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PAPAVERINE/ETHAVERINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Papaverine is a benzylisoquinoline derivative with smooth muscle relaxant properties. It is primarily used in peripheral or cerebral vascular disease.

Specific Substances

    A) PAPAVERINE
    1) 6,7-dimethoxy-1-veratrylisoquinoline
    2) ETHAVERINE/PAPAVERINE
    ETHAVERINE
    1) 1-(3,4-Diethoxybenzyl)-6,7-diethoxyisoquinoline
    2) ETHAVERINE/PAPAVERINE

    1.2.1) MOLECULAR FORMULA
    1) PAPAVERINE HYDROCHLORIDE: C20H21NO4.HCl

Available Forms Sources

    A) FORMS
    1) Papaverine is available as 30 mg/mL solution for injection and 150 mg extended-release capsules (Prod Info papaverine hcl injection, 2006; Prod Info papaverine hcl sustained-release oral capsules, 2005).
    B) USES
    1) Papaverine hydrochloride injection is used to treat various conditions accompanied by spasm of smooth muscle, such as vascular spasm associated with acute myocardia infarction (coronary occlusion), angina pectoris, peripheral and pulmonary embolism, peripheral vascular disease in which there is a vasospastic element, or certain cerebral angiospastic states, and visceral spasm, as in ureteral, biliary, or gastrointestinal colic (Prod Info papaverine hcl injection, 2006). Papaverine hydrochloride sustained-release capsule is used for the relief of cerebral and peripheral ischemia associated with arterial spasm and myocardial ischemia complicated with dysrhythmias (Prod Info papaverine hcl sustained-release oral capsules, 2005).

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 THERAPEUTIC USE
    1) Nausea, anorexia, abdominal discomfort, constipation, diarrhea, malaise, vertigo, headache, flushing, sweating, tachycardia, mild hypotension and sedation are reported. Hyperpnea and apnea have been seen following rapid IV injection.
    B) WITH POISONING/EXPOSURE
    1) Nausea, vomiting, weakness, CNS depression, nystagmus, diplopia, diaphoresis, flushing, dizziness, and tachycardia are common. In large overdoses, lactic acidosis, respiratory alkalosis, hyperglycemia, and hypokalemia have been reported. An infant developed seizures and respiratory arrest after receiving an opium poppy preparation containing papaverine. She recovered following supportive care.
    0.2.3) VITAL SIGNS
    A) Tachycardia and hypotension are common; bradycardia may occur. Both hyperpnea and apnea have been reported after rapid IV injection.
    0.2.5) CARDIOVASCULAR
    A) Sinus tachycardia and hypotension are common. Ventricular dysrhythmias have occurred with IV injection.
    0.2.6) RESPIRATORY
    A) Hyperpnea, apnea, and respiratory alkalosis may occur.
    0.2.7) NEUROLOGIC
    A) Lethargy and coma may occur. Dizziness and syncope have been reported following therapeutic use.
    0.2.8) GASTROINTESTINAL
    A) Nausea, vomiting, abdominal pain.
    0.2.9) HEPATIC
    A) Hepatotoxicity has been noted with chronic ingestion.
    0.2.11) ACID-BASE
    A) Severe lactic acidosis and respiratory alkalosis have been reported.

Laboratory Monitoring

    A) Monitor EKG, arterial blood gases, blood pH, electrolytes, plasma pyruvate and lactate.

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) Monitor arterial blood gases and pH.
    C) Monitor ECG and vital signs.
    D) METABOLIC ACIDOSIS: Correct hypotension. For severe acidosis (pH less than 7.1) administer IV sodium bicarbonate. 1 to 2 mEq/kg is an appropriate starting dose.
    E) Replace potassium deficits.
    F) HYPOTENSION: Administer IV fluids 10 to 20 mL/kg.
    1) If not effective, administer dopamine, norepinephrine, and/or calcium chloride may be tried. Dose: Calcium chloride 1 g IV over 5 to 10 minutes. Monitor ECG and calcium levels.
    G) HEART BLOCK may respond to IV calcium (calcium chloride 1 g IV over 5 to 10 minutes) , atropine, isoproterenol and/or glucagon (2 to 5 mg IV, continuous infusion if responsive). Temporary pacing may be needed.

Range Of Toxicity

    A) Toxic amount is unknown; 15 gm produced severe acidosis in an adult.
    B) Doses as high as 1 gram orally produced only minimal side effects. Intravenous doses of 30 and 65 milligrams caused the death of 2 adults which was preceded by hyperpnea, tachypnea, and apnea.

Clinical Effects

Summary Of Exposure

    A) WITH THERAPEUTIC USE
    1) Nausea, anorexia, abdominal discomfort, constipation, diarrhea, malaise, vertigo, headache, flushing, sweating, tachycardia, mild hypotension and sedation are reported. Hyperpnea and apnea have been seen following rapid IV injection.
    B) WITH POISONING/EXPOSURE
    1) Nausea, vomiting, weakness, CNS depression, nystagmus, diplopia, diaphoresis, flushing, dizziness, and tachycardia are common. In large overdoses, lactic acidosis, respiratory alkalosis, hyperglycemia, and hypokalemia have been reported. An infant developed seizures and respiratory arrest after receiving an opium poppy preparation containing papaverine. She recovered following supportive care.

Vital Signs

    3.3.1) SUMMARY
    A) Tachycardia and hypotension are common; bradycardia may occur. Both hyperpnea and apnea have been reported after rapid IV injection.

Cardiovascular

    3.5.1) SUMMARY
    A) Sinus tachycardia and hypotension are common. Ventricular dysrhythmias have occurred with IV injection.
    3.5.2) CLINICAL EFFECTS
    A) CONDUCTION DISORDER OF THE HEART
    1) WITH THERAPEUTIC USE
    a) Transient ventricular ectopic beats may be noted, especially following rapid IV or intracoronary injection (Prod Info papaverine hcl injection, 2006).
    b) RISK FACTORS: In patients with acute coronary thrombosis, the occurrence of ventricular dysrhythmias can be serious and attempts should be made to decrease myocardial irritability(Prod Info papaverine hcl sustained-release oral capsules, 2005) .
    c) Intracoronary injection of 14 and 15 mg of papaverine resulted in increased QT interval, premature ventricular complexes, and torsades de pointes in two patients. One patient was cardioverted, and the other normalized spontaneously 4 minutes later (Wilson & White, 1998).
    B) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Orthostatic hypotension may occur (S Sweetman , 2001). Transient hypotension and bradycardia were seen in 6 of 75 patients after intracavernous injection of papaverine 60 mg. Accompanying symptoms included dizziness, pallor, and sweating (Wespes & Schulman, 1988).
    C) TACHYCARDIA
    1) WITH THERAPEUTIC USE
    a) Sinus tachycardia may be noted.
    2) WITH POISONING/EXPOSURE
    a) Sinus tachycardia may develop after overdose (Prod Info papaverine hcl injection, 2006).
    D) HEART BLOCK
    1) WITH THERAPEUTIC USE
    a) AV dissociation may occur following intravenous administration (HSDB , 2001).
    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) Ventricular fibrillation has been observed following large IV doses in animals (Wegria & Nickerson, 1942).

Respiratory

    3.6.1) SUMMARY
    A) Hyperpnea, apnea, and respiratory alkalosis may occur.
    3.6.2) CLINICAL EFFECTS
    A) ALKALOSIS
    1) WITH POISONING/EXPOSURE
    a) Respiratory alkalosis has been noted in a large overdose of 15 g of papaverine in an adult (Vaziri et al, 1981).
    B) HYPERVENTILATION
    1) Fatal hyperpnea and apnea were described in 2 elderly patients receiving 30 to 65 mg of papaverine IV (Sagall & Dorfman, 1945).
    C) RESPIRATORY ARREST
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: An 18-day-old infant developed seizures and respiratory arrest after receiving a water-based opium poppy preparation containing papaverine for a cough. Following supportive care, including phenytoin and antibiotic therapy for pneumonia, her condition gradually improved and she was discharged without further sequelae (Kahramaner et al, 2014).

Neurologic

    3.7.1) SUMMARY
    A) Lethargy and coma may occur. Dizziness and syncope have been reported following therapeutic use.
    3.7.2) CLINICAL EFFECTS
    A) COMA
    1) WITH THERAPEUTIC USE
    a) Decreased consciousness may be noted. Brief coma lasting 3 hours was reported following injection of 80 mg (normal dose 30 to 120 milligrams by slow intramuscular or intravenous injection) of papaverine intramuscularly in a 21-year-old man (Ilan & Gemer, 1988; S Sweetman , 2001).
    B) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: An 18-day-old infant developed seizures and respiratory arrest after receiving a water-based opium poppy preparation containing papaverine for a cough. Following supportive care, including phenytoin and antibiotic therapy for pneumonia, her condition gradually improved and she was discharged without further sequelae (Kahramaner et al, 2014).
    C) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Systemic effects which have included dizziness and syncope have been reported infrequently during therapeutic intracavernosal injection of papaverine and appear to be related to hypotensive effects (S Sweetman , 2001).
    2) WITH POISONING/EXPOSURE
    a) Dizziness and weakness have been reported after overdose(Prod Info papaverine hcl injection, 2006).
    D) LETHARGY
    1) WITH POISONING/EXPOSURE
    a) CNS depression, weakness, nystagmus and diplopia, have been reported after overdose(Prod Info papaverine hcl injection, 2006).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SEIZURES
    a) Seizures were noted in animals receiving large doses (Prod Info papaverine hcl injection, 2006).

Gastrointestinal

    3.8.1) SUMMARY
    A) Nausea, vomiting, abdominal pain.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA, VOMITING AND DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Nausea, vomiting, diarrhea and abdominal pain may occur following therapeutic use, but are considered rare events (Prod Info papaverine hcl injection, 2006).

Hepatic

    3.9.1) SUMMARY
    A) Hepatotoxicity has been noted with chronic ingestion.
    3.9.2) CLINICAL EFFECTS
    A) LIVER DAMAGE
    1) WITH THERAPEUTIC USE
    a) A hypersensitivity-mediated hepatotoxic effect has been described following chronic therapy (usually 3 to 6 weeks), which may be accompanied by fever and eosinophilia and recurs promptly on rechallenge.
    1) This reaction may be more common in elderly patients (Pathy & Reynolds, 1980; Kiaer et al, 1974; Driemen, 1973; Ronnov-Jessen & Tjernlund, 1969; Geiger, 1981) .
    B) CIRRHOSIS OF LIVER
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 71-year-old nonalcoholic woman was reported to develop cirrhosis and chronic active hepatitis 6 years after initiating therapy with papaverine 400 mg/day. Jaundice resolved after discontinuation and returned after inadvertent rechallenge. An immune mechanism, documented by positive antinuclear antibody, was presumed (Poncin et al, 1986).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) PRIAPISM
    1) WITH THERAPEUTIC USE
    a) Priapism has been associated with intracavernous injection of papaverine (Borgstrom, 1988); patients should be instructed to seek medical help if an erection lasts for more than 4 hours (Prod Info papaverine hcl injection, 2006).
    b) Detumescence can be effected by aspiration of blood from the corpus or by local injection of an alpha-adrenergic agonist such as adrenaline, metaraminol, or phenylephrine.
    c) Metaraminol, also administered by intercavernous injection, has been used successfully to treat this complication (Fernandez et al, 1987). Surgical intervention may be required (Halsted et al, 1986).
    d) Nodule formation at the injection site is a frequent complication of intracavernous therapy for impotence, but does not usually result in treatment discontinuation (Kursh et al, 1988).
    e) Other local effects may include: hematoma, infection, and potentially fibrosis and penile distortion following long-term therapy . Pain and penile curvature have been noted (Corriere et al, 1988). Penile ulcer has also been reported as a complication after subcutaneous injection (Borgstrom, 1988).

Acid-Base

    3.11.1) SUMMARY
    A) Severe lactic acidosis and respiratory alkalosis have been reported.
    3.11.2) CLINICAL EFFECTS
    A) LACTIC ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) Severe lactic acidosis and respiratory alkalosis have been reported after overdose (Vaziri et al, 1981).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Elevated plasma pyruvate, hyperglycemia, and hypokalemia were described following overdose of 15 g of papaverine in an adult (Vaziri et al, 1981).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor EKG, arterial blood gases, blood pH, electrolytes, plasma pyruvate and lactate.
    4.1.2) SERUM/BLOOD
    A) ACID/BASE
    1) Monitor blood gases and blood pH.
    B) BLOOD/SERUM CHEMISTRY
    1) Monitor electrolytes, and plasma pyruvate and lactate.
    2) Serum alkaline phosphatase was elevated in 60% of elderly patients receiving papaverine. Transaminases were high in 13%, and eosinophils increased in 2% (Drieman, 1973). These parameters should be monitored in patients receiving chronic therapy.
    C) HEMATOLOGIC
    1) Eosinophils were elevated in 2% of elderly patients receiving papaverine (Drieman, 1973)
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Monitor ECG as indicated.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Monitor EKG, arterial blood gases, blood pH, electrolytes, plasma pyruvate and lactate.

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).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor blood gases and blood pH.
    2) Monitor ECG and vital signs.
    B) ACIDOSIS
    1) METABOLIC ACIDOSIS: Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate, 1 to 2 mEq/kg is a reasonable starting dose(Kraut & Madias, 2010). Monitor serum electrolytes and arterial or venous blood gases to guide further therapy.
    2) Replace potassium deficits.
    C) HYPOTENSIVE EPISODE
    1) Administer IV saline solution 10 to 20 mL/kg.
    2) CALCIUM
    a) Calcium ameliorates cardiovascular effects of other calcium antagonists and may theoretically be useful in papaverine overdose. DOSE: Administer IV calcium gluconate 10%, 0.2 to 0.5 mL/kg/dose up to 10 mL/dose over 5 to 10 minutes. Repeat dose as needed. Monitor ECG and plasma calcium levels.
    3) 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).
    D) BRADYCARDIA
    1) SUMMARY: May respond to IV calcium, atropine, isoproterenol, and/or glucagon. Ventricular pacing may be required.
    2) CALCIUM
    a) Calcium ameliorates cardiovascular effects of other calcium antagonists and may theoretically be useful in papaverine overdose. DOSE: Administer IV calcium gluconate 10%, 0.2 to 0.5 mL/kg/dose up to 10 mL/dose over 5 to 10 minutes. Repeat dose as needed. Monitor ECG and plasma calcium levels.
    3) 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).
    4) 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).
    5) GLUCAGON
    a) Glucagon has been used with overdose of other calcium channel blocking agents, optimal dose not established. Administer 2 to 5 mg IV, a continuous infusion may be established in patients with bradycardia responsive to glucagon boluses.

Range Of Toxicity

Summary

    A) Toxic amount is unknown; 15 gm produced severe acidosis in an adult.
    B) Doses as high as 1 gram orally produced only minimal side effects. Intravenous doses of 30 and 65 milligrams caused the death of 2 adults which was preceded by hyperpnea, tachypnea, and apnea.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) PAPAVERINE (ORAL) - 1 capsule (150 milligrams extended release) every 12 hours; in difficult cases one capsule every 8 hours or two capsules every 12 hours may be used (Prod Info papaverine hcl sustained-release oral capsules, 2005).
    2) INTRAVENOUS OR INTRAMUSCULAR - Supplied as a 30 mg/mL solution. Usual dose is 1 to 4 to (30 to 120 mg) every 3 hours as needed (Prod Info papaverine hcl injection, 2005).
    7.2.2) PEDIATRIC
    A) SPECIFIC SUBSTANCE
    1) PAPAVERINE - Usual dose: 30 mg per 250 mL of arterial catheter infusion solution (Griffin & Siadaty, 2005; Heulitt et al, 1993).

Minimum Lethal Exposure

    A) CASE REPORT
    1) Death was reported in 2 adults after receiving intravenous doses of 30 and 65 milligrams; symptoms began as hyperpnea, tachypnea and eventually apnea along with the absence of heart sounds. Death may have resulted from either cardiac or respiratory disturbance (reviewed in HSDB, 2000).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) A toxic dose has not been established.
    2) Ingestion of 15 grams in an adult produced severe acidosis (Vaziri et al, 1981).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAMUSCULAR)MOUSE:
    a) 175 mg/kg (RTECS, 2001)
    2) LD50- (INTRAPERITONEAL)MOUSE:
    a) 91 mg/kg (RTECS, 2001)
    3) LD50- (ORAL)MOUSE:
    a) 162 mg/kg (RTECS, 2001)
    4) LD50- (SUBCUTANEOUS)MOUSE:
    a) 170 mg/kg (RTECS, 2001)
    5) LD50- (INTRAPERITONEAL)RAT:
    a) 59600 mcg/kg (RTECS, 2001)
    6) LD50- (ORAL)RAT:
    a) 325 mg/kg (RTECS, 2001)
    7) LD50- (SUBCUTANEOUS)RAT:
    a) 151 mg/kg (RTECS, 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Papaverine hydrochloride, a benzylisoquinoline opium alkaloid, relaxes the smooth musculature of large blood vessels including the coronary, peripheral, cerebral and pulmonary arteries. It also stimulates respiration by acting on carotid and aortic body chemoreceptors (Prod Info papaverine hcl injection, 2006).

Physicochemical

Physical Characteristics

    A) PAPAVERINE HYDROCHLORIDE appears as white crystals or white, crystalline powder (Prod Info papaverine hcl injection, 2006), which are odorless (S Sweetman , 2001) and practically insoluble in ether and soluble in chloroform. One gram dissolves in about 30 mL of water and in 120 mL of alcohol. The solution for injection is a clear, colorless to pale yellow solution (Prod Info papaverine hcl injection, 2006).

Ph

    A) 3 to 4.5 (2% solution in water) (S Sweetman , 2001)

Molecular Weight

    A) PAPAVERINE HYDROCHLORIDE: 375.85 (Prod Info papaverine hcl injection, 2006)

References

General Bibliography

    1) Alaspaa AO, Kuisma MJ, Hoppu K, et al: Out-of-hospital administration of activated charcoal by emergency medical services. Ann Emerg Med 2005; 45:207-12.
    2) Borgstrom E: Penile ulcer as complication in self-induced papaverine erections. Urology 1988; 32:416-417.
    3) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    4) Corriere JN Jr, Fishman IJ, & Benson GS: Development of fibrotic penile lesions secondary to the intracorporeal injection of vasoactive agents. J Urol 1988; 140:615-617.
    5) Dagnone D, Matsui D, & Rieder MJ: Assessment of the palatability of vehicles for activated charcoal in pediatric volunteers. Pediatr Emerg Care 2002; 18:19-21.
    6) Driemen P: Papaverine - hepatotoxic or not?. J Am Geriatr Soc 1973; 21:202-205.
    7) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    8) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    9) Fernandez JA, Basha MA, & Wilson GC: Emergency treatment of papaverine priapism. J Emerg Med 1987; 5:289-291.
    10) Geiger GS: Elevations in serum transaminases and alkaline phosphatase secondary to papaverine hydrochloride. Drug Intell Clin Pharm 1981; 14:127-129.
    11) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    12) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    13) Griffin MP & Siadaty MS: Papaverine prolongs patency of peripheral arterial catheters in neonates. J Pediatr 2005; 146(1):62-65.
    14) Guenther Skokan E, Junkins EP, & Corneli HM: Taste test: children rate flavoring agents used with activated charcoal. Arch Pediatr Adolesc Med 2001; 155:683-686.
    15) HSDB : Hazardous Substances Data Bank. National Library of Medicine. Bethesda, MD (Internet Version). Edition expires 2001; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    16) Halsted DS, Weigel JW, & Noble MJ: Papaverine-induced priapism: 2 case reports. J Urol 1986; 136:109-110.
    17) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    18) Heulitt MJ, Farrington EA, O'Shea TM, et al: Double-blind, randomized, controlled trial of papaverine-containing infusions to prevent failure of arterial catheters in pediatric patients. Crit Care Med 1993; 21(6):825-829.
    19) Ilan Y & Gemer O: Papaverine-induced coma. Eur J Clin Pharmacol 1988; 33:651.
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    35) Product Information: papaverine hcl sustained-release oral capsules, papaverine hcl sustained-release oral capsules. Eon Labs,Inc, Laurelton, NY, 2005.
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