Antihistamines (histamine H1-antagonists) vary in their interaction profiles by sedative potential,route of metabolism, and cardiotoxicity (QT interval prolongation) .
The older antihistamines (e.g. chlorphenamine,diphenhydramine and hydroxyzine) are also referred to as sedating antihistamines or first-generation antihistamines. As former name suggests they have potential to cause additive sedative effects with other sedating drugs. This type of interaction is discussed elsewhere,see CNS depressants + CNS depressants interaction. The sedating antihistamines also tend to have antimuscarinic (also called anticholinergic) adverse effects and so therefore may interact additively with other antimuscarinic-type drugs. This is also discussed elsewhere,see Antimuscarinics + Antimuscarinics interaction.
The newer (non-sedating antihistamines or second-generation antihistamines) have a low potential to cause sedative effects. This appears to be because they are substrates for P-glycoprotein, an efflux transporter found in many organs, which would have effect of actively ejecting any drug molecules that crossed blood-brain barrier. Nevertheless, sedation may occur on rare occasions and patients should be advised to be alert to possibility of drowsiness if they have not taken drug before. Any drowsiness is likely to become apparent after first few doses, and would indicate that additive sedative effects with other sedating drugs might be expected. The antihistamines are listed,by sedative potential, in table 1 below,(below).
Some of sedating antihistamines, such as diphenhydramine, are inhibitors of cytochrome P450 isoenzyme CYP2D6. None of non-sedating antihistamines are known to inhibit cytochrome P450 isoenzymes, but some are substrates for CYP3A4 including astemizole, desloratadine, ebastine, loratadine, mizolastine, and terfenadine, see table 2 below,. This has important consequences for potential cardiotoxicity of astemizole and terfenadine, see (c) below. Loratadine and desloratadine are also substrates for CYP2D6,and mizolastine is also metabolised by glucuronidation. Cetirizine,levocetirizine and fexofenadine are minimally metabolised. Where pharmacokinetic interactions occur with fexofenadine,these appear to be mediated via drug transporters such as P-glycoprotein and/or organic anion transport polypeptide (OATP). For more information see Drug transporter proteins,.
Important drug interactions occur with non-sedating antihistamines astemizole and terfenadine
mines can block potassium channels, lengthening QT interval and increasing risk of potentially fatal cardiac arrhythmias (torsade de pointes). Therefore, dangerous interactions may result when other drugs reduce metabolism of astemizole or terfenadine, usually by inhibition of cytochrome P450 isoenzyme CYP3A4. Such drugs include macrolides’, and azoles, . Adverse interactions are also predicted when astemizole or terfenadine are used with drugs that prolong QT interval, see Antihistamines + Drugs that prolong QT interval. Due to these potentially fatal interactions, astemizole has been withdrawn from many countries, while terfenadine has been withdrawn in US and reclassified as a prescription-only medicine in UK. Apart from possibly ebastine, loratadine and mizolastine, where information is inconclusive, none of other non-sedating antihistamines have been clearly shown to be associated with QT prolongation (see ‘table 2 below,). Therefore,even when pharmacokinetic interactions result in increased levels, these are unlikely to be clinically important in terms of cardiotoxicity.
Acrivastine,Astemizole,* Cetirizine, Desloratadine, Ebastine,* Fexofenadine, Levocetirizine, Loratadine, Mizolastine,* Rupatadine, Terfenadine*
Azatadine,Brompheniramine, Buclizine, Chlorphenamine, Cinnarizine, Clemastine, Cyclizine, Cyproheptadine, Dexchlorpheniramine, Flunarizine, Meclozine, Mepyramine, Mequitazine, Pheniramine, Tripelennamine, Triprolidine
Alimemazine,Bromazine, Carbinoxamine, Dimenhydrinate, Diphenhydramine, Doxylamine, Hydroxyzine, Promethazine, Trimeprazine
Antazoline,Azelastine, Emedastine, Epinastine, Levocabastine, Olopatadine
(See reference number *)Important QT prolongation known to occur (astemizole,terfenadine), or may possibly occur (ebastine, mizolastine), see table 2 below,p. 583
Drug blocks HERG† potassium channel in vitro
Yes. See Azoles,p. 584
Yes. See Azoles,p. 584,or Macrolides, p. 589
Yes. See Azoles,p. 584,or Macrolides, p. 589
Yes,in one study10
Yes. See Azoles,p. 584,or Nefazodone, p. 592
Yes. See Azoles,p. 584,or Macrolides, p. 589
Yes. See Azoles,p. 584
Yes. See Azoles,p. 584,Macrolides, p. 589,or Nefazodone, p. 592
Yes. See Azoles,p. 584,or Macrolides, p. 589
Blocking HERG channels results in prolongation of QT interval
Zhou Z,Vorperian VR, Gong Q, Zhang S, January CT. Block of HERG potassium channels by antihistamine astemizole and its metabolites desmethylastemizole and norastemizole. J Cardiovasc Electrophysiol (1999) 10,836–43.
Craft TM. Torsade de pointes after astemizole overdose. BMJ (1986) 292,660.
Snook J,Boothman-Burrell D, Watkins J, Colin-Jones D. Torsade de pointes ventricular tachycardia associated with astemizole overdose. Br J Clin Pract (1988) 42,257–9.
Simons FER,Kesselman MS, Giddins NG, Pelech AN, Simons KJ. Astemizole-induced torsade de pointes. Lancet (1988) ii,624.
Bishop RO,Gaudry PL. Prolonged Q-T interval following astemizole overdose. Arch Emerg Med (1989) 6,63–5.
Hasan RA,Zureikat GY, Nolan BM. Torsade de pointes associated with astemizole overdose treated with magnesium sulfate. Pediatr Emerg Care (1993) 9,23–5.
Gowardman J. QT prolongation on standard dose of astemizole. N Z Med J (1996) 109,38.
Vorperian VR,Zhou Z, Mohammad S, Hoon TJ, Studenik C, January CT. Torsade de pointes with an antihistamine metabolite: potassium channel blockade with desmethylastemizole. J Am Coll Cardiol (1996) 28,1556–61.
Ko CM,Ducic I, Fan J, Shuba YM, Morad M. Suppression of mammalian K+ channel family by ebastine. J Pharmacol Exp Ther (1997) 281,233–44.
Crumb WJ. Loratadine blockade of K+ channels in human heart: comparison with terfenadine under physiological conditions. J Pharmacol Exp Ther (2000) 292,261–4.
Kuchar DL,Walker BD, Thorburn CW. Ventricular tachycardia following ingestion of a commonly used antihistamine,Med J Aust (2002) 176, 429–30.
Sager PT,Veltri EP. Ventricular tachycardia following ingestion of a commonly used antihistamine. Med J Aust (2003) 178,245–6.
Kuchar DL,Walker BD, Thorburn CW. In reply. Med J Aust (2003) 178,246.
Taglialatela M,Pannaccione A, Castaldo P, Giorgio G, Annunziato L. Inhibition of HERG1 K(+) channels by novel second-generation antihistamine mizolastine. Br J Pharmacol (2000) 131,1081–8.
Woosley RL,Chen Y, Freiman JP, Gillis RA. Mechanism of cardiotoxic actions of terfenadine. JAMA (1993) 269,1532–6.
MacConnell TJ,Stanners AJ. Torsades de pointes complicating treatment with terfenadine. Br Med J (1991) 302,1469.
June RA,Nasr I. Torsades de pointes with terfenadine ingestion. Am J Emerg Med (1997) 15,542–3.
Renard S,Ostorero M, Yvorra S, Zerrouk Z, Bargas E, Bertocchio P, Pracchia S, Ebagosti A. Torsades de pointes caused by cetirizine overdose. Arch Mal Coeur Vaiss (2005) 98; 157–61.
Pinto YM,van Gelder IC, Heeringa M, Crijns HJ. QT lengthening and life-threatening arrhythmias associated with fexofenadine. Lancet (1999),353, 980.
Scherer CR,Lerche C, Decher N, Dennis AT, Maier P, Ficker E, Busch AE, Wollnik B, Steinmeyer K. The antihistamine fexofenadine does not affect Ikr currents in a case report of drug-induced cardiac arrhythmia. Br J Pharmacol (2002) 137,892–900.
| Table 1 Systemic antihistamines (classified by sedative potential) and topical antihistamines | |
|---|---|
| Sedative potential | Antihistamine |
| Non-sedative | Acrivastine, Astemizole,* Cetirizine, Desloratadine, Ebastine,* Fexofenadine, Levocetirizine, Loratadine, Mizolastine,* Rupatadine, Terfenadine* |
| Sedating | Azatadine, Brompheniramine, Buclizine, Chlorphenamine, Cinnarizine, Clemastine, Cyclizine, Cyproheptadine, Dexchlorpheniramine, Flunarizine, Meclozine, Mepyramine, Mequitazine, Pheniramine, Tripelennamine, Triprolidine |
| Significantly sedating | Alimemazine, Bromazine, Carbinoxamine, Dimenhydrinate, Diphenhydramine, Doxylamine, Hydroxyzine, Promethazine, Trimeprazine |
| Topical use (mainly) | Antazoline, Azelastine, Emedastine, Epinastine, Levocabastine, Olopatadine |
| Table 2 Metabolism and cardiac effects o | f non-sedating antihistamines | ||||
|---|---|---|---|---|---|
| Drug | Drug blocks the HERG† potassium channel in vitro | QTc interval prolongation shown in pharmacological studies with drug alone | QTc interval prolongation shown in pharmacological studies with CYP3A4 inhibitors | Case reports of torsade de pointes with drug alone | Case reports of torsade de pointes with CYP3A4 inhibitors |
| Metabolised by CYP3A4 | |||||
| Astemizole | Yes1 | Yes2 | Yes. See Azoles, p. 584 | Several2-8 | Yes. See Azoles, p. 584, or Macrolides, p. 589 |
| Desloratadine | No | No | No | No | No |
| Ebastine | Yes9 | Uncertain | Yes. See Azoles, p. 584, or Macrolides, p. 589 | No | No |
| Loratadine | Yes, in one study10 | No | Yes. See Azoles, p. 584, or Nefazodone, p. 592 | Possible case11-13 | Yes. See Azoles, p. 584, or Macrolides, p. 589 |
| Mizolastine | Yes14 | Uncertain | Yes. See Azoles, p. 584 | No | No |
| Terfenadine | Yes10,15 | Yes | Yes. See Azoles, p. 584, Macrolides, p. 589, or Nefazodone, p. 592 | A few16,17 | Yes. See Azoles, p. 584, or Macrolides, p. 589 |
| Not metabolised by CYP3A4 | |||||
| Cetirizine | No | No | No | Possible case18 | No |
| Fexofenadine | No | No | No | Possible case19,20 | No |
| Levocetirizine | No | No | No | No | No |
| Table 3 Metabolism and cardiac effects o | f non-sedating antihistamines | ||||
|---|---|---|---|---|---|
| Drug | Drug blocks the HERG† potassium channel in vitro | QTc interval prolongation shown in pharmacological studies with drug alone | QTc interval prolongation shown in pharmacological studies with CYP3A4 inhibitors | Case reports of torsade de pointes with drug alone | Case reports of torsade de pointes with CYP3A4 inhibitors |
| Metabolised by CYP3A4 | |||||
| Astemizole | Yes1 | Yes2 | Yes. See Azoles, p. 584 | Several2-8 | Yes. See Azoles, p. 584, or Macrolides, p. 589 |
| Desloratadine | No | No | No | No | No |
| Ebastine | Yes9 | Uncertain | Yes. See Azoles, p. 584, or Macrolides, p. 589 | No | No |
| Loratadine | Yes, in one study10 | No | Yes. See Azoles, p. 584, or Nefazodone, p. 592 | Possible case11-13 | Yes. See Azoles, p. 584, or Macrolides, p. 589 |
| Mizolastine | Yes14 | Uncertain | Yes. See Azoles, p. 584 | No | No |
| Terfenadine | Yes10,15 | Yes | Yes. See Azoles, p. 584, Macrolides, p. 589, or Nefazodone, p. 592 | A few16,17 | Yes. See Azoles, p. 584, or Macrolides, p. 589 |
| Not metabolised by CYP3A4 | |||||
| Cetirizine | No | No | No | Possible case18 | No |
| Fexofenadine | No | No | No | Possible case19,20 | No |
| Levocetirizine | No | No | No | No | No |
| Table 4 Metabolism and cardiac effects o | f non-sedating antihistamines | ||||
|---|---|---|---|---|---|
| Drug | Drug blocks the HERG† potassium channel in vitro | QTc interval prolongation shown in pharmacological studies with drug alone | QTc interval prolongation shown in pharmacological studies with CYP3A4 inhibitors | Case reports of torsade de pointes with drug alone | Case reports of torsade de pointes with CYP3A4 inhibitors |
| Metabolised by CYP3A4 | |||||
| Astemizole | Yes1 | Yes2 | Yes. See Azoles, p. 584 | Several2-8 | Yes. See Azoles, p. 584, or Macrolides, p. 589 |
| Desloratadine | No | No | No | No | No |
| Ebastine | Yes9 | Uncertain | Yes. See Azoles, p. 584, or Macrolides, p. 589 | No | No |
| Loratadine | Yes, in one study10 | No | Yes. See Azoles, p. 584, or Nefazodone, p. 592 | Possible case11-13 | Yes. See Azoles, p. 584, or Macrolides, p. 589 |
| Mizolastine | Yes14 | Uncertain | Yes. See Azoles, p. 584 | No | No |
| Terfenadine | Yes10,15 | Yes | Yes. See Azoles, p. 584, Macrolides, p. 589, or Nefazodone, p. 592 | A few16,17 | Yes. See Azoles, p. 584, or Macrolides, p. 589 |
| Not metabolised by CYP3A4 | |||||
| Cetirizine | No | No | No | Possible case18 | No |
| Fexofenadine | No | No | No | Possible case19,20 | No |
| Levocetirizine | No | No | No | No | No |