Terfenadine

Terfenadine structure

Terfenadine is an antihistamine that was historically administered for treating allergic reactions. Originated and brought to the global market by Hoechst Marion Roussel, which later evolved into Sanofi-Aventis, Terfenadine gained notable recognition and was sold under a myriad of brand monikers such as:

• Seldane in the United States
• Triludan in the United Kingdom
• Teldane in Australia

By the year 1990, the manufacturers proudly highlighted that terfenadine had been prescribed to a staggering 100 million patients globally1. However, due to potential heart-related side effects, it was soon replaced by fexofenadine in the ensuing decade.

Pharmacology and Metabolism

One of the notable characteristics of terfenadine is its status as a prodrug. This implies that terfenadine is not directly active in itself but undergoes metabolism to produce an active agent, in this case, fexofenadine. This metabolic transformation predominantly occurs in the liver and is orchestrated by the enzyme, cytochrome P450, particularly the CYP3A4 isoform.

Terfenadine synthesis

Interestingly, owing to its almost complete metabolism post-ingestion, traces of terfenadine are typically absent in the bloodstream. Yet, at elevated doses, terfenadine can exhibit cardiotoxic effects. Fortunately, fexofenadine, its active counterpart, doesn't share this adverse trait.

Mechanism of Action

Apart from its primary function as an antihistamine, terfenadine serves as a potassium channel blocker, specifically targeting Kv11.1 encoded by the hERG gene. Notably, fexofenadine, the active metabolite, doesn't have this potassium channel blocking property, ensuring the absence of cardiotoxicity linked with its use.

Risk Factors and Interactions

Terfenadine's long-term use does not necessarily guarantee its safe profile. Potential dangers can arise due to unforeseen interactions with specific medications or foods that inhibit the CYP3A4 enzyme, responsible for its metabolism. Examples include the antibiotic erythromycin and certain foods like grapefruit. Any alteration or addition in the dosage of these CYP3A4 inhibitors complicates the body's ability to process and expel terfenadine, leading to its accumulation.

At escalated plasma concentrations, terfenadine can have deleterious impacts on the heart, inducing complications such as ventricular tachycardia and torsades de pointes, both life-threatening heart rhythm disorders.

Conclusion

While Terfenadine marked a significant step in the realm of antihistamines, its associated risks eventually led to its substitution with safer alternatives like fexofenadine. A deep understanding of drug interactions and metabolic pathways is crucial to ensure the safe and effective use of therapeutic agents. First Generation Antihistamines

• Brompheniramine
• Carbinoxamine
• Chlorcyclizine
• Chlorpheniramine
• Clemastine
• Cyclizine
• Cyproheptadine
• Dexbrompheniramine
• Dexchlorpheniramine
• Dimenhydrinate
• Diphenhydramine
• Doxylamine
• Hydroxyzine
• Meclizine
• Phenyltoloxamine
• Promethazine
• Triprolidine

Second Generation Antihistamines

• Acrivastine
• Cetirizine
• Fexofenadine
• Levocetirizine
• Loratadine
• Desloratadine