1Your Heart & Valves
HMG CoA Reductase Inhibitors Therapy – Statins
Yüklə 1,2 Mb.
|
- Bu səhifədəki naviqasiya:
- 8.2.1Statin - Effects on Cholesterol
- 8.2.2NONLIPID EFFECTS OF STATINS
- 8.2.3Adverse Events when taking Statins with Multiple Drugs
- 8.2.3.1General Statin interactions with drug regimes.
- 8.2.3.2Drugs Increasing Risk of Myopathy/Rhabdomyolysis
- 8.2.3.3Statin Associated FDA Reports of Rhabdomyolysis
- 8.2.3.4Statin interactions with warfarin
- 8.2.4Statin Clinical Pharmacokinetics
- 8.2.5Human Cytochrome P450 Isoenzymes that Oxidize Drugs
- 8.2.6Inhibitors/Inducers of Cytochrome P450 Enzymatic Pathway
- 8.3Angiotensin Converting Enzyme (ACE) Inhibitors Therapy
8.2HMG CoA Reductase Inhibitors Therapy – StatinsHMG CoA reductase inhibitors (statins) retard the progression of both coronary disease and of aortic stenosis. In some studies, this retardation is related to a fall in low density lipoprotein (LDL), cholesterol, but in others, retardation has occurred without a consistent relationship to cholesterol, suggesting that statin agents may have effects other than simple cholesterol lowering to account for their effects on the aortic valve. Although aortic valve replacement and its timing have been the major foci of the therapy of aortic stenosis, it is possible that in the future, aggressive therapy with statins and other agents might block or slow the progression of the valve lesion, forestalling or even preventing the need for aortic valve replacement. 8.2.1Statin - Effects on CholesterolStatins lower total cholesterol 18% to 26%, lower undesirable Low Density Lipoprotein-Cholesterol (LDL-C) 20% to 60%, raised desirable High-Density Lipoprotein-Cholesterol (HDL-C) 5% to 7%, and lowered triglycerides 11% to 17%. 8.2.1.1FDA-Approved Drug Daily Dosage and Usual Decrease in LDL CholesterolAtorvastatin Initial: 10 mg 35%-40% Maximum: 80 mg 50%-60% Fluvastatin Initial: 20 mg 20%-25% Maximum: 40 mg 30%-35% Lovastatin Initial: 20 mg 25%-30% Maximum: 80 mg 35%-40% Mevacor Initial: 20 mg 25%-30% Maximum: 80 mg 35%-40% Pravastatin Initial: 40 mg 30%-35% Maximum: 80 mg 35%-40% Rosuvastatin Initial: 10 mg 40%-45% Maximum: 40 mg 50%-60% Simvastatin Initial: 20 mg 35%-40% Maximum: 80 mg 45%-50% 8.2.2NONLIPID EFFECTS OF STATINSSome pathophysiologic data suggest that statins are also beneficial in the acute setting. For example, in the short term (weeks to months) statins have been shown to:
8.2.3Adverse Events when taking Statins with Multiple Drugs –Avoiding the concomitant use of drugs with the potential to inhibit CYP-dependent metabolism may decrease the risk of statin-associated myopathy. Alternatively, if drug therapy with a potent CYP inhibitor is inevitable, choosing a statin without relevant CYP metabolism (eg, pravastatin) should be considered. 8.2.3.1General Statin interactions with drug regimes.Simvastatin, (35.8%); cerivastatin, (31.9%); atorvastatin, (12.2%); pravastatin, (11.8%); lovastatin, (6.7%); and fluvastatin, (1.7%). Statins are the primary cause of 72% of FDA reported cases and suspected secondary cause in 28% of cases. In clinical trials and post marketing surveillance, there are three statins that are not metabolised by the cytochrome P450 3A4 system (fluvastatin, rosuvastatin and pravastatin) and have exhibited very low propensities to elicit myopathy when combined with other agents. These agents should be considered initially when contemplating combination lipid-lowering regimens for coronary prevention. FDA reports of rhabdomyolysis/Myopathy, the breakdown of muscle fibers resulting in the release of muscle fiber contents into the circulation, that may be manifested by muscle pain and in extreme cases dark or cola coloured urine without significant elevations in serum creatine phosphokinase (CPK) levels, thus pointing out the inadequacy of CK testing for statin-associated myopathy. Rhabdomyolysis/Myopathy is generally observed between 1-2 weeks and 4 months after initiation of therapy. Myalgias and weakness resolve within days to 4 weeks after discontinuation. 8.2.3.2Drugs Increasing Risk of Myopathy/Rhabdomyolysis
8.2.3.3Statin Associated FDA Reports of Rhabdomyolysis
8.2.3.4Statin interactions with warfarinThe interactions between statins and warfarin are complex. Warfarin goes through several different CYP450 pathways, any of which might serve as a source of interactions with statins. However, whereas most of the interactions previously described result in inhibited statin metabolism, interactions with warfarin tend to work in the opposite direction and inhibit warfarin metabolism. The clinical result is an increase in the international normalized ratio (INR), a standardized measure of prothrombin time. The CYP3A4-dependent statins (simvastatin, lovastatin, and atorvastatin) all have the potential to raise the INR in patients taking warfarin; the effect is variable, and monitoring INR is important to determine whether the warfarin dosage must be adjusted. Fluvastatin, metabolized through the CYP2C9 pathway, can also interfere with warfarin metabolism and raise the INR. Rosuvastatin can raise the INR without raising warfarin concentrations, which implies that its effect is not mediated through the CYP450 system but is more likely caused by a partial displacement of warfarin from its protein-bound state in circulation. For patients taking multiple medications, it is especially important to select agents that are least likely to incur an additional risk of interaction; for patients who require the addition of lipid-lowering pharmacotherapy to a drug regimen that is already complex, the preferred agents would be the statins that are least dependent on the CYP450 system in general and on CYP3A4 in particular. Pravastatin is unique among the statins in that it produces no change in the INR in patients taking warfarin, which demonstrates its lack of involvement in the CYP450 pathways and an absence of effects on warfarin protein binding, but it has caused an increased INR when combined with the anticoagulant fluindione. Clinicians should monitor the INR closely after starting statin therapy in any patient receiving anticoagulation therapy; rabdomyolysis and renal failure can occrred within days 8.2.4Statin Clinical Pharmacokinetics
8.2.5Human Cytochrome P450 Isoenzymes that Oxidize Drugs
8.2.6Inhibitors/Inducers of Cytochrome P450 Enzymatic Pathway
8.3Angiotensin Converting Enzyme (ACE) Inhibitors TherapyThe narrowing of the vessels increases the pressure within the vessels and can cause high blood pressure (hypertension). Angiotensin II is formed from angiotensin I in the blood by the enzyme, angiotensin converting enzyme (ACE). ACE inhibitors are medications that slow (inhibit) the activity of the enzyme, which decreases the production of angiotensin II. As a result, the blood vessels enlarge or dilate, and the blood pressure is reduced. This lower blood pressure makes it easier for the heart to pump blood and can improve the function of a failing heart. In addition, the progression of kidney disease due to high blood 8.4Alcohol TherapyThere is compelling epidemiological evidence suggesting that regular light-to-moderate alcohol intake is associated with reduced atheromatous morbidity and mortality. It is interesting to note that while atherogenesis takes many decades, the beneficial effects of alcohol accrue only in later life. The reasons for this are uncertain but the effects may be a combination of plaque stabilisation, analogous to the effects of some cholesterol lowering drugs which affect coronary endpoints relatively quickly, and an antithrombotic effect. To prove causation requires the correct temporal sequence, an ability to control for confounders, plausible biological explanations, and a consistent and specific effect (ischaemic heart disease appears to be one of the few diseases alcohol benefits). It is only the relatively small apparent benefit that precludes definitive statements on causation; it is possible that an as yet unrecognised confounding variable could explain the findings. In addition, over 30 years of research has not revealed a definite alternative explanation. Alcohol, especially in excess, does have detrimental effects, which in many groups outweigh its benefits. Indeed, other interventions, including dietary modification, are far more effective at reducing cardiovascular endpoints. The vast majority of those who abstain do so for a reason, which would preclude advising them to take up alcohol, for example, dislike of the taste/effects, past/family history of alcohol abuse, medical contraindication, or moral/ethical/religious objections. However, one can reassure our patients that regular light-to-moderate alcohol intake, especially in those at risk, whose diet is steadfastly Western will, at the very least, do no harm and almost certainly lead to benefit. Is there evidence to enable us to advise what to drink? Although the epidemiological evidence suggests not, there are at least theoretical reasons why red wines rich in flavonoids and resveratrol may hold extra benefit. Flavonoids, being found particularly in grape skins, occur in the highest concentrations in grape varieties with thick skins grown in hot climates. Cabernet sauvignon based wines from Australia, South America, and the southern Mediterranean are particularly rich sources. Syrah (shiraz) and merlot are good too. Wines from this grape form Burgundy, Sancerre, New Zealand, and the north west United States are particularly rich in resveratrol. Merlot, gammay, syrah, zinfandel, and pinotage wines may also be too. of Yüklə 1,2 Mb. Dostları ilə paylaş:
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
