Pseudoephedrine and phenylephrine are sympathomimetic drugs that are widely available in nonprescription nasal decongestants and cold preparations. These remedies often contain antihistamines and cough suppressants, such as dextromethorphan. Nonprescription ephedrine-containing cough and cold preparations as well as ephedrine-containing dietary supplements were widely consumed until 2004, when their use was banned by the FDA because of the unacceptable risk for toxicity. Ephedrine and ephedra-containing herbal preparations (eg, ma huang and “herbal ecstasy”), often combined with caffeine, were also used as alternatives to the amphetamine derivative “ecstasy” or as adjuncts to body-building or weight loss programs. Phenylpropanolamine (PPA) had been marketed as a nonprescription decongestant and appetite suppressant for many years but was removed from the US market in 2000 and subsequently in many other countries because of an association with hemorrhagic stroke in women. The availability of nonprescription pseudoephedrine is limited in many states because it can be used to manufacture illicit methamphetamine. The FDA issued an advisory in 2008 recommending against the use of cough and cold medicines (which contain decongestants as well as antihistamines and/or dextromethorphan) in children younger than 2 years of age because of reports of serious and life-threatening side effects, including fatalities.

All these agents stimulate the adrenergic system, with variable effects on alpha- and beta-adrenergic receptors, depending on the compound. Generally, these agents stimulate the CNS much less than do other phenylethylamines (see “Amphetamines,”).

1. PPA and phenylephrine are direct alpha₁-adrenergic agonists. In addition, PPA produces mild beta₁-adrenergic stimulation and acts in part indirectly by enhancing norepinephrine release.
2. Ephedrine and pseudoephedrine have both direct and indirect alpha- and beta-adrenergic activity but clinically produce more beta-adrenergic stimulation than does PPA or phenylephrine.
3. Pharmacokinetics. Peak effects occur within 1-3 hours, although absorption may be delayed with sustained-release products. Pseudoephedrine, ephedrine and PPA are primarily renally cleared. Elimination half-lives are 3-9 hours (see also Table II-63,).

Table II-51 lists the usual therapeutic doses of each agent. Patients with autonomic insufficiency and those taking monoamine oxidase (MAO) inhibitors may be extraordinarily sensitive to these and other sympathomimetic drugs, developing severe hypertension after ingestion of even subtherapeutic doses. Patients with chronic kidney disease may experience toxicity with therapeutic dosing of pseudoephedrine, ephedrine, and PPA due to reduced renal clearance.

1. PPA, phenylephrine, and ephedrine have low toxic-to-therapeutic ratios. Toxicity often occurs after ingestion of just 2-3 times the therapeutic dose. Strokes and cardiac toxicity have been reported after therapeutic doses of ephedra and PPA.
2. Pseudoephedrine is less toxic, with symptoms occurring after four- to five-fold the usual therapeutic dose.

The time course of intoxication by these drugs is usually brief, with resolution within 4-6 hours (unless sustained-release preparations are involved). The major toxic effect is hypertension, which may lead to headache, confusion, seizures, and intracranial hemorrhage. Toxicity can also include anxiety and agitation, particularly with co-ingestion of antihistamines, caffeine or dextromethorphan.

1. Intracranial hemorrhage may occur in normal, healthy young persons after what appears to be only a modest elevation of blood pressure (ie, 170/110 mm Hg) and is often associated with focal neurologic deficits, coma, or seizures.
2. Bradycardia or atrioventricular (AV) block is common in patients with moderate-to-severe hypertension associated with PPA and phenylephrine owing to the baroreceptor reflex response. The presence of drugs such as antihistamines and caffeine may enhance the hypertensive effects of PPA and phenylephrine by preventing this reflex bradycardia.
3. Myocardial infarction and diffuse myocardial necrosis have been associated with phenylephrine, ephedra use, and PPA intoxication. Acute left ventricular failure can be seen in the context of severe hypertension.

Is based on a history of ingestion of diet pills or decongestant medications and the presence of hypertension. Bradycardia or AV block suggests PPA or phenylephrine. Severe headache, focal neurologic deficits, or coma should raise the possibility of intracerebral hemorrhage.

1. Specific levels. Serum drug levels are not generally available and do not alter treatment. In high doses, these agents may produce positive results for amphetamines on the urine drug screen (see Table I-32,) but can be distinguished with confirmatory testing. Many of these amines produce a positive result on urine drug screen immunoassays for amphetamines.
2. Other useful laboratory studies include electrolytes, glucose, BUN, creatinine, cardiac troponin, 12-lead ECG and ECG monitoring, and CT head scan if intracranial hemorrhage is suspected.

1. Emergency and supportive measures
   1. Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen.
   2. Treat hypertension aggressively (see hypertension and Item B below). Treat seizures and ventricular tachyarrhythmias if they occur. Do not treat reflex bradycardia except indirectly by lowering blood pressure.
   3. Monitor the vital signs and ECG for a minimum of 4-6 hours after exposure and longer if a sustained-release preparation has been ingested.
2. Specific drugs and antidotes
   1. Hypertension. Treat hypertension if the diastolic pressure is higher than 100-105 mm Hg, especially in a patient with no prior history of hypertension. If there is intracranial hemorrhage, lower the diastolic pressure cautiously to no lower than 90 mm Hg and consult a neurosurgeon immediately.
      1. Use a vasodilator such as phentolamine or nitroprusside.
      2. Caution: Do not use beta blockers to treat hypertension without first giving a vasodilator; otherwise, paradoxical worsening of the hypertension may result.
      3. Many patients have moderate orthostatic variation in blood pressure; therefore, for immediate partial relief of severe hypertension, try placing the patient in an upright position.
   2. Arrhythmias
      1. Tachyarrhythmias usually respond to low-dose esmolol or metoprolol.
      2. Caution: Do not treat AV block or sinus bradycardia associated with hypertension; increasing the heart rate with atropine may abolish this reflex response that serves to limit hypertension, resulting in worsening hypertension.
   3. Treat anxiety and agitation with benzodiazepines.
3. Decontamination . Administer activated charcoal orally if conditions are appropriate (see Table I-37,). Gastric lavage is not necessary after small-to-moderate ingestions if activated charcoal can be given promptly.
4. Enhanced elimination. Dialysis and hemoperfusion are not effective. Urinary acidification may enhance elimination of PPA, ephedrine, and pseudoephedrine but can exacerbate rhabdomyolysis-associated kidney injury and is not recommended.