ANTIHISTAMINE/DECONGESTANT

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Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) CAS 87848-99-5

1) CAS 3964-81-6
2) CAS 3978-86-7 (azatadine maleate)

1) CAS 118-23-0
2) CAS 1808-12-4 (bromodiphenhydramine hydrochloride)

1) CAS 86-22-6
2) CAS 980-71-2 (brompheniramine maleate)

1) CAS 486-16-8
2) CAS 3585-38-2 (carbinoxamine maleate)

1) CAS 132-22-9 (chlorpheniramine)
2) CAS 113-92-8 (chlorpheniramine maleate)

1) CAS 15686-51-8
2) CAS 14976-57-9 (clemastine fumarate)

1) CAS 132-21-8
2) CAS 2391-03-9 (dexbrompheniramine maleate)

1) CAS 25523-97-1
2) CAS 2438-32-6 (dexchlorpheniramine maleate)

1) CAS 469-21-6
2) CAS 562-10-7 (doxylamine succinate)

1) CAS 82-88-2
2) CAS 569-59-5 (phenindamine tartrate)

1) CAS 86-21-5
2) CAS 3269-83-8 (pheniramine aminosalicylate)
3) CAS 132-20-7 (pheniramine maleate)

1) CAS 92-12-6
2) CAS 1176-08-5 (phenyltoloxamine citrate)

1) CAS 60-87-7
2) CAS 58-33-3 (promethazine hydrochloride)
3) CAS 17693-51-5 (promethazine theoclate)

1) CAS 59-33-6 (pyrilamine maleate)

1) CAS 50679-08-8

1) CAS 486-12-4
2) CAS 550-70-9 (triprolidine hydrochloride, anhydrous)
3) CAS 6138-79-0 (triprolidine hydrochloride, monohydrate)

1) CAS 59-42-7
2) CAS 13998-27-1 (phenylephrine acid tartrate)
3) CAS 61-76-7 (phenylephrine hydrochloride)

1) CAS 14838-15-4
2) CAS 154-41-6 (phenylpropanolamine hydrochloride)

1) CAS 90-82-4
2) CAS 345-78-8 (pseudoephedrine hydrochloride)
3) CAS 7460-12-0 (pseudoephedrine sulfate)

1) ANTIHISTAMINE (WITH DECONGESTANT)
2) DECONGESTANT (WITH ANTIHISTAMINE)
3) ANTIHISTAMINES-DECONGESTANTS
4) DECONGESTANTS-ANTIHISTAMINE

Available Forms Sources

1) Cough and cold preparations comprise the largest number of products in the category of antihistamine-decongestant combinations.

a) ANTIHISTAMINES

1) ACRIVASTINE: 8 mg capsules
2) AZATADINE: 1 mg sustained-release tablets
3) BROMODIPHENHYDRAMINE: 12.5 mg/5 mL syrup
4) BROMPHENIRAMINE: 1 mg chewable tablets; 2 mg/5 mL and 4 mg/5 mL liquids; 4 mg tablets; 4 mg capsules; 6 mg and 12 mg sustained-release capsules; 12 mg sustained-release tablets.
5) CARBINOXAMINE: 2 mg/mL oral drops; 4 mg/5 mL syrup; 4 mg tablets; 8 mg sustained-release tablets.
6) CHLORPHENIRAMINE: 0.5 mg/mL and 10 mg/mL oral drops; 0.5 mg/5 mL, 1 mg/ 5 mL, 2 mg/5 mL, 2.5 mg/5 mL, 3 mg/5 mL, and 4 mg/5 mL liquids; 0.5 mg and 1 mg chewable tablets; 1 mg, 2 mg, 4 mg, 6 mg, and 8 mg tablets; 4 mg, 5 mg, 8 mg, and 12 mg sustained-release tablets; 4 mg, 8 mg, 10 mg, and 12 mg sustained- release capsules.
7) CLEMASTINE: 1.34 mg sustained-release tablets
8) DESLORATADINE - Oral tablet: 5 mg light blue round coated tablet packaged in bottles of 100 and 500. Also available in disintegrating tablets, extended release (12 hours) formulations and oral syrup. Refer to LORATADINE AND RELATED AGENTS as indicated.
9) DEXBROMPHENIRAMINE: 2 mg and 3 mg tablets; 6 mg sustained-release tablets.
10) DEXCHLORPHENIRAMINE: 2 mg/5 mL liquid
11) DIPHENHYDRAMINE: Refer to DIPHENHYDRAMINE AND RELATED AGENTS as indicated.
12) DOXYLAMINE: 6.25 mg tablets; 6.25 mg capsules; 1.25 mg/5 mL liquid; 12.5 mg powder.
13) LORATADINE: 5 mg sustained-release tablets. Refer to LORATADINE AND RELATED AGENTS as indicated.
14) PHENINDAMINE: 25 mg tablets; 24 mg sustained-release tablets.
15) PHENIRAMINE: 8 mg and 16 mg sustained-release capsules; 10 mg/mL oral drops; 3.3 mg/5 mL, 4 mg/5 mL, 6.25 mg/5 mL, and 13.3 mg/5 mL liquids.
16) PHENYLTOLOXAMINE: 25 mg tablets; 25 mg capsules; 2 mg/mL oral drops; 2 mg/5 mL, 4 mg/5 mL, and 7.5 mg/5 mL liquids; 15 mg sustained-release tablets; 8 mg, 16 mg, and 50 mg sustained-release capsules.
17) PROMETHAZINE: 6.25 mg/5 mL syrup
18) PYRILAMINE: 12.5 mg and 25 mg tablets; 10 mg/mL oral drops; 3.3 mg/5 mL, 4 mg/5 mL, 6.25 mg/5 mL, 8.33 mg/5 mL, 12.5 mg/5 mL, and 40 mg/5 mL liquids; 8 mg and 25 mg sustained-release tablets; 16 mg sustained-release capsules.
19) TERFENADINE: 60 mg sustained-release tablets
20) TRIPROLIDINE: 1.25 mg/5 mL syrup; 2.5 mg tablets.

b) DECONGESTANTS

1) The most common decongestants (sympathomimetics) found in the cough and cold (antihistamine-decongestant) combination preparations are phenylephrine, phenylpropanolamine, and pseudoephedrine.
2) PHENYLEPHRINE: 1.25 mg/mL oral drops; 1.25 mg/5 mL, 5 mg/5 mL, and 10 mg/5 mL liquids; 5 mg, 10 mg, and 25 mg tablets; 10 mg, 15 mg, and 20 mg sustained- release tablets; 20 mg sustained-release capsules.
3) PHENYLPROPANOLAMINE: 5 mg/mL and 20 mg/mL oral drops; 5 mg/5 mL, 6.25 mg/ 5 mL, and 12.5 mg/5 mL liquids; 9.4 mg, 12.5 mg, 18.7 mg, 25 mg, 40 mg, and 50 mg tablets; 25 mg capsules; 15 mg, 25 mg, 40 mg, 50 mg, and 75 mg sustained-release tablets; 25 mg and 75 mg sustained-release capsules.
4) PSEUDOEPHEDRINE: 25 mg/mL oral drops; 15 mg/5 mL, 30 mg/5 mL, 45 mg/5 mL, and 60 mg/5 mL liquids; 30 mg and 60 mg tablets; 60 mg capsules; 120 mg sustained-release tablets; 60 mg, 65 mg, and 120 mg sustained- release capsules.

2) Many of the cough and cold products may also contain antitussives, anticholinergics, salicylates, and/or acetaminophen.

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: Antihistamines with decongestants (sympathomimetic agents) are primarily used for symptomatic relief of seasonal allergies and upper respiratory tract infections. Occasionally used as a drug of abuse for their hallucinogenic effects, primarily by adolescents.
B) EPIDEMIOLOGY: Poisoning is common, but rarely severe. May occur via oral, parenteral or dermal (patches or cream) routes.
C) PHARMACOLOGY: Antihistamines are competitive antagonists of histamine (H1 and H2) receptors. Second generation antihistamines tend to be less sedating as they do not cross the blood-brain barrier as readily as the first generation antihistamines. Decongestants are sympathomimetic agents that act as alpha agonists leading to decreased nasal congestion.
D) TOXICOLOGY: Anticholinergic (primarily antimuscarinic) effects develop in overdose due to antagonism of central H1 receptors. Large overdoses of H1 blockers, particularly diphenhydramine, may cause sodium channel antagonism. Decongestants can lead to sympathomimetic (e.g., hypertension, tachycardia, hyperventilation, intercranial hemorrhage) symptoms.
E) WITH THERAPEUTIC USE

1) COMMON: ANTIHISTAMINES: Mild sedation, dizziness, impaired coordination, and mild anticholinergic effects. Paradoxical excitation can develop in some patients. SYMPATHOMIMETICS: Hypertension, tachycardia, insomnia, anxiety, nervousness, and restlessness may occur.

F) WITH POISONING/EXPOSURE

1) GENERAL: Severe overdose may cause hypertension, tachycardia, toxic psychosis, seizures, intracranial hemorrhage, and/or coma, and may occur as a result of either antihistamine or decongestant (sympathomimetic) toxicity. The antihistamine effects usually predominate over sympathomimetic effects in adult exposures; while either the antihistamine or sympathomimetic effects may predominate in pediatric exposures.
2) MILD TO MODERATE POISONING: Somnolence, anticholinergic effects (i.e., mydriasis, flushing, fever, dry mouth, and decreased bowel sounds), tachycardia, mild hypertension, and nausea and vomiting are common after overdose. Agitation, confusion and hallucinations may develop with moderate poisoning.
3) SEVERE POISONING: Severe effects may include agitated delirium, psychosis, seizures, coma, hypotension, QRS widening, and ventricular dysrhythmias, including torsades de pointe, but are generally only reported in adults after very large, deliberate ingestions. Rhabdomyolysis and renal failure may rarely develop in patients with prolonged agitation, coma or seizures.

0.2.3)

A) Hyperthermia, hypertension, and an increase in respiratory rate have been reported. Tachycardia is common.

0.2.4)

A) Anticholinergic effects, such as mydriasis, eye dryness, nasal dryness and stuffiness, and mouth and throat dryness, can occur.

0.2.5)

A) Hypertension, ECG abnormalities, atrioventricular (AV) block, cardiogenic shock, and cardiac arrest have been reported.

0.2.6)

A) Adult respiratory distress syndrome (ARDS) and aspiration have been reported.

0.2.7)

A) Somnolence, toxic psychosis (agitation, anxiety, hallucinations), seizures, intracranial hemorrhages, dystonia, dyskinesia, and coma may occur.

0.2.8)

A) Gastroenteritis (nausea, vomiting, and diarrhea) may occur following therapeutic doses of antihistamines.

0.2.10)

A) Renal failure, associated with rhabdomyolysis, has been reported following ingestion of phenylpropanolamine.
B) Urinary retention may occur following therapeutic administration of antihistamines.

0.2.13)

A) Hemolytic anemia, thrombocytopenia, or agranulocytosis may occur following therapeutic use of antihistamines, although these are rare occurrences.

0.2.15)

A) Rhabdomyolysis has been reported following antihistamine and decongestant ingestions.

0.2.20)

A) There have been few reported teratogenic effects in humans associated with antihistamine use, but animal studies have suggested that certain antihistamines have teratogenic potential.
B) Specific malformations in humans have been documented with the first trimester use of phenylephrine.
C) Small amounts of antihistamines and decongestants are excreted in breast milk.

Laboratory Monitoring

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) The majority of antihistamine overdoses requires only supportive care; give activated charcoal if patient presents shortly after ingestion; sedate with benzodiazepines for agitation and delirium. Hypertension and tachycardia are generally mild and well tolerated, and do not require specific treatment. Physostigmine can be used to establish a diagnosis, it may also help avoid an invasive, costly work-up, but should only be given in a setting where intensive monitoring and resuscitation are available. It should NOT be given if there is a history or ECG (QRS widening) evidence that suggests a tricyclic antidepressant poisoning.

B) MANAGEMENT OF SEVERE TOXICITY

1) Orotracheal intubation for airway protection should be performed early. Gastric lavage may be of benefit, if the patient presents soon after a large ingestion; administer activated charcoal as well. GI decontamination should be performed only in patients who can protect their airway or who are intubated. Severe delirium may develop and require large doses of benzodiazepines for sedation. Seizures (may rarely progress to status epilepticus) may require aggressive use of benzodiazepines, propofol and/or barbiturates. Monitor for QRS widening and ventricular dysrhythmias; treat with intravenous sodium bicarbonate (1 to 2 mEq/kg IV bolus starting dose, titrate to blood pH 7.45 to 7.55), or lidocaine if sodium bicarbonate unsuccessful. Monitor core temperature and treat hyperthermia with aggressive benzodiazepine sedation to control agitation and external cooling. Clinical manifestations may be prolonged due to delayed absorption in the setting of an anticholinergic ileus.

C) DECONTAMINATION

1) PREHOSPITAL: Not recommended because of the potential for somnolence and seizures. For dermal exposure, remove patches and wash skin thoroughly.
2) HOSPITAL: Activated charcoal if recent, substantial ingestion, and patient able to protect airway. Consider gastric lavage in recent, large (greater than 1 g) ingestion, but first protect the airway.

D) AIRWAY MANAGEMENT

1) Perform early in patients with severe intoxication (i.e., seizures, dysrhythmias, severe delirium or hyperthermia).

E) ANTIDOTE

1) Physostigmine is indicated to reverse the CNS effects caused by clinical or toxic dosages of agents capable of producing anticholinergic syndrome; however, long lasting reversal of anticholinergic signs and symptoms is generally not achieved because of the relatively short duration of action of physostigmine (45 to 60 minutes). It is most often used diagnostically to distinguish anticholinergic delirium from other causes of altered mental status. CAUTION: If tricyclic antidepressants are coingested, physostigmine may precipitate seizures and dysrhythmias. DOSES: ADULT: 2 mg IV at a slow controlled rate, no more than 1 mg/min. May repeat doses at intervals of 10 to 30 min if severe symptoms recur. For patients with prolonged anticholinergic delirium consider a continuous infusion, start at 2 mg/hr and titrate to effect. CHILD: 0.02 mg/kg by slow IV injection, at a rate no more than 0.5 mg/minute. Repeat dosage at 5 to 10 minute intervals as long as the toxic effect persists and there is no sign of cholinergic effects. MAXIMUM DOSAGE: 2 mg total. Physostigmine will not reverse symptoms of sympathomimetic overdose.

F) DYSRHYTHMIAS

1) QRS widening or ventricular tachycardia may respond to sodium bicarbonate. A reasonable starting dose is 1 to 2 mEq/kg bolus; repeat as needed. Endpoints include resolution of dysrhythmias, narrowing of QRS complex and blood pH 7.45 to 7.55. Use lidocaine if sodium bicarbonate is not successful.

G) SEIZURES

1) Most seizures are self-limited or respond to intravenous benzodiazepines. Patients with recurrent or recalcitrant seizures should be treated with propofol or barbiturates.

H) HYPERTHERMIA

1) Control agitation with benzodiazepines, initiate aggressive external cooling measures (i.e., remove patient clothing, cover with a wet sheet or keep skin damp and direct fans at the patient's skin to enhance evaporation).

I) DELIRIUM

1) Sedate patient with benzodiazepines until the patient is sleepy. Large doses (greater than 10 mg of lorazepam) may be required.

J) ENHANCED ELIMINATION

1) Hemodialysis or hemoperfusion are of no value.

K) PATIENT DISPOSITION

1) HOME CRITERIA: Asymptomatic children (other than mild drowsiness or stimulation) with acute inadvertent ingestions may be monitored at home.
2) OBSERVATION CRITERIA: Patients with deliberate ingestions and symptomatic patients should be sent to a health care facility for observation for 6 to 8 hours.
3) ADMISSION CRITERIA: Patients with significant persistent central nervous system toxicity (i.e., hallucinations somnolence, delirium, coma) or persistent tachycardia should be admitted. Patients with coma, seizures, dysrhythmias, or delirium should be admitted to an intensive care setting.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (i.e., seizures, dysrhythmias, severe delirium, coma) or in whom the diagnosis is not clear.

L) PITFALLS

1) Physostigmine is generally not advised for long term management as anticholinergic effects generally recur 30 to 45 minutes after physostigmine administration. Toxicity may be delayed and prolonged secondary to prolonged absorption due to anticholinergic ileus.

M) PHARMACOKINETICS

1) Depends on the specific antihistamine, though onset of action for most is between 15 to 60 minutes with variable duration of effect and half-life. Most are highly protein binding with primarily hepatic metabolism for elimination. The volume of distribution tends to be large (e.g., 4 to 8 L/kg for diphenhydramine).

N) DIFFERENTIAL DIAGNOSIS

1) Anticholinergic or sympathomimetic poisoning from other substances; ingestion of a purely sympathomimetic agent usually results in less mydriasis, usually no visual hallucinations, usually have moist skin; CNS infection; ethanol/benzodiazepine/barbiturate withdrawal.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.1)

A) Hyperthermia, hypertension, and an increase in respiratory rate have been reported. Tachycardia is common.

3.3.2)

A) HYPERVENTILATION has been reported.

1) CASE REPORT (CHILD) - A 5-month-old male developed a respiratory rate of 64/minute after receiving 18 doses of a medication containing carbinoxamine maleate, pseudoephedrine hydrochloride, and dextromethorphan hydrobromide. Forty eight hours later, following supportive care, the patient's respiratory rate was 32/minute.

a) The total amount administered to the infant was carbinoxamine 18 mg, pseudoephedrine 270 mg, and dextromethorphan 67.5 mg (Myer et al, 1985).

3.3.3)

A) HYPERTHERMIA has been reported following antihistamine ingestions (Wyngaarden & Seevers, 1951; Magera et al, 1981) and following ingestions of antihistamine-decongestant combination products (Myer et al, 1985).

3.3.4)

A) HYPERTENSION has been observed following ingestions of antihistamine- decongestant combination products (Pentel et al, 1982; Burton et al, 1985; Woo et al, 1985).

1) Hypertension is most commonly the result of sympathomimetic toxicity due to vasoconstriction caused by stimulation of alpha-adrenergic receptors of vascular smooth muscle (Burton et al, 1985; Woo et al, 1985).

3.3.5)

A) TACHYCARDIA is common with sympathomimetics as a direct effect and with antihistamines as an anticholinergic effect (Burton et al, 1985; Myer et al, 1985).

Heent

3.4.1)

A) Anticholinergic effects, such as mydriasis, eye dryness, nasal dryness and stuffiness, and mouth and throat dryness, can occur.

3.4.3)

A) MYDRIASIS - Dilated pupils and blurred vision have been reported following ingestions of antihistamine-decongestant combination products and is due to the anticholinergic effect of the antihistamine (Weesner et al, 1982; Ackland, 1984; Burton et al, 1985; Myer et al, 1985) Hamden-Allen & Nixon, 1991).
B) EYE DRYNESS - Dryness of the eyes has been reported as an adverse effect following administration of antihistamine-decongestant combination ophthalmic preparations (Farber, 1982; Halperin et al, 1983).

3.4.5)

A) NASAL DRYNESS - Wyngaarden & Seevers (1951) have reported nasal dryness and stuffiness as an anticholinergic effect of antihistamines (Wyngaarden & Seevers, 1951).

3.4.6)

A) THROAT DRYNESS - Mouth and throat dryness has occurred an antihistaminic, anticholinergic effect (Wyngaarden & Seevers, 1951).

Cardiovascular

3.5.1)

A) Hypertension, ECG abnormalities, atrioventricular (AV) block, cardiogenic shock, and cardiac arrest have been reported.

3.5.2)

A) HYPERTENSIVE EPISODE

1) Hypertension has been reported following ingestions of phenylpropanolamine and pseudoephedrine as single ingredients (Horowitz et al, 1980; Pentel et al, 1982; Howrie & Wolfson, 1983; Larson & Rogers, 1986) as well as in antihistamine- decongestant combination medications (Pentel et al, 1982; Burton et al, 1985; Mariani, 1986)
2) Phenylpropanolamine has an extremely low therapeutic index and may produce severe or even life-threatening hypertension at less than 3 times the maximal OTC dose of 37.5 mg (Pentel et al, 1982).
3) Hypertension developed, following ingestions of phenylpropanolamine, in 14% of the 92 cases studied by Larson & Rogers (1986), 69% of which were 13 years of age or older. The average ingestion of phenylpropanolamine in these cases was 13.6 mg/kg (range: 1.7 mg/kg to 60 mg/kg).

B) ELECTROCARDIOGRAM ABNORMAL

1) Several cases of prolonged QTc and QRS intervals and non-specific ST and T wave changes were reported with antihistamine ingestions (Donovan et al, 1992). The widened QTc and QRS intervals appeared to be related to seizure activity.
2) Pentel et al (1982) reported two cases of ECG abnormalities after ingestion of antihistamine-decongestant combination medications .

a) CASE REPORT - In the first case, a 24-year-old female ingested phenylpropanolamine 50 mg, chlorpheniramine 4 mg, and belladonna alkaloids 0.2 mg, and developed hypertension, tachycardia, dyspnea, headache, blurred vision, and nausea. The ECG showed inferolateral ST segment depression. The patient's creatinine kinase and MB isoenzyme fraction were elevated, but returned to normal 36 hours later. The electrocardiographic ST-T abnormalities persisted for 48 hours and then returned to norma (Pentel et al, 1982a).
b) CASE REPORT - In the second case reported by Pentel et al (1982), a 13-year-old female ingested phenylpropanolamine 400 mg, chlorpheniramine 64 mg, and isopropamide 20 mg, and developed hypertension, tachycardia, and a headache two hours later. The patient's creatinine kinase and MB isoenzyme fraction was elevated, but returned to normal 36 to 48 hours later. The ECG showed inferolateral ST segment depression, and ventricular bigeminy which resolved spontaneously. The electrocardiographic ST segment abnormalities resolved over 48 hours (Pentel et al, 1982a).

C) CONDUCTION DISORDER OF THE HEART

1) CASE REPORT - A 15-year-old female developed severe hypertension and dysrhythmias following ingestion of an anorectic medication containing phenylpropanolamine and caffeine. An ECG revealed frequent premature ventricular contractions and premature atrial contractions, together with paroxysms of ventricular and atrial tachycardia. Atropine and lidocaine was administered to resolve the dysrhythmias (Peterson & Vasquez, 1973).
2) CASE REPORT - Weesner et al (1982) reported a case of a 14-year-old female who ingested 15 to 18 capsules of a combination medication, each capsule containing ephedrine 25 mg, caffeine 200 mg, and phenylpropanolamine 50 mg.

a) Approximately 1.5 hours after ingestion, she developed a heart rate of 180 beats/minute and frequent aberrant beats. An ECG revealed premature ventricular contractions, junctional ectopic beats, and premature atrial contractions, as well as short periods of ventricular tachycardia.
b) The patient received lidocaine infusions which did not resolve the dysrhythmias. Due to the lack of response to lidocaine, she received an intravenous infusion of propranolol and converted to normal sinus rhythm (Weesner et al, 1982).

3) CASE SERIES - Larson and Rogers (1986) conducted a prospective study to determine the toxicity of phenylpropanolamine. Tachycardia developed in approximately 22% of the 92 cases studied, 70% of which were four years of age or younger (Larson & Rogers, 1986).
4) CASE REPORT - A 15-year-old female ingested approximately 450 mg phenylpropanolamine and 1.8 mg belladonna alkaloids, in a sustained-release preparation, and developed hypertension and sinus tachycardia.

a) Thirty hours after ingestion of the medication, the patient developed increasing breathlessness, hemoptysis, persistent tachycardia, and bilateral crepitations at both lung bases.
b) The patient expired 35 hours after ingestion of the medication (Logie & Scott, 1984).

5) CASE REPORT - Tachycardia (133 beats/minute) and tremors were reported in a 24-year-old female approximately 3 days after beginning therapy with a combination product containing clemastine and phenylpropanolamine as well as an acetaminophen and codeine combination product. The symptoms resolved within 30 minutes after administration of cyproheptadine (Egsieker et al, 2000).

D) ATRIOVENTRICULAR BLOCK

1) CASE REPORT - Two cases of Wenckebach-type second degree AV block, along with hypertension and bradycardia, were observed following the overdose of phenylpropanolamine 575 mg by a 16-year-old in one case report and of phenylpropanolamine 325 mg, chlorpheniramine 26 mg, aspirin 5850 mg, and caffeine 390 mg by a 13-year-old in the second case report.

a) All symptoms disappeared in approximately 5 to 6 hours in both cases with gastrointestinal decontamination and observation only (Woo et al, 1985).

2) CASE REPORT - Burton et al (1985) reported a case of a 24-year-old male who ingested approximately 400 mg phenylpropanolamine, 350 mg phenylephrine, 175 mg chlorpheniramine, 525 mg phenyltoloxamine. Three hours later, the patient developed hypertension and bradycardia. The ECG revealed nearly complete AV block with occasional AV conduction. All symptoms resolved 24 hours later, following gastrointestinal decontamination and observation (Burton et al, 1985).

E) HYPOTENSIVE EPISODE

1) CASE REPORT - Freedberg et al (1987) reported the case of a patient who developed cardiogenic shock several hours after ingesting pyrilamine maleate in a suicide attempt. The patient claimed to have taken 10 g of the pyrilamine maleate. An intra-aortic balloon counterpulsation was used to reverse the cardiogenic shock (Freedberg et al, 1987).

F) CARDIAC ARREST

1) CASE REPORT - A 16-year-old female with a history of recurrent episodes of paroxysmal hypertension and seizures, experienced two episodes of cardiac arrest, each episode following a generalized seizure. After several months of labwork to determine the cause of the hypertension, seizures, and cardiac arrest, GLC and IR spectroscopy determined the presence of phenylpropanolamine (Hyams et al, 1985).

Respiratory

3.6.1)

A) Adult respiratory distress syndrome (ARDS) and aspiration have been reported.

3.6.2)

A) ACUTE LUNG INJURY

1) CASE REPORT - A 15-year-old female ingested approximately 450 mg phenylpropanolamine and 1.8 mg belladonna alkaloids in a suicide attempt. Thirty hours later, the patient developed increasing breathlessness, frothy hemoptysis, persistent tachycardia, and bilateral crepitations at both lung bases. The patient died 35 hours after ingestion. A necropsy revealed features of the lungs that are compatible with early adult respiratory distress syndrome (Logie & Scott, 1984).

B) SUFFOCATING

1) CASE REPORT - Wilkinson (1987) reported a case of a 24-year-old female undergoing surgery who had ingested approximately 300 mg phenylpropanolamine and 24 mg chlorpheniramine prior to surgery. The patient regurgitated a large quantity of watery fluid while under anesthesia. Bronchial suction was performed after a short period of ventilation, and a small quantity of fluid was obtained. It is possible that the anticholinergic effects from the chlorpheniramine caused decreased gastric motility, thus contributing to the aspiration (Wilkinson, 1987).

Neurologic

3.7.1)

A) Somnolence, toxic psychosis (agitation, anxiety, hallucinations), seizures, intracranial hemorrhages, dystonia, dyskinesia, and coma may occur.

3.7.2)

A) DROWSY

1) Uden et al (1984) conducted a study to determine pediatric usage of antihistamines and incidence of toxicity. The most common adverse effect in children less than five years of age was somnolence (Uden et al, 1984).
2) Somnolence was reported in 36% of the 92 cases studied by Larson and Rogers (1986) (Larson & Rogers, 1986).

B) PSYCHOTIC DISORDER

1) Toxic psychosis has been reported following therapeutic doses of phenylpropanolamine/chlorpheniramine combinations (Orson & Bassow, 1981; Hamden-Allen & Nixon, 1991), and pseudoephedrine/carbinoxamine combinations (Cockrell, 1987) in children. Toxic psychosis is characterized by agitation, anxiety, disorientation, and hallucinations.
2) Toxic psychosis has been reported in adults receiving phenylpropanolamine as a single ingredient (Dietz, 1981) and pseudoephedrine/triprolidine combinations (Leighton, 1982; Lambert, 1987).
3) CASE REPORT - Agitation, confusion, and paranoid delusions occurred on 3 separate occasions in an adult taking therapeutic doses of antihistamines and decongestants, either alone or in combinations (Brown et al, 1990).

C) SEIZURE

1) Antihistamines may precipitate epileptiform seizures in patients with pre-existing focal lesions of the CNS (Reilly et al, 1968; Fink, 1969) and have produced generalized seizures after overdose ingestions (Wyngaarden & Seevers, 1951; Magera et al, 1981).
2) CASE REPORT (CHILD) - An 18-month-old male developed grand mal seizures after ingesting three doses of pyrilamine maleate used to treat gastro- enteritis. The patient was given diphenhydramine intravenously to control the seizures, but he developed status epilepticus and died 10 hours later (Reyes-Jacang & Wenzl, 1969).
3) Phenylpropanolamine, in overdose ingestions, has been reported to cause severe hypertension followed by generalized seizures (Peterson & Vasquez, 1973; Howrie & Wolfson, 1983; Hyams et al, 1985). The hypertension and seizures resolved following discontinuation of phenylpropanolamine.

D) INTRACRANIAL HEMORRHAGE

1) Excessive phenylpropanolamine ingestion has been reported to induce intracerebral and subarachnoid hemorrhages, a fairly rare occurrence (Mesnard & Ginn, 1984; Maertens et al, 1987; Forman et al, 1989). It is possible that hypertension may be a cause of the phenylpropanolamine- induced hemorrhages.
2) CASE REPORT - Jackson et al (1985) reported a case of a 30-year-old male, with a past history of drug abuse, who was brought into the ED comatose. Several hours prior to admission, the patient ingested phenylpropanolamine 75 mg and caffeine 200 mg, and injected intravenously pentazocine 250 mg and tripelennamine 250 mg. On arrival to the ED, the patient was hypertensive, tachycardic, and hyperpyrexic. The patient was declared brain dead forty- eight hours after admission. An autopsy revealed intracranial hemorrhage from several sites (Jackson et al, 1985a)

E) DYSTONIA

1) CASE REPORT (CHILD) - Lavenstein and Cantor (1976) reported a case of a 3-year-old male who developed dystonic posturing, restlessness, torticollis, and slurred speech two hours after the second dose of diphenhydramine hydrochloride 25 mg. During the next 18 hours, there was gradual diminuation of the abnormal movements and a return of normal speech (Lavenstein & Cantor, 1976).
2) CASE REPORT (CHILD) - A 3-year-old boy presented with restlessness, arm flexion, leg extension, and increased muscle tone after receiving a cold preparation containing diphenhydramine and phenylpropanolamine for two days. The dystonic reaction quickly resolved following benztropine administration (Joseph & King, 1995).

F) DYSKINESIA

1) Acute dyskinesia was reported after therapeutic use of dexbrompheniramine (Barone & Raniolo, 1980) and a combination medication containing dextromethorphan, ephedrine, doxylamine, acetaminophen, and alcohol (Favis, 1976).
2) Delayed onset of blepharospasm, facial dyskinesia, and involuntary head, face, and tongue movements have been described after chronic ingestion of chlorpheniramine (Davis, 1976), a brompheniramine/phenylephrine/ phenylpropanolamine combination (Thach et al, 1975), and a chlorpheniramine/ phenylpropanolamine/isopropamide combination (Thach et al, 1975).

G) COMA

1) CASE SERIES - In a series of 30 antihistamine overdoses, grade 3 and 4 coma was reported in 15 cases. The duration of the coma was an average of 3.9 hours (range: 1 to 14 hours) (Jacobsen et al, 1984).

H) TREMOR

1) Parkinson-like tremors of the upper extremities, occurring at rest, and head bobbing were reported in a 24-year-old female approximately 3 days after beginning therapy with a clemastine/phenylpropanolamine combination product and an acetaminophen/codeine combination product. The tremors completely resolved 30 minutes after administration of cyproheptadine (Egsieker et al, 2000). It was suggested that the patient's tremors may have been due to an increase in serotonin activity related to her recent use of phenylpropanolamine.

Gastrointestinal

3.8.1)

A) Gastroenteritis (nausea, vomiting, and diarrhea) may occur following therapeutic doses of antihistamines.

3.8.2)

A) GASTROENTERITIS

1) Gastrointestinal upset, including nausea, vomiting, and/or diarrhea, may occur especially with the ethylenediamine derivatives of the antihistamines (Simons et al, 1982).

Genitourinary

3.10.1)

A) Renal failure, associated with rhabdomyolysis, has been reported following ingestion of phenylpropanolamine.
B) Urinary retention may occur following therapeutic administration of antihistamines.

3.10.2)

A) RENAL FAILURE SYNDROME

1) CASE REPORT - Swenson et al (1982) described two cases of acute renal failure associated with the ingestion of phenylpropanolamine. In one of these patients renal failure developed after 3 weeks of ingesting therapeutic doses whereas signs and symptoms of renal failure were noted 5 days after ingesting 1.5 to 2.5 grams of PPA in the other case presented. In both cases, non-traumatic rhabdomyolysis was also present (Swenson et al, 1982).

B) RETENTION OF URINE

1) Urinary retention has been reported as an anticholinergic effect of antihistamines (Wyngaarden & Seevers, 1951). Discontinuation of the antihistamine usually resolves the urinary retention.

Hematologic

3.13.1)

A) Hemolytic anemia, thrombocytopenia, or agranulocytosis may occur following therapeutic use of antihistamines, although these are rare occurrences.

3.13.2)

A) HEMOLYTIC ANEMIA

1) Hemolytic anemia is a rare adverse effect that has been reported following therapeutic use of dexchlorpheniramine and tripelennamine. The anemia usually resolves after discontinuation of the medications (Crumbley, 1950; Duran-Suarez et al, 1981).

B) THROMBOCYTOPENIC DISORDER

1) Thrombocytopenia has been reported following administration of chlorpheniramine (Eisner et al, 1975; Deringer & Maniatis, 1976). Thrombocytopenia usually resolved after discontinuation of chlorpheniramine and administration of prednisone.

C) AGRANULOCYTOSIS

1) Drug-induced agranulocytosis, a rare adverse effect, has been associated with ingestions of brompheniramine (Hardin & Padilla, 1978) and chlorpheniramine (Hardin, 1988).

Musculoskeletal

3.15.1)

A) Rhabdomyolysis has been reported following antihistamine and decongestant ingestions.

3.15.2)

A) RHABDOMYOLYSIS

1) There have been several case reports of rhabdomyolysis occurring after doxylamine overdose complicated by decreased urinary output and increased creatinine phosphokinase levels. Intravenous hydration, urine alkalinization with sodium bicarbonate, and diuresis with furosemide was associated with increased urinary output and return of the creatinine phosphokinase levels to normal (Mendoza et al, 1987; Frankel et al, 1993; Soto et al, 1993).
2) CASE REPORT - Rhabdomyolysis secondary to doxylamine overdose has occurred in 7 of 442 cases referred to one poison center (Koppel et al, 1987). Secondary causes of rhabdomyolysis (compression, shock, seizures, or hypokalemia) did not occur in any of these seven patients.
3) CASE REPORT - Swenson et al (1982) described two cases of non-traumatic rhabdomyolysis associated with the ingestion of phenylpropanolamine. In both cases, acute renal failure was also present (Swenson et al, 1982).

Reproductive

3.20.1)

3.20.2)

A) PREGNANCY CATEGORY

1) The manufacturers have classified the following products as FDA pregnancy category C:

1) BROMODIPHENHYDRAMINE (Briggs et al, 1998)
2) BROMPHENIRAMINE (Prod Info B-VEX(R) suspension, 2005)
3) CARBINOXAMINE (Briggs et al, 1998)
4) CHLORPHENIRAMINE (Prod Info P-TANN SUSPENSION oral suspension, 2006)
5) DEXBROMPHENIRAMINE (Briggs et al, 1998)
6) PHENIRAMINE (Briggs et al, 1998)
7) PHENYLEPHRINE AND KETOROLAC (ophthalmic solution) (Prod Info OMIDRIA(TM) ophthalmic solution injection, 2014)
8) PHENYLPROPANOLAMINE(Briggs et al, 1998)
9) PHENYLTOLOXAMINE (Briggs et al, 1998)
10) PROMETHAZINE (Prod Info Promethazine Hydrochloride IM, IV injection, 2009)
11) PSEUDOEPHEDRINE (Briggs et al, 1998)
12) PYRILAMINE (Briggs et al, 1998)
13) TERFENADINE (Briggs et al, 1998)
14) TRIPROLIDINE (Prod Info ZYMINE(TM) LIQUID oral syrup, 2002)

2) The manufacturers have classified the following products as FDA pregnancy category B:

1) ACRIVASTINE/PSEUDOEPHEDRINE (Prod Info Semprex(R)-D oral capsules, 2014)
2) AZATADINE (Briggs et al, 1998)
3) DEXCHLORPHENIRAMINE (Prod Info dexchlorpheniramine maleate extended release tablets, 1998)
4) DIPHENHYDRAMINE (Briggs et al, 1998)
5) DOXYLAMINE (Briggs et al, 1998)

B) CONGENITAL MALFORMATIONS

1) ANTIHISTAMINES

a) BROMPHENIRAMINE MALEATE has been associated with an increasing frequency of congenital malformations in humans. It, therefore, should not be used during pregnancy (Heinonen et al, 1977).

2) DECONGESTANTS

a) Specific malformations in humans have been documented with the first trimester use of phenylephrine. Minor malformations (such as inguinal hernia and clubfoot) have been associated with decongestants (sympathomimetics) and first trimester use (Heinonen et al, 1977a).

C) LACK OF EFFECT

1) Analysis of 17,776 pregnancies in the Swedish Medical Birth Registry found that infants born to mothers who used antihistamines during pregnancy had a malformation rate equal to that normally expected (3.17% for antihistamine use vs 3.16% in the general population). A slightly reduced rate of cardiovascular defects was also seen in the offspring of women using antihistamines during pregnancy. Reduced risks of premature births, low birth weight, and small size for gestational age were also seen with use of antihistamines. The most common antihistamines used by women in this study were clemastine, promethazine, cyclizine, meclizine, cetirizine, terfenadine, and loratadine (Kallen, 2002).
2) CHLORPHENIRAMINE

a) There was no significant increase in the incidence of congenital abnormalities overall in the offspring of 1070 mothers who were exposed to chlorpheniramine during the first trimester of pregnancy nor among 3931 offspring exposed anytime during pregnancy (Heinonen et al, 1977). However, eye and ear abnormalities were significantly associated with first trimester use (relative risk, 2.89), although this would not be suggestive of a major teratogen. The incidence of congenital malformations observed in 275 infants exposed to chlorpheniramine during the first trimester was not increased as reported in the Boston Collaborative Drug Surveillance Program (Jick et al, 1982; Aselton et al, 1985).

3) LORATADINE

a) No increase in the rate of fetal abnormalities was found in women who took loratadine during pregnancy compared with women who took other antihistamines and a control group with unexposed infants in a prospective cohort study. The incidence of malformation was 2.3% for loratadine, 4% for other antihistamines and 3% for the control group (p=0.553). This corresponds to a relative risk (RR) for the loratadine group of 0.77 (95% confidence interval (CI), 0.27 to 2.19) compared with the control group and an RR of 0.56 (95% CI, 0.18 to 1.77) compared with the other antihistamine group. When analyzing only those infants exposed to antihistamines during the first trimester, the malformation rates were 0.8% for loratadine, 4.8% for others, and 3% for the control group (p=0.152; loratadine vs control: RR, 0.27; 95% CI 0.04 to 1.94; loratadine vs others: RR, 0.17; 95% CI 0.02 to 1.33). The loratadine group had a higher incidence of miscarriage (11.4% vs others: 4.9% and vs control: 7.2%), but the women using loratadine had a significantly higher maternal age than those in the other groups (31.5 years vs. 30 years in other two groups, p=0.005). In this study, 68 patients (25.5%) took chlorpheniramine (Diav-Citrin et al, 2003).

D) ANIMAL STUDIES

1) ACRIVASTINE/PSEUDOEPHEDRINE

a) In animal studies, no evidence of teratogenicity was observed in rabbits given acrivastine and pseudoephedrine at 10 and 7 times the recommended human daily doses, respectively (Prod Info Semprex(R)-D oral capsules, 2014).

3.20.3)

A) FETAL DISTRESS

1) Phenylephrine and phenylpropanolamine may cause vasoconstriction of uterine vessels and the reduction of uterine blood flow resulting in fetal hypoxia (Smith & Corbascio, 1970).

3.20.4)

A) BREAST MILK

1) Antihistamines may be excreted into the breast milk in small amounts. Their use is not recommended in nursing mothers due to possible hyperactivity/irritability in infants (USPDI, 1999).

a) ACRIVASTINE/PSEUDOEPHEDRINE HYDROCHLORIDE: It is unknown whether acrivastine is excreted in human milk, although pseudoephedrine is excreted in human milk. Acrivastine/pseudoephedrine hydrochloride should be used in nursing mothers only when the potential benefit justifies the potential risks to the nursing infant (Prod Info Semprex(R)-D oral capsules, 2014).
b) CASE REPORT: A case report described drowsiness, irritability, high-pitched crying, and anorexia in a breastfed 10-week-old infant within 12 hours of maternal ingestion of clemastine 1 mg twice daily. Maternal plasma and corresponding breast milk levels were 20 and 5 to 10 mcg/L, with none detected in the infant. Symptoms resolved after discontinuation of the clemastine (Kok et al, 1982).
c) CASE REPORT: Maternal use of a sustained-release antihistamine/decongestant combination (containing dexbrompheniramine and d-isoephedrine) resulted in irritability, disturbed sleep patterns and excessive crying in her breastfed infant (Mortimer, 1977).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Monitor vital signs (including temperature) and mental status.
B) Antihistamine plasma levels are not clinically useful or readily available.
C) No specific lab work is needed in most patients. Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (i.e., agitation delirium, seizures, coma, hypotension).
D) Monitor creatinine phosphokinase in patients with prolonged agitation, seizures or coma; monitor renal function urine output in patients with rhabdomyolysis.
E) Obtain a basic metabolic panel in patients with moderate to severe toxicity to monitor for acidosis and dehydration.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Blood/serum/plasma concentrations are generally not useful for guiding therapy, but may be helpful in confirming the diagnosis.
2) Plasma creatinine kinase should be measured to rule out rhabdomyolysis (Koppel et al, 1987).
3) Many antihistamine-decongestant combinations are also combined with acetaminophen or salicylates. Blood levels should be monitored for possible concurrent acetaminophen or salicylate ingestion.
4) Monitor renal function tests in symptomatic patients.

4.1.3)

A) OTHER

1) If the plasma creatinine kinase is elevated, urine myoglobin should also be measured (Koppel et al, 1987a).

4.1.4)

A) OTHER

1) ECG

a) Monitor ECG in symptomatic patients.

Methods

1) The assay methods of GC/MS, HPLC, and HP-TLC have been used to determine the amount of doxylamine in the blood from a doxylamine overdose death.

a) HPLC provided a quantitative result of 1.2 mg/L in the blood and HP-TLC and GC/MS confirmed this result with additional quantitative data (Siek & Dunn, 1993).

2) The HP-TLC method presents all metabolites and their relative quantities and is used to complement the HPLC assay method (Siek & Dunn, 1993).
3) Gas chromatography with nitrogen-phosphorus detection and gas chromatography-mass spectrometry were used to quantitatively determine the presence of brompheniramine and pseudoephedrine, respectively, in the blood and liver following the fatal intoxication of a 2-month-old infant. The infant had been given a combination cold medication, that also contained dextromethorphan, via a baby bottle (Boland et al, 2003).

Treatment

Life Support

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with significant persistent central nervous system toxicity (i.e., hallucinations somnolence, delirium, coma) or persistent tachycardia should be admitted. Patients with coma, seizures, dysrhythmias, or delirium should be admitted to an intensive care setting.

6.3.1.2) HOME CRITERIA/ORAL

A) Asymptomatic children (other than mild drowsiness or stimulation) with an acute inadvertent ingestion may be monitored at home.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (i.e., seizures, dysrhythmias, severe delirium, coma) or in whom the diagnosis is not clear.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Patients with deliberate ingestions and symptomatic patients should be sent to a health care facility for observation for 6 to 8 hours.

Monitoring

Oral Exposure

6.5.1)

A) EMESIS/NOT RECOMMENDED

1) Emesis is not recommended because of the potential for somnolence and seizures. For dermal exposure, remove patches and wash skin thoroughly.

B) ACTIVATED CHARCOAL

1) Activated charcoal should NOT be administered at home or en route to the hospital due to the potential loss of consciousness or seizure.
2) Activated charcoal is recommended, in the hospital setting, if the patient is awake and able to protect his/her airway and the amount ingested has the potential to cause toxicity.
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).

6.5.2)

A) SUMMARY

1) Anticholinergics slow GI motility; sustained-release preparations are available. Gastric decontamination may be successful even if delayed.

B) 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

b) ADVERSE EFFECTS/CONTRAINDICATIONS

6.5.3)

A) MONITORING OF PATIENT

1) Monitor vital signs (including temperature) and mental status.
2) No specific lab work is needed in most patients.
3) Obtain an ECG and institute continuous cardiac monitoring in patients with significant toxicity (i.e., agitation, delirium, seizures, coma, hypotension).
4) Monitor creatinine phosphokinase in patients with prolonged agitation, seizures, or coma; monitor renal function and urine output in patients with rhabdomyolysis.
5) Obtain a basic metabolic panel in patients with moderate to severe toxicity to monitor for acidosis and dehydration.

B) AIRWAY MANAGEMENT

1) Perform early in patients with severe intoxication (i.e., seizures, dysrhythmias, severe delirium or hyperthermia).

C) TACHYARRHYTHMIA

1) Sedation with benzodiazepines may be useful in agitated patients.
2) TACHYCARDIA SUMMARY

a) Evaluate patient to be sure that tachycardia is not a physiologic response to dehydration, anemia, hypotension, fever, sepsis, or hypoxia. Sinus tachycardia does not generally require treatment unless hemodynamic compromise develops.
b) If therapy is required, a short acting, cardioselective agent such as esmolol is generally preferred (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
c) ESMOLOL/ADULT LOADING DOSE

1) Infuse 500 micrograms/kilogram (0.5 mg/kg) IV over 1 minute (Neumar et al, 2010).

d) ESMOLOL/ADULT MAINTENANCE DOSE

1) Follow loading dose with infusion of 50 mcg/kg per minute (0.05 mg/kg per minute) (Neumar et al, 2010).
2) EVALUATION OF RESPONSE: If response is inadequate, infuse second loading bolus of 0.5 mg/kg over 1 minute and increase the maintenance infusion to 100 mcg/kg (0.1 mg/kg) per minute. Reevaluate therapeutic effect, increase in the same manner if required to a maximum infusion rate of 300 mcg/kg (0.3 mg/kg) per minute (Neumar et al, 2010).
3) The manufacturer recommends that a maximum of 3 loading doses be used (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
4) END POINT OF THERAPY: As the desired heart rate or blood pressure is approached, omit loading dose and adjust maintenance infusion as required (Prod Info BREVIBLOC(TM) intravenous injection, 2012).

e) CAUTION

1) Esmolol is a short acting beta-adrenergic blocking agent with negative inotropic effects. Esmolol should be avoided in patients with asthma, obstructive airway disease, decompensated heart failure and pre-excited atrial fibrillation (wide complex irregular tachycardia) or atrial flutter (Neumar et al, 2010).

D) VENTRICULAR ARRHYTHMIA

1) Because some antihistamines have sodium blocking properties dysrhythmias may respond to administration of sodium bicarbonate (Clark & Vance, 1992; Clark, 1993). An initial dose of 1 milliequivalent/kilogram is appropriate, repeated as needed with careful monitoring of blood pH.
2) Use lidocaine if sodium bicarbonate is not successful.

a) 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).

b) 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).

c) LIDOCAINE/MONITORING PARAMETERS

1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).

3) Severe dysrhythmias may respond to physostigmine.

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) HYPERTENSIVE EPISODE

1) Monitor vital signs regularly. For mild/moderate hypertension without evidence of end organ damage, pharmacologic intervention is generally not necessary. Sedative agents such as benzodiazepines may be helpful in treating hypertension and tachycardia in agitated patients, especially if a sympathomimetic agent is involved in the poisoning.
2) For hypertensive emergencies (severe hypertension with evidence of end organ injury (CNS, cardiac, renal), or emergent need to lower mean arterial pressure 20% to 25% within one hour), sodium nitroprusside is preferred. Nitroglycerin and phentolamine are possible alternatives.
3) SODIUM NITROPRUSSIDE/INDICATIONS

a) Useful for emergent treatment of severe hypertension secondary to poisonings. Sodium nitroprusside has a rapid onset of action, a short duration of action and a half-life of about 2 minutes (Prod Info NITROPRESS(R) injection for IV infusion, 2007) that can allow accurate titration of blood pressure, as the hypertensive effects of drug overdoses are often short lived.

4) SODIUM NITROPRUSSIDE/DOSE

a) ADULT: Begin intravenous infusion at 0.1 microgram/kilogram/minute and titrate to desired effect; up to 10 micrograms/kilogram/minute may be required (American Heart Association, 2005). Frequent hemodynamic monitoring and administration by an infusion pump that ensures a precise flow rate is mandatory (Prod Info NITROPRESS(R) injection for IV infusion, 2007). PEDIATRIC: Initial: 0.5 to 1 microgram/kilogram/minute; titrate to effect up to 8 micrograms/kilogram/minute (Kleinman et al, 2010).

5) SODIUM NITROPRUSSIDE/SOLUTION PREPARATION

a) The reconstituted 50 mg solution must be further diluted in 250 to 1000 mL D5W to desired concentration (recommended 50 to 200 mcg/mL) (Prod Info NITROPRESS(R) injection, 2004). Prepare fresh every 24 hours; wrap in aluminum foil. Discard discolored solution (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

6) SODIUM NITROPRUSSIDE/MAJOR ADVERSE REACTIONS

a) Severe hypotension; headaches, nausea, vomiting, abdominal cramps; thiocyanate or cyanide toxicity (generally from prolonged, high dose infusion); methemoglobinemia; lactic acidosis; chest pain or dysrhythmias (high doses) (Prod Info NITROPRESS(R) injection for IV infusion, 2007). The addition of 1 gram of sodium thiosulfate to each 100 milligrams of sodium nitroprusside for infusion may help to prevent cyanide toxicity in patients receiving prolonged or high dose infusions (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

7) SODIUM NITROPRUSSIDE/MONITORING PARAMETERS

a) Monitor blood pressure every 30 to 60 seconds at onset of infusion; once stabilized, monitor every 5 minutes. Continuous blood pressure monitoring with an intra-arterial catheter is advised (Prod Info NITROPRESS(R) injection for IV infusion, 2007).

8) NITROGLYCERIN/INDICATIONS

a) May be used to control hypertension, and is particularly useful in patients with acute coronary syndromes or acute pulmonary edema (Rhoney & Peacock, 2009).

9) NITROGLYCERIN/ADULT DOSE

a) Begin infusion at 10 to 20 mcg/min and increase by 5 or 10 mcg/min every 5 to 10 minutes until the desired hemodynamic response is achieved (American Heart Association, 2005). Maximum rate 200 mcg/min (Rhoney & Peacock, 2009).

10) NITROGLYCERIN/PEDIATRIC DOSE

a) Usual Dose: 29 days or Older: 1 to 5 mcg/kg/min continuous IV infusion. Maximum 60 mcg/kg/min (Laitinen et al, 1997; Nam et al, 1989; Rasch & Lancaster, 1987; Ilbawi et al, 1985; Friedman & George, 1985).

G) HYPOTENSIVE EPISODE

1) Cardiogenic shock rarely occurs, but may require use of an intraaortic balloon pump (Freedberg et al, 1987).

H) DRUG-INDUCED DYSTONIA

1) DIAZEPAM: Acute dystonic reactions to antihistamines may be treated with oral or intravenous diazepam (CHILD: 0.1 to 0.3 milligram/kilogram slowly, ADULT: up to 10 milligrams, may be repeated as necessary).
2) BENZTROPINE: Benztropine, 0.02 milligrams/kilogram IV, was given to a 3-year-old child who developed a dystonic reaction following administration of a cold preparation containing diphenhydramine and phenylpropanolamine. The dystonia resolved within 5 minutes after benztropine administration (Joseph & King, 1995).

I) DELIRIUM

1) Sedate patient with benzodiazepines until the patient is sleepy. Large doses (greater than 10 mg of lorazepam) may be required.

J) BODY TEMPERATURE ABOVE REFERENCE RANGE

K) RHABDOMYOLYSIS

1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).
6) MANNITOL/INDICATIONS

a) Osmotic diuretic used in the management of rhabdomyolysis and myoglobinuria (Zimmerman & Shen, 2013).

7) RHABDOMYOLYSIS/MYOGLOBINURIA

a) ADULT: TEST DOSE: (for patients with marked oliguria or those with inadequate renal function) 0.2 g/kg IV as a 15% to 25% solution infused over 3 to 5 minutes to produce a urine flow of at least 30 to 50 mL/hr; a second test dose may be given if urine flow does not increase within 2 to 3 hours. The patient should be reevaluated if there is inadequate response following the second test dose (Prod Info MANNITOL intravenous injection, 2009). TREATMENT DOSE: 50 to 100 g IV as a 15% to 25% solution may be used. The rate should be adjusted to maintain urinary output at 30 to 50 mL/hour (Prod Info mannitol IV injection, urologic irrigation, 2006) OR 300 to 400 mg/kg or up to 100 g IV administered as a single dose (Prod Info MANNITOL intravenous injection, 2009).
b) PEDIATRIC: Dosing has not been established in patients less than 12 years of age(Prod Info Mannitol intravenous injection, 2009). TEST DOSE (for patients with marked oliguria or those with inadequate renal function): 0.2 g/kg or 6 g/m(2) body surface area IV as a 15% to 25% solution infused over 3 to 5 minutes to produce a urine flow of at least 30 to 50 mL/hr; a second test dose may be given if urine flow does not increase; TREATMENT DOSE: 0.25 to 2 g/kg or 60 g/m(2) body surface area IV as a 15% to 20% solution over 2 to 6 hours; do not repeat dose for persistent oliguria (Prod Info MANNITOL intravenous injection, 2009).

8) ADVERSE EFFECTS

a) Fluid and electrolyte imbalance, in particular sodium and potassium; expansion of the extracellular fluid volume leading to pulmonary edema or CHF exacerbations(Prod Info MANNITOL intravenous injection, 2009).

9) PRECAUTION

a) Contraindicated in well-established anuria or impaired renal function not responding to a test dose, pulmonary edema, CHF, severe dehydration; caution in progressive oliguria and azotemia; do not add to whole blood for transfusions(Prod Info Mannitol intravenous injection, 2009); enhanced neuromuscular blockade observed with tubocurarine(Miller et al, 1976).

10) MONITORING PARAMETERS

a) Renal function, urine output, fluid balance, serum potassium, serum sodium, and serum osmolality (Prod Info Mannitol intravenous injection, 2009).

L) PHYSOSTIGMINE

1) PHYSOSTIGMINE/INDICATIONS

a) Physostigmine is indicated to reverse the CNS effects caused by clinical or toxic dosages of agents capable of producing anticholinergic syndrome; however, long lasting reversal of anticholinergic signs and symptoms is generally not achieved because of the relatively short duration of action of physostigmine (45 to 60 minutes) (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008). It is most often used diagnostically to distinguish anticholinergic delirium from other causes of altered mental status (Frascogna, 2007; Shannon, 1998).
b) Physostigmine should not be used in patients with suspected tricyclic antidepressant overdose, or an ECG suggestive of tricyclic antidepressant overdose (eg, QRS widening). In the setting of tricyclic antidepressant overdose, use of physostigmine has precipitated seizures and intractable cardiac arrest (Stewart, 1979; Newton, 1975; Pentel & Peterson, 1980; Frascogna, 2007).

2) DOSE

a) ADULT: BOLUS: 2 mg IV at slow controlled rate, no more than 1 mg/min. May repeat doses at intervals of 10 to 30 min, if severe symptoms recur (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008). INFUSION: For patients with prolonged anticholinergic delirium, a continuous infusion of physostigmine may be considered. Starting dose is 2 mg/hr, titrate to effect (Eyer et al, 2008)
b) CHILD: 0.02 mg/kg by slow IV injection, at a rate no more than 0.5 mg/minute. Repeat dosage at 5 to 10 minute intervals as long as the toxic effect persists and there is no sign of cholinergic effects. MAXIMUM DOSAGE: 2 mg total (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).
c) AVAILABILITY: Physostigmine salicylate is available in 2 mL ampules, each mL containing 1 mg of physostigmine salicylate in a vehicle containing sodium metabisulfite 0.1%, benzyl alcohol 2%, and water (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).

3) CAUTIONS

a) Relative contraindications to the use of physostigmine are asthma, gangrene, diabetes, cardiovascular disease, intestinal or urogenital tract mechanical obstruction, peripheral vascular disease, cardiac conduction defects, atrioventricular block, and in patients receiving choline esters and depolarizing neuromuscular blocking agents (decamethonium, succinylcholine). It may cause anaphylactic symptoms and life-threatening or less severe asthmatic episodes in patients with sulfite sensitivity (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).
b) Too rapid IV administration of physostigmine has resulted in bradycardia, hypersalivation leading to respiratory difficulties, and possible seizures (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008).

4) ATROPINE FOR PHYSOSTIGMINE TOXICITY

a) Atropine should be available to reverse life-threatening physostigmine-induced, toxic cholinergic effects (Prod Info physostigmine salicylate intravenous injection, intramuscular injection, 2008; Frascogna, 2007). Atropine may be given at half the dose of previously given physostigmine dose (Daunderer, 1980).

Enhanced Elimination

1) Hemodialysis or hemoperfusion are of no value in this setting.

1) Urinary excretions of chlorpheniramine, phenylpropanolamine, and pseudoephedrine are increased when the pH of the urine is acidic (Paton & Webster, 1985; USPDI, 1999), however acid diuresis is NOT recommended to enhance elimination in overdose, as the risks of acidemia and acute tubular necrosis in patients with rhabdomyolysis far outweigh any potential benefits.

Abstracts

Case Reports

1) A 24-year-old male developed a nearly complete AV block with a pulse of 40 beats per minute and hypertension following ingestion of approximately 1600 mg phenylpropanolamine, 400 mg phenylephrine, 200 mg chlorpheniramine, and 600 mg phenyltoloxamine. No treatment other than gastrointestinal tract decontamination was required and the patient was discharged asymptomatic 2 days after admission (Burton et al, 1985).
2) A previously healthy 13-year-old female ingested phenylpropanolamine 25 mg, chlorpheniramine 2 mg, aspirin 450 mg, and caffeine 30 mg. Approximately 75 minutes after ingestion she was alert but light-headed. Her blood pressure was 130/100 mmHg, pulse 58 beats per minute and irregular, and temperature 36.3 degrees C (97.4 degrees F). ECG revealed sinus bradycardia with a Wenckebach type second degree AV block.

a) Emesis was induced with ipecac and activated charcoal was administered. Five hours later, blood pressure was 110/80 mmHg and the heart block disappeared (Woo et al, 1985).

3) A 16-year-old female ingested phenylpropanolamine 525 mg. Three hours post- ingestion, blood pressure was 180/90 mmHg and pulse 40 beats per minute and irregular. EKG revealed sinus bradycardia with second degree AV block (Wenckebach pattern). Six hours later, following gastric decontamination, her blood pressure returned to normal and the heart block disappeared (Woo et al, 1985).

1) A 5-year-old boy experienced hallucinations for 18 hours after ingesting 60 ml of triprolidine/pseudoephedrine syrup (Ackland, 1984).

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) NOTE: Please refer to ANTIHISTAMINES and DECONGESTANTS documents for specific dosing of individual agents.
B) ACRIVASTINE/PSEUDOEPHEDRINE

1) The recommended dosage is one capsule (8 mg of acrivastine and 60 mg of pseudoephedrine hydrochloride per capsule) orally every 4 to 6 hours four times a day (Prod Info Semprex(R)-D oral capsules, 2014).

7.2.2)

A) NOTE: Please refer to ANTIHISTAMINES and DECONGESTANTS documents for specific dosing of individual agents.
B) ACRIVASTINE/PSEUDOEPHEDRINE

1) 12 YEARS AND OLDER: The recommended dosage is one capsule (8 mg of acrivastine and 60 mg of pseudoephedrine hydrochloride per capsule) orally every 4 to 6 hours four times a day (Prod Info Semprex(R)-D oral capsules, 2014).
2) LESS THAN 12 YEARS OF AGE: The safety and effectiveness of pseudoephedrine hydrochloride/acrivastine have not been evaluated (Prod Info Semprex(R)-D oral capsules, 2014).

C) CHLORPHENIRAMINE/PHENYLEPHRINE

1) Greater than 6 years of age: 5 to 10 mL of oral suspension every 12 hours (Prod Info R-TANNA PEDIATRIC SUSPENSION oral suspension, 2010).
2) 2 to 6 years: 2.5 to 5 mL of oral suspension every 12 hours (Prod Info R-TANNA PEDIATRIC SUSPENSION oral suspension, 2010).
3) Less than 2 years of age: Titrate dose individually (Prod Info R-TANNA PEDIATRIC SUSPENSION oral suspension, 2010).

D) DIPHENHYDRAMINE/PHENYLEPHRINE

1) CHEWABLE TABLETS

a) 12 years and older: 1 to 2 tablets every 12 hours (Prod Info DYTAN-D(TM) oral suspension, oral chewable tablet, 2003).
b) 6 to 11 years: 1/2 to 1 tablet every 12 hours (Prod Info DYTAN-D(TM) oral suspension, oral chewable tablet, 2003).

2) ORAL SUSPENSION

a) 12 years and older: 5 to 10 mL every 12 hours (Prod Info DYTAN-D(TM) oral suspension, oral chewable tablet, 2003).
b) 6 to 11 years: 2.5 to 5 mL every 12 hours (Prod Info DYTAN-D(TM) oral suspension, oral chewable tablet, 2003).
c) 2 to 5 years: 1.25 to 2.5 mL every 12 hours (Prod Info DYTAN-D(TM) oral suspension, oral chewable tablet, 2003).

Minimum Lethal Exposure

1) DIPHENHYDRAMINE HYDROCHLORIDE

a) CHILD: A 6-month-old infant developed seizures one hour after ingesting an unknown quantity of diphenhydramine. The patient died 2 hours after ingestion (Wyngaarden & Seevers, 1951).
b) CHILD: A 2-year-old male ingested 474 mg of diphenhydramine and developed hyperpyrexia, seizures, and subsequently, coma. The patient died 13 hours after ingestion (Wyngaarden & Seevers, 1951).

2) PHENYLPROPANOLAMINE

a) ADULT: A 15-year-old female ingested approximately 450 mg phenylpropanolamine and 1.8 mg belladonna alkaloids in a suicide attempt. Thirty hours later, the patient developed hypertension, increasing breathlessness, frothy hemoptysis, persistent tachycardia, and bilateral crepitations at both lung bases. The patient died 35 hours after ingestion (Logie & Scott, 1984).
b) ADULT: A 30-year-old male ingested phenylpropanolamine 75 mg and caffeine 200 mg, injected intravenously pentazocine 250 mg and tripelennamine 250 mg, and developed hypertension, tachycardia, and hyperpyrexia as a result. The patient subsequently went into a coma and was declared brain dead 48 hours later (Jackson et al, 1985).

3) PYRILAMINE MALEATE

a) CHILD: An 18-month-old male developed grand-mal seizures after administration of 150 mg (50 mg every 8 hours for 3 doses) pyrilamine maleate. Diphenhydramine 30 mg was administered intravenously for control of the seizures, but the patient developed status epilepticus and died 10 hours later (Reyes-Jacang & Wenzl, 1969).

Maximum Tolerated Exposure

1) CHLORPHENIRAMINE

a) An adult ingested 400 mg with no reported serious adverse effects (Wyngaarden & Seevers, 1951).

2) PSEUDOEPHEDRINE

a) Doses of up to 180 mg produce no measurable effect on blood pressure or heart rate (Pentel, 1984).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) SPECIFIC SUBSTANCE

a) DOXYLAMINE

1) Plasma levels are reported to be approximately 100 nanograms/milliliter (0.1 microgram/milliliter) after a therapeutic dose (Mendoza et al, 1987).

b) PHENYLPROPANOLAMINE

1) Serum concentrations are reported to be approximately 60 to 200 nanograms/ milliliter after a therapeutic dose (Pentel, 1984).

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) SPECIFIC SUBSTANCE

a) BROMPHENIRAMINE/PSEUDOEPHEDRINE

1) The toxicology results following a fatal intoxication of a 2-month-old infant, involving a combination cold medication containing brompheniramine, pseudoephedrine, and dextromethorphan, were as follows:

Specimen	Brompheniramine	Pseudoephedrine	Dextromethorphan
Blood	0.40 mg/L	14.4 mg/L	0.50 mg/L
Liver	0.16 mg/kg	16 mg/kg	0.57 mg/kg

a) The infant had been given the cold medication via a baby bottle. Analysis of the liquid within the bottle showed that the total amounts of brompheniramine, pseudoephedrine, and dextromethorphan, remaining in the bottle, were 1.4 mg, 40 mg, and 9.4 mg, respectively (Boland et al, 2003).

b) DOXYLAMINE -

1) In a review of 109 cases, no correlation was found between the amounts ingested or plasma levels and the frequency and extent of symptoms (Koppel et al, 1987a).
2) Rhabdomyolysis was reported in a patient with a plasma level of 7.5 micrograms/milliliter (Mendoza et al, 1987).

c) PYRILAMINE -

1) A pyrilamine blood concentration of 121 nanograms/milliliter was measured in a 46-year-old female after she ingested 10 grams of pyrilamine maleate (Freedberg et al, 1987).
2) A pyrilamine blood concentration of 11 milligrams/liter was measured in a 25-year-old female following a suspected fatal pyrilamine overdose (Johnson, 1981).

Toxicity Information

7.7.1)

A) CARBINOXAMINE MALEATE

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 166 mg/kg (Budavari, 1996)

B) CHLORPHENIRAMINE

1) LD50- (ORAL)MOUSE:

a) 162 mg/kg (Budavari, 1996)

C) CLEMASTINE FUMARATE

1) LD50- (ORAL)MOUSE:

a) 730 mg/kg (Budavari, 1996)

2) LD50- (ORAL)RAT:

a) 3550 mg/kg (Budavari, 1996)

D) DIPHENHYDRAMINE HYDROCHLORIDE

1) LD50- (ORAL)RAT:

a) 500 mg/kg (Budavari, 1996)

E) DOXYLAMINE

1) LD50- (ORAL)MOUSE:

a) 470 mg/kg (Budavari, 1996)

F) PHENINDAMINE HYDROGEN TARTRATE

1) LD50- (ORAL)RAT:

a) 280 mg/kg (Budavari, 1996)

G) PHENYLEPHRINE

1) LD50- (INTRAPERITONEAL)RAT:

a) 17 mg/kg (Budavari, 1996)

2) LD50- (SUBCUTANEOUS)RAT:

a) 33 mg/kg (Budavari, 1996)

H) PHENYLPROPANOLAMINE

1) LD50- (ORAL)RAT:

a) 1490 mg/kg (Budavari, 1996)

I) PHENYLTOLOXAMINE DIHYDROGEN CITRATE

1) LD50- (ORAL)MOUSE:

a) 246 mg/kg (Hoekstra et al, 1953)

J) PHENYLTOLOXAMINE HYDROCHLORIDE

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 163 mg/kg (Hoekstra et al, 1953)

2) LD50- (ORAL)MOUSE:

a) 424 mg/kg (Hoekstra et al, 1953)

K) PROMETHAZINE HYDROCHLORIDE
L) PSEUDOEPHEDRINE HYDROCHLORIDE

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 1.0 mmole/kg (Budavari, 1996)

M) PYRILAMINE

1) LD50- (ORAL)MOUSE:

a) 312 mg/kg (Budavari, 1996)

N) TERFENADINE

1) LD50- (ORAL)MOUSE:

a) Greater than 2000 mg/kg (Budavari, 1996)

2) LD50- (ORAL)RAT:

a) Greater than 2000 mg/kg (Budavari, 1996)

Pharmacology Toxicology

Pharmacologic Mechanism

Toxicologic Mechanism

1) The toxicity of antihistamines is related to their anticholinergic (antimuscarinic) activity with the exception of toxic exposure to loratadine, terfenadine, and astemizole. The action of acetylcholine at muscarinic receptors is blocked.
2) Some evidence suggests that certain metabolites are involved in the toxicity of some antihistamines (Chow et al, 1988).

Physicochemical

Animal Toxicology

Clinical Effects

11.1.3)

A) ACUTE, LOW EXPOSURE causes signs including depression, drowsiness, salivation and vomiting (Humphreys, 1988). The most common side effect seen around therapeutic doses is sedation; alternatively, hyperexcitability may occur (Medleau, 1990).
B) CHLORPHENIRAMINE - In a study of 45 dogs given various antihistamines, chlorpheniramine maleate most consistently produced side effects (Scott & Buerger, 1988).

11.1.13)

A) OTHER

1) MEPYRAMINE, when injected intravenously, may cause transient nervous signs, including incoordination and visual disturbances, in horses and cattle (Humphreys, 1988).
2) ACUTE, HIGH EXPOSURE could produce spasmolysis, an antifibrillatory action on the myocardium, excitement, and seizures (Humphreys, 1988).

Treatment

11.2.1)

A) GENERAL TREATMENT

1) Begin treatment immediately.
2) Keep animal warm and do not handle unnecessarily.
3) Sample vomitus, blood, urine, and feces for analysis.
4) ANIMAL POISON CONTROL CENTERS

a) ASPCA Animal Poison Control Center, An Allied Agency of the University of Illinois, 1717 S. Philo Rd, Suite 36, Urbana, IL 61802, website www.aspca.org/apcc
b) It is an emergency telephone service which provides toxicology information to veterinarians, animal owners, universities, extension personnel and poison center staff for a fee. A veterinary toxicologist is available for consultation.
c) The following 24-hour phone number is available: (888) 426-4435. A fee may apply. Please inquire with the poison center. The agency will make follow-up calls as needed in critical cases at no extra charge.

11.2.2)

A) GENERAL

1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.

11.2.4)

A) GASTRIC DECONTAMINATION

1) DOGS/CATS

a) EMESIS AND LAVAGE - If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os.

1) Dogs may vomit more readily with 1 tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os.
2) Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage.
3) Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).

b) ACTIVATED CHARCOAL - Administer activated charcoal. Dose: 2 grams/kilogram per os or via stomach tube.
c) CATHARTIC - Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram). If access to these agents is limited, give 5 to 15 milliliters magnesium oxide (Milk of Magnesia) per os for dilution.

2) HORSES/CATTLE

a) EMESIS - Do not attempt to induce emesis in ruminants (cattle) or equids (horses).
b) ACTIVATED CHARCOAL - Give 250 to 500 grams activated charcoal in a water slurry per os or via stomach tube.
c) CATHARTIC - Administer an oral cathartic:

1) Mineral oil (small ruminants and swine, 60 to 200 milliliters; equids and cattle, 0.5 to 1 gallon)
2) Magnesium sulfate (ruminants and swine, 1 to 2 grams/kilogram; equine, 0.2 to 0.9 gram/kilogram)
3) Milk of Magnesia (small ruminants, up to 0.25 gram/kilogram in 1 to 3 gallons warm water; adult cattle up to 1 gram/kilogram in 1 to 3 gallons warm water or 2 to 4 boluses MgOH per os)
4) Give these solutions via stomach tube and monitor for aspiration.

11.2.5)

A) DOGS/CATS

1) Maintain vital functions: as necessary.
2) DECONTAMINATE as specified above.
3) SEIZURES -

a) DIAZEPAM - Dose of diazepam for DOGS & CATS: 0.5 milligram/kilogram intravenous bolus; may repeat dose every ten minutes for four total doses. Give slowly over 1 to 2 minutes.
b) PHENOBARBITAL may be used as adjunct treatment at 5 to 30 milligrams/kilogram over 5 to 10 minutes intravenously.
c) REFRACTORY SEIZURES - Consider anesthesia or heavy sedation. Administer pentobarbital to DOGS & CATS at a dose of 3 to 15 milligrams/kilogram intravenously slowly to effect. May need to repeat in 4 to 8 hours. Be sure to protect the airway.

B) RUMINANTS/HORSES/SWINE

1) Maintain vital functions: secure airway, supply oxygen and begin supportive fluid therapy if necessary.
2) DECONTAMINATE as specified above.
3) SEIZURES may be controlled with diazepam. Doses of diazepam, given slowly intravenously: HORSES: 1 milligram/kilogram; CATTLE, SHEEP AND SWINE: 0.5 to 1.5 milligrams/kilogram.

Range Of Toxicity

11.3.1)

A) SPECIFIC TOXIN

1) INDICATIONS - Antihistamines are commonly used in the treatment of canine atopy.
2) CHLORPHENIRAMINE - Dose for DOGS is 2 to 12 milligrams 2 to 3 times daily (Medleau, 1990).
3) DIPHENHYDRAMINE HCL - Dose for DOGS is 2 to 4 milligrams/ kilogram three times daily (Medleau, 1990).
4) TRIMEPRAZINE - Dose for DOGS is 1 to 2 milligrams/kilogram three times daily (Medleau, 1990).
5) CYPROHEPTADINE - Dose for DOGS is 0.3 to 2 milligrams/kilogram two times daily (Medleau, 1990).
6) HYDROXYZINE HCL - Dose for DOGS is 2 milligrams/kilogram three times daily (Medleau, 1990).
7) TERFENADINE - Dose for DOGS is 4 to 10 milligrams/kilogram two times daily (Medleau, 1990).
8) DOXYLAMINE SUCCINATE -

a) INJECTABLE - DOGS & CATS - 0.5 to 1 milligram/pound body weight two to three times daily. HORSES: 25 milligrams/100 pounds body weight (Prod Info, 1988).
b) TABLETS - Dosage for DOGS & CATS: 1 to 2 milligrams/pound body weight per day, divided into 3 or 4 equal doses (Prod Info, 1988).

11.3.2)

A) LACK OF INFORMATION

1) No specific information on a minimal toxic dose was available at the time of this review.

Continuing Care

11.4.1)

11.4.1.2) DECONTAMINATION/TREATMENT

A) GENERAL TREATMENT

1) Begin treatment immediately.
2) Keep animal warm and do not handle unnecessarily.
3) Sample vomitus, blood, urine, and feces for analysis.
4) ANIMAL POISON CONTROL CENTERS

11.4.2)

11.4.2.2) GASTRIC DECONTAMINATION

A) GASTRIC DECONTAMINATION

1) DOGS/CATS

a) EMESIS AND LAVAGE - If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os.

2) HORSES/CATTLE

Sources

1) DOXYLAMINE SUCCINATE -

a) INJECTABLE - A product marketed as A-H Injection contains 11.36 milligrams doxylamine succinate and 5 milligrams chlorobutanol (preservative) per milliliter. It comes in vials of 250 milliliters (Prod Info, 1988).
b) TABLET - A-H Tablets contain 100 milligrams doxylamine succinate each and come in bottles of 50 tablets (Prod Info, 1988).

Other

1) DOG

a) TERATOGENICITY - Antihistamines, especially hydroxyzine, may be teratogenic and should not be used in pregnant dogs (Medleau, 1990).

References

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ANTIHISTAMINE/DECONGESTANT

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Genitourinary

Hematologic

Musculoskeletal

Reproductive

Monitoring Parameters Levels

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Toxicity Information

Pharmacologic Mechanism

Toxicologic Mechanism

Clinical Effects

Treatment

Range Of Toxicity

Continuing Care

Sources

Other

General Bibliography