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SALICYLAMIDE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Salicylamide is a relatively weak analgesic, antiinflammatory, and antipyretic agent. It is the amide derivative of salicylic acid, but is not metabolized to salicylate.

Specific Substances

    1) Salicylamide
    2) 2-Hydroxybenzamide
    3) o-hydroxybenzamide
    4) Molecular Formula: C7-H7-NO2
    5) CAS 65-45-2

Available Forms Sources

    A) FORMS
    1) In the United States, salicylamide is available in combination products in various doses and forms.
    B) USES
    1) Salicylamide is used orally in combination products as an analgesic-antipyretic-antiinflammatory agent. It is also applied topically in rubefacient preparations to reduce muscular and rheumatic pain (S Sweetman , 2002).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) ANIMAL STUDIES - Salicylamide might be predicted to cause hypotension and CNS and respiratory depression, based on limited animal data.
    B) WITH POISONING/EXPOSURE
    1) There has been limited experience with salicylamide in human poisonings. Common signs and symptoms of salicylate poisoning seem NOT to be present with salicylamide.
    0.2.7) NEUROLOGIC
    A) Dizziness was a common side effect during therapeutic use.
    0.2.20) REPRODUCTIVE
    A) Salicylamide is teratogenic for rats, producing skeletal abnormalities.

Laboratory Monitoring

    A) Salicylate toxic blood levels and Done's nomogram are not applicable.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Salicylamide overdose information is limited. Treatment is symptomatic and supportive. Common signs and symptoms of salicylate poisoning seem NOT to be present with salicylamide.
    B) 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.
    C) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    D) Diuresis is not useful.

Range Of Toxicity

    A) Toxicity appears to be low. Doses as high as 24 grams have been tolerated in adults.

Clinical Effects

Summary Of Exposure

    A) ANIMAL STUDIES - Salicylamide might be predicted to cause hypotension and CNS and respiratory depression, based on limited animal data.
    B) WITH POISONING/EXPOSURE
    1) There has been limited experience with salicylamide in human poisonings. Common signs and symptoms of salicylate poisoning seem NOT to be present with salicylamide.

Cardiovascular

    3.5.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HYPOTENSION
    a) Hypotension has occurred in animal toxicity studies (Boxill et al, 1958).

Respiratory

    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) APNEA
    a) Respiratory failure may occur and was the cause of death in animals (Boxill et al, 1958).

Neurologic

    3.7.1) SUMMARY
    A) Dizziness was a common side effect during therapeutic use.
    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness was a common side effect during therapeutic use (Chan, 1996; Litter et al, 1951).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CNS DEPRESSION
    a) Studies in animals indicate that salicylamides in overdose produce central nervous system depression (rather than stimulation as seen early with salicylates) (Boxill et al, 1958).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) WITH POISONING/EXPOSURE
    a) Three adults developed relatively mild symptoms such as vomiting, epigastric pain, dizziness and drowsiness after ingesting OTC cold preparations containing up to 23.4 grams of salicylamide. These medications also contained acetaminophen, caffeine, chlorpheniramine, phenylpropanolamine, dextromethorphan, phenylephrine and menthol. These ingredients may have also contributed to the patient's symptoms. Another patient was asymptomatic. It is suggested that salicylamide in overdosage contributes little to the toxicity of other drugs present in OTC medications (Chan, 1996).

Genitourinary

    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) RENAL TUBULAR NECROSIS
    a) In animal models of analgesic nephropathy combinations of aspirin, salicylamide, and caffeine produced a lesser but significant incidence of renal papillary necrosis as combinations of aspirin, phenacetin, and caffeine (Nanra et al, 1980).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) LYELL'S TOXIC EPIDERMAL NECROLYSIS, SUBEPIDERMAL TYPE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - Toxic epidermal necrolysis was reported in a 4-year-old girl receiving therapeutic doses of salicylamide for 3 days (Luderschmidt et al, 1985).
    B) URTICARIA
    1) WITH THERAPEUTIC USE
    a) CASE REPORT - Use of a teething jelly containing 8% salicylamide was associated with urticaria in a 4-month-old and 16-month-old infant (Bentley-Phillips, 1968).

Reproductive

    3.20.1) SUMMARY
    A) Salicylamide is teratogenic for rats, producing skeletal abnormalities.
    3.20.2) TERATOGENICITY
    A) SKELETAL MALFORMATION
    1) Salicylamide is teratogenic for rats, producing skeletal abnormalities (Halstead & Roe, 1981; Knight & Roe, 1978).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Salicylate toxic blood levels and Done's nomogram are not applicable.
    4.1.2) SERUM/BLOOD
    A) OTHER
    1) Done's nomogram is not applicable for salicylamides.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor for CNS and respiratory depression.
    b) Monitor blood pressure.

Methods

    A) MULTIPLE ANALYTICAL METHODS
    1) Salicylamide can be detected by fluorometry (Veresh et al, 1971), colorimetric methods (Levy & Matsuzawa, 1967); and gas chromatography (de Boer et al, 1979).
    2) Ferric chloride reagent may produce a violet color in urine with salicylamides (Litter et al, 1951).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Salicylate toxic blood levels and Done's nomogram are not applicable.

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) SUPPORT
    1) There is limited salicylamide overdose information. In case of salicylamide overdose ingestion, treatment is symptomatic and supportive.
    B) 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).
    C) MONITORING OF PATIENT
    1) Monitor blood pressure closely. Observe for CNS depression.

Enhanced Elimination

    A) DIURESIS
    1) Diuresis is not useful, since the drug is mainly metabolized and such a small percentage is handled by renal mechanisms.

Range Of Toxicity

Summary

    A) Toxicity appears to be low. Doses as high as 24 grams have been tolerated in adults.

Therapeutic Dose

    7.2.1) ADULT
    A) SUMMARY
    1) In the United States, salicylamide is available in combination products in various doses and forms. It is usually given in doses 325 to 650 mg taken 3 or 4 times per day (S Sweetman , 2002; Kastrup, 1986).
    B) ASPIRIN/SALICYLAMIDE/ACETAMINOPHEN/CAFFEINE
    1) ORAL TABLETS: 304 mg (2 tablets) every 4 hours; MAX: 1,216 mg (8 tablets) every 24 hours (OTC Product Information, as posted to the DailyMed site 04/2013).
    7.2.2) PEDIATRIC
    A) ASPIRIN/SALICYLAMIDE/ACETAMINOPHEN/CAFFEINE
    1) ORAL TABLETS
    a) UNDER 12 YEARS: Consult a physician (OTC Product Information, as posted to the DailyMed site 04/2013).
    b) 12 YEARS AND OLDER: 304 mg (2 tablets) every 4 hours; MAX: 1,216 mg (8 tablets) in 24 hours (OTC Product Information, as posted to the DailyMed site 04/2013).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) Toxicity appears to be low.
    2) Doses as high as 24 grams/day have been tolerated in adults (Litter et al, 1951).
    3) Three adults developed relatively mild symptoms such as vomiting, epigastric pain, dizziness and drowsiness after ingesting OTC cold preparations containing up to 23.4 grams of salicylamide. These medications also contained acetaminophen, caffeine, chlorpheniramine, phenylpropanolamine, dextromethorphan, phenylephrine and menthol. These ingredients may have also contributed to the patient's symptoms. Another patient was asymptomatic. It is suggested that salicylamide in overdosage contributes little to the toxicity of other drugs present in OTC medications (Chan, 1996).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)MOUSE:
    1) 300 mg/kg (RTECS, 2000)
    B) LD50- (ORAL)RAT:
    1) 980 mg/kg (RTECS, 2000)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Salicylamide is not a salicylate as it lacks a free carboxyl group. Further, on administration it is not converted to salicylic acid in the body.

Toxicologic Mechanism

    A) Hypotension appeared to be related to peripheral vasodilation in animals (Litter et al, 1951).
    B) In animals, salicylamide depresses multineural reflexes and produces flaccid paralysis and anticonvulsant effects (Sollman, 1964).

Physicochemical

Physical Characteristics

    A) Salicylamide is a white, odorless crystalline powder, with slight solubility in water and chloroform (JEF Reynolds , 2000).

Ph

    A) 5.2-6.0 (saturated solution)

Molecular Weight

    A) 137.13 (JEF Reynolds , 2000)

References

General Bibliography

    1) Alam SN, Roberts RJ, & Fischer LJ: Age-related differences in salicylamide and acetaminophen conjugation in man. J Pediatr 1977; 90:130-135.
    2) 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.
    3) Bentley-Phillips B: Infantile urticaria caused by salicylamide teething powder (letter). Br J Dermatol 1968; 80:341.
    4) Boxill GC, Nash CB, & Wheeler AG: Comparative pharmacology and toxicological evaluation of N-acetyl P aminophenol, salicylamide and acetyl-salicylic acid. J Am Pharm Assoc 1958; 47:479-487.
    5) Chan TY: Salicylamide toxicity in overdose (letter). Int J Clin Pharmacol Therap 1996; 34:366.
    6) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    7) 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.
    8) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    9) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    10) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    11) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    12) 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.
    13) Halstead PK & Roe DA: Effect of salicylamide on skeletal glycosaminoglycan sulfation and calcification in fetal rat limbs. Drug Nutrient Interaction 1981; 1:75-86.
    14) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    15) JEF Reynolds : Martindale: The Extra Pharmacopoeia (electronic version). The Pharmaceutical Press. London, UK (Internet Version). Edition expires 2000; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    16) Kastrup EK: Facts and Comparisons, JB Lippincott, St. Louis, MO, 1986, pp 249.
    17) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    18) Knight E & Roe DA: Effects of salicylamide and protein restriction on the skeletal development of the rat fetus. Teratology 1978; 18:17-22.
    19) Levy G & Matsuzawa T: Pharmacokinetics of salicylamide elimination in man. J Pharmacol Exp Ther 1967; 156:285-293.
    20) Litter M, Moreno AR, & Donin L: Salicylamide pharmacology, fate and clinical use. J Pharmacol Exp Ther 1951; 101:119-124.
    21) Luderschmidt C, Linderkamp O, & Ring J: Drug-induced toxic epidermal necrolysis (Lyell's syndrome) in a 4-year-old girl. Eur J Pediatr 1985; 144:91-93.
    22) Nanra RS, Daniel V, & Howard M: Analgesic nephropathy induced by common proprietary mixtures. Med J Aust 1980; 1:486-487.
    23) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    24) OTC Product Information: PAIN STOPPERS Regular Strength Pain Reliever oral tablets, acetaminophen aspirin caffeine salicylamide oral tablets. North Safety Products LLC, Smithfield, RI, as posted to the DailyMed site 04/2013.
    25) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    26) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    27) Product Information: dopamine hcl, 5% dextrose IV injection, dopamine hcl, 5% dextrose IV injection. Hospira,Inc, Lake Forest, IL, 2004.
    28) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    29) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.
    30) S Sweetman : Martindale: The Complete Drug Reference, (internet version). Pharmaceutical Press. London, UK (Internet Version). Edition expires 2002; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    31) Song CS, Bonkowsky HL, & Tschudy DP: Salicyamide metabolism in acute intermittent porphyria. Clin Pharmacol Ther 1974; 15:431.
    32) Spiller HA & Rogers GC: Evaluation of administration of activated charcoal in the home. Pediatrics 2002; 108:E100.
    33) Thakore S & Murphy N: The potential role of prehospital administration of activated charcoal. Emerg Med J 2002; 19:63-65.
    34) Veresh SA, Hom FS, & Miskel JJ: Spectrophoto-fluorometric determination of salicylamide in blood serum and urine. J Pharm Sci 1971; 60:1092-1095.
    35) Waschek JA, Rubin GM, & Tozer T: Dose-dependent bioavilability and metabolism of salicylamide in dogs. J Pharmacol Exp Ther 1984; 230:89-93.
    36) de Boer AG, Gubbens-Stibbe JM, & de Koning FH: Assay of underivatized salicylamide in plasma, saliva and urine. J Chromatog 1979; 162:457-460.