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Table 5 Adverse Effects of First-Generation H1 Antihistamines Versus Second-Generation H1 Antihistamines

From: H1 Antihistamines: Current Status and Future Directions

 

First Generation*,**,‡

Second Generation**,‡

CNS (mechanism: interference with neurotransmitter effect of histamine through H1 receptor)

After usual doses, may cause drowsiness, fatigue, somnolence, dizziness, impairment of cognitive function, memory, and psychomotor performance, headache, dystonia, dyskinesia, agitation, confusion, and hallucinations.

None with fexofenadine at doses up to 360 mg (off label); none with desloratadine 5 mg or loratadine 10 mg, although dose-related CNS effects may occur at higher doses; cetirizine doses 10 mg or higher may cause sedation in adults.

 

May cause adverse CNS effects in newborns if taken by the mother immediately before parturition; may cause irritability, drowsiness, or respiratory depression in nursing infants

No CNS adverse effects reported in newborns or nursing infants

Cardiac§ (mechanisms: multiple; antimuscarinic effects; α-adrenergic receptor blockade; blockade of cardiac ion currents [IKr and, less commonly, INa, Ito, IKi, and IKs])

Dose-related sinus tachycardia; reflex tachycardia, prolonged atrial refractive period, and supraventricular arrhythmias; dose-related prolongation of the QTc interval and ventricular arrhythmias reported for cyproheptadine, diphenhydramine, doxepin, hydroxyzine, promethazine, and others

No major concerns in any country (such as the United States or Canada), in which regulatory approval was withdrawn for astemizole and terfenadine

Other sites (mechanisms: blockade of muscarinic, α-adrenergic, and serotonin receptors)

After usual doses: may cause mydriasis (pupillary dilation), dry eyes, dry mouth, urinary retention and hesitancy, decreased gastrointestinal motility, constipation, memory deficits; peripheral vasodilation, postural hypotension, dizziness; appetite stimulation and weight gain (cyproheptadine, ketotifen); contraindicated in individuals with glaucoma or prostatic hypertrophy

None reported

Toxicity after overdose (mechanisms: multiple)

CNS effects such as extreme drowsiness, lethargy, confusion, delirium, and coma in adults; paradoxical excitation, irritability, hyperactivity, insomnia, hallucinations, seizures, and respiratory depression/arrest in infants and young children; in both adults and children, CNS adverse effects predominate over cardiac adverse effects; death may occur within hours after ingestion of drug in untreated patients; rhabdomyolysis has also been reported

No serious toxicity or fatality reported

Abuse of drugs (mechanisms: through H1 and other receptors in the CNS)

Euphoria, hallucinations and "getting high" reported for diphenhydramine, dimenhydrinate, and others

None reported

Teratogenicity after use in pregnancy||

FDA Category B (chlorpheniramine, diphenhydramine) or C (hydroxyzine, ketotifen)

FDA Category B (cetirizine, emedastine, levocetrizine, loratadine) or C (azelastine, epinastine, desloratadine, fexofenadine, olopatadine)

Carcinogenicity/tumor promotion

None reported in humans

None documented in humans

  1. *Most first-generation H1 antihistamines have not been prospectively studied for their adverse effects. The information is based on descriptions of adverse effects in case reports and case series published during the past 60 to 70 years. First-generation H1 antihistamines, particularly in the phenothiazine class, have been associated with sudden infant death syndrome, although causality has never been proven. First-generation H1 antihistamines such asdiphenhydramine or doxepin, applied topically to the skin, may cause contact dermatitis and if applied to abraded skin, they potentially cause systemic adverse effects.
  2. **Rarely, bothfirst-and second-generation H1 antihistamines are reported to cause adverse effects for which the mechanisms are incompletely understood:fixed-drug eruption, photosensitivity, urticaria, anaphylaxis, fever, liver enzyme elevation/hepatitis, agranulocytosis.
  3. ‡Intranasal or ophthalmic formulations of H1 antihistamines such as azelastine, emedastine, epinastine, levocabastine, ketotifen, and olopatadine have not been optimally studied using objective tests for adverse effects. They maycause stinging or burning upon application. Some of these formulations contain benzalkonium chloride 0.01%, which can dissolve contact lenses and should therefore be applied 10 minutes before insertion of lenses. Azelastine and emedastine may cause dysgeusia (bitter taste).
  4. §IKr, rapid component of the delayed rectifier potassium current; INa, sodium current; Ito, transient outward potassium current; IKi, inward rectifying current; IKs, slow component of the delayed rectifier potassium current.
  5. ||US FDA.
  6. Category A, animal studies and human studies negative; no H1 antihistamines in this category.
  7. Category B, animal studies negative, human data not available; or animal studies positive, human data negative.
  8. Category C, animal studies positive, human data not available; or neither animal nor human data available.
  9. Category D, animal studies positive or negative; human studies or reports positive.
  10. Adapted from Simons [2].