Torsade de pointes after astemizole overdose.

Craft, Tim

doi:10.1136/bmj.292.6521.660

Cited by 145 publications

(45 citation statements)

References 1 publication

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“…By 1986 several reports appeared of classic torsades de pointes ventricular arrhythmia [47,48] due to these two antihistamines, which were subsequently withdrawn from the market. In some cases off-label doses had been prescribed; in others excessively high plasma levels occurred due to co-administration of other drugs such as macrolide antibiotics or imidazole antifungals which, like terfenadine and astemizole, are metabolised via the cytochrome p450 enzyme pathway.…”

Section: Cardiotoxicitymentioning

confidence: 99%

Antihistamines in Dermatology

Greaves¹

2005

Skin Pharmacol Physiol

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Along with antibiotics, antihistamines are the most widely used systemic drugs in dermatology. This is attributable to the major role played by histamine in common diseases such as urticaria and atopic eczema. Of the currently recognised four subtypes of G protein-coupled histamine receptors, only the H₁ and H₂ subtypes have been positively identified in human skin. Traditionally believed to be competitive antagonists of histamine, H₁ and H₂ antihistamines are now considered to behave as inverse agonists. By consensus, H₁ antihistamines are classified as ‘first generation’ (associated with troublesome side-effects including somnolence, anti-adrenergic and atropine-like actions) and ‘second-generation’ compounds (in which these side-effects are reduced or absent). The main indications for H₁ antihistamines in skin are suppression of pruritus in urticaria and atopic eczema, both of which are associated with increased mast cell numbers and tissue histamine levels. However the evidence basis for use in atopic eczema is ambiguous and controversial, even though these drugs are widely used in practice. Currently, significant side-effects are mainly confined to the first-generation compounds and are especially troublesome in the elderly. Psychomotor impairment may persist throughout the day following administration. Anti-cholinergic and anti-α-adrenergic blockade and cardiotoxicity (torsade de pointes) may also occur with first-generation antihistamines. Two early low-sedation second-generation antihistamines caused arrhythmias in a small number of patients but these compounds have now been withdrawn. Generally, the second-generation H₁ antihistamines are well tolerated.

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Section: Cardiotoxicitymentioning

confidence: 99%

Antihistamines in Dermatology

Greaves¹

2005

Skin Pharmacol Physiol

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“…Over the past 30 years, second-generation antihistamines have been developed, which have less central activity and therefore do not cause the drowsiness. Overdose of both first-and second-generation antihistamines can cause severe cardiac arrhythmia (Hestand and Teske, 1977;Craft, 1986;Taglialatela et al, 2000) by directly inhibiting cardiac K ＋ currents (Taglialatela et al, 1999). These findings led us to hypothesize that chlorpheniramine, one of first-generation antihistamines, may exert arrhythmic effects by affecting K ＋ currents.…”

Section: Introductionmentioning

confidence: 99%

Block of hERG K+ Channel by Classic Histamine H1 Receptor Antagonist Chlorpheniramine

Hong

2009

Korean J Physiol Pharmacol

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Chlorpheniramine is a potent first-generation histamine H1 receptor antagonist that can increase action potential duration and induce QT prolongation in several animal models. Since block of cardiac human ether-a-go-go-related gene (hERG) channels is one of leading causes of acquired long QT syndrome, we investigated the acute effects of chlorpheniramine on hERG channels to determine the electrophysiological basis for its proarrhythmic potential. W e examined the effects of chlorpheniramine on the hERG channels expressed in Xenopus oocytes using two-microelectrode voltage-clamp techniques. Chlorpheniramine induced a concentration-dependent decrease of the current amplitude at the end of the voltage steps and hERG tail currents. The IC50 of chlorpheniramine-dependent hERG block in Xenopus oocytes decreased progressively relative to the degree of depolarization. Chlorpheniramine affected the channels in the activated and inactivated states but not in the closed states. The S6 domain mutations Y652A and F656A partially attenuated (Y652A) or abolished (F656A) the hERG current block. These results suggest that the H1 antihistamine, chlorpheniramine is a blocker of the hERG channels, providing a molecular mechanism for the drug-induced arrhythmogenic side effects.

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“…Since many of the patients to whom H2 antagonists are administered intravenously are frequently ill, it may be argued that any association with life-threatening arrhythmias is a reflection of the underlying disorder. It is also possible that the arrhythmias are related to the high histamine levels often seen in seriously ill patients (10,55), since recent reports suggest an association between ventricular arrhythmias and the use of H1 antagonists (11).…”

Section: Discussionmentioning

confidence: 99%

H2-receptor antagonism is not pro-arrhythmic in a chronic canine model

Uprichard¹,

Harron²

1990

Basic Res Cardiol

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Seven to 28 days after coronary artery ligation, programmed electrical stimulation was performed in conscious dogs. Groups of 6 previously inducible dogs in which no arrhythmia could presently be achieved were randomly allocated to receive quinidine, cimetidine, ranitidine or placebo. Results were assessed for the drugs' ability to induce ventricular tachycardia or fibrillation, and compared with placebo using Fisher's Exact Test. In the placebo group 4/6 dogs remained unchanged, one developed an arrhythmia, and one died. With quinidine, 3/6 dogs developed an arrhythmia (0.5 mg/kg, 4.0 mg/kg, 4.0 mg/kg) and three died (4 mg/kg, 8 mg/kg, 16 mg/kg) (p less than 0.05 compared with placebo). With cimetidine, 4/6 dogs remained unchanged, one developed an arrhythmia after 4 mg/kg, and one died after 0.5 mg/kg. After ranitidine 3/6 dogs remained unchanged and three died (1.0 mg/kg, 4.0 mg/kg, 16.0 mg/kg). PR, QTc, QRS, refractory periods, and mean systolic pressure remained unchanged after placebo, cimetidine, and ranitidine, but QTc increased (p less than 0.05) and mean systolic pressure fell (p less than 0.01) after quinidine. Heart rate did not change following placebo, but increased (p less than 0.05) after each of the three drug treatments. These results fail to show a significant arrhythmogenic effect of cimetidine or ranitidine in a model validated by the significant pro-arrhythmic effects of quinidine. The cause of death in all cases was ventricular fibrillation.

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Torsade de pointes after astemizole overdose.

Cited by 145 publications

References 1 publication

Antihistamines in Dermatology

Antihistamines in Dermatology

Block of hERG K+ Channel by Classic Histamine H1 Receptor Antagonist Chlorpheniramine

H2-receptor antagonism is not pro-arrhythmic in a chronic canine model

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