Sinus arrest caused by atenolol‐verapamil combination

Misra, Mukul; Thakur, Ranjan K.; Bhandari, Kumar

doi:10.1002/clc.4960100613

Cited by 16 publications

(7 citation statements)

References 8 publications

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“…Although placebo was ingested daily during the control phase, the slightly red color in urine during the rifampicin phase did not allow a true blinding of the phases. Previous studies have reported that the calcium channel antagonists verapamil and diltiazem can increase the arrhythmogenic potential of atenolol (Findlay et al 1984;Misra et al 1987;Sagie et al 1991). A pharmacodynamic mechanism can explain these interactions, because both the two calcium-channel antagonists and atenolol can cause bradycardia.…”

Section: Discussionmentioning

confidence: 99%

Effect of Rifampicin on the Pharmacokinetics of Atenolol

Lilja

Juntti‐Patinen

Neuvonen

2006

Basic Clin Pharma Tox

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Also poorly metabolized drugs, including certain b-blocking agents, can be susceptible to drug interactions caused by transporter inhibitors and inducers. Thus, our aim was to investigate the effect of rifampicin on the pharmacokinetics of atenolol in healthy people. In a randomized cross-over study with two phases, nine healthy volunteers received a 5-day pretreatment with rifampicin (600 mg daily) or placebo. On day 6, a single 100 mg dose of atenolol was administered orally. The plasma concentrations of atenolol and its excretion into urine were measured up to 33 hr after dosing. Systolic and diastolic blood pressures and heart rate were recorded in a sitting position before the intake of atenolol and 2, 4, 6, and 10 hr later. During the rifampicin phase, the mean area under the plasma concentration-time curve (AUC 0-≤ ) of atenolol was decreased to 81% and renal clearance increased to 109% of the placebo phase values (PϽ0.05). Rifampicin pretreatment reduced, albeit not statistically significantly, also the peak plasma concentration (C max ), AUC 0-33 hr , and amount of atenolol excreted to 85% (PΩ0.139), 81% (PΩ0.053), and 86% (PΩ0.12) of the respective placebo phase values. The average heart rate and diastolic blood pressure were slightly higher during the rifampicin phase compared with the placebo phase (PϽ0.05). To conclude, although the inducing effect of rifampicin may not have been at its maximum by day 6, rifampicin has only a minor effect on the pharmacokinetics of atenolol evidenced by a slight reduction in its bioavailability.Atenolol is a cardioselective b-adrenoceptor-blocking agent used in the treatment of coronary heart disease, hypertension, and certain cardiac arrhythmias. The oral bioavailability is about 50%, mainly due to incomplete absorption (Dollery 1999). Metabolism only plays a negligible role in its elimination, and over 90% of the absorbed atenolol dose can be found as unchanged drug in urine. The mean elimination half-life of atenolol is approximately 6 hr (Wan et al. 1979).Also poorly metabolized compounds can be susceptible to pharmacokinetic drug-drug interactions. For instance, plasma concentrations of digoxin and celiprolol can be increased by concomitant itraconazole ingestion (Partanen et al. 1996;Lilja et al. 2003), and reduced by pretreatment with rifampicin (Greiner et al. 1999;Lilja et al. 2004). A previous study suggests that verapamil can increase plasma concentrations of atenolol (Keech et al. 1988). Furthermore, in a case report, blood pressure lowering effect of atenolol was found to be decreased during concomitant rifampicin (Goldberg et al. 2003).Rifampicin is a potent inducer of several cytochrome P450 enzymes and some transporters, and concomitant use of rifampicin with other drugs can reduce their absorption and increase their elimination (Greiner et al. 1999;Fromm et al. 2000;Niemi et al. 2003). The present study was conducted to investigate possible effects of rifampicin on the pharmacokinetics of atenolol in healthy persons.Author for corresponden...

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Section: Discussionmentioning

confidence: 99%

Effect of Rifampicin on the Pharmacokinetics of Atenolol

Lilja

Juntti‐Patinen

Neuvonen

2006

Basic Clin Pharma Tox

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“…Co‐administration of atenolol with verapamil and diltiazem can cause symptomatic bradycardia and sinus arrest (Findlay et al 1984; Misra et al 1987; Sagie et al 1991). This can be explained as a pharmacodynamic interaction, because both calciumchannel antagonists and atenolol have a negative chronotropic effect.…”

Section: Discussionmentioning

confidence: 99%

Effect of Itraconazole on the Pharmacokinetics of Atenolol

Lilja

Backman

Neuvonen

2005

Basic Clin Pharma Tox

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Our objective was to evaluate the effect of itraconazole on the pharmacokinetics of atenolol in healthy volunteers. In a randomized cross-over study with two phases, 10 healthy volunteers had 200 mg itraconazole orally or placebo for 2 days b.i.d., and in the morning of day 3, one hour after the last ingestion of itraconazole or placebo, each subject received 50 mg atenolol. The plasma concentrations of atenolol and its excretion into urine were measured up to 33 hr. Blood pressures and heart rate were recorded up to 10 hr. Itraconazole had no statistically significant effect on any of the pharmacokinetic or pharmacodynamic variables of atenolol. If anything, itraconazole increased the area under the plasma concentration-time curve (+12%; P = 0.159), peak plasma concentration (+19%; P = 0.165), and amount of atenolol excreted into urine (+13%; P = 0.166) suggesting a slight increase of atenolol bioavailability. It can be concluded that itraconazole does not have a clinically relevant effect on the pharmacokinetics of atenolol.

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“…It is widely known that the synergistic effects of β-adrenergic blockers and calcium channel blockers of the verapamil or diltiazem type on BP, myocardial contractility and conductance may result in hypotension, bradycardia and heart failure [102][103][104][105][106]. Older patients in particular, in whom heart failure, sinus node disease and impairment of the cardiac conduction system are more common, may be at an increased risk for this type of interaction.…”

Section: Calcium Channel Blockersmentioning

confidence: 99%

“…Diltiazem [102][103][104][105][106]124,125] Negative inotropism Impairment of AV-conduction Heart failure AV-block Nifedipine [107] Negative inotropism Heart failure (rare)…”

Section: Renal Eliminationmentioning

confidence: 99%

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Antihypertensive therapy: special focus on drug interactions

Maas

Böger²

2003

Expert Opinion on Drug Safety

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Today, the lifetime risk of patients aged 55-65 years to receive antihypertensive drugs approaches 60%. Yet, recent trials suggest that hypertension is not adequately controlled in the majority of patients. The prevalence of hypertension increases with advancing age, as does the prevalence of comorbid conditions and the total number of medications taken. Multi-drug therapy, advancing age and comorbid conditions are also key risk factors for adverse drug reactions and drug interactions. In this review, the authors evaluate the most frequently used antihypertensive drugs (diuretics, beta-adrenergic blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers, angiotensin II receptor Type 1 blockers and alpha-adrenergic blockers) with special reference to pharmacodynamic and pharmacokinetic drug interactions. As the spectrum of drugs prescribed is constantly changing, safety yesterday does not imply safety today and safety today does not imply safety tomorrow. Furthermore, therapeutic efficacy should not be neglected over concerns regarding drug interactions. Many patients are at risk of clinically relevant drug interactions involving antihypertensive drugs but, presently, even more patients may be at risk of suffering from the consequences of their inadequately treated hypertension. In this respect, the authors discuss controversial viewpoints on the overall clinical relevance of drug interactions occurring at the level of cytochrome P450 metabolism.

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Sinus arrest caused by atenolol‐verapamil combination

Cited by 16 publications

References 8 publications

Effect of Rifampicin on the Pharmacokinetics of Atenolol

Effect of Rifampicin on the Pharmacokinetics of Atenolol

Effect of Itraconazole on the Pharmacokinetics of Atenolol

Antihypertensive therapy: special focus on drug interactions

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