QT time prolongation
Adverse drug events
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Explanations of the substances for patients
The changes in exposure mentioned relate to changes in the plasma concentration-time curve [AUC]. We did not detect any change in exposure to amiodarone. We cannot currently estimate the influence of diltiazem. Diltiazem exposure increases to 143%, when combined with amiodarone (143%).
The pharmacokinetic parameters of the average population are used as the starting point for calculating the individual changes in exposure due to the interactions.
Amiodarone has a mean oral bioavailability [ F ] of 55%, which is why the maximum plasma levels [Cmax] tend to change with an interaction. The terminal half-life [ t12 ] is rather long at 1884 hours and constant plasma levels [ Css ] are only reached after more than 7536 hours. The protein binding [ Pb ] is 96% strong. The metabolism takes place via CYP2C8 and CYP3A4, among others and the active transport takes place in particular via PGP.
Diltiazem has a low oral bioavailability [ F ] of 39%, which is why the maximum plasma level [Cmax] tends to change strongly with an interaction. The terminal half-life [ t12 ] is rather short at 6 hours and constant plasma levels [ Css ] are reached quickly. The protein binding [ Pb ] is moderately strong at 77.5% and the volume of distribution [ Vd ] is very large at 350 liters. which is why, with a mean hepatic extraction rate of 0.53, both liver blood flow [Q] and a change in protein binding [Pb] are relevant. The metabolism takes place via CYP2D6 and CYP3A4, among others and the active transport takes place in particular via PGP.
|Serotonergic Effects a||0||Ø||Ø|
Rating: According to our knowledge, neither amiodarone nor diltiazem increase serotonergic activity.
Recommendation: As a precaution, attention should be paid to anticholinergic symptoms, especially after increasing the dose and at doses in the upper therapeutic range.
Rating: Diltiazem only has a mild effect on the anticholinergic system. The risk of anticholinergic syndrome with this medication is rather low if the dosage is in the usual range. According to our findings, amiodarone does not increase anticholinergic activity.
QT time prolongation
Rating: Amiodarone can trigger potentially torsades de pointes ventricular arrhythmias. We do not know of any QT-prolonging potential for diltiazem.
General adverse effects
|Side effects||∑ frequency||ami||dil|
|Loss of appetite||6.5 %||6.5||n.a.|
|Coordination problem||6.5 %||6.5||n.a.|
Blurred vision (6.5%): amiodarone
Optic neuritis: amiodarone
Visual loss: amiodarone
Peripheral edema (6.3%): diltiazem
Bradycardia (2.6%): amiodarone, diltiazem
Heart failure (1.9%): amiodarone, diltiazem
Atrioventricular block: diltiazem
Ventricular arrhythmia: amiodarone
Myocardial infarction: diltiazem
Fatigue (4.8%): diltiazem
Headache (4.6%): diltiazem
Peripheral neuropathy: amiodarone
Pseudotumor cerebri: amiodarone
Hyperthyroidism (2%): amiodarone
Acute respiratory distress syndrome (2%): amiodarone
Cough (2%): diltiazem
Pulmonary fibrosis: amiodarone
Allergic skin reactions like pruritus and rash: diltiazem
Stevens johnson syndrome: amiodarone
Toxic epidermal necrolysis: amiodarone
Hepatotoxicity: amiodarone, diltiazem
Hypersensitivity reaction: amiodarone
Renal failure: amiodarone
Based on your
Abstract: The calcium antagonists are valuable and widely used agents in the management of essential hypertension and angina. There is an increasing number of new agents to add to the 3 prototype substances nifedipine, diltiazem and verapamil. These new agents are dihydropyridines structurally related to nifedipine. However, they tend to have longer elimination half-lives (t 1/2 beta) and may be suitable for twice-daily administration. Amlodipine is an exception with a t 1/2 beta in excess of 30h. Apart from elimination rates, however, the pharmacokinetic characteristics of the newer agents have a notable tendency to resemble those of the established agents. They are highly cleared drugs, are relatively highly protein bound. As they are subject to significant first-pass metabolism, old age and hepatic impairment will increase their plasma concentrations due to a reduced first-pass effect. Renal impairment does little to their pharmacokinetics since the fraction eliminated unchanged by the kidney is small. For most agents, plasma concentration-response relationships have been described. Interesting areas for further research include chronopharmacokinetics, stereoselective pharmacokinetics and lipid solubility. Drugs affecting hepatic blood flow and drug metabolising capacity have predictable interaction potential. Some of the newer calcium antagonists will, like verapamil, increase plasma digoxin concentrations. Verapamil and diltiazem decrease phenazone (antipyrine) metabolism and therefore tend to decrease the metabolism of other drugs.
Abstract: We have investigated the pharmacokinetics of 14C-labeled diltiazem, 20 mg, given as an i.v. infusion over 20 min in 10 healthy volunteers. This disposition of the drug could be described using a two-compartment model with half-lives of 0.40 +/- 0.48 h (mean +/- SD) in the alpha phase and 2.77 +/- 0.82 h in the beta phase. Systemic clearance was 992 +/- 159 ml/min; the volume of the central compartment was 119 +/- 77 L, and the volume of distribution at steady state was 209 +/- 56 L. The concentrations of metabolites (deacetyldiltiazem, N-demethyldiltiazem, and N-demethyl-deacetyldiltiazem) were low, and no pharmacokinetic parameters for these could be calculated. The median cumulative excretion of radioactivity during 120 h was 87.3%. The drug was mainly excreted in urine (71.1 +/- 7.8%), and the remaining amounts was excreted in feces. There were slight but significant decreases in supine systolic and diastolic blood pressures and heart rate. The PQ interval was significantly prolonged for 5 h, and in multiple regression analyses there were good correlations (p less than 0.01) between PQ intervals and logarithms of plasma concentrations of diltiazem.
Abstract: Six healthy male volunteers received single doses of diltiazem hydrochloride on three occasions separated by at least 10 days. Modes of administration were: 10-minute intravenous infusion of a 20-mg dose; oral administration of 120 mg in solution form; and oral administration of 120 mg as two 60-mg sustained-release tablets. Diltiazem concentrations were measured by electron-capture gas chromatography in multiple plasma samples drawn during the 36 hours after dosage. Following intravenous administration, mean (+/- S.E.) pharmacokinetic variables were: elimination half-life, 11.2 (+/- 2.1) hours; volume of distribution, 11.1 (+/- 3.0) liters/kg; and total clearance, 11.5 (+/- 0.7) ml/min/kg. Oral diltiazem in solution form was rapidly absorbed, with peak plasma levels attained at 38 (+/- 6) minutes after the dose. Absolute systemic availability averaged 44% (+/- 4%). Oral administration of sustained-release tablets yielded, as predicted, slower absorption, with peak plasma concentrations attained at an average of 165 (+/- 22) minutes after dosage. Thus, oral diltiazem is incompletely bioavailable after oral administration, mainly because of first-pass hepatic extraction.
Abstract: Amiodarone is considered to be safe in patients with prior QT prolongation and torsades de pointes taking class I antiarrhythmic agents who require continued antiarrhythmic drug therapy. However, the safety of amiodarone in advanced heart failure patients with a history of drug-induced torsades de pointes, who may be more susceptible to proarrhythmia, is unknown. Therefore, the objective of this study was to assess amiodarone safety and efficacy in heart failure patients with prior antiarrhythmic drug-induced torsades de pointes. We determined the history of torsades de pointes in 205 patients with heart failure treated with amiodarone, and compared the risk of sudden death in patients with and without such a history. To evaluate the possibility that all patients with a history of torsades de pointes would be at high risk for sudden death regardless of amiodarone treatment, we compared this risk in patients with a history of torsades de pointes who were and were not subsequently treated with amiodarone. Of 205 patients with advanced heart failure, 8 (4%) treated with amiodarone had prior drug-induced torsades de pointes. Despite similar severity of heart failure, the 1-year actuarial sudden death risk was markedly increased in amiodarone patients with than without prior torsades de pointes (55% vs 15%, p = 0.0001). Similarly, the incidence of 1-year sudden death was markedly increased in patients with prior torsades de pointes taking amiodarone compared with such patients who were not subsequently treated with amiodarone (55% vs 0%, p = 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)
Abstract: OBJECTIVE: In a previous study of diltiazem (DTZ) pharmacokinetics in renal transplant patients, we speculated that a polymorphic enzyme could be involved in O-demethylation of diltiazem. The aim of this in vitro study was to investigate whether O-demethylation of DTZ is mediated by cytochrome P450-2D6 (CYP2D6). METHODS: DTZ was incubated with transfected human liver epithelial (THLE) cells expressing CYP2D6 (T5-2D6 clone). Metabolism of DTZ was studied over a concentration range of 12.5-400 microM and in the presence of quinidine (a CYP2D6 inhibitor) or erythromycin (a CYP3A4 inhibitor). THLE cells lacking CYP2D6 activity (T5-neo clone) were used as control. The culture medium of the cells, in which DTZ was dissolved, was analysed for DTZ and metabolites prior to and after 8 h of incubation using high-performance liquid chromatography (HPLC, UV detection). Authentic O-demethyl-DTZ (Mx) was not available, and this metabolite was therefore not identifiable. RESULTS: Desacetyl-O-demethyl-DTZ (M4) was exclusively produced during incubations of DTZ with THLE cells expressing CYP2D6. The rate of M4 formation was described using Michaelis Menten kinetics in the concentration range of DTZ used. Production of M4 was inhibited by quinidine, but not erythromycin. An unidentified chromatographic peak, which was interpreted to be Mx, showed the same pattern of formation as M4 both in absence and presence of inhibitors. N-demethylated metabolites, formed by CYP3A4, were not observed in any of the cell lines. CONCLUSION: Evidence was provided in vitro that O-demethylation of DTZ is mediated by the polymorphic isoenzyme CYP2D6. Involvement of CYP2D6 in the metabolism of DTZ may have clinical implications regarding pharmacokinetic variability and interactions.
Abstract: It has earlier been shown that the isoenzymes CYP2D6 and CYP3A4 are involved in O- and N-demethylation of diltiazem (DTZ), respectively. Apparently, CYP3A4 plays a more prominent role than CYP2D6 in the overall metabolism of DTZ. However, previous observations indicate that the opposite might be true for the pharmacologically active metabolite desacetyl-DTZ (M1). Thus, the aim of the present in vitro investigation was to study the relative affinity of M1 to CYP2D6 and CYP3A4. Immortalized human liver epithelial cells transfected with either CYP2D6 or CYP3A4 were used as a model system, and the presence of M1 and its metabolites in the cell culture medium was analyzed by high-performance liquid chromatography/UV detection both before and following 90 min of incubation. The estimated K(m) value for the CYP2D6-mediated O-demethylation of M1 was approximately 5 microM. In comparison, the affinity of M1 to CYP3A4 (N-demethylation) was about 100 times lower (K(m), approximately 540 microM) than to CYP2D6. These in vitro data suggest that M1 metabolism via CYP2D6, in contrast to the parent drug, probably is the preferred pathway in vivo. Metabolism mediated through CYP2D6 is associated with a substantial interindividual variability, and since M1 expresses pharmacological activity, individual CYP2D6 metabolic capacity might be an aspect to consider when using DTZ.
Abstract: OBJECTIVES: Recently, it was shown in vitro that the polymorphic enzyme cytochrome P450 (CYP) 2D6 mediates O-demethylation of diltiazem. The aim of this study was to compare the pharmacokinetics of diltiazem and its major metabolites in healthy human volunteers representing different CYP2D6 genotypes. METHODS: Norwegians of Caucasian origin were screened for their CYP2D6 genotype on the LightCycler (Roche Diagnostics, Mannheim, Germany) by melting-curve analysis of allele-specific fluorescence resonance energy transfer probes hybridized to polymerase chain reaction-amplified deoxyribonucleic acid. The first 5 individuals identified with genotypes corresponding to a homozygous extensive, heterozygous extensive, or homozygous poor CYP2D6-metabolizing phenotype, respectively, were voluntarily enrolled in the pharmacokinetic study. The participants received diltiazem, 120 mg, as a single oral dose, and plasma samples were collected up to 24 hours after administration. Plasma samples were purified by solid phase extraction. Diltiazem and 7 phase I metabolites were analyzed by liquid chromatography-mass spectrometry. RESULTS: The pharmacokinetics of diltiazem was not significantly different between the subgroups. However, the systemic exposure of the pharmacologically active metabolites desacetyl diltiazem and N-demethyldesacetyl diltiazem was > or = 5 times higher in poor CYP2D6 metabolizers than in extensive CYP2D6 metabolizers (P <.01). CONCLUSIONS: CYP2D6 activity does not have a major impact on the disposition of diltiazem. In contrast, desacetyl diltiazem and N-demethyldesacetyl diltiazem are markedly accumulated in individuals expressing a deficient CYP2D6 phenotype. Because these metabolites exhibit pharmacologic properties of possible importance, individual CYP2D6 activity might be an aspect to consider in the clinical use of diltiazem.
Abstract: PURPOSE: To assess the possibility of using CYP2D6 10 +/- CYP3A5*3 as biomarkers to predict the pharmacokinetics of diltiazem and its two metabolites among healthy Chinese subjects. METHODS 41 healthy Chinese were genotyped for CYP3A5 3 and CYP2D6 10, and then received a single oral dose of diltiazem hydrochloride capsules (300 mg). Multiple blood samples were collected over 48 h, and the plasma concentrations of diltiazem, N-desmethyl diltiazem and desacetyl diltiazem were determined by HPLC-MS/MS. The relationships between the genotypes and pharmacokinetics were investigated. RESULTS: The pharmacokinetics of diltiazem, N-desmethyl diltiazem were not significantly affected by both CYP3A5 3 and CYP2D6*10 alleles. However, the systemic exposure of the pharmacologyically active metabolites, desacetyl diltiazem, was 2-fold higher in CYP2D6 10/10 genotype carriers than in 1/10 or 1/1 ones (AUC(o-inf) of CYP2D6 1/1, 1/10 and 10/10 are 398.2 +/- 162.9, 371,0 69.2 and 726.2 +/- 468.1 respectively, p <0.05). CONCLUSIONS: Two of the most frequent alleles, CYP3A5 3 and CYP2D6 10, among Chinese do not have major impacts on the disposition of diltiazem and N-desmethyl diltiazem. However, the desacetyl diltiazem showed 2-fold accumulation in individuals with CYP2D6 10/10 genotype. Despite this, the effect of genotype of CYP2D6 on clinical outcome of diltiazem treatment is expected to be limited.
Abstract: Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers.
Abstract: BACKGROUND: The most common acquired cause of Long QT syndrome (LQTS) is drug induced QT interval prolongation. It is an electrophysiological entity, which is characterized by an extended duration of the ventricular repolarization. Reflected as a prolonged QT interval in a surface ECG, this syndrome increases the risk for polymorphic ventricular tachycardia (Torsade de Pointes) and sudden death. METHOD: Bibliographic databases as MEDLINE and EMBASE, reports and drug alerts from several regulatory agencies (FDA, EMEA, ANMAT) and drug safety guides (ICH S7B, ICH E14) were consulted to prepare this article. The keywords used were: polymorphic ventricular tachycardia, adverse drug events, prolonged QT, arrhythmias, intensive care unit and Torsade de Pointes. Such research involved materials produced up to December 2017. RESULTS: Because of their mechanism of action, antiarrhythmic drugs such as amiodarone, sotalol, quinidine, procainamide, verapamil and diltiazem are associated to the prolongation of the QTc interval. For this reason, they require constant monitoring when administered. Other noncardiovascular drugs that are widely used in the Intensive Care Unit (ICU), such as ondansetron, macrolide and fluoroquinolone antibiotics, typical and atypical antipsychotics agents such as haloperidol, thioridazine, and sertindole are also frequently associated with the prolongation of the QTc interval. As a consequence, critical patients should be closely followed and evaluated. CONCLUSION: ICU patients are particularly prone to experience a QTc interval prolongation mainly for two reasons. In the first place, they are exposed to certain drugs that can prolong the repolarization phase, either by their mechanism of action or through the interaction with other drugs. In the second place, the risk factors for TdP are prevalent clinical conditions among critically ill patients. As a consequence, the attending physician is expected to perform preventive monitoring and ECG checks to control the QTc interval.
Abstract: Amiodarone is one of the most commonly used antiarrhythmic drugs. Despite its well-known side effects, amiodarone is considered to be a relatively safe drug, especially in short-term usage to prevent life-threatening ventricular arrhythmias. Our case demonstrates an instance where short-term usage can yield drug side effect.
Abstract: BACKGROUND: Anticholinergic drugs put elderly patients at a higher risk for falls, cognitive decline, and delirium as well as peripheral adverse reactions like dry mouth or constipation. Prescribers are often unaware of the drug-based anticholinergic burden (ACB) of their patients. This study aimed to develop an anticholinergic burden score for drugs licensed in Germany to be used by clinicians at prescribing level. METHODS: A systematic literature search in pubmed assessed previously published ACB tools. Quantitative grading scores were extracted, reduced to drugs available in Germany, and reevaluated by expert discussion. Drugs were scored as having no, weak, moderate, or strong anticholinergic effects. Further drugs were identified in clinical routine and included as well. RESULTS: The literature search identified 692 different drugs, with 548 drugs available in Germany. After exclusion of drugs due to no systemic effect or scoring of drug combinations (n = 67) and evaluation of 26 additional identified drugs in clinical routine, 504 drugs were scored. Of those, 356 drugs were categorised as having no, 104 drugs were scored as weak, 18 as moderate and 29 as having strong anticholinergic effects. CONCLUSIONS: The newly created ACB score for drugs authorized in Germany can be used in daily clinical practice to reduce potentially inappropriate medications for elderly patients. Further clinical studies investigating its effect on reducing anticholinergic side effects are necessary for validation.