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Strong CYP3A4 inhibitors include clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, and loperamide. Moderate CYP3A4 inhibitors include amiodarone, erythromycin, fluconazole, miconazole, diltiazem, verapamil, delavirdine, amprenavir, fosamprenavir, and conivaptan.
Strong inducers include enzalutamide and phenytoin. Moderate inducers include carbamazepine, topiramate, phenobarbital, rifampicin, efavirenz, and pioglitazone. CYP2C19 CYP2C19 substrates include antidepressants, antiepileptics, proton pump inhibitors, clopidogrel, propranolol, carisoprodol, cyclophosphamide, and warfarin. If necessary, reduce the dose of the substrate medication and monitor patients closely for ADEs and toxicity.
The dose of CBD may need to be reduced. Strong inhibitors include fluvoxamine and fluoxetine. Other inhibitors include proton pump inhibitors, cimetidine, ketoconazole, clopidogrel, fluconazole, and efavirenz.
CYP2C19 inducers include rifampin, carbamazepine, phenobarbital, phenytoin, and St. An increase in CBD dose may be necessary. CYP2C9 CYP2C9 substrates include rosiglitazone, buprenorphine, montelukast, celecoxib, sulfonylureas, losartan, naproxen, phenobarbital, phenytoin, rosuvastatin, valsartan, and warfarin.
Commonly used medications such as acetaminophen, ibuprofen, and naproxen are substrates of these enzymes. Interactions with over-the-counter naproxen and ibuprofen could lead to significant side effects eg, bleeding. UGT1A9 substrates include regorafenib, acetaminophen, canagliflozin, sorafenib, irinotecan, propofol, mycophenolate, valproic acid, haloperidol, ibuprofen, dabigatran, and dapaglifozin.
UGT2B7 substrates include hydromorphone, losartan, ibuprofen, naproxen, ezetimibe, lovastatin, simvastatin, carbamazepine, and valproate. The significance of this interaction was demonstrated using ethanol as a substrate. Drug Transporters The drug transporter enzymes breast cancer resistance protein BCRP and the bile salt export pump BSEP play a role in the efflux of xenobiotics from tissues and transport into excretion pathways.
Recommend avoidance of coadministration. BSEP substrates include paclitaxel, digoxin, statins, telmisartan, glyburide, ketoconazole, rosiglitazone, and celecoxib. Despite some individual variations based on genetic polymorphisms in some isoforms, certain interactions can be predicted. For example, quinidine and diphenhydramine inhibit the CYP2D6 isoform, thereby inhibiting the metabolism of beta-blockers and prolonging negative chronotropic and inotropic effects.
Antihypertensive agents also may interact with each other. For instance, the combination of verapamil and metoprolol decreases the systemic clearance of verapamil while increasing the bioavailability of metoprolol. Water-soluble beta blockers that are not metabolized in the liver, such as sotalol, nadolol, and atenolol, are less likely to be affected by these metabolic drug interactions.
Inhibitors of CYP3A4, such as the azole antifungal agents ketoconazole and itraconazole, can increase the effects of calcium channel blockers and lead to hypotension. Cimetidine, another CYP3A4 inhibitor, increases the bioavailability of nifedipine.
Grapefruit juice also down-regulates CYP3A4 in the small-intestine wall, which can result in large increases in the bioavailability of felodipine and nisoldipine, and smaller increases in the bioavailability of nifedipine and verapamil. Patients taking medications that would be increased in concentration by inhibitors of CYP3A4 metabolism should avoid grapefruit juice.
Although angiotensin-converting enzyme inhibitors are partially metabolized in the CYP3A4 system, they are not significantly involved in P interactions. These medications demonstrate increased bioavailability when given with ketoconazole, a CYP2C9 system inhibitor, and decreased bioavailability when given with rifampin, a CYP2C9 activator.
Interpretation: In older patients receiving a calcium-channel blocker, use of erythromycin or clarithromycin was associated with an increased risk of hypotension or shock requiring admission to hospital. Preferential use of azithromycin should be considered when a macrolide antibiotic is required for patients already receiving a calcium-channel blocker.
Abstract Background: The macrolide antibiotics clarithromycin and erythromycin may potentiate calcium-channel blockers by inhibiting cytochrome P isoenzyme 3A4. Norepinephrine was administrated immediately. We also prescribed intravenous calcium gluconate, insulin-glucose infusion, and oral calcium polystyrene sulfonate at once. The electrophysiologist from our hospital suggested temporary pacemaker placement.
However, the patient was relatively circulatory stable. More importantly, her arrythmia should be secondary to hyperkalemia which we could reverse within a couple of hours. Concerned with these, a non-cuffed catheter was placed in her femoral vein at the bedside.
Continuous renal replacement therapy CRRT was provided for 22 h starting on day 15 of admission. On day 16 of admission, she recovered to normal sinus rhythm Fig.
So, nifedipine 30 mg bid was resumed. On day 19 on admission, the urine output was ml and voriconazole was restarted. For this second episode of anuria onset, we realized that decreased urine output certainly had some connection with voriconazole usage. Through reviewing the case, reading references, and communicating with pharmacists, we hypothesized that the episode of hypotension was induced by the drug interaction of CCB and voriconazole.
We determined that she should use antihypertensive drugs that do not metabolize from CYP3A4. Voriconazole was resumed without incident. She was under medical observation for 3 more days and her condition remained stable prior to discharge from the hospital. Her AAV has stayed in remission and she has not had any further episodes of hyperkalemia or arrhythmia. The patient developed hypotension and AKI, and this was followed by hyperkalemia and sinus arrest with a junctional escape rhythm.
Voriconazole, a commonly used antifungal triazole, has potent inhibitory effects on CYP3A4 [ 5 ]. Hypotension from co-prescribing voriconazole together with nifedipine has been reported [ 6 , 10 ]. Hypotension induced by concomitant use of CCB and macrolide antibiotics, particularly erythromycin and clarithromycin, are more frequently reported [ 7 , 8 , 9 ].
Like in our case, voriconazole can raise the blood concentration of nifedipine and excessively potentiate its hypotensive effect, resulting in ischemic AKI through renal hypoperfusion [ 10 ]. Unfortunately, the nifedipine concentration could not be tested in our institute. Furthermore, there are significant individual variances in the disposition of nifedipine, and genetic factors are considered to play an important role [ 13 , 14 ].
Nifedipine is a vessel dilator and in overdose the effective blood volume could be lower than normal. Hence, the kidney will retain sodium and water to compensate for the decreased effective blood volume. In our case, the patient retained 6Kg fluids to maintain the circulating blood volume. These consequences are consistent with a previously reported case, in which 4Kg fluids were retained [ 10 ]. This also happened in the previous case, and the authors speculated that it was because of impaired kidney autoregulation on top of impaired kidney function [ 10 ].
The impaired kidney is much more vulnerable to relative hypotension than the normal kidney which may further predispose to AKI. In our case, hyperkalemia followed AKI. Then sinus arrest with junctional escape rhythm and low HR followed hyperkalemia which in turn undermined the cardiac output and blood pressure, hence further decreasing kidney perfusion. Our case occurred using oral voriconazole. Some studies report intravenous voriconazole is associated with more episodes of AKI, because of the cyclodextrin vehicle, sulphobutylether-beta-cyclodextrin, which is cleared by the kidney and has been associated with nephrotoxicity [ 15 ].
This rare case warns us of the severe consequences of drug interactions. One should always be very careful when co-administrating medications, and we suggest clinicians consult pharmacists if possible. The dataset supporting the conclusions of this article is included within the article.
Other regarding data and material can be obtained from the first author. Epidemiology of hypertension in CKD. Adv Chronic Kidney Dis. Article Google Scholar. Prevalence of hypertension in renal disease. Nephrol Dial Transplant. In vitro metabolism of midazolam, triazolam, nifedipine, and testosterone by human liver microsomes and recombinant cytochromes p role of cyp3a4 and cyp3a5.
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