be corrected with pyridoxine. Neuropathies are most frequently associated with chronic ingestion of therapeutic doses of hydralazine. Hyperglycemia induced by diazoxide may be reversed by insulin or oral hypoglycemic agents.
    L) PHARMACOKINETICS
    1) DIAZOXIDE: well absorbed, 90% protein bound, hepatic metabolism and renal elimination, half life 20 to 36 hours.
    2) HYDRALAZINE: moderate absorption, onset 1 hour, 90% protein bound, hepatic metabolism, half-life 3 to 5 hours.
    3) MINOXIDIL: well absorbed, onset 1 hour, duration 12 to 18 hours, hepatic metabolism with renal elimination, little protein binding, volume of distribution 2 to 3 L/kg, half life 4 hours.
    4) ILOPROST: low oral bioavailability, 60% protein bound, volume of distribution 0.6 to 0.9 L/kg, oxidized with 50% renal elimination of metabolites, half life 20 to 30 minutes.
    5) FENOLDOPAM: well absorbed but extensive first pass metabolism (thus only used parenterally), hepatic metabolism and renal elimination of metabolites, volume of distribution 0.6 to 0.7 L/kg, half life 5 to 10 minutes.
    M) DIFFERENTIAL DIAGNOSIS
    1) Mild hypotension is caused by many exposures. More severe symptoms should prompt consideration of other diagnoses

Range Of Toxicity

    A) Severe toxicity is very rare following isolated overdose from these medications. An adult survived an ingestion of 10 g hydralazine. A toddler developed only tachycardia after ingesting 100 mg minoxidil. An adult developed hypotension and a non-ST-elevation myocardial infarction after ingesting 1200 mg minoxidil.
    B) THERAPEUTIC DOSE: ADULTS: DIAZOXIDE: 1 to 3 mg/kg up to a single dose of 150 mg. HYDRALAZINE: Oral: 40 to 200 mg/day. Parenteral 20 to 40 mg intravenously or intramuscularly. MINOXIDIL: 10 to 100 mg/day. FENOLDOPAM: 0.05 to 0.1 mcg/kg/min and the dose should be titrated no more frequently than every 15 minutes.
    C) THERAPEUTIC DOSE: PEDIATRIC: DIAZOXIDE: 1 to 3 mg/kg/dose IV, up to a maximum of 150 mg/dose. HYDRALAZINE: ORAL: 0.75 to 7.5 mg/kg/day in 4 divided doses (up to 200 mg/day). PARENTERAL: Usual dose is 1.7 to 3.5 mg/kg/day in divided doses every 4 to 6 hours. MINOXIDIL: ORAL: Up to 50 mg/daily or 5 mg/kg/24 hrs. FENOLDOPAM: The safety and efficacy in children has not been established

Clinical Effects

Summary Of Exposure

    A) USES: These agents are used for the treatment of hypertension, peripheral vascular disease and pulmonary hypertension. Minoxidil is also used to treat hair loss.
    B) PHARMACOLOGY: Hydralazine, diazoxide and minoxidil cause vasodilation by directly relaxing vascular smooth muscle. Iloprost is a prostacyclin PGI(2) analog that dilates pulmonary and systemic arteries. Fenoldopam is a D1 dopamine receptor agonist.
    C) TOXICOLOGY: Toxicity is generally an extension of the pharmacological effect, primarily hypotension. Hydralazine has an active metabolite that binds to cellular proteins and may trigger an autoimmune response.
    D) EPIDEMIOLOGY: Exposures are uncommon and deaths are extremely rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: All of these agents will cause a dose-related decrease in blood pressure.
    2) ADVERSE EFFECTS BY AGENT: Hydralazine: lupus-like syndrome, auto-immune dermal, liver and renal disease. Diazoxide: Hyperglycemia, hyperosmolar coma. Minoxidil: Hair growth. Fenoldopam: Tachycardia.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: All of these medications cause dose-related hypotension following overdose, often accompanied by tachycardia.
    2) SEVERE TOXICITY: Hydralazine: One case of electrocardiographic changes suggesting myocardial ischemia and acidosis without profound hypotension has been reported following hydralazine overdose. Diazoxide: A case of 2:1 heartblock has been reported following rapid IV injection. Minoxidil: Profound hypotension and myocardial ischemia have been reported following large overdoses. Fenoldopam: No reports of significant toxicity.

Vital Signs

    3.3.4) BLOOD PRESSURE
    A) HYPOTENSION: Severe hypotension may occur (McCormick et al, 1989; Legras et al, 1996; Prod Info Corlopam(R), fenoldopam, 1997).
    1) MINOXIDIL: Severe and prolonged (72 hours) hypotension was reported following ingestion of a single 10 mg dose of minoxidil (Allon et al, 1986).

Heent

    3.4.3) EYES
    A) DIAZOXIDE: Lacrimation occurred in 6 of 30 patients receiving 200 to 400 mg of diazoxide (Grant & Schuman, 1993). Dogs given overdoses of 10 to 40 times therapeutic doses have developed reversible cataracts (Schiavo et al, 1975; Schiavo, 1976).
    B) HYDRALAZINE: Lacrimation, blurred vision, and edema of the eyelids have occurred (Gombos, 1983).
    C) BUFLOMEDIL: Mydriasis has been reported following acute overdoses (Legras et al, 1996; Alberti et al, 1994).
    D) FENOLDOPAM: During a clinical study involving 12 patients with open-angle glaucoma or ocular hypertension, the patients' intraocular pressure increased following fenoldopam infusion with escalating doses ranging from 0.05 to 0.5 mcg/kg/minute over a 3.5 hour period. The intraocular pressure returned to baseline values 2 hours after discontinuation of fenoldopam (Prod Info Corlopam(R), fenoldopam, 1997).

Cardiovascular

    3.5.1) SUMMARY
    A) Hypotension, tachycardia, palpitations and cardiac dysrhythmias may occur. Severe hypotension may result in myocardial and cerebral ischemia, as well as other end-organ dysfunction.
    B) ECG abnormalities, ventricular fibrillation and cardiac arrest have been reported following buflomedil overdoses.
    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) MINOXIDIL
    a) CASE REPORT: Severe hypotension requiring dopamine infusion for 3 days was reported following an ingestion of "a couple of swigs" of topical 2% minoxidil in a 36-year-old male. The amount ingested was estimated to be 1000 mg (McCormick et al, 1989). Systolic blood pressure was 44 mmHg by palpation following oral ingestion of an estimated 1200 mg minoxidil topical solution (MacMillan et al, 1993).
    b) Prolonged hypotension has been reported after an initial 10 mg dose (Allon et al, 1986).
    c) CASE SERIES: Hypotension was reported in 69% of 224 ingestions (Rose & Tomaszewski, 1993).
    d) CASE REPORT: A 26-year-old female developed progressively worsening hypotension after ingesting 60 mL of 5% minoxidil solution in a suicide attempt. The patient's blood pressure normalized following administration of dopamine and phenylephrine (Farrell & Epstein, 1999).
    2) BUFLOMEDIL: Hypotension was reported in several cases of buflomedil overdoses in young adults (Bacis et al, 2003; Vandemergel et al, 2000; Legras et al, 1996).
    3) FENOLDOPAM: During fenoldopam clinical studies for severe hypertension, patients with a history of end-organ damage, 4 of 137 patients (3%) withdrew from the study due to severe hypotension (Prod Info Corlopam(R), fenoldopam, 1997).
    B) TACHYARRHYTHMIA
    1) MINOXIDIL
    a) Tachycardia developed in 38% of 224 minoxidil ingestions (Rose & Tomaszewski, 1993).
    b) Poff & Rose (1992) report ECG findings of tachycardia (122 bpm) along with ST-segment depression and inverted T-waves which persisted for 8 hours.
    c) CASE REPORT: A 26-year-old female presented with tachycardia (130 bpm) within 1 hour after intentionally ingesting 60 mL of 5% minoxidil solution. Following the administration of saline, the patient suddenly developed bradycardia (20 bpm), severe hypotension, and became comatose. The patient's heart rate increased to 120 bpm following intubation and atropine administration. Tachycardia resolved 5 days post-ingestion (Farrell & Epstein, 1999).
    2) BUFLOMEDIL: In a series of 5 patients with buflomedil overdose, all presented with tachycardia (Legras et al, 1996).
    3) FENOLDOPAM may cause dose-related tachycardia, usually with infusion rates greater than 0.1 mcg/kg/minute (Prod Info Corlopam(R), fenoldopam, 1997).
    C) ISCHEMIA
    1) HYDRALAZINE: Myocardial ischemia has been reported after therapeutic doses of hydralazine in patients with preexisting cardiomyopathy and in a combined ethanol/hydralazine overdose in a 27-year-old woman.
    a) Tachycardia and electrolyte abnormalities may have contributed to the ischemic ECG changes in this patient, although hydralazine has been shown to produce myocardial necrosis in rats (Smith & Ferguson, 1992).
    2) MINOXIDIL: Angina pectoris and hemorrhagic pericarditis were reported after minoxidil overdose (Krehlik et al, 1985). Pericardial effusion was seen with minoxidil therapy (Zarate et al, 1980). A non-Q wave infarction followed oral ingestion of 1200 mg topical minoxidil solution (MacMillan et al, 1993).
    D) ATRIOVENTRICULAR BLOCK
    1) DIAZOXIDE: CASE REPORT: A 2:1 heart block occurred in a 6-month-old infant following an intravenous dose of diazoxide. Five mg/kg was injected over 15 seconds in a volume of 2.25 mL (Mauer & Mirkin, 1972).
    2) BUFLOMEDIL: CASE SERIES: Legras et al (1996) report 5 cases of buflomedil overdoses. ECG revealed first degree AV block in 2 patients. All had prolonged QRS durations and enlarged S wave. QT interval was prolonged and a flattened T wave occurred in most of these patients. ECG abnormalities appear to be typical findings in buflomedil overdoses.
    E) CARDIAC ARREST
    1) BUFLOMEDIL
    a) CASE REPORT: Cardiac arrest was reported in 2 adult patients, 1 and 3 hours following buflomedil overdoses. Both had previous excellent health, and both recovered following epinephrine and sodium bicarbonate therapy (Legras et al, 1996).
    b) CASE REPORT: Cardiac arrest occurred, requiring cardiopulmonary resuscitation, mechanical ventilation, and epinephrine administration, in a 23-year-old following an intentional overdose ingestion of buflomedil (total dose 18 grams). The patient recovered 48 hours later (Vandemergel et al, 2000).
    F) VENTRICULAR FIBRILLATION
    1) BUFLOMEDIL: CASE REPORT: Ventricular fibrillation was reported in a 19-year-old female following an overdose of 3 grams (Athanaselis et al, 1984).
    G) ELECTROCARDIOGRAM ABNORMAL
    1) MINOXIDIL: A 26-year-old woman developed hypotension, tachycardia, and T-wave inversions and ST depression in the inferior and anterolateral ECG leads after ingesting 60 milliliters (3 grams) of 5% minoxidil (Farrell & Epstein, 1999).
    H) CONGESTIVE HEART FAILURE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: An infant with hyperinsulinism developed fluid retention, congestive heart failure and respiratory failure after treatment with diazoxide (17 milligrams/kilogram/day) and octreotide (12 micrograms/kilogram/day). He improved dramatically when diazoxide was discontinued(Silvani et al, 2004).

Respiratory

    3.6.1) SUMMARY
    A) Pulmonary edema has been reported following buflomedil overdoses.
    B) Respiratory depression may occur with buflomedil intoxication.
    3.6.2) CLINICAL EFFECTS
    A) ACUTE RESPIRATORY INSUFFICIENCY
    1) BUFLOMEDIL: Respiratory depression is common following buflomedil overdoses.
    a) CASE SERIES: Several young adult females who overdosed on buflomedil suffered from respiratory depression. Hypoxia and respiratory acidosis were reported. All recovered following mechanical ventilation (Alberti et al, 1994; Legras et al, 1996).
    B) ACUTE LUNG INJURY
    1) BUFLOMEDIL: CASE REPORT: Pulmonary edema has been reported following a fatal buflomedil overdose in a 19-year-old female (Athanaselis et al, 1984).

Neurologic

    3.7.1) SUMMARY
    A) Headache, dizziness and sweating may occur with any of the vasodilators. Peripheral neuropathy has been reported following long term hydralazine therapy. Hyperglycemic, non-ketotic coma may occur with diazoxide.
    B) Seizures and coma may occur with buflomedil toxicity.
    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) FENOLDOPAM: Headache and dizziness have been reported with therapeutic use of fenoldopam (Prod Info Corlopam(R), fenoldopam, 1997).
    B) SECONDARY PERIPHERAL NEUROPATHY
    1) HYDRALAZINE: Peripheral neuropathies have been noted following chronic hydralazine therapy.
    C) COMA
    1) DIAZOXIDE: Several cases of hyperglycemia, hyperosmolar, non-ketoacidotic coma have been reported following diazoxide therapy (Lancaster-Smith et al, 1974).
    2) MINOXIDIL: Coma was reported 2 hours post-ingestion in a 36-year-old man after ingestion of 1000 mg of minoxidil. By 12 hours post-ingestion he was lethargic but arousable (McCormick et al, 1989).
    3) BUFLOMEDIL: Coma appears to be a common effect of buflomedil toxic ingestions and may occur following a period of seizures (Alberti et al, 1994; Legras et al, 1996; Vandemergel et al, 2000).
    D) SEIZURE
    1) BUFLOMEDIL
    a) Seizures are an expected outcome of acute buflomedil overdose. Coma may occur following seizure activity. Abnormal EEG readings have been reported in several patients following seizures (Bacis et al, 2003; Alberti et al, 1994; Legras et al, 1996; Athanaselis et al, 1984; Vandemergel et al, 2000).
    b) Recurrent myoclonic seizures were reported in a 75-year-old female who was taking buflomedil 900 mg/day. Toxicological analysis revealed a buflomedil overdose with a peak buflomedil plasma concentration of 6.3 mg/L (normal range 4 to 4.5 mg/L). The patient recovered, following discontinuation of the buflomedil, without further recurrence of seizures (Chiffoleau et al, 2000). It was determined that the patient's physician had recently switched the patient from the brand name drug to the generic drug, but the patient misunderstood the switch and was taking both drugs concurrently.
    E) DROWSY
    1) MINOXIDIL: CASE SERIES: Lethargy was present in 31% of 224 ingestions (Rose & Tomaszewski, 1993).

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea and vomiting are common following therapeutic administration of fenoldopam.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) FENOLDOPAM: Nausea and vomiting commonly occur with therapeutic use of fenoldopam (Prod Info Corlopam(R), fenoldopam, 1997).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) HEPATIC FAILURE
    1) ECARAZINE: Tameda et al (1996) reported 7 cases of fulminant hepatic failure that developed after beginning ecarazine therapy. Each patient developed jaundice, increased liver enzymes, and malaise. Four of the seven patients subsequently died.

Genitourinary

    3.10.1) SUMMARY
    A) Glomerulonephritis has been reported following chronic administration of hydralazine.
    3.10.2) CLINICAL EFFECTS
    A) GLOMERULONEPHRITIS
    1) HYDRALAZINE: Glomerulonephritis has been reported following long term hydralazine treatment averaging more than 7 years. Hematuria and renal insufficiency may be reversible when hydralazine is discontinued (Bjorek et al, 1985).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) CONTACT DERMATITIS
    1) MINOXIDIL: Allergic contact dermatitis has been reported when minoxidil has been used in the treatment of baldness (Alomar & Smandia, 1988; Tosti et al, 1985; Valsechi & Cainelli, 1987; Degreef et al, 1985).
    2) HYDRALAZINE: CASE REPORT: Occupational contact dermatitis was reported in a 54-year-old male who was working in the pharmaceutical industry. The patient had developed eczema on the hands, forearms, and axillae. Skin patch tests with products he handled showed positive results with propranolol, bendroflumethiazide, and hydralazine (Pereira et al, 1996).
    B) EXCESSIVE HAIR GROWTH
    1) There have been several case reports of women applying 5% topical minoxidil, over a period of 2 to 3 months, to treat androgenetic alopecia and subsequently developing severe hypertrichosis of the face and extremities. The excessive hair growth on the face and limbs gradually disappeared over a period of several months after discontinuation of minoxidil (Peluso et al, 1997).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) DIAZOXIDE: Hyperglycemia has been reported following diazoxide therapy (Lancaster-Smith et al, 1974).
    B) GYNECOMASTIA
    1) MINOXIDIL may produce breast tenderness or gynecomastia (Mackay et al, 1981).

Immunologic

    3.19.1) SUMMARY
    A) A lupus-like syndrome occurs in 10 to 20% of patients on chronic hydralazine therapy.
    3.19.2) CLINICAL EFFECTS
    A) DRUG-INDUCED LUPUS ERYTHEMATOSUS
    1) HYDRALAZINE: Chronic use of hydralazine (18 months of therapy) has been associated with a lupus erythematosus-like syndrome, which develops almost exclusively in patients of the slow acetylator phenotype (Timbrell et al, 1984).
    a) This complication which may start as a serum-sickness like illness, occurs in about 1% to 2% of patients treated with hydralazine (Yemini et al, 1989a).
    B) ACUTE ALLERGIC REACTION
    1) MINOXIDIL has produced various hypersensitivity reactions such as rash and thrombocytopenia (Mackay et al, 1981).

Reproductive

    3.20.1) SUMMARY
    A) While there are no adequate and well-controlled studies of diazoxide use in pregnant women, diazoxide has been shown to cross the placental barrier and appear in cord blood.
    B) Fenoldopam mesylate is classified as US Food and Drug Administration Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women, so the drug should be used by pregnant mothers only if clearly needed.
    C) Newborns of mothers taking hydralazine have been reported to have thrombocytopenia, fetal distress, and other effects. Data from a single patient indicate that hydralazine administration produces extremely low levels in breast milk, suggesting safety of the drug during the breastfeeding period.
    3.20.2) TERATOGENICITY
    A) HYDRALAZINE
    1) In one study, 40 newborns were exposed to hydralazine during the first trimester of pregnancy. One infant was born with hypospadias (Rosa & Baum, 1995). Experience with its prolonged use in pregnancy is not extensive, and neonatal thrombocytopenia and fetal distress have been reported (Widerlov et al, 1980). Hydralazine has caused premature atrial contractions in a fetus (Lodeiro et al, 1989). A lupus-like syndrome was reported for a female treated with hydralazine for pregnancy-induced hypertension. The fetus died 36 hours after delivery from a pericardial effusion and cardiac tamponade. A postmortem examination suggested a lupus-like syndrome (Yemini et al, 1989).
    B) ISOXSUPRINE
    1) One retrospective study in 54 mother-child pairs exposed to isoxsuprine during the first 4 months of pregnancy reported 3 congenital malformations. This was not considered statistically significant and does not support teratogenic risks of isoxsuprine during pregnancy (Heinonen et al, 1977; Schardein, 1976). Isoxsuprine was free of toxic neonatal or maternal effects during oral dosing up to 40 mg daily in 1 series of 590 women (Briscoe, 1966). With oral therapy, cord isoxsuprine concentrations are less than 2 nanogram/milliliter (ng/mL), whereas symptoms are most likely to occur with cord levels greater than 10 ng/mL. Ileus appears to be unrelated to cord levels of isoxsuprine, while the incidence of hypotension (systolic blood pressure at least 10 mmHg below normal within the first 6 hours) and hypocalcemia (less than 7.5 mg/dL between 16 and 48 hours of life) was directly related to cord isoxsuprine levels, rising to 89% and 100%, respectively, with cord concentrations greater than 10 ng/mL (Brazy et al, 1981).(Brazy et al, 1981a). No adverse effects were reported in 38 premature infants born to mothers who received IV isoxsuprine (80 to 160 mg/day for 1 to 2 days) and continued to the end of labor (Kero et al, 1973).
    2) In 6 out of 9 apparently healthy newborn infants, prolonged tocolytic therapy with isoxsuprine resulted in myocardial ischemia which persisted for several weeks (Gemelli et al, 1990). Exposed neonates have experienced irregular heart beats or fetal distress (Zobel, 1967) and tachycardia (up to 54%) (Brazy et al, 1981a; Schenkon et al, 1980), hypotension, hypocalcemia, hypoglycemia, ileus (up to 33%) (Brazy et al, 1981; Brazy & Marcos, 1979), and death associated with respiratory distress (Schenkon et al, 1980; Brazy & Marcos, 1979) following maternal IV or IM exposure to isoxsuprine; these side effects primarily occurred in infants less than 33 weeks gestation, infusion rates greater than 0.25 mg/min (Brazy et al, 1981a), or when maternal hypotension and tachycardia developed (Brazy & Marcos, 1979).
    C) MINOXIDIL
    1) Congenital anomalies and hypertrichosis were observed in a newborn infant whose mother had received minoxidil 10 mg daily throughout pregnancy. The mother had also received captopril 50 mg daily and propranolol 160 mg daily during pregnancy. At birth, an omphalocele was observed, as well as pronounced hypertrichosis of the back and extremities; dysmorphic facial features were present (depressed nasal bridge, low set ears and micrognathia). Other anomalies included undescended testes, circumferential midphallic constriction and bilateral fifth finger clinodactyly. A neurologic examination was normal, and there were no obvious skeletal abnormalities. Hypertrichosis had decreased significantly by 2 months of age (Kaler et al, 1987).
    2) A 1770-g female infant born at 32 weeks of gestation manifested cyanotic heart disease and died on day 2. Autopsy revealed transposition of the great vessels with pulmonic bicuspid valvular stenosis (Rosa et al, 1987).
    D) ANIMAL STUDIES
    1) DIAZOXIDE
    a) Fetal skeletal anomalies were observed in rats following oral administration of diazoxide in reproduction studies. Skeletal and cardiac teratogenicities were reported after IV administration in rabbits (Prod Info PROGLYCEM(R) oral suspension, 2012).
    b) In rats and dogs, no effects were seen; skeletal abnormalities were seen in rabbit kits (Schardein, 1985).
    2) FENOLDOPAM MESYLATE
    a) No fetal harm was demonstrated at the highest dose tested in reproductive studies (Prod Info CORLOPAM (R) intravenous injection solution, 2015).
    3) HYDRALAZINE
    a) No teratogenicity was demonstrated in rats administered hydralazine in animal studies. However, teratogenic effects, including cleft palate and malformations of facial and cranial bones, were observed in mice at 20 to 30 times the maximum daily human dose of 200 to 300 mg and possibly in rabbits at 10 to 15 times the maximum daily human dose (Prod Info hydralazine HCl intravenous injection, intramuscular injection, 2012; Prod Info hydralazine HCl oral tablets, 2012).
    4) ILOPROST
    a) Continuous IV administration of iloprost at a dose of 0.01 mg/kg/day to pregnant Han-Wistar rats resulted in shortened digit of the thoracic extremity in the fetuses and pups. Similar studies in Sprague-Dawley rats given oral doses of up to 50 mg/kg/day, rabbits given IV doses of up to 0.5 mg/kg/day, and in monkeys up to 0.04 mg/kg/day, did not result in digit abnormalities or other gross structural abnormalities in the offspring. Sprague-Dawley rats given maternally toxic oral doses of up to 250 mg/kg/day delivered fewer viable fetuses. Intravenous doses of 1 mg/kg/day administered to Han-Wistar rats was embryolethal in 15 of 44 litters (Prod Info VENTAVIS(R) inhalation solution, 2012).
    5) MINOXIDIL
    a) Increased fetal resorption was observed in rabbits, but not rats, administered 5 times the maximum recommended oral human dose. No teratogenicity was observed following subQ administration to pregnant rats at the maternally toxic dose of 80 mg/kg/day. There was no teratogenicity observed in rabbits either (Prod Info minoxidil oral tablets, 2003).
    3.20.3) EFFECTS IN PREGNANCY
    A) LACK OF INFORMATION
    1) FENOLDOPAM MESYLATE
    a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info CORLOPAM (R) intravenous injection solution, 2015).
    2) ILOPROST
    a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info VENTAVIS(R) inhalation solution, 2012).
    B) PLACENTAL BARRIER
    1) While there are no adequate and well-controlled studies of diazoxide use in pregnant women, diazoxide has been shown to cross the placental barrier and appear in cord blood. Fetal or neonatal hyperbilirubinemia, thrombocytopenia (Prod Info PROGLYCEM(R) oral suspension, 2012), altered carbohydrate metabolism, resulting in hyperglycemia (Smith et al, 1982; Milsap & Auld, 1980) and possibly other adverse effects that have been reported in adults may occur if the drug is administered to the mother prior to delivery. Infants whose mothers received oral diazoxide during the last 19 to 60 days of pregnancy have experienced alopecia and hypertrichosis lanuginosa (Prod Info PROGLYCEM(R) oral suspension, 2012).
    C) PREGNANCY CATEGORY
    1) Fenoldopam mesylate is classified as Pregnancy Category B (Prod Info CORLOPAM (R) intravenous injection solution, 2015).
    2) Diazoxide, hydralazine, and iloprost are classified as US Food and Drug Administration (FDA) Pregnancy Category C (Prod Info PROGLYCEM(R) oral suspension, 2012; Prod Info hydralazine HCl intravenous injection, intramuscular injection, 2012; Prod Info hydralazine HCl oral tablets, 2012; Prod Info VENTAVIS(R) inhalation solution, 2012).
    3) Isoxsuprine is no longer approved for use in the United States. However, it was previously also classified as US FDA Pregnancy Category C (Prod Info isoxsuprine hcl oral tablets, 2005).
    4) Minoxidil topical formulation is available over the counter; however, previously it was available as an oral formulation with a US FDA Pregnancy Category C (Prod Info minoxidil oral tablets, 2003).
    D) LACK OF EFFECT
    1) HYDRALAZINE
    a) While clinical experience does not show evidence of adverse effects on the human fetus following maternal administration during pregnancy, there are no adequate and well-controlled studies of hydralazine in pregnant women (Prod Info hydralazine HCl intravenous injection, intramuscular injection, 2012; Prod Info hydralazine HCl oral tablets, 2012).
    E) ANIMAL STUDIES
    1) DIAZOXIDE
    a) Increased fetal resorptions and delayed parturition were observed in rats following oral administration of diazoxide in reproduction studies. In animals, the drug has been shown to cross the placental barrier. IV administration to pregnant sheep, goats, and swine resulted in an appreciable increase in blood glucose level and degeneration of the beta cells of the Islets of Langerhans in the fetus (Prod Info PROGLYCEM(R) oral suspension, 2012).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) DIAZOXIDE
    a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation in humans (Prod Info PROGLYCEM(R) oral suspension, 2012).
    2) FENOLDOPAM MESYLATE
    a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation in humans (Prod Info CORLOPAM (R) intravenous injection solution, 2015).
    3) HYDRALAZINE
    a) At the time of this review, no studies were available to assess the potential effects of exposure to this agent during lactation in humans (Prod Info hydralazine HCl intravenous injection, intramuscular injection, 2012; Prod Info hydralazine HCl oral tablets, 2012).
    4) ILOPROST
    a) At the time of this review, no studies were available to assess the potential effects of exposure to this agent during lactation in humans (Prod Info VENTAVIS(R) inhalation solution, 2012).
    5) ISOXSUPRINE
    a) At the time of this review, no studies were available to assess the potential effects of exposure to this agent during lactation in humans (Prod Info isoxsuprine hcl oral tablets, 2005).
    B) BREAST MILK
    1) HYDRALAZINE levels were measured in a single patient taking hydralazine while breastfeeding. Results showed a higher fraction of unmetabolized hydralazine in milk than plasma, but the overall levels (hydralazine plus hydrazone metabolites) were at a lower concentration in milk than plasma. Furthermore, the estimated dose contained in 75 mL of breast milk was only 0.013 mg and; therefore, not clinically significant (Liedholm et al, 1982).
    2) MINOXIDIL is excreted in breast milk, with plasma concentrations being slightly higher than milk concentrations 1 hour post administration of a 7.5 mg oral dose (Valdivieso et al, 1985).
    a) RECOMMENDATION: Hypertrichosis was not described in the infant of this patient after 2 months of exposure to minoxidil, however, the drug should not be administered for long periods during breast feeding until more data are available.
    C) ANIMAL STUDIES
    1) FENOLDOPAM MESYLATE
    a) This drug is excreted in the breast milk of lactating rats (Prod Info CORLOPAM (R) intravenous injection solution, 2015).
    2) ILOPROST
    a) IV administration of iloprost at doses of 1 mg/kg/day to lactating Han-Wistar rats resulted in higher mortality in nursing pups. In Sprague-Dawley rats given toxic oral doses of iloprost clathrate 250 mg/kg/day (13% iloprost by weight), higher mortality was observed in nursing pups. In rats administered iloprost IV, less than 1% of iloprost dose was observed in their milk. In animals exposed to iloprost during lactation, no postnatal development or reproductive disturbances were observed (Prod Info VENTAVIS(R) inhalation solution, 2012).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) FENOLDOPAM MESYLATE
    a) No impairment of fertility was demonstrated at the highest dose tested in reproductive studies (Prod Info CORLOPAM (R) intravenous injection solution, 2015).
    2) ILOPROST
    a) No impairment of fertility was demonstrated in male or female Han-Wistar rats administered IV iloprost at 1 mg/kg/day (Prod Info VENTAVIS(R) inhalation solution, 2012).
    3) MINOXIDIL
    a) A dose-dependent reduction in conception rate was observed in male and female rats administered 1 to 5 times the maximum recommended human oral dose (Prod Info minoxidil oral tablets, 2003).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) No specific lab work is needed in most patients.
    C) Drug concentration monitoring is not clinically useful or readily available.
    D) Institute continuous cardiac monitoring and obtain an ECG.
    E) Monitor for seizure activity and CNS depression, especially in buflomedil overdoses.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Plasma levels are generally not clinically useful for most vasodilators (Ellenhorn & Barceloux, 1988).
    2) Monitor renal function as hypotension may lead to renal insufficiency.
    4.1.3) URINE
    A) OTHER
    1) Maintain adequate urine output to ensure appropriate fluid balance and adequate perfusion of the kidneys.
    2) ASSAY INTERFERENCE: A false positive urine assay for phencyclidine (Syva RapidTest solid-phase chromatographic monoclonal immunoassay) was reported after buflomedil overdose(Bacis et al, 2003).
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Institute continuous cardiac monitoring and obtain an ECG.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Obtain a chest x-ray in patients with respiratory failure or suspected pulmonary edema.

Methods

    A) CHROMATOGRAPHY
    1) Quantitative analysis of buflomedil in biological samples has been achieved using gas chromatography coupled with a mass spectrometric detector, after liquid/solid extraction of the specimen. The method described by de Giovanni & Fucci (1991) is suitable for analysis of biological fluids collected at autopsy.
    2) Tracqui et al (1995) described a high pressure liquid chromatographic method with diode-array detection that was used for quantification of buflomedil in blood, urine, and gastric contents following a fatal ingestion.
    3) A rapid method for measuring buflomedil in biologic fluids using HPLC with UV detection has been described (Forfar-Bares et al, 2002).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who develop persistent hypotension should be admitted until symptoms resolve.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Children and adults can be managed at home if overdose was inadvertent, was less than 2 times the therapeutic dose for their weight, and no signs or symptoms are present.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in decision making whether or not admission is advisable, managing patients with severe toxicity, or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Symptomatic patients, those with deliberate ingestions or ingestions of more than twice the therapeutic dose for weight should be sent to a health care facility for 6 hours of observation.

Monitoring

    A) Monitor vital signs and mental status.
    B) No specific lab work is needed in most patients.
    C) Drug concentration monitoring is not clinically useful or readily available.
    D) Institute continuous cardiac monitoring and obtain an ECG.
    E) Monitor for seizure activity and CNS depression, especially in buflomedil overdoses.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital decontamination is not recommended.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) Consider activated charcoal after large, recent ingestions.
    2) 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.
    3) 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).
    6.5.3) TREATMENT
    A) 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) NOREPINEPHRINE
    a) 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).
    b) DOSE
    1) 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).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    4) PRECAUTIONS
    a) MINOXIDIL: In treating hypotension due to minoxidil, avoid cardiac stimulating sympathomimetics such as epinephrine and norepinephrine. When a vital organ is underperfused, use phenylephrine, vasopressin, dopamine or angiotensin II (Prod Info minoxidil oral tablets, 2003).
    b) HYDRALAZINE: In animal models, hydralazine-induced myocardial necrosis was enhanced with concomitant beta-adrenergic agonist administration (Joseph & Balazs, 1986). Due to these theoretical concerns, it has been suggested that vasopressors with prominent beta-adrenergic effects be avoided in patients with hypotension secondary to hydralazine overdose.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and mental status.
    2) No specific lab work is needed in most patients.
    3) Drug concentration monitoring is not clinically useful or readily available.
    4) Institute continuous cardiac monitoring and obtain an ECG.
    5) Monitor for seizure activity and CNS depression, especially in buflomedil overdoses.
    6) HYPERGLYCEMIA following diazoxide overdose can be marked. However hyperglycemia can be reversed with prompt insulin therapy and restoration of electrolyte and fluid balance (Prod Info, Proglycem(R), 1994). Monitor blood glucose for up to 7 days following overdose.
    C) VENTRICULAR ARRHYTHMIA
    1) SUMMARY: QRS widening and ventricular dysrhythmias associated with buflomedil intoxication (multifocal PVCs, ventricular tachycardia, flutter and fibrillation) may respond to serum alkalinization therapy to pH 7.45 to 7.55 by IV boluses of sodium bicarbonate (Legras et al, 1996).
    a) Intubation and hyperventilation may be used as an adjunct to sodium bicarbonate to achieve serum alkalinization, with careful monitoring of blood gases to avoid profound alkalemia.
    b) Dysrhythmias unresponsive to this therapy may respond to lidocaine, or electrical defibrillation if indicated. Quinidine, disopyramide, and procainamide should be avoided in buflomedil intoxication as their effects on myocardial conduction are similar.
    2) 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).
    3) AMIODARONE
    a) AMIODARONE/INDICATIONS
    1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).
    b) AMIODARONE/ADULT DOSE
    1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010).
    c) AMIODARONE/PEDIATRIC DOSE
    1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).
    d) ADVERSE EFFECTS
    1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010).
    D) TACHYARRHYTHMIA
    1) The positive myocardial inotropic effects induced by hydralazine were inhibited by verapamil and propranolol in experiments using isolated animal hearts (Azuma et al, 1987).
    2) Calcium channel blockers or beta blockers may be considered in patients with persistent tachycardia or myocardial ischemia (Smith & Ferguson, 1992).
    E) 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).
    F) ACUTE LUNG INJURY
    1) ONSET: Onset of acute lung injury after toxic exposure may be delayed up to 24 to 72 hours after exposure in some cases.
    2) NON-PHARMACOLOGIC TREATMENT: The treatment of acute lung injury is primarily supportive (Cataletto, 2012). Maintain adequate ventilation and oxygenation with frequent monitoring of arterial blood gases and/or pulse oximetry. If a high FIO2 is required to maintain adequate oxygenation, mechanical ventilation and positive-end-expiratory pressure (PEEP) may be required; ventilation with small tidal volumes (6 mL/kg) is preferred if ARDS develops (Haas, 2011; Stolbach & Hoffman, 2011).
    a) To minimize barotrauma and other complications, use the lowest amount of PEEP possible while maintaining adequate oxygenation. Use of smaller tidal volumes (6 mL/kg) and lower plateau pressures (30 cm water or less) has been associated with decreased mortality and more rapid weaning from mechanical ventilation in patients with ARDS (Brower et al, 2000). More treatment information may be obtained from ARDS Clinical Network website, NIH NHLBI ARDS Clinical Network Mechanical Ventilation Protocol Summary, http://www.ardsnet.org/node/77791 (NHLBI ARDS Network, 2008)
    3) FLUIDS: Crystalloid solutions must be administered judiciously. Pulmonary artery monitoring may help. In general the pulmonary artery wedge pressure should be kept relatively low while still maintaining adequate cardiac output, blood pressure and urine output (Stolbach & Hoffman, 2011).
    4) ANTIBIOTICS: Indicated only when there is evidence of infection (Artigas et al, 1998).
    5) EXPERIMENTAL THERAPY: Partial liquid ventilation has shown promise in preliminary studies (Kollef & Schuster, 1995).
    6) CALFACTANT: In a multicenter, randomized, blinded trial, endotracheal instillation of 2 doses of 80 mL/m(2) calfactant (35 mg/mL of phospholipid suspension in saline) in infants, children, and adolescents with acute lung injury resulted in acute improvement in oxygenation and lower mortality; however, no significant decrease in the course of respiratory failure measured by duration of ventilator therapy, intensive care unit, or hospital stay was noted. Adverse effects (transient hypoxia and hypotension) were more frequent in calfactant patients, but these effects were mild and did not require withdrawal from the study (Wilson et al, 2005).
    7) However, in a multicenter, randomized, controlled, and masked trial, endotracheal instillation of up to 3 doses of calfactant (30 mg) in adults only with acute lung injury/ARDS due to direct lung injury was not associated with improved oxygenation and longer term benefits compared to the placebo group. It was also associated with significant increases in hypoxia and hypotension (Willson et al, 2015).
    G) NEUROPATHY
    1) Peripheral neuropathies may be corrected with pyridoxine (Raskin & Fishman, 1965). Neuropathy is most commonly associated with chronic therapeutic ingestion of HYDRALAZINE.

Enhanced Elimination

    A) HEMODIALYSIS
    1) DIAZOXIDE
    a) Both peritoneal and hemodialysis have been reported to lower diazoxide blood levels in overdose patients (Prod Info, Proglycem(R), 1994).
    2) MINOXIDIL
    a) Although the manufacturer reports that minoxidil and its metabolites are removed by hemodialysis in the absence of functional renal tissue (Prod Info Loniten(R), minoxidil, 1994), another report states that hemodialysis does not affect the plasma half-life (Smith, 1980).
    b) Plasma levels decreased an average of 32% during 6 4-hour dialysis sessions in one patient. Clearance was 47.9 mL/minute (Bennett et al, 1980).

Abstracts

Case Reports

    A) ADULT
    1) HYDRALAZINE: A 27-year-old woman ingested 2,000 mg (28 mg/kg) of hydralazine along with ethanol (initial BAL 306 mg/dL).
    a) Her presenting signs two hours post-ingestion included hypotension (90/48), sinus tachycardia (132), hypokalemia (3.2 mmol/L), marked ST segment depression on EKG, and lactic acidosis (pH 7.3; HCO3 11.6).
    b) Despite EKG evidence of myocardial ischemia, there were no complaints of chest pain and serial CPK-MB fractions remained below 3%. The hypotension responded to IV fluids and the potassium spontaneously rose to 4.4 mmol/L three hours after admission.
    c) Laboratory and EKG findings were normal 24 hours post-ingestion (Smith & Ferguson, 1992).
    2) MINOXIDIL: A 36-year-old developed severe toxicity (coma, hypotension, tachycardia) after ingestion of 50 mL of a 2% topical minoxidil preparation (1000 milligrams) (McCormick et al, 1989). Similar symptoms (pulse 140 bpm; systolic pressure 44 mmHg by palpitation; disorientation to time and place; slurred speech) were described in a 52-year-old man who ingested 60 mL of 2% topical minoxidil (1200 mg) plus 12 ounces of cognac (MacMillan et al, 1993).
    a) MINOXIDIL: A 20-year-old female presented 90 minutes after ingestion of an unknown quantity of beer and wine (blood alcohol 56 mg/dL) and perhaps as many as 65 minoxidil 10 mg tablets. Initial BP was 108/64 mmHg with a pulse of 124 bpm, and normal neurologic exam (Poff & Rose, 1992).
    b) EKG changes noted included ST-segment depression and T wave inversion which persisted for more than 8 hours.
    c) Treatment included lavage, charcoal, and adjusting fluid rates and positioning. Blood pressure dropped to 106/30 mmHG 3 hours after ingestion, and reached a nadir of 92/38 mmHg.
    d) At 3 hours, total and glucuronide minoxidil serum levels were 3140 and 1472 ng/mL, respectively.
    3) BUFLOMEDIL: A 20-year-old female ingested 10.8 grams buflomedil in a suicide attempt. One hour after the ingestion she developed a generalized seizure followed by cardiac arrest. She was resuscitated and transferred to ICU with coma, myoclonic jerks, and fixed dilated pupils. Cardiac conduction abnormalities, consisting of prolonged QRS duration, enlarged S wave, ST-T changes, and prolonged QT interval were present. EEG was abnormal, with diffuse slow-wave activity and depressed electrogenesis.
    a) Treatment consisted of clonazepam for myoclonus, gastric lavage and activated charcoal, sedation, and mechanical ventilation. Recovery was complete, and the patient was discharged after 11 days (Legras et al, 1996).
    4) BUFLOMEDIL: A 19-year-old female died 2.5 hr after ingesting 3 grams of buflomedil. Prior to death she developed seizures, pulmonary edema, and ventricular fibrillation (Athanaselis et al, 1984).
    B) PEDIATRIC
    1) MINOXIDIL: Isles et al (1981) described a case of minoxidil overdose in a 2-year-old boy (approximately twenty 5 mg tablets). One hour post-ingestion, EKG revealed sinus tachycardia and the child's pulse rate was 160 with a blood pressure of 120/80 mmHg. No other cardiovascular symptoms were observed.
    a) Blood pressure varied from 110 to 150/70 to 90 mmHg during admission (period of 48 hours).

Range Of Toxicity

Summary

    A) Severe toxicity is very rare following isolated overdose from these medications. An adult survived an ingestion of 10 g hydralazine. A toddler developed only tachycardia after ingesting 100 mg minoxidil. An adult developed hypotension and a non-ST-elevation myocardial infarction after ingesting 1200 mg minoxidil.
    B) THERAPEUTIC DOSE: ADULTS: DIAZOXIDE: 1 to 3 mg/kg up to a single dose of 150 mg. HYDRALAZINE: Oral: 40 to 200 mg/day. Parenteral 20 to 40 mg intravenously or intramuscularly. MINOXIDIL: 10 to 100 mg/day. FENOLDOPAM: 0.05 to 0.1 mcg/kg/min and the dose should be titrated no more frequently than every 15 minutes.
    C) THERAPEUTIC DOSE: PEDIATRIC: DIAZOXIDE: 1 to 3 mg/kg/dose IV, up to a maximum of 150 mg/dose. HYDRALAZINE: ORAL: 0.75 to 7.5 mg/kg/day in 4 divided doses (up to 200 mg/day). PARENTERAL: Usual dose is 1.7 to 3.5 mg/kg/day in divided doses every 4 to 6 hours. MINOXIDIL: ORAL: Up to 50 mg/daily or 5 mg/kg/24 hrs. FENOLDOPAM: The safety and efficacy in children has not been established

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) DIAZOXIDE
    a) 1 to 3 mg/kg up to a single dose of 150 mg by undiluted, rapid (over 10 to 30 seconds) IV injection. May be repeated at 5 to 15 minute intervals until adequate blood pressure reduction has occurred (Prod Info Loniten(R), minoxidil, 1994).
    2) FENOLDOPAM
    a) In clinical trials, doses ranging from 0.01 to 1.6 mcg/kg/min as IV infusions, have been studied. However, lower initial doses (0.03 to 0.1 mcg/kg/min) titrated slowly to effect have been shown to cause less reflex tachycardia than doses greater than 0.3 mcg/kg/min. The specific drug dose rate and infusion rates are individualized according to body weight and according to the desired pharmacodynamic effect (Prod Info Corlopam(R), fenoldopam, 1997).
    b) The recommended increments for titration are 0.05 to 0.1 mg/kg/min and the dose should be titrated no more frequently than every 15 minutes. Fenoldopam should be given only as a continuous infusion; do NOT give by IV bolus (Prod Info Corlopam(R), fenoldopam, 1997).
    3) HYDRALAZINE
    a) INJECTION: The recommended dose is 20 to 40 mg via IM or IV, repeated as necessary. Injection should only be used when oral administration is not possible (Prod Info HYDRALAZINE HYDROCHLORIDE injection solution, 2013).
    b) ORAL: Initiate therapy at 10 mg 4 times daily for the first 2 to 4 days. Increase the dose to 25 mg 4 times daily for the remainder of the first treatment week. For all remaining weeks, increase the dose to 50 mg 4 times daily. Maintain dosage at lowest effective dose (Prod Info HYDRALAZINE HYDROCHLORIDE oral tablets, 2013).
    c) ORAL TABLET IN RESISTANT PATIENTS: Doses up to 300 mg/day may be required. Consider a lower hydralazine dose when combined with thiazide, reserpine, or beta-blocker therapy and titrate individually to lowest therapeutic dose (Prod Info HYDRALAZINE HYDROCHLORIDE oral tablets, 2013).
    4) MINOXIDIL
    a) Begin with 5 mg/day as a single dose. Dose may be increased to 10, 20, or 40 mg daily in single or multiple doses. MAXIMUM: 100 mg/day (Prod Info Loniten(R), minoxidil, 1994).
    7.2.2) PEDIATRIC
    A) SPECIFIC SUBSTANCE
    1) DIAZOXIDE
    a) HYPERINSULINISM
    1) INFANTS
    a) ORAL: The usual dose is 8 to 15 mg/kg/day orally in 2 or 3 divided doses (divided every 8 to 12 hours) (Prod Info PROGLYCEM(R) oral capsules, suspension, 2008; Ismail & Werther, 2005; de Lonlay et al, 2002; Tyrrell et al, 2001; Aynsley-Green et al, 2000; Touati et al, 1998; Dacou-Voutetakis et al, 1998).
    2) CHILDREN
    a) ORAL: The usual dose is 3 to 8 mg/kg/day orally in 2 or 3 divided doses (divided every 8 to 12 hours) (Prod Info PROGLYCEM(R) oral capsules, suspension, 2008).
    2) FENOLDOPAM
    a) HOSPITALIZED INFANTS AND CHILDREN UNDER 12 YEARS OF AGE OR WEIGHING AT LEAST 2 KG OR FULL TERM
    1) IV CONTINUOUS INFUSION: In clinical trials the usual initial dose was 0.2 mcg/kg/min with an observed effect on mean arterial pressure (MAP) within 5 minutes. Doses were increased up to 0.3 to 0.5 mcg/kg/min every 20 to 30 minutes. The maximum effect was realized after 20 to 25 minutes of continuous infusion. Blood pressure and heart rate returned to near baseline within 30 minutes of discontinuing an average 4-hour infusion. Blood pressure and heart rate should be monitored continuously during infusion (Prod Info CORLOPAM(R) IV injection, 2004).
    2) A MAXIMUM infusion at doses greater than 0.8 mcg/kg/min resulted in tachycardia without further decrease in MAP (Prod Info CORLOPAM(R) IV injection, 2004).
    3) HYDRALAZINE
    a) INTRAMUSCULAR OR INTRAVENOUS
    1) The usual dose is 0.1 to 0.5 mg/kg/dose IV/IM every 4 to 6 hours. MAXIMUM DOSE: Should not exceed 20 mg/dose (Flynn & Tullus, 2009; Prod Info hydralazine hcl injection, 2003; Fivush et al, 1997; Deal et al, 1992; Artman & Graham, 1987; Beekman et al, 1984).
    b) ORAL
    1) The usual dose is 0.25 to 1 mg/kg/dose up to a MAXIMUM of 50 mg/dose orally every 6 to 8 hours. Dose may be titrated over 3 to 4 weeks, up to a MAXIMUM of 7.5 mg/kg/day or 200 mg/day (Flynn & Tullus, 2009; Robinson et al, 2005; Prod Info hydralazine hcl oral tablets, 2005; Artman & Graham, 1987; Artman et al, 1987; Beekman et al, 1984).
    4) MINOXIDIL
    a) ORAL
    1) CHILDREN UNDER 12 YEARS OF AGE: The usual initial dose is 0.2 mg/kg once daily. The dose may be increased by increments of 50% to 100% until the desired blood pressure is obtained. A dose range between 0.25 and 1 mg/kg/day is usually effective (Prod Info minoxidil oral tablets, 2003). MAXIMUM DOSE: Should not exceed 50 mg/day. The use of minoxidil in pediatric populations (particularly infants) is limited. Cautious administration and titration are recommended (Prod Info minoxidil oral tablets, 2003; Smith, 1980; Sinaiko et al, 1980; Kosman, 1980).

Minimum Lethal Exposure

    A) SUMMARY
    1) The minimal toxic or lethal dose is not well established in the literature for these drugs.
    2) The severity of intoxication should be determined from the clinical signs and symptoms.
    B) SPECIFIC SUBSTANCE
    1) BUFLOMEDIL: As little as 3 g has proven fatal in a 19-year-old woman who died 2.5 hours following ingestion (Athanaselis et al, 1984).

Maximum Tolerated Exposure

    A) SPECIFIC SUBSTANCE
    1) BUFLOMEDIL
    a) A 15-year-old girl survived a 3 g ingestion. She presented to the ED with seizures, areflexia, mydriasis and hypoxemia (Alberti et al, 1994).
    b) Legras et al (1996) presented 5 cases of young women who survived buflomedil overdoses after suffering various degrees of cardiotoxicity and seizures:
    1) A 16-year-old ingested 3 g and presented to the ED with coma, seizures, mydriasis, and tachycardia. ECG revealed repolarization abnormalities.
    2) An 18-year-old presented to the with hypotension, seizures, coma and mydriasis following a 9 g ingestion in addition to other medications. Repolarization abnormalities were present on ECG.
    3) A 21-year-old ingested an unknown quantity of buflomedil and presented to the ED with coma, myoclonus, hypotension and mydriasis. ECG showed prolonged PR interval, ST-T changes, flattened T waves and prolonged QT interval.
    4) A 21-year-old ingested an unknown quantity of buflomedil in addition to other drugs and suffered a cardiac arrest following a generalized seizure.
    5) A 20-year-old ingested 10.8 g and was admitted to the ED one hour later with a generalized seizure followed by cardiac arrest.
    2) HYDRALAZINE
    a) An adult survived after allegedly taking 10 g of hydralazine (Prod Info hydralazine hydrochloride oral tablets, 2009).
    3) MINOXIDIL
    a) Limited data are available regarding OVERDOSAGE of minoxidil. Recovery was reported on one patient following overdosage of 50 mg in combination with 500 mg of a barbiturate (Prod Info Loniten(R), minoxidil, 1994).
    b) A 2-year-old child who ingested 100 mg developed only sinus tachycardia (Isles et al, 1981).
    c) A 52-year-old developed severe toxicity (disorientation to time and place, hypotension, tachycardia, a non-Q wave infarction) after ingestion of 60 mL of a 2% topical minoxidil preparation (1200 mg) in addition to 12 ounces cognac (MacMillan et al, 1993).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) SPECIFIC SUBSTANCE
    a) BUFLOMEDIL
    1) Serum blood concentrations of buflomedil were 24.8 mg/L at 2 to 3 hours following a 3 gram overdose in a 15-year-old female. Urine concentrations were 324.4 mg/L (Alberti et al, 1994).
    2) Serum plasma level was 27.4 mg/L 3 hours following a 10.8 gram overdose in a 20-year-old female (Legras et al, 1996).
    3) Serum plasma level was 4.9 mg/L 12 hours following ingestion of an unknown quantity of buflomedil (Legras et al, 1996).
    4) Drug concentration of buflomedil following a fatal 3 gram overdose was measured at 63.4 mg/L shortly after ingestion (Athanaselis et al, 1984).
    5) Post mortem buflomedil blood concentration was 275 micrograms/mL following an ingestion of an unknown amount of buflomedil (Tracqui et al, 1995).
    6) In another case postmortem blood concentration was 51 micrograms/ml after ingestion of an unknown amount of buflomedil(Neri et al, 2004).
    b) MINOXIDIL
    1) Mean serum levels of minoxidil for 2.5 mg orally, 5 mg orally, 1% topically, 2% topically, and 3% topically were 32.8 nanograms/milliliter, 59.2 nanograms/mL, 1.1 nanograms, 1.7 nanograms, and 2.8 nanograms respectively (Spindler, 1987).
    2) With 100 mg daily does, peak serum levels are reported to range from 1600 to 2400 ng/mL (Prod Info Loniten(R), minoxidil, 1994).
    3) Minoxidil serum levels of 3140 Ng/mL 3 hours after ingestion of an unknown (maximum 65) number of 10 mg tablets was reported (Poff & Rose, 1992).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) CADRALAZINE -
    1) LD50- (ORAL)MOUSE:
    a) 825 mg/kg (RTECS, 2001)
    2) LD50- (ORAL)RAT:
    a) 2060 mg/kg (RTECS, 2001)
    B) DIAZOXIDE -
    1) LD50- (ORAL)MOUSE:
    a) 444 mg/kg (RTECS, 2001)
    2) LD50- (ORAL)RAT:
    a) 980 mg/kg (RTECS, 2001)
    C) HYDRALAZINE -
    1) LD50- (ORAL)MOUSE:
    a) 122 mg/kg (RTECS, 2001)
    2) LD50- (ORAL)RAT:
    a) 90 mg/kg (RTECS, 2001)
    D) ISOXSUPRINE -
    1) LD50- (ORAL)MOUSE:
    a) 200 mg/kg (RTECS, 2001)
    E) MINOXIDIL -
    1) LD50- (ORAL)RAT:
    a) 1321 mg/kg (RTECS, 2001)
    F) TODRALAZINE -
    1) LD50- (ORAL)RAT:
    a) 318 mg/kg (RTECS, 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The major effect of HYDRALAZINE, MINOXIDIL and DIAZOXIDE is a direct relaxation of vascular smooth muscle. This effect is seen more on arterioles than veins. Diastolic blood pressure is frequently lowered more than systolic.
    1) An increase in heart rate, stroke volume and cardiac output is commonly seen.
    B) The vasodilating effect of ISOXSUPRINE appears to be a combination of direct musculotropic and beta-adrenergic agonist activity (reviewed in Goldfrank, 1994).

Physicochemical

Physical Characteristics

    A) DIAZOXIDE - White to creamy-white odorless, crystalline powder (S Sweetman , 2000)
    B) HYDRALAZINE HYDROCHLORIDE: White to off-white, odorless, crystalline powder; soluble in water, slightly soluble in alcohol, and very slightly soluble in ether; melting point, about 275 degrees C (Prod Info HYDRALAZINE HYDROCHLORIDE oral tablets, 2013; Prod Info HYDRALAZINE HYDROCHLORIDE injection solution, 2013).
    C) MINOXIDIL - White to off-white crystalline solid (S Sweetman , 2000)

Ph

    A) HYDRALAZINE HYDROCHLORIDE: 3.4 to 4.4 (solution) (Prod Info HYDRALAZINE HYDROCHLORIDE injection solution, 2013)

Molecular Weight

    A) HYDRALAZINE HYDROCHLORIDE: 196.64 (Prod Info HYDRALAZINE HYDROCHLORIDE oral tablets, 2013; Prod Info HYDRALAZINE HYDROCHLORIDE injection solution, 2013)

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