Rifampicin and anti-hypertensive drugs in chronic kidney disease: Pharmacokinetic interactions and their clinical impact

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 prospective study, hypertensive CKD 5D patients with TB were followed after rifampicin initiation. Blood pressure (BP) was ≤140/90 mmHg with stable anti-HT requirement at inclusion. Serum amlodipine, metoprolol, and prazosin levels were estimated by high-performance liquid chromatography at baseline and 3, 7, 10, and 14 days after rifampicin initiation. BP and anti-HT requirement were monitored for 2 weeks or until stabilization. All 24 patients in the study had worsening of hypertension after rifampicin and 83.3% required increase in drugs to maintain BP <140/90 mmHg. Serial amlodipine levels were estimated in 16 patients; metoprolol and prazosin in four patients each. Drug levels declined by >50% in all patients and became undetectable in 50-75%. Drug requirement increased from 4.5 ± 3.6 to 8.5 ± 6.4 units (P < 0.0001). Mean time to first increase in dose was 6.5 ± 3.6 days. Eleven (46%) patients experienced a hypertensive crisis at 9.1 ± 3.8 days. Three of them had a hypertensive emergency with acute pulmonary edema. In two patients, rifampicin had to be discontinued to achieve BP control. In conclusion, rifampicin caused a significant decrease in blood levels of commonly used anti hypertensives. This decrease in levels correlated well with worsening of hypertension. Thus, we suggest very close BP monitoring in CKD patients after rifampicin initiation.

Pregnane X Receptor Activator Rifampin Increases Blood Pressure and Stimulates Plasma Renin Activity

“…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.…”

Predicting Interactions between Rifampin and Antihypertensive Drugs Using the Biopharmaceutics Drug Disposition Classification System

“…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).…”

“…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).…”

Rifampicin reverses nicardipine effect inducing uncontrolled essential hypertension

“…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.…”