Abstract:Patients on dialysis have an increased incidence of tuberculosis (TB). Rifampicin, a first-line antitubercular therapy (ATT) drug, is a potent inducer of hepatic cytochrome P450 (CYP). There is potential for pharmacokinetic interaction between rifampicin and anti-hypertensives that are CYP substrates: amlodipine and metoprolol. Therefore, hypertensive patients receiving rifampicin-based ATT are at risk for worsening of hypertension. However, this hypothesis has not yet been systematically studied. In this pros… Show more
“…Prior publications have reported the hypertensive effect of tuberculosis treatment with rifampin, but all the studies involved patients with existing antihypertensive medications. [26][27][28][29][30] Thus, the BP-elevating effect is mostly explained by drug-drug interactions involving the PXR-mediated induction of drug metabolism and transport by rifampin. A study with patients requiring maintenance hemodialysis demonstrated dramatically lower concentrations of amlodipine, metoprolol, and prazosin after the start of rifampin-based antitubercular therapy with 46% of the 24 patients experiencing hypertensive crisis.…”
We conducted a clinical trial with 22 healthy volunteers to investigate the effects of pregnane X receptor (PXR) agonist rifampin on blood pressure (BP). The study was randomized, crossover, single‐blind, and placebo‐controlled. Rifampin 600 mg or placebo once daily was administered for a week and the 24‐hour ambulatory BP was monitored at the end of each arm on the eighth day. Rifampin elevated the mean systolic and diastolic 24‐hour BP (4.7 mmHg, P < 0.0001, and 3.0 mmHg, P < 0.001, respectively) as well as the mean heart rate (3.5 bpm, P = 0.038). The serum renin concentration and the plasma renin activity were increased. Although rifampin increased circulating 4β‐hydroxycholesterol (4βHC) as expected, the plasma 4βHC concentration strongly negatively correlated with 24‐hour BP, especially systolic, in both rifampin and placebo arms (rifampin systolic BP, r = −0.69, P < 0.001; placebo systolic BP, r = −0.70, P < 0.001). The 4βHC, an agonist for liver X receptor (LXR), induced renin expression modestly in LXR‐α expressing Calu‐6 cells but only at unphysiologically high 4βHC concentrations. In conclusion, rifampin stimulates renin activity and has a hypertensive effect. This finding should be considered when designing interaction studies involving rifampin or other PXR agonists. Furthermore, PXR may represent a putative therapeutic target for the treatment of hypertension.
“…Prior publications have reported the hypertensive effect of tuberculosis treatment with rifampin, but all the studies involved patients with existing antihypertensive medications. [26][27][28][29][30] Thus, the BP-elevating effect is mostly explained by drug-drug interactions involving the PXR-mediated induction of drug metabolism and transport by rifampin. A study with patients requiring maintenance hemodialysis demonstrated dramatically lower concentrations of amlodipine, metoprolol, and prazosin after the start of rifampin-based antitubercular therapy with 46% of the 24 patients experiencing hypertensive crisis.…”
We conducted a clinical trial with 22 healthy volunteers to investigate the effects of pregnane X receptor (PXR) agonist rifampin on blood pressure (BP). The study was randomized, crossover, single‐blind, and placebo‐controlled. Rifampin 600 mg or placebo once daily was administered for a week and the 24‐hour ambulatory BP was monitored at the end of each arm on the eighth day. Rifampin elevated the mean systolic and diastolic 24‐hour BP (4.7 mmHg, P < 0.0001, and 3.0 mmHg, P < 0.001, respectively) as well as the mean heart rate (3.5 bpm, P = 0.038). The serum renin concentration and the plasma renin activity were increased. Although rifampin increased circulating 4β‐hydroxycholesterol (4βHC) as expected, the plasma 4βHC concentration strongly negatively correlated with 24‐hour BP, especially systolic, in both rifampin and placebo arms (rifampin systolic BP, r = −0.69, P < 0.001; placebo systolic BP, r = −0.70, P < 0.001). The 4βHC, an agonist for liver X receptor (LXR), induced renin expression modestly in LXR‐α expressing Calu‐6 cells but only at unphysiologically high 4βHC concentrations. In conclusion, rifampin stimulates renin activity and has a hypertensive effect. This finding should be considered when designing interaction studies involving rifampin or other PXR agonists. Furthermore, PXR may represent a putative therapeutic target for the treatment of hypertension.
“…The search of electronic databases resulted in 271 records in PubMed, 55 records in CNKI, and 60 records in WanFang, of which 39 were duplicates and 304 were not relevant. Within the remaining 43 records, seven studies were excluded on full‐text screening due to the lack of pharmacokinetic data, unreasonable discussion, recalculation of another study, or translation of a previous study 56–62 . As a result, 13 case reports, 20 pre‐post studies, and 3 cohort studies were included (Figure 4).…”
Section: Resultsmentioning
confidence: 99%
“…Within the remaining 43 records, seven studies were excluded on full-text screening due to the lack of pharmacokinetic data, unreasonable discussion, recalculation of another study, or translation of a previous study. [56][57][58][59][60][61][62] As a result, 13 case reports, 20 pre-post studies, and 3 cohort studies were included ( Figure 4).…”
Study Objective
Lack of blood pressure control is often seen in hypertensive patients concomitantly taking antituberculosis medications due to the complex drug‐drug interactions between rifampin and antihypertensive drugs. Therefore, it is of clinical importance to understand the underlying mechanisms of these interactions to help formulate recommendations on the use of antihypertensive drugs in patients taking these medications concomitantly. Our objective was to assess the reliability of the Biopharmaceutics Drug Disposition Classification System (BDDCS) to predict potential interactions between rifampin and antihypertensive drugs and thus provide recommendations on the choice of antihypertensive drugs in patients receiving rifampin.
Design
Evidence‐based in vitro and in vivo predictions of drug‐drug interactions.
Measurements and Main Results
We systematically evaluated interactions between rifampin and antihypertensive drugs using the theory of the BDDCS, taking into consideration the role of drug transporters and metabolic enzymes involved in these interactions. We provide recommendations on the selection of antihypertensive drugs for patients with tuberculosis. Antihypertensive drugs approved by the U.S. Food and Drug Administration and the China National Medical Products Administration were included in this study. The drugs were classified into four categories under the BDDCS classification. Detailed information on cytochrome P450 (CYP) enzymes and drug transporters for each antihypertensive drug was searched in PubMed and other electronic databases. This information was combined with the effects of rifampin on CYP enzymes and drug transporters, and the direction and relative extent of the potential interactions between rifampin and antihypertensive drugs were predicted. Recommendations were then made using the theory of BDDCS. A thorough systematic literature review was performed, and data from all published human studies and case reports were summarized for the validation of our predictions. Interventional and observational studies published in PubMed and two Chinese databases (CNKI and WanFang) through December 16, 2019, were included, and data were extracted for validation of the predictions. Using the BDDCS theory, class 3 active drugs were predicted to exhibit minimal interactions with rifampin. On reviewing case reports and pre‐post studies, the predictions we made were found to be reliable. When antituberculosis medications that include rifampin are started in patients with hypertension, it is recommended that the use of calcium channel blockers and classes 1 and 2 β‐blockers be avoided. Angiotensin‐converting enzyme inhibitors, olmesartan, class 3 β‐blockers, spironolactone, and hydrochlorothiazide would be preferable because clinically relevant interactions would not be expected.
Conclusion
Application of the BDDCS to predict interactions between rifampin and antihypertensive drugs for patients with both tuberculosis and hypertension was found to be reliable. It should be noted, however, that bas...
“…Agrawal A et al . showed in 20 hypertensive dialyzed patients treated with amlodipine and rifampicin a reduction of more than 50% of plasma level of amlodipine in all patients reaching an undetectable level in 50%‐75% of patients.…”
Dihydropyridine calcium-channel blockers are a known substrate for the cytochrome P450 isoform 3A4. Rifampicin, an antitubercular agent, is one of the most potent inducers of hepatic and intestinal CYP3A4 thus increasing dihydropyridine metabolism. We report a case of a 67-year-old hypertensive female treated with a four-drug antihypertensive regimen including a dihydropyridine (nicardipine 50 mg bid), who was admitted for septic arthritis of the knee requiring antibiotic treatment with teicoplanin 400 mg od and rifampicin 600 mg bid. Six days after rifampicin initiation, she presented with Posterior Reversible Encephalopathy Syndrome due to uncontrolled hypertension. We hypothesized that disequilibrium of previously controlled hypertension was partially due to nicardipine ineffectiveness. Plasma nicardipine concentration was assessed through high-performance liquid chromatography 5 hours after coadministration of the two drugs and proved undetectable.
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