Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The HMG-CoA reductase inhibitors (statins) are effective in both the primary and secondary prevention of ischaemic heart disease. As a group, these drugs are well tolerated apart from two uncommon but potentially serious adverse effects: elevation of liver enzymes and skeletal muscle abnormalities, which range from benign myalgias to life-threatening rhabdomyolysis. Adverse effects with statins are frequently associated with drug interactions because of their long-term use in older patients who are likely to be exposed to polypharmacy. The recent withdrawal of cerivastatin as a result of deaths from rhabdomyolysis illustrates the clinical importance of such interactions. Drug interactions involving the statins may have either a pharmacodynamic or pharmacokinetic basis, or both. As these drugs are highly extracted by the liver, displacement interactions are of limited importance. The cytochrome P450 (CYP) enzyme system plays an important part in the metabolism of the statins, leading to clinically relevant interactions with other agents, particularly cyclosporin, erythromycin, itraconazole, ketoconazole and HIV protease inhibitors, that are also metabolised by this enzyme system. An additional complicating feature is that individual statins are metabolised to differing degrees, in some cases producing active metabolites. The CYP3A family metabolises lovastatin, simvastatin, atorvastatin and cerivastatin, whereas CYP2C9 metabolises fluvastatin. Cerivastatin is also metabolised by CYP2C8. Pravastatin is not significantly metabolised by the CYP system. In addition, the statins are substrates for P-glycoprotein, a drug transporter present in the small intestine that may influence their oral bioavailability. In clinical practice, the risk of a serious interaction causing myopathy is enhanced when statin metabolism is markedly inhibited. Thus, rhabdomyolysis has occurred following the coadministration of cyclosporin, a potent CYP3A4 and P-glycoprotein inhibitor, and lovastatin. Itraconazole has been shown to increase exposure to simvastatin and its active metabolite by at least 10-fold. Pharmacodynamically, there is an increased risk of myopathy when statins are coprescribed with fibrates or nicotinic acid. This occurs relatively infrequently, but is particularly associated with the combination of cerivastatin and gemfibrozil. Statins may also alter the concentrations of other drugs, such as warfarin or digoxin, leading to alterations in effect or a requirement for clinical monitoring. Knowledge of the pharmacokinetic properties of the statins should allow the avoidance of the majority of drug interactions. If concurrent therapy with known inhibitors of statin metabolism is necessary, the patient should be monitored for signs and symptoms of myopathy or rhabdomyolysis and the statin should be discontinued if necessary.
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PMID:Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. 1203 92

Study aim was to investigate the association of lipoprotein (a) [Lp(a)] level with the development of cardiovascular complications in long-term follow-up period after coronary artery bypass grafting (CABG). Patients with chronic ischemic heart disease (IHD) (n = 361, 88% men, mean age 55 +/- 9 years) who had had CABG were included in the study. Before surgery we assessed presence of classical risk factors, left ventricular ejection fraction, concentrations of lipids and Lp(a) in blood serum. During follow-up (from 1 to 140, mean 66 +/- 34 months) we registered cardiac deaths, nonfatal myocardial infarctions (MI), strokes, repeat procedures of revascularization, and hospitalizations due to relapse or progression of angina pectoris. Information on prognosis was obtained from 263 patients. In 109 of them we registered 142 serious events including cardiac death n = 20 (14%), nonfatal MI n = 14 (10%), myocardial revascularization (n = 35), 29 (20%) with stenting), repeat CABG n = 6 (4%), hospitalization due to angina pectoris n = 53 (37%), stroke n = 4 (3%), noncardiac outcome n = 16 (10%). In subjects with hyperlipidemia (a) [HLp(a) - Lp(a) > 30 mg/l] survival after CABG was lower (log rank p < 0.001): 11 of 93 (11.3%) and 9 of 170 (5.2%) patients died among those with Lp(a) > 30 and < 30 mg/I, respectively. Relative risk (RR) of any cardiovascular complication was 3.24 (95% confidence interval [CI] 2.18 to 4.83, p < 0.001), of death - 2.89 (95% CI 1.31 to 6.35, p < 0.01), and of MI A 1.01 (95% CI 1.00 to 1.02; p = 0.02). RR of development of MI and cardiac death in patients with HLp(a) in 5 years was 2.61 (95% CI 1.11 to 5.74; p = 0.02), in 10 years - 2.95 (95% CI 1.50 to 5.79; p < 0.001). In patients with chronic IHD high level of Lp(a) can serve as independent predictor of unfavorable events including death and nonfatal MI during 10 years after CABG.
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PMID:[High level of lipoprotein (a) as a predictor of poor long-term prognosis after coronary artery bypass surgery]. 2162 97

Pharmacokinetics and antithrombotic effects of the Factor Xa inhibitor rivaroxaban were studied in subjects with mild renal insufficiency concurrently taking the P-glycoprotein and moderate CYP3A inhibitor verapamil, a drug commonly administered to patients with hypertension, ischemic heart disease, or atrial fibrillation. Age-matched controls with normal renal function were studied concurrently. Subjects' overall mean age was 59 years. Mean creatinine clearance values in the 2 groups were 105 and 71 mL/min. After single 20-mg oral doses, rivaroxaban area under the curve (AUC) was increased by a factor of 1.11 (ratio of geometric means [RGM]) in mild renal insufficiency compared to controls. Verapamil coadministration independently increased AUC to the same extent in both the mild renal insufficiency and control groups (RGM, 1.39 and 1.43). Concurrent mild renal insufficiency and verapamil produced additive inhibition compared to controls without verapamil (RGM, 1.58). Prothrombin time (PT) prolongation and Factor Xa inhibition tracked plasma rivaroxaban, and were enhanced by verapamil. Concentration-response relationships for PT (linear) and Factor Xa inhibition (hyperbolic) were unaffected by renal function or verapamil. The absolute and relative increases in rivaroxaban AUC caused by verapamil in mild renal insufficiency subjects are potentially associated with an increased bleeding risk. Modification of recommended dosage may be required in this combination of circumstances to reduce risk to patients.
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PMID:Impaired Rivaroxaban Clearance in Mild Renal Insufficiency With Verapamil Coadministration: Potential Implications for Bleeding Risk and Dose Selection. 2919 98