Statins - Induced Transaminitis

<b>Introduction </b><br /><br /><ul><li><span style="background: white; text-indent: -0.25in;">The most commonly reported hepatic adverse effect is the phenomenon known as <b>transaminitis</b></span><b style="background-color: white; text-indent: -0.25in;">, </b><span style="background-color: white; text-indent: -0.25in;">in which liver enzyme levels are elevated (transient) in the absence of proven hepatotoxicity and commonly occurs in the first 12 weeks of therapy. </span><span style="background-color: white; text-indent: -0.25in;"> </span></li><li><span style="background-color: white; text-indent: -0.25in;">This class effect is usually asymptomatic, reversible, and dose-related.</span></li><li><span style="background: white; text-indent: -0.25in;">There are changing data on the occurrence of these negative hepatic effects, recommendations on their actual risk, monitoring required, and safety of use in those with preexisting hepatic disorders.</span></li></ul><br /><b>Effects of Statins on The Liver</b><br /><ul><li><span style="background: white; text-indent: -0.25in;">Statins exert a potent inhibition of hepatic 3-hydroxyl-3-methylglutaryl coenzyme A reductase, which accounts for the reduction in LDL cholesterol observed with these drugs.</span></li><li><span style="background: white; text-indent: -0.25in;">Although the underlying mechanism remains unclear, hepatotoxicity may result from changes in the lipid components of the hepatocyte membrane, leading to an increase in its permeability with a subsequent “leakage” of liver enzymes.</span></li><li><span style="background: white; text-indent: -0.25in;">This is supported by the observation that elevations in aminotransferase levels.</span></li></ul><div><br /></div><div class="MsoNormal"><b><span style="line-height: 107%;">Incidence of Elevation of Liver Enzymes During Statin Treatment<span style="font-size: 14pt;"><o:p></o:p></span></span></b></div><ul><li><span style="background: white; text-indent: -0.25in;">The incidence of elevated aminotransferase levels with different types of statins generally <b>did not exceed 3%</b> of the studied patients' sample.</span><span style="text-indent: -0.25in;"> </span></li><li><span style="background: white; text-indent: -0.25in;">There seems to be a <b>direct relationship</b> between the <b>statin dose</b> and the <b>incidence of transaminitis.</b></span><span style="text-indent: -0.25in;"><b> </b></span></li><li>The reported average incidence of elevations in serum aminotransferase levels to >3x ULN was < 1% in patients receiving low to moderate doses.</li><li>Similarly, the incidence of transaminitis increases up to 2% to 3% in those receiving high doses of statins.</li><li><span style="background: white; text-indent: -0.25in;">The incidence of <b>transaminase elevations is similar among all statins,</b> despite their different pharmacokinetic characteristics</span></li><li>Most cases of transaminitis exhibit spontaneous improvement without the need for drug discontinuation, probably a result of the development of adaptation or tolerance.</li></ul><div></div><div><b>Management and Monitoring</b></div><div><b><br /></b></div><div><b><br /></b></div><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody><tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhZ5Jtpp03r9vmhoH3DVjVy1Er2SxORFkorP2jttTeHcjkkKTRVjQAlDN6eMC3r7pBKcqYcX_guz4of4GeB1w4fHIJUirSIq0D5b1keGjim0t-4G6jSR2dnY5wWc3NbqVNaMkTQkJtUuYU/s1600/Statin+Algorithm.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img alt="" border="0" data-original-height="605" data-original-width="454" height="640" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhZ5Jtpp03r9vmhoH3DVjVy1Er2SxORFkorP2jttTeHcjkkKTRVjQAlDN6eMC3r7pBKcqYcX_guz4of4GeB1w4fHIJUirSIq0D5b1keGjim0t-4G6jSR2dnY5wWc3NbqVNaMkTQkJtUuYU/s640/Statin+Algorithm.jpg" title="Algorithm for management of abnormal liver enzymes before and during statin treatment" width="480" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;">Algorithm for Management of Abnormal Liver Enzymes Before and During Statin Treatment</td></tr></tbody></table><br /><br /><b>Statins in Preexisting Liver Dysfunction</b><br /><div><ul><li>US FDA continues to recommend that statins be contraindicated in patients with chronic liver disease; however, several authors have recommended starting <b>low-dose statin</b> treatment (because of the possible greater incidence of liver enzyme elevations with higher doses) and having levels rechecked 2 weeks later.</li><li><span style="background: white; text-indent: -0.25in;">LFT monitoring should be performed every month for the first 3 to 4 months and 4 times a year thereafter.</span></li><li><span style="font-size: 7pt; font-stretch: normal; font-variant-numeric: normal; line-height: normal;">  </span><span style="background: white; text-indent: -0.25in;">If the levels of transaminases increase to > 3X baseline values, discontinuation of the drug should be considered.</span></li><li>Clinical correlation with worsening of underlying disease, as well as exclusion of alcohol abuse and drug interactions, should be done before attempting permanent discontinuation of the drug. </li><li>Once levels return to baseline, rechallenge can be considered. </li></ul><div><br /></div><div><b>Conclusion</b></div><div><ul></ul><ul><li><span style="background: white;">The latest reviewed data indicate or support the recommendation from US FDA that “all currently marketed statins appear to be associated with a very low risk of serious liver injury.”</span></li><li><span style="background: white;">Clinicians should not withhold statin therapy for patients whose transaminase elevations have no clinical relevance or are attributable to known stable chronic conditions. Evaluating other causes for alteration in LFTs should be made before establishing a causal relationship with a statin agent.</span></li><li><span style="background: white;">Statin use need not be avoided in patients with preexisting liver dysfunction if its use is clearly indicated.</span></li><li>However, as reported in literature, potential of statins to cause significant and serious hepatic effects should not be overlooked in daily clinical practice</li></ul></div><div></div><div><b>References </b></div><div><ul></ul><ol><li><span style="font-family: inherit;">Rossana M. Calderon, MD, Luigi X. Cubeddu, MD, Ronald B. Goldberg, MD, and Eugene R. Schiff, MD. Statins in the Treatment of Dyslipidemia in the Presence of Elevated Liver Aminotransferase Levels: A Therapeutic Dilemma. <i>Mayo Clinic Proceedings 2010 Apr; 85(4): 349–356<b>.</b></i></span></li><li><span style="font-family: inherit; font-size: small;">Jimmy Jose. Statins and its hepatic effects: Newer data, implications, and changing recommendations. <i>J Pharm Bioallied Sci. 2016 Jan-Mar; 8(1): 23–28.</i></span></li><li><span style="font-family: inherit; font-size: small;">Edward Onusko MD. Statins and elevated liver tests: What’s the fuss?.<i>J Fam Pract </i><i>2008 July;57(7):449-452.</i></span></li><li><span style="font-family: inherit; font-size: small;">US Food and Drug Administration (FDA) <span class="ref-journal" style="text-indent: -0.25in;">P<i>h</i><span class="ref-journal">RMA/FDA/ASSLD drug induced hepatotoxicity white paper post marketing considerations: November 2000.</span></span></span></li><li><span style="font-family: inherit; font-size: small;"><span style="background: white none repeat scroll 0% 0%; text-indent: -0.25in;">US Department of Health and Human Services. Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) </span><span class="ref-journal" style="text-indent: -0.25in;">Guidance for industry: drug-induced liver injury: premarketing clinical evaluation</span><span style="text-indent: -0.25in;"> Published July 2009 </span></span></li></ol></div></div>

general interaction pharmacokinetics side effect Statins - Induced Transaminitis

Introduction  The most commonly reported hepatic adverse effect is the phenomenon known as transaminitis , in which liver enzyme levels are ...

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Hyponatremia : ACEi vs CCB

<div class="MsoNormalCxSpFirst" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto;"><span style="font-family: Verdana,sans-serif;"><b>Symptoms</b></span></div><span style="font-family: Verdana,sans-serif;"> </span><ul style="margin-top: 0cm;" type="disc"><li class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto; mso-list: l6 level1 lfo1; tab-stops: list 36.0pt;"><span style="font-family: Verdana,sans-serif;">presented with signs and symptoms of hyponatremia (eg, nausea, malaise, headache, lethargy, seizures, coma, respiratory depression) </span></li><li class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto; mso-list: l6 level1 lfo1; tab-stops: list 36.0pt;"><span style="font-family: Verdana,sans-serif;">decreased serum sodium levels (101-109 mEq/L)</span></li></ul><span style="font-family: Verdana,sans-serif;"> </span><div class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto;"><span style="font-family: Verdana,sans-serif;"><b>ACE Inhibitors</b></span></div><span style="font-family: Verdana,sans-serif;"> </span><ul style="margin-top: 0cm;" type="disc"><li class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto; mso-list: l0 level1 lfo2; tab-stops: list 36.0pt;"><span style="font-family: Verdana,sans-serif;">Frequency is unreported</span></li><li class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto; mso-list: l0 level1 lfo2; tab-stops: list 36.0pt;"><span style="font-family: Verdana,sans-serif;">ACE inhibitors alone can precipitate hyponatremia without co-administration of thiazide diuretics</span></li><li class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto; mso-list: l0 level1 lfo2; tab-stops: list 36.0pt;"><span style="font-family: Verdana,sans-serif;">hyponatremia induced by ACE inhibitors appears to be dilutional and is accompanied by features of SIADH</span></li><li class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto; mso-list: l0 level1 lfo2; tab-stops: list 36.0pt;"><span style="font-family: Verdana,sans-serif;">discontinuing the ACE inhibitor leads to resolution of the hyponatremia</span></li><li class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto; mso-list: l0 level1 lfo2; tab-stops: list 36.0pt;"><span style="font-family: Verdana,sans-serif;">Patients may show hypokalaemia if thiazide or loop diuretics are used concomitantly with ACE inhibitors</span></li><li class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto; mso-list: l0 level1 lfo2; tab-stops: list 36.0pt;"><span style="font-family: Verdana,sans-serif;"> </span></li></ul><span style="font-family: Verdana,sans-serif;"> </span><div class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto;"><span style="font-family: Verdana,sans-serif;"><b>Mechanism & Risk</b></span></div><span style="font-family: Verdana,sans-serif;"> </span><ul style="margin-top: 0cm;" type="disc"><li class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto; mso-list: l2 level1 lfo3; tab-stops: list 36.0pt;"><span style="font-family: Verdana,sans-serif;">It is postulated that ACE inhibitors at low doses cannot block the conversion of angiotensin I to angiotensin II in the brain. Increased circulating angiotensin I is converted to angiotensin II in the brain causing thirst stimulation and consequently SIADH.</span></li><li class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto; mso-list: l2 level1 lfo3; tab-stops: list 36.0pt;"><span style="font-family: Verdana,sans-serif;">risk for hyponatremia may be greater in patients on concomitant diuretic therapy or who have congestive heart failure.</span></li></ul><span style="font-family: Verdana,sans-serif;"> </span><div class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto;"><span style="font-family: Verdana,sans-serif;"><b>Calcium Channel Blockers</b></span></div><span style="font-family: Verdana,sans-serif;"> </span><ul style="margin-top: 0cm;" type="disc"><li class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto; mso-list: l1 level1 lfo4; tab-stops: list 36.0pt;"><span style="font-family: Verdana,sans-serif;">In theory, calcium channel antagonists with natriuretic properties could cause hyponatremia.</span></li><li class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto; mso-list: l1 level1 lfo4; tab-stops: list 36.0pt;"><span style="font-family: Verdana,sans-serif;">A case of amlodipine-associated hyponatremia has been reported.</span></li><li class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto; mso-list: l1 level1 lfo4; tab-stops: list 36.0pt;"><span style="font-family: Verdana,sans-serif;">calcium channel antagonist– related hyponatremia, if it exists, is extremely rare.</span></li></ul><span style="font-family: Verdana,sans-serif;"> </span><div class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto;"><span style="font-family: Verdana,sans-serif;"><b>Management</b></span></div><span style="font-family: Verdana,sans-serif;"> </span><ul style="margin-top: 0cm;" type="disc"><li class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto; mso-list: l3 level1 lfo5; tab-stops: list 36.0pt;"><span style="font-family: Verdana,sans-serif;">In mild to moderate cases with a normovolaemic fluid status clinically, ceasing the offending drug and gentle fluid restriction would improve serum sodium levels gradually within a week.</span></li><li class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto; mso-list: l3 level1 lfo5; tab-stops: list 36.0pt;"><span style="font-family: Verdana,sans-serif;">In an acutely unwell patient due to severe drug induced hyponatraemia, severe fluid restriction or infusion of hypertonic saline may be require</span></li><li class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto; mso-list: l3 level1 lfo5; tab-stops: list 36.0pt;"><span style="font-family: Verdana,sans-serif;">May consider changing therapy and monitoring patient for improvement</span></li></ul><span style="font-family: Verdana,sans-serif;"> </span><div class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto;"><span style="font-family: Verdana,sans-serif;"><b>Alternatives</b></span></div><span style="font-family: Verdana,sans-serif;"> </span><ul style="margin-top: 0cm;" type="disc"><li class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto; mso-list: l4 level1 lfo6; tab-stops: list 36.0pt;"><span style="font-family: Verdana,sans-serif;">Diuretics are not recommended as have higher likelihood of causing hyponatremia</span></li><li class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto; mso-list: l4 level1 lfo6; tab-stops: list 36.0pt;"><span style="font-family: Verdana,sans-serif;">ARBs are also established to cause hyponatremia and no available data on comparison with ACEi</span></li><li class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto; mso-list: l4 level1 lfo6; tab-stops: list 36.0pt;"><span style="font-family: Verdana,sans-serif;">Beta Blockers- <span lang="EN-IN" style="mso-ansi-language: EN-IN;">Beta blockade, especially of the Beta 1 receptor at the macula densa, inhibits renin release, & the release of aldosterone. This causes hyponatermia and hyperkalemia</span></span></li></ul><span style="font-family: Verdana,sans-serif;"> </span><div class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto;"><span style="font-family: Verdana,sans-serif;"><b>References:</b></span></div><span style="font-family: Verdana,sans-serif;"> </span><ol start="1" style="margin-top: 0cm;" type="1"><li class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto; mso-list: l5 level1 lfo7; tab-stops: list 36.0pt;"><span style="font-family: Verdana,sans-serif;"><a href="http://www.gpnotebook.co.uk/simplepage.cfm?ID=x20120201092040500242">http://www.gpnotebook.co.uk/simplepage.cfm?ID=x20120201092040500242</a></span></li><li class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto; mso-list: l5 level1 lfo7; tab-stops: list 36.0pt;"><span style="font-family: Verdana,sans-serif;"><a href="https://www.pjms.com.pk/issues/aprjun207/article/casereport3.html">https://www.pjms.com.pk/issues/aprjun207/article/casereport3.html</a></span></li><li class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto; mso-list: l5 level1 lfo7; tab-stops: list 36.0pt;"><span style="font-family: Verdana,sans-serif;">Jenny A. Van Amburgh. Can Lisinopril Cause Hyponatremia? - <i>Medscape</i> - Jul 28, 2011</span></li><li class="MsoNormalCxSpMiddle" style="line-height: normal; margin-bottom: .0001pt; margin-bottom: 0cm; mso-add-space: auto; mso-list: l5 level1 lfo7; tab-stops: list 36.0pt;"><span style="font-family: Verdana,sans-serif;"><i>American Journal of Kidney Diseases, </i>Vol 52, No 1 (July), 2008: pp 144-153</span></li></ol>

Indication side effect Hyponatremia : ACEi vs CCB

Symptoms presented with signs and symptoms of hyponatremia (eg, nausea, malaise, headache, lethargy, seizures, coma, respiratory depression...

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