PHARMACOLOGY IN HEART DISEASES BY PATHOLOGY

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BGCOLOR="#FFFFFF" TEXT="#080000"> <div> <I>PHARMACOLOGY IN HEART DISEASES BY PATHOLOGY</I></div> <bR> <div> <B><U>ANTICOAGULANTS</U></b></div> <div> <B>Unfractionated Heparin</b> <B>Coumadin</b> <B>Antiplatelets</b> <B>(ASA, ticlopidine, clopedigril)</b><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT><B>Low molecular weight Heparins</b><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT><B>Glycoprotein IIB/IIIA inhibitors</b><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <bR> <bR> <bR> <DIV ALIGN="LEFT"></DIV> <div> <B>ISCHEMIC HEART DISEASE</b></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b70168ff00ff00.gif" HEIGHT="24" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Angina Drug Therapy General:</b><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Ranges from intensive medical management (unstable angina) with the goal of preventing progression to MI or death to symptom control </div> <div> <B><IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Drug therapy may include: - </b></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Nitrates - </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Beta-blockers - </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Calcium channel blockers - </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Heparin, </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">ASA or other anticoagulant/antiplatelet agents - </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Analgesics (morphine) </div> <div> <B><U><IMG BORDER="0" SRC="Symb075c00b700f0ff000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Non-Drug Therapy:</U></b><U> </U><FONT SIZE="3" COLOR="#000000" FACE="Arial" >Therapy may require cardiac catheterization and myocardial revascularization: CABG, PTCA, or </FONT><U>stenting</U><FONT SIZE="3" COLOR="#000000" FACE="Arial" >. </FONT></div> <DIV ALIGN="LEFT"></DIV> <div> <B>ISCHEMIC HEART DISEASE LECTURE</b></div> <div> <B><IMG BORDER="0" SRC="Symb075c00b70168ff00ff00.gif" HEIGHT="24" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Angina Drug Therapy:</b><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <B>Antithrombotic Agents for Angina</b> </div> <div> Generally ASA, <FONT SIZE="4" COLOR="#0000FF" FACE="Arial" ><U>Unfractionated heparin, Low molecular wt. Heparins</U></FONT> are used in ischemic syndromes. Grades refer to that found in the AHCPR guidelines or those from The CHEST supplement. </div> <bR> <bR> <div> <B>Stable angina </b>- ASA to be taken qd 160-325mg/day and continued indefinitely with unstable angina (ticlopidine is alternative 250mg bid for patients with ASA allergy) </div> <bR> <bR> <div> <B>Unstable angina </b>- ASA to be taken qd 160-325 mg/day and continued indefinitely with unstable angina (ticlopidine is alternative 250mg bid for patients with ASA allergy as will be clopedigrel-early in 1998 </div> <div> Heparin (IV) (in contrast to subcutaneous) should be started as soon as a diagnosis of intermediate- or high-risk unstable angina is made <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>(stength of evidence = A)</U></FONT>. Give a bolus and maintenance infusion. In addition ASA should be used in all patients with the diagnosis of unstable angina as soon as possible after presentation unless a definite contraindication is present (eg. life-threatening hemorrhage or predisposition to such hemorrhage like a bleeding peptic ulcer or a clear history of severe hypersensitivity to ASA <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>(strength of evidence = A)</U></FONT>. The heparin should be continued for 2-5 days or until revascularization is performed goal aPTT of 1.5 - 2 times control (unstable angina).<FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U> (Heparin dosing information and nomogram)</U></FONT></div> <bR> <bR> <div> Most recently, the EPILOG investigators reported that inhibition of the platelet glycoprotein IIb/IIIa receptor with abciximab (Reopro®) together with low-dose, weight-adjusted heparin, markedly reduces the risk of acute ischemic complications in patients undergoing PTCA without increasing the risk of hemorrhage. The current use of abciximab is evolving and its recommended use is not certain at this point-other than for patients undergoing PTCA who are at high risk for closure. (refer to the anticoagulant lecture). For patients with unstable angina or non-Q wave infarction, low- molecular weight heparin (enoxaparin) given 1mg/kg subcutaneously q12 hours, was more effective than unfractionated heparin plus aspirin in reducing the risk of recurrent angina, myocardial infarction or death. </div> <div> This according to the <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>ESSENCE </U></FONT>trial. There were however, an increase in minor bleeds but not major bleeds. It remains a dynamic state for the role of LMWHs and unstable angina. </div> <div> Refer to the anticoagulant lectures. -</div> <div>  <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>Monitor</U></FONT>: Heparin should be monitored by following aPTT. If used IV, draw an aPTT 6 hours after starting the infusion (given the 60-90 min half-life of heparin) and then follow the heparin nomogram . If Heparin is given subcutaneously, aPTT is typically not followed. This is because the doses used do not consistently change aPTT. They do, however at high doses (around 15,000U/dose) affect aPTT at the 6 hour post sq dose time fairly consistently and in this case (rarely used) aPTT can be monitored. In either case, heparin should be monitored with Hg, HCT, clinical signs of bleeding (nose IV site etc.), </div> <bR> <bR> <div> <B>Typical LD for heparin is from 75-100 U/kg, and a MD of between 15-20 U/kg to start. </b></div> <div> <B><U>Reversal of bleeding due to heparin.?</U></b></div> <div> <B>Primary prevention </b>- If free of history of AMI, stroke, or TIA and < 50 years old, ASA is not recommended - If >50 years old, ASA should be taken (160-325mg/day) and continued indefinitely if they have at least one additional major risk factor for CAD and are free of contraindications <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>(Grade A for men, C for women) </U></FONT></div> <div> <B>Miscellaneous</b>: platelet inhibiting agents flavonoids- phenolic compounds found in may fruits and vegetables (purple grape juice). Role at this time is unclear. Similarly glycoprotein IIBIIIA inhibitors, and low molecular weight heparin's role remain unclear at this time. Nonetheless, studies evaluating these agents are published and in the works</div> <div> <B>Beta-Blockers for Angina</b></div> <div> <B>Clinical Use: Recommendation:</b> IV (for high-risk patients) or oral (for immediate- and low-risk patients) beta blockers should be started in the absence of contraindications <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>(strength of evidence = B)</U></FONT>. </div> <div> <B>Recommendation:</b> Choice of the specific agent is not as important as ensuring that appropriate candidates receive this therapy. If there are concerns about patient intolerance due to existing pulmonary disease, especially asthma, LV dysfunction, or risk of hypotension or severe bradycardia, initial selection should favor a short-acting agent, such as propranolol or metoprolol or the ultra short-acting agent esmolol. Mild wheezing or a history of COPD should prompt a trial of a short-acting agent as a reduced dose (e.g., 2.5 mg IV metoprolol, 12.5 mg oral metoprolol, or 25 µg/kg/min esmolol as initial doses) rather than complete avoidance of beta-blocker therapy <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>(strength of evidence = C)</U></FONT>.</div> <div> <B>Recommendation: </b>IV metoprolol is given in 5mg increments by slow (over 1-2 minutes) IV administration repeated every 5 minutes for a total initial dose of 15mg followed in 1 to 2 hours by 25 to 50 mg by mouth every 6 hours. If a very conservative regimen is desired with metoprolol, initial doses can be reduced to 1 to 2 mg. </div> <div> IV propranolol is given as an initial dose of 0.5 to 1.0 mg, followed in 1 to 2 hours by 40 to 80mg by mouth every 6 to 8 hours. </div> <div> IV esmolol is given as a starting maintenance dose of 0.05 mg/kg/min with titration in increments of 0.05 mg/kg/min every 10 to 15 minutes as tolerated by blood pressure until the desired therapeutic response has been obtained, limiting symptoms develop, or a dose of 0.20 mg/kg/min is reached. An optional loading dose of 0.5 mg/kg may be given by slow IV administration (2 to 5 minutes) for more rapid onset of action.</div> <div> In patients suitable for a longer acting agent, IV atenolol can be initiated with a 5mg IV dose followed 5 minutes later by a second 5mg IV dose and then 50 to 100mg orally per day initiated 1 to 2 hours after the IV dose. This is also most economical relative to esmolol. </div> <div> <B>Monitoring </b>during IV beta-blocker therapy should include frequent checks of heart rate and blood pressure and continuous ECG monitoring, as well as auscultation for rales or bronchospasm. After the initial IV load, patients without limiting side effects may be converted to an oral regimen. The target heart rate for beta blockade is 50 to 60 beats per minute. Selection of the oral agent should be based on the clinician's familiarity with the agent as well as the risk of adverse effects<FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U> (strength of evidence = C).</U></FONT></div> <div> <B>Beta-blockers should be started in the absence of contraindications</b> (IV for high-risk patients) or oral for intermediate and low-risk patients Consider pt. intolerance due to pulmonary disease, especially asthma, LV dysfunction, risk of hypotension or severe bradycardia, diabetes, lipid disorders </div> <div> <B>Mechanism</b>: reduce cardiac work by negative inotrope, negative chronotrope and hypotensive (central and renin blocking) effects </div> <div> <B>Pharmacologic issues:</b> high first pass, modest half-life, variable protein binding, cardioselectivity (dose dependent), intrinsic sympathomimetic activity, alpha-blockade </div> <div> <B>Monitor</b>: SE's are extension of pharmacologic effects, bradycardia, hypotension, CHF, depression abrupt withdrawal, impotence, diabetes (Sx and Symptoms) lipid effects (decr. HDL, incr. trigs), reactive airway disease.</div> <bR> <bR> <div> <B><U>More about Pharmaoclogic Features or Issues Relating to Beta-Blockers</U></b></div> <div> <B><U>A summary of the properties of various available beta-blockers</U></b></div> <div> <B>1. Intrinsic Sympathomimetic Activity (ISA)</b></div> <div> <B>2. Lyphophilicity, Hydrophilicity and CNS Side Effects of Beta-Blockers </b></div> <div> <B>3. Structure Activity Relationship of Beta-blockers:</b> </div> <div> <B>4. Concentration-Effect Relationships:</b></div> <div> <B>5. Stereopharmacology </b></div> <div> <B>6. Polymorphic Drug Oxidation </b></div> <div> <B>7. Clearance Concepts </b></div> <div> <B>8. Drug Interactions</b> -</div> <div> --------------------------------------------------------</div> <div> <B>Summary of the Available Beta-Blockers and Their Pharmacologic Properties</b><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <TABLE BORDER="2" CELLPADDING="1" CELLSPACING="1" WIDTH="656" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="BOX" RULES="ALL" ALIGN="BOTTOM" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=CENTER HEIGHT= 39 WIDTH="92"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="39" ALIGN="bottom" WIDTH="92" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="39" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="92"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="39" ALIGN="bottom" WIDTH="92" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="39" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="92"><div> <B>Beta-Blockers</b></div> </tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="39" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="71"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="39" ALIGN="bottom" WIDTH="71" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="39" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="244"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="39" ALIGN="bottom" WIDTH="244" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="39" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> </tR> <tR> <tD VALIGN=CENTER HEIGHT= 57 WIDTH="92"><div> <B>Non Selective</b></div> </tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="57" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="92"><div> <B>Non Selective</b></div> </tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="57" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="92"><div> <B>Selective</b></div> </tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="57" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER><NOBR><div> <B>Selective</b></div> </NOBR></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="57" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="244"><div> <B>With </b></div> <div> <B>Alpha-blocking </b></div> <div> <B>Activity</b></div> </tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="57" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> </tR> <tR> <tD VALIGN=CENTER HEIGHT= 39 WIDTH="92"><div> <B>No</b><FONT SIZE="3" COLOR="#FF00FF" FACE="Arial" ><B> ISA*</b></FONT></div> </tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="39" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="92"><div> <B>With </b></div> <div> <B>ISA</b></div> </tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="39" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="92"><div> <B>No ISA</b></div> </tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="39" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="71"><div> <B>With </b></div> <div> <B>ISA</b></div> </tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="39" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="244"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="39" ALIGN="bottom" WIDTH="244" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="39" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> </tR> <tR> <tD VALIGN=CENTER HEIGHT= 20 WIDTH="92"><div> <B>Nadolol</b></div> </tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="92"><div> <B>Pindolol</b></div> </tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="92"><div> <B>Atenolol</b></div> </tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER><NOBR><div> <B>Acebutolol</b></div> </NOBR></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="244"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="244" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> </tR> <tR> <tD VALIGN=CENTER HEIGHT= 20 ><NOBR><div> <B>Propranolol</b></div> </NOBR></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER><NOBR><div> <B>Carteolol</b></div> </NOBR></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER><NOBR><div> <B>Metoprolol</b></div> </NOBR></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="71"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="71" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="244"><div> <B>Labetalol</b></div> </tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> </tR> <tR> <tD VALIGN=CENTER HEIGHT= 20 WIDTH="92"><div> <B>Timolol</b></div> </tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER><NOBR><div> <B>Penbutolol</b></div> </NOBR></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="92"><div> <B>Esmolol</b></div> </tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="71"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="71" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="244"><div> <B>Carvedilol**</b></div> </tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> </tR> <tR> <tD VALIGN=CENTER HEIGHT= 20 WIDTH="92"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="92" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="92"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="92" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER><NOBR><div> <B>Betaxolol</b></div> </NOBR></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="71"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="71" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="244"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="244" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> </tR> <tR> <tD VALIGN=CENTER HEIGHT= 20 WIDTH="92"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="92" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="92"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="92" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER><NOBR><div> <B>Bisoprolol</b></div> </NOBR></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="71"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="71" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="244"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="244" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> </tR> <tR> <tD VALIGN=CENTER HEIGHT= 39 WIDTH="92"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="39" ALIGN="bottom" WIDTH="92" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="39" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="92"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="39" ALIGN="bottom" WIDTH="92" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="39" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="92"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="39" ALIGN="bottom" WIDTH="92" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="39" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="71"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="39" ALIGN="bottom" WIDTH="71" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="39" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="244"><div> <B>*Intrinsic Sympathomimetic Activity</b></div> </tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="39" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> </tR> <tR> <tD VALIGN=CENTER HEIGHT= 20 WIDTH="92"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="92" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="92"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="92" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="92"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="92" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="71"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="71" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> <tD VALIGN=CENTER WIDTH="244"><div> <B>**cardioselective</b></div> </tD> <tD VALIGN=CENTER WIDTH="2"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="20" ALIGN="bottom" WIDTH="2" HSPACE="0" VSPACE="0"></tD> </tR> </TABLE></div> <div> <B>Intrinsic sympathomimetic activity is a property of select beta-blockers which confirs some degree of agonist activity to the antagonist at low levels of sympathetic tone (rest</b></div> <div> <B>1. Intrinsic Sympathomimetic Activity (ISA)</b></div> <div> Clinical importance of ISA is controversial. There are theoretical arguments for using beta-blockers with ISA (some which have been clinically studied that assist the clinical pharmacologist in choosing an appropriate agent for a specific patient.</div> <bR> <div> <B>Considerations: -</b> Not all Beta-Blockers with ISA have an equal amount of ISA. Pindolol greater than Acebutalol. - The partial agonist activity of a beta-blocker is not the same in all tissues (beta2 agonist activity at arteriolar smooth muscle is greater than that at bronchiolar smooth muscle) - Although the degree of ISA exerted by a beta blocking drug is linearly related to the dose used, the net affects of beta blockade and partial agonist stimulation are inversely related to the degree of sympathetic drive (the pharmacodynamic effects of ISA are maximally observed during periods of low sympathetic drive) - Physiological implications of ISA: a. less negative chronotropic activity b. less negative inotropic activity c. less peripheral vasoconstriction d. less bronchoconstriction</div> <div> To expand on the implications one might consider the use of a Beta-Blocker with ISA to produce less peripheral vasoconstriction than ones without. Less vasoconstriction is a result of a direct effect of stimulating vasodilator beta2 receptors in the resistance vessels as well as the indirect effect of less depression of left ventricular pumping function which also may result in less intense reflex vasoconstriction. Patients at a risk of undesirable bradycardia may perhaps derive benefit from a drug with ISA. This may include the elderly since they are more dependent upon heart rate in order to preserve cardiac output.</div> <div> Therapeutic Effects of ISA Containing Beta-Blockers (Pindolol, Acebutalol)</div> <bR> <div> <B>A. Heart rate.</b> Beta-blocking drugs with ISA result in less reduction in resting heart rate than do those without this property. B. Left ventricular function. Theoretical advantage of a beta-blocker with ISA may include an improvement in pumping function of the heart through a direct positive inotropic stimulation of myocardial contractility, allowing less a reduction in heart rate (and thereby and increase in cardiac output) and also by offsetting the increase in left ventricular afterload (caused by unopposed alpha agonist activity secondary to beta-blockade from beta blockers without ISA) C. Peripheral Blood Flow and Vascular Resistance. Beta-blockers with ISA, through a direct stimulation of beta2 receptors in arteriolar resistance vessels and by minimizing the indirect reflect vasoconstriction mediated through alpha-1 adrenoceptors, may have an overall reduction in the depression of left ventricular pumping activity than beta-blockers without ISA. D. Bronchoconstriction. Beta-blockers with ISA may have less bronchoconstricting effects than beta-blockers without this property although there is no evidence that possession of ISA by a beta-blocking drug confirms any benefit to the asthmatic patients. E. Exercise capacity. Beta-blockers with ISA may cause less reflex vasoconstriction in striated muscle which together with the direct partial agonist stimulation of beta2 vasodilator receptors in vessels supplying these active muscles, may account for the lessor reduction in exercise muscle blood flow. The lesser increase in airway resistance during exercise can also be expected to enhance exercise performance. F. Blood Flow, Metabolism and Function of Ischemic Myocardium. Beta-blockers affect oxygen consumption by reducing heart rate and contractility however, also inherently increase energy requirements by causing ventricular dilation and enhanced afterload. Beta-blockers with ISA appears to prevent an increase in vascular resistance. G. Metabolic Effects. There may be some theoretical support for the property of ISA reducing the beta-blocker induced reductions in HDL for both those beta-blockers that are non-selective and those that are beta1 selective. H. Withdrawal Phenomenon. This phenomenon is thought to occur between 1 and 21 days after abrupt cessation of beta-blockade therapy may be related to increased numbers or augmented sensitivity of beta adrenoceptors in the heart among other mechanisms. There may be an apparent decrease in this phenomenon for individuals withdrawn abruptly form beta-blockers possessing ISA. Summary</div> <div> Good clinical evidence supporting the use of beta-blockers with ISA for these theoretical potential advantages listed above is lacking. Although some studies have demonstrated some benefit, these arguments are provided mainly to assist the clinician in having some basis for supporting the use of a beta-blocker with ISA in specific individuals requiring a beta-blocker. The majority of these statements were taken directly from the reference Intrinsic Sympathomimetic Activity: Clinical Fact or Fiction. S.H. Taylor, American Journal of Cardiology 1983 52: pg. 16D-26D.</div> <bR> <bR> <div> <B>4. Lyphophilicity, Hydrophilicity and CNS Side Effects of Beta-Blockers </b></div> <div> Relative lyphophilicity or hydrophilicity has been yet another grounds on which to distinguish between choices of beta-blockers available today. Generally speaking, beta-blockers with a higher degree of lyphophilicity are typically associated with a greater first-pass extraction, lower F (bioavailability) are highly metabolized, larger Vd, greater penetration into the brain, and shorter half-lives. Although it is generally felt that CNS penetration as a function of lyphophilicity is thought to be a marker of the likelihood of a beta-blocker to induce CNS side effects, recent data comparing beta-blockers with different degrees of lyphophilicity occasionally have produced conflicting results. As a result of these results in conflict with this generality, other hypotheses have been postulated in an attempt to explain these deviations.</div> <div> 1. It is not clearly known whether it is as a result of a beta-blocker's ability to block beta-receptors in the brain versus 5HT receptors in the brain that may contribute to its CNS side effects. 2. Actual brain levels achieved may correlate better than each drug's lyphophilicity to their propensity to cause CNS side effects. 3. Specific chemical constituents of the beta-blocker molecules may be more closely related to a beta-blocker's ability to induce CNS side effects. Example the indole ring of pindolol. </div> <div> Once again, the CNS side effects of beta-blockers are numerous and in some cases nonspecific.</div> <div> Tiredness Depression Dizziness Hallucinations Fatigue Delirium Lightheadedness Somnolence Lethargy Dreaming Drowsiness Vertigo Headache</div> <div> It is important to make the point that crossing the blood brain barrier is not essentially synonymous with the ability to cause side effects and thereby lyphophilicity may not be a direct indicator of a propensity of a given beta-blocker to </div> <div> induce CNS side effects.</div> <bR> <bR> <div> <B>5. Structure Activity Relationship of Beta-blockers:</b> The nature of substituants on the aromatic ring determines whether the effect is predominantly activation or blockade. In addition, para-substitution on the aromatic ring typically confers beta-1 selectivity. The alphatic hydroxy group appears to be essential for activity given the molecular chirality levorotary forms typically being more potent than the dextrorotary forms. Example sotalol which is considered a class III antiarrhythmic agent is made up of d-sotalol and l-sotalol. The l-sotalol is responsible for most of the beta-blocking effects while the d-sotalol is most responsible for the racemic mixtures class III antiarrhythmic properties. For most beta-blockers, it is the l-enantiomer which is mostly responsible for the clinically important beta-blocking effects of the drug.</div> <bR> <bR> <div> <B>7. Concentration-Effect Relationships:</b> - numerous articles claim a poor relationship between concentration of a given beta-blocker and effect yet others quote an "effective concentration range". Who is right? Perhaps both. What is important to realize is that the relationship between the PK and pharmacodynamics of this class of agents is determined by the model used. For example when modeling the response of beta-blockers using inhibition of post-exercise induced heart rate changes, there is a maximum effect (compatable with life) that can be expected from any concentration of a beta-blocker. Thus the ÒEmaxÓ model may best describe this effect-concentration relationship at higher concentrations. However, it may be possible at lower concentrtations that a linear model may work best for this relationship as well. </div> <bR> <bR> <div> <B>8. Stereopharmacology </b>- many beta-blockers have a chiral carbon and are marketed as racemic mixtures of each enantiomer - enantiomers can have a different effect and/or magnitude of effect at the various end organs (targeted or incidental). They also have different pharmacokinetics and may display stereoselective metabolism. If select drug-drug inteactions occur with such agents, this may have clinical consequenses given the different effects of various enantiomers. Carvedilol is one such example. </div> <bR> <bR> <div> <B>9. Polymorphic Drug Oxidation </b>- certain beta-blockers have exhibited differences in their metabolism that can be shown to be genetically determined. The consequences of these genetic differences in metabolism have been examined in some beta-blockers (metoprolol, carvedilol, sotalol, propranolol) and are being explored in still others.</div> <bR> <bR> <div> <B>10. Clearance Concepts </b>- High clearance drugs are blood flow dependent (low clearance drugs are Clint dependent) and therefore are most likely (compared to low clearance drugs) to be influenced by interventions which affect liver blood flow. - High clearance drugs also tend to have low bioavailabilities. Metoprolol</div> <bR> <bR> <div> <B>11. Drug Interactions</b> - pharmacokinetic: CYP2D6 inhibitors for metoprolol, timolol, carvedilol, propranolol?, drugs which reduce liver blood flow, - pharmacodynamic (combinations with other negative chronotropes/inotropes, antihypertensives or drugs which block the effects of the antihypertensive action of beta-blockers)</div> <div> ---------------------------------------------</div> <div> <B>Nitrates for Angina</b><FONT SIZE="3" COLOR="#800080" FACE="Arial" > </FONT><FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>( </U></FONT><FONT SIZE="3" COLOR="#000000" FACE="Arial" >(and also morphine sulfate)</FONT></div> <div> <B>Clinical Use: </b></div> <div> <B>Recommendation: </b>Patients whose symptoms are not fully relieved with three sublingual NTG tablets and initiation of beta-blocker therapy (when possible), as well as all nonhypotensive high-risk unstable angina patients, may benefit from IV NTG, and such therapy is recommended in the absence of contraindications. IV NTG should be started at a dose of 5 to 10 µg/min by continuous infusion and titrated up by 10 µg/min every 5 to 10 minutes until relief of symptoms or limiting side effects (headache or hypotension with SBP < 90 mmHg or more than 30 percent below starting mean arterial pressure levels if significant hypertension is present) (strength of evidence = B). </div> <div> <B>Recommendation:</b> Patients on IV NTG should be switched to oral or topical nitrate therapy once they have been symptom-free for 24 hours (strength of evidence = C). Tolerance to nitrates is dose- and duration-dependent and typically becomes significant only after 24 hours of continuous therapy. Responsiveness to nitrates can be restored by increasing the dose or switching the patient to a nonparenteral form of therapy and using a nitrate-free interval. As long as the patient's symptoms are not adequately controlled, the former option should be selected. Topical, oral, or buccal nitrates should be given with a 6- to 8-hour nitrate-free interval (strength of evidence = C).</div> <div> <B>Mechanism:</b> reduce cardiac work afterload and preload reduction as well as coronary dilatation and possibly antiplatelet effects11 ´ Pharmacologic issues: variable bioavailability, short half-life, tolerance ´ Monitor: SE's are extension of pharmacologic effects, hypotension, headache, especially post withdrawal ´ Other issues: multiple dosage forms, durations of action, cost, compliance ´ If symptoms not relieved with a 3 sl NTG tablet and initiation of beta-blocker therapy (when possible), IV NTG is recommended ´ IV NTG should start at 5-10 mcg/min continuous infusion and titrated up by 10 mcg/min q5-10 min until relief of symptoms or limiting side effects (headache/hypotension SBP < 90) or dose exceeds 200 mcg/min ´ Switch to oral nitrates within 24 hours when possible</div> <div> <B>Nitrate Tolerance</b> Main limitation of long-term prophylactic nitrate therapy is the development of tolerance (both to hemodynamic effects on exercise capacity). <B>Definition</b>: decrease in response to a given amount of nitrate or the need of increased amounts of nitrate to maintain a continuous effect. Numerous trials, using exercise testing to assess the efficacy of nitrate therapy, have shown an attenuation of antianginal effect with chronic therapy . Tolerance can develop with all forms of nitrate therapy that maintain continuous blood levels of the drug . Tolerance can develop after only a few doses. Ensuring an adequate nitrate free period with thrice daily dosing of oral nitrates is extremely difficult and complied with in less than 50% of patients 12for most patients prescribed isosorbide dinitrate.</div> <div> <B>Mechanism of Nitrate Tolerance: </b>- the leading theory on the mechanism involves the depletion of sulfhydryl groups in vascular tissues with a subsequent decrease in production of the potent vasodilator nitric oxide, the end product of organic nitrate metabolism. - Oxidation or depletion of sulfhydryl groups necessary for the conversion of organic nitrates to nitric oxide leads to an eventual reduction in cGMP formation and thus loss of vascular response to the drug. - In support of this mechanism, exogenous supplementation of sulfhydryl sources has been shown to enhance nitrate action or reverse pharmacological tolerance . - </div> <div> Pharmacologic means of preventing nitrate tolerance have included the use of various sulfhydryl donors including acetylcysteine, methionine and captopril. This method cannot be recommended, however, due to conflicting data on its effectiveness and the additional cost and adverse effects associated with sulfhydryl donor therapy. -additional evidence suggests that systemic neurohormonal responses during chronic nitrate administration may be at least partly responsible for the development of tolerance toward nitrates. </div> <div> Several investigators have reported the development of counterregulatory neurohormonal forces during chronic nitrate administration, such as increased plasma norepinephrine and plasma renin activity, that occur in response to reduced renal blood flow . - Activation of the sympathetic and renin-angiontensin systems following vasodilation with nitrates may lead to a degree of vasoconstriction and sodium retention that effectively counteracts the beneficial effects of nitrates on the vascular system. Moreover, the nonsulfhydryl compounds enalapril and hydralazine have been shown to prevent the development of tolerance during chronic nitrate administration, presumably due to their ability to antagonize these counterregulatory neurohormonal factors. - the mechanism underlying the development of nitrate tolerance may be more complex than previously imagined and requires further study. </div> <div> <B>- a nitrate holiday</b> ("nitrate free period" or NFP) of at least 10 hours and preferably up to 14 hours is recommended to avoid tolerance or to allow the offset of tolerance already established. Nitrate-free intervals of 10-12 hours have undoubtedly proven beneficial in avoiding the development of tolerance and subsequent loss of efficacy. - For example, regular-release isosorbide dinitrate, which is administered 3-4 times daily, may be scheduled at 7AM, Noon, and 5PM. Isosorbide-5-mononitrate and sustained release preparations of nitroglycerin or isosorbide dinitrate may be given twice daily at 8AM and 3PM, allowing an 8-12 hour nitrate holiday. - Removal of nitroglycerin ointment paper and residual ointment at bedtime - a nitroglycerin transdermal patch placed at 8AM may be removed at bedtime. - patients with angina in early morning should consider placing the once-daily patch in the evening and removing it in the early afternoon - An intravenous nitroglycerin infusion is often of short duration and tolerance may not be an issue. However, if continued for more than 24 hours, a loss of hemodynamic effect may require upwards dose titration to maintain efficacy. Discontinuing the infusion for at least 6 hours, if possible, may help prevent the development of tolerance. - patients may develop rebound angina during the nitrate-free period. - it is well documented that the incidence of myocardial infarction and sudden death are high in the early morning hours. - for patients experiencing nocturnal angina during unprotected intervals, concomitant use of another antianginal agent should be considered.</div> <div> <B>Nitrate Formulations Are Many and Diverse:</b>Nitroglycerin Ointment - Onset 20-60 min, duration 2-8 hrs, dosed 0.5 to 1 inch tid with NFP (1 inch [2%] = 15mg) - Care should be taken by applicant if not patient. Nitroglycerin Patch - Onset 40-60 min, duration 8 hrs, dose 0.2, 0.4, 0.6 mg/hr - 12 hours on 12 hours off (choose off time carefully)</div> <div> <B>Mononitrates </b>Issues of metabolism - ISDN has a high first pass effect --> low blood levels of ISDN (F = 26%) in contrast to the 100% bioavailability of IS-5-mononitrate - Majority of effect from ISDN is due to IS-5-MN - Approx. 26% enters systemic circ. from po dose</div> <div> <B>Isosorbide-5-Mononitrate </b></div> <div> <B>Pharmacokinetics </b>- Peak absorption (immed. release) is within 60 min. (longer for sustained release) - Absolute bioavailability approx. 100% - ISMN half-life approx. 4-5 hours ´ Pharmacodynamics - Peak effect -14 hours - Duration of effect approx. 12 hours (angina and ETT) ´ Elimination - Hepatic --> inactive metabolites</div> <div> <B>Patient Information:</b> </div> <div> <B>Nitrates </b>: </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Discuss issue of tolerance (rational ISDN-ISMN, importance of following instructions) </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Do not crush or chew IMDUR tablets </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Potential for hypotension and headache with all nitrates ´ </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">ISMO or ISDN are not choice for immediate anti-anginal effect </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Eccentric dosing (7 hour separation) for twice daily administered IS-5-mononitrates (practically difficult for many patients to remember unique dosing scheme) ´ </div> <div> <IMG BORDER="0" SRC="Symb075c00b700f000000000.gif" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">sl NTG-storage, dating, dosing ---------------------------------------------------------------------------------------------------------------- </div> <div> <B>Morphine Sulfate</b></div> <div> <B>Recommendation: </b>Morphine sulfate at a dose of 2 to 5 mg IV is recommended for any patient whose symptoms are not relieved after three serial sublingual NTG tablets or whose symptoms recur with adequate anti-ischemic therapy unless contraindicated by hypotension or intolerance. Morphine may be repeated every 5 to 30 minutes as needed to relieve symptoms and maintain patient comfort</div> <div> ANTIDYSRHYTHMICS </div> <div> Dysrhythmias are common in the cardiac surgical patient. A stable cardiac rhythm requires depolarization and repolarization in a spatially and temporally coordinated manner, and dysrhythmias occur when this coordination is disturbed. The mechanisms for dysrhythmias can be divided into abnormal impulse initiation, abnormal impulse conduction, or combinations of both. </div> <div> Abnormal impulse initiation occurs as a result of increased automaticity (spontaneous depolarization of tissue that does not normally have pacemaking activity) or as a result of triggered activity from abnormal after depolarizations during phase 3 or 4 of the action potential. Abnormal conduction often involves re-entry phenomena, with recurrent depolarization around a circuit owing to unilateral conduction block in ischemic or damaged myocardium and retrograde activation via an alternate pathway through normal tissue. In this simplistic view, it is logical that dysrhythmias could be suppressed by slowing the conduction velocity of ectopic foci, allowing normal pacemaker cells to control heart rate by prolonging the action potential duration (and hence refractory period) to block conduction into a limb of a re-entry circuit, or by overdrive suppression with higher extrinsic heart rates. </div> <div> Antidysrhythmic agents often are classified by a scheme originally proposed by Vaughan Williams and subsequently modified, and although alternative schemes have been proposed and may be more logical,  we will organize our discussion using the Vaughan Williams system of four major drug categories. In this scheme, Class I agents are those with local anesthetic properties that block na <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>channels, Class II drugs are beta-blocking agents, Class III drugs prolong action potential duration, and Class IV are calcium entry blockers. </div> <div>  <A NAME="subsect198"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Class I Agents </div> <div> Although each of the Class I agents blocks na <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>channels, they may be subclassified on the basis of electrophysiological differences. These differences can be explained, to some extent, by consideration of the kinetics of the interaction of the drug and the na <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>channel.] Class I drugs bind most avidly to open (phase 0 of the action potential—</div> <div> or inactivated (phase 2) na <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>channels. Dissociation from the channel occurs during the resting (phase 4) state. If the time constant for dissociation is long in comparison to the diastolic interval (corresponding to phase 4), drug will accumulate in the channel to reach a steady-state, slowing conduction in normal tissue. This occurs with Class Ia (procainamide, quinidine, disopyramide) and Class Ic (encainide, flecainide, lorcainide, propafenone) drugs. In contrast, for the Class Ib drugs (lidocaine, tocainide, mexilitine), the time constant for dissociation from the na <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>channel is short, drug does not accumulate in the channel, and conduction velocity is minimally affected. However, in ischemic tissue the depolarized state is more persistent, leading to greater accumulation of agent in the na <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>channel, and slowing conduction in the damaged myocardium. </div> <div>  <A NAME="subsect2141"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> CLASS Ia </div> <div> Procainamide probably is the Class Ia drug most commonly used in the perioperative period. Procainamide has a variety of electrophysiological effects.</div> <div>  As noted earlier, conduction velocity in atrial, His-Purkinje, and ventricular tissue is decreased as a result of na <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>channel blockade. Action potential duration and effective refractory period are also increased. However, procainamide also has mild vagolytic (anticholinergic) effects that may lead to a decreased AV nodal refractory period and an increased ventricular response in supraventricular tachycardia. Despite these effects, procainamide remains an effective treatment of supraventricular tachycardia, especially if other drugs are given that reduce AV nodal conduction. </div> <div> The primary intraoperative use of procainamide is intravenous therapy for ventricular arrhythmias after failure of lidocaine. Administration may be limited by side effects of hypotension and decreased cardiac output.</div> <bR> <bR> <div> The loading dose is 20–30 mg/min, up to 17 mg/kg, although lower total doses are more commonly employed, and should be followed by an intravenous infusion of 20–80 µg/kg/min. Since it prolongs action potential duration, a potential overdose often is heralded by widening of the QRS complex. The elimination of procainamide involves hepatic metabolism, acetylation to a metabolite with antiarrhythmic and toxic side effects, and renal elimination of this metabolite. Thus the infusion rate for patients with significant hepatic or renal disease should be at the lower end of this range. Oral procainamide also may be used in the perioperative period. The usual dose is 50 mg/kg/day and a sustained release form is available so that dosing every 3–4 hours can be avoided. The side effects of oral procainamide include GI symptoms, CNS complaints (headache, insomnia), and a lupus-like syndrome with rash, agranulocytosis, myalgesia, pleuritis, pericarditis, and fever.</div> <div> Quinidine is another Class Ia agent often encountered in the perioperative period. It is seldom administered by the intravenous route because of decreased cardiac contractility and hypotension.</div> <bR> <bR> <div>  The direct electrophysiological effects are similar to procainamide; however, its indirect anticholinergic effects are more pronounced. This vagolytic property may increase conduction through the AV node and increase the rate of ventricular response in atrial fibrillation or flutter. Usually it should be given in conjunction with digoxin or a beta-blocking agent when used for the treatment of atrial fibrillation or flutter. </div> <bR> <div>  It is also effective in the treatment of ventricular arrhythmias. The usual oral dose for an adult is 300–600 mg every 6–8 hours. Side effects include tinnitus, headache, visual disturbances, and GI symptoms. The cardiac depressant effect is heralded by widening of the QRS complex. It should be noted also that quinidine is highly protein bound and may increase free digoxin levels and effects by competing for protein binding sites.</div> <div> Less commonly encountered Class Ia antiarrhythmics are disopyramide and diphenylhydantoin.</div> <bR> <div> The electrophysiological effects of disopyramide are very similar to procainamide and quinidine and its usefulness is limited by negative inotropic effects. Diphenylhydantoin has electro-physiological effects that resemble both Class Ia and Class Ib drugs. Its primary use is the treatment of dysrhythmics caused by digitalis toxicity. </div> <div>  <A NAME="subsect2142"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> CLASS Ib </div> <div> Class Ib drugs include what is probably the most widely administered dysrhythmic agent, lidocaine. Lidocaine is a na <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>channel blocker that has little effect on conduction velocity in normal tissue but slows conduction in ischemic myocardium.</div> <bR> <div> Other electrophysiological effects include a decrease in action potential duration but a small increase in the ratio of effective refractory period to action potential duration. The exact role of these electrophysiological effects on dysrhythmia suppression is unclear. Lidocaine has no significant effect on atrial tissue and is indicated for the treatment of ventricular dysrhythmia.</div> <div>  One of the major advantages of lidocaine is its pharmacokinetics.</div> <div>  After an initial bolus dose of 1–1.5 mg/kg, plasma levels decrease rapidly because of redistribution to muscle, fat, and other tissues. Effective plasma concentrations are maintained only by following the bolus dose with an infusion of 20–50 µg/kg/min. Elimination occurs via hepatic metabolism to active metabolites that are cleared by the kidney. Consequently, the dose should be reduced by approximately 50 percent in patients with liver or kidney disease. The primary toxic effects are associated with the CNS, and a lidocaine overdose may cause drowsiness, depressed level of consciousness, or seizures in very high doses. Negative inotropic or hypotensive effects are less pronounced than with most other anti-dysrhythmics. </div> <div> The other Class Ib drugs likely to be encountered in the perioperative period are tocainide and mexiletine. Their electrophysiological effects are very similar to lidocaine. These drugs are available for oral administration only.</div> <div>  <A NAME="subsect2143"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> CLASS Ic </div> <div> The final category of na <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>channel-blocking drugs, the Class Ic agents, include flecainide, encainide, and propafenone. These drugs markedly decrease conduction velocity.</div> <bR> <div> They were developed, in large part, for the suppression of ventricular dysrhythmia. However, enthusiasm for flecainide and encainide waned since the Cardiac Arrhythmia Suppression Trial (CAST) study. </div> <bR> <div>  This multi-center trial of encainide, flecainide, and moricizine found that although ventricular arrhythmias were suppressed, the incidence of sudden death was greater with encainide and flecainide than placebo. Propafenone is available for oral use. The usual adult dose is 150–300 mg every 8 hours. It has beta-blocking (with resultant negative inotropic effects) as well as na <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>channel-blocking activity; lengthens the PR, QRS, and QT duration; and may be used to treat both atrial and ventricular dysrhythmia. </div> <bR> <div>  <A NAME="subsect199"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Class II Agents </div> <div> Beta-receptor blocking agents are another important group of antidysrhythmics (denoted Class II in the Vaughan Williams scheme). However, because of their use as anti-hypertensive as well as antidysrhythmic agents, they are discussed elsewhere in this chapter. </div> <div>  <A NAME="subsect1100"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Class III Agents </div> <div> Bretylium, amiodarone, and sotalol are Class III agents in the Vaughan Williams scheme. These drugs have a number of complex ion channel-blocking effects, but possibly the most important activity is k <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>channel blockade. [<FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>27 </U></FONT>] Since the flux of k <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>out of the myocyte is responsible for repolarization, an important electrophysiological effect of Class III drugs is prolongation of the action potential.</div> <bR> <div>  Amiodarone also has na <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>and ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>channel-blocking activity, whereas sotalol has beta-blocking activity. </div> <div> Bretylium is the Class III agent that has the longest history of use in the United States. Its primary use and efficacy are for treatment of ventricular tachycardia or fibrillation that is refractory to lidocaine or countershock.</div> <bR> <div>  It is not effective in the treatment of atrial arrhythmias. Usually it is administered as an intravenous bolus of 5–10 mg/kg with an infusion of 1–2 mg/min. Its use may be limited by hemodynamic effects. Initially it induces norepinephrine release from adrenergic nerve terminals, and then subsequently prevents norepinephrine release. This leads to a transient increase in heart rate and blood pressure with the initial dose followed by decreases in heart rate, systemic vascular resistance, and blood pressure that may be quite pronounced.</div> <div> Sotalol is a nonselective beta-blocking agent that also has k <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>channel-blocking activity.</div> <bR> <div> It is available for intravenous and oral administration and has an approved indication for the treatment of life-threatening ventricular arrhythmias, although it is also effective against atrial arrhythmias. It is not a first-line therapy and should be reserved for dysrhythmias refractory to other therapy. In patients with significant ventricular impairment, the beta-blocking effects may lead to heart failure.</div> <div> Amiodarone, which has become available for routine intravenous use in the United States recently, has been described as the “most effective, most toxic, and most studied antidysrhythmic agent available”</div> <div>  As noted in the preceding, it has a variety of ion channel-blocking activities.</div> <bR> <div> The resultant electrophysiological effects are complex, and there also are differences in the acute and chronic effects. Acutely (after intravenous administration), there is little change in heart rate or a mild tachycardia, little change in QRS duration or QT interval, and an increase in AV nodal refractory period. After chronic use, there may be significant bradycardia and increases in action potential duration in AV nodal and ventricular tissue, with increased QRS duration and QT interval. </div> <div> The primary indication for amiodarone is ventricular tachycardia or fibrillation refractory to other therapy. It is the most efficacious agent for reducing ventricular arrhythmias and suppresses the incidence of post-myocardial infarction sudden death.</div> <bR> <div>  Also, it is effective, in doses lower than those used for ventricular dysrhythmia, for the treatment of atrial dysrhythmia, and is effective in converting atrial fibrillation to sinus rhythm. </div> <div> Amiodarone can be administered by both the oral and intravenous routes. The pharmacokinetics of amiodarone are unusual and are characterized by a huge distribution volume (~60 L/kg), a very long duration of action, and an active metabolite.</div> <bR> <div>  Because of these distinctive pharmacokinetic properties, steady-state plasma levels are achieved slowly. Oral administration for a typical adult consists of a loading regimen of 80–1600 mg/day (in two or three doses) for 10 days, then 600–800 mg/d for 4–6 weeks, and then maintenance doses of 200–600 mg/d. For intravenous loading 75–150 mg may be given over 10 min for acute therapy in an adult followed first by a secondary loading infusion of 30–60 mg/h for 6 hours and then the maintenance infusion of 15–30 mg/h. Sometimes much larger doses are needed. </div> <div> There are numerous adverse reactions to amiodarone. The most serious is pulmonary toxicity, which may progress from dyspnea and cough to a fibrosing alveolitis with hypoxia.</div> <bR> <div> Thyroid abnormalities also are common.</div> <bR> <div> Amiodarone's structure is similar to thyroxine (T4) and triodothyronine (T3). It suppresses the conversion of T4 to T3 and some of its electrophysiological effects may be caused by altered thyroid function. </div> <div> Amiodarone originally was used as an antianginal agent because of its vasodilating effects, including coronary vasodilation. </div> <bR> <div>  It decreases beta-receptor density, apparently via an antithyroid action. </div> <bR> <div> ] Cardiac output usually is maintained after administration, but hypotension can occur with intravenous therapy. </div> <div>  <A NAME="subsect1101"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Class IV Agents </div> <div> Another prominent category of antidysrhythmics, calcium entry blockers (Class IV in the Vaughan Williams scheme), are discussed elsewhere in this chapter, but their roles as antiarrhythmics, especially verapamil and diltiazem, are considered here. In sinoatrial and atrioventricular nodal tissue, ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>channels contribute significantly to phase 0 depolarization and the AV nodal refractory period is prolonged by ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>entry blockade. <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U> </U></FONT></div> <bR> <div> This explains the effectiveness of verapamil and diltiazem in the treatment of supraventricular arrhythmias. Also it is clear why these drugs are negative inotropes. </div> <div> Both verapamil and diltiazem are effective in slowing the ventricular response to atrial fibrillation, flutter, or paroxysmal supraventricular tachycardia and in converting these dysrhythmias to a sinus rhythm.</div> <bR> <div> Verapamil can be used both orally or intravenously. The intravenous dose is 0.07–0.15 mg/kg with the dose repeated in 30 min if there is an inadequate response. It has greater negative inotrope effects than diltiazem and, for this reason, the recent introduction of intravenous diltiazem has led to its supplanting, to some degree, verapamil in the acute treatment of supraventricular arrhythmias. The intravenous dose of diltiazem is 0.25 mg/kg with a second dose of 0.35 mg/kg if the response is inadequate after 15 min. The loading dose should be followed by an infusion of 5–15 mg/h. </div> <div>  <A NAME="subsect1102"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Other Drugs </div> <div> One of the difficulties of the Vaughan Williams classification of antidysrhythmics is that not all drugs can be incorporated into this scheme. Three examples are digoxin, adenosine, and magnesium, each of which has important uses in the perioperative period. </div> <div> Digoxin inhibits na <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>/k <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>-ATPase, leading to decreased intracellular k <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>, a less negative resting membrane potential, increased slope of phase 4 depolarization, and decreased conduction velocity. These direct effects, however, usually are dominated by indirect effects, including inhibition of reflex responses to congestive heart failure and a vagotonic effect.</div> <bR> <div> The net effect is greatest at the AV node, where conduction is slowed and refractory period is increased. This explains the effectiveness of digoxin in slowing the ventricular response to atrial fibrillation. The major disadvantages of digoxin are the relatively slow onset of action and numerous side effects. These latter include GI and CNS complaints, but of greatest concern is eliciting other dysrhythmias, specifically nonparoxysmal junctional tachycardia, ventricular ectopy, and excessive block atrioventricular junctional with a ventricular escape rhythm. </div> <div> Adenosine is an endogenous nucleoside that has an electrophysiological effect very similar to acetylcholine. Adenosine decreases AV node conductivity, and its primary antidysrhythmic effect is to break AV nodal reentrant tachycardia. </div> <bR> <div>  An intravenous dose of 100–200 mcg/kg is the treatment of choice for paroxysmal supraventricular tachycardia. Adverse effects, such as bronchospasm, are short-lived because its plasma half-life is so short (1–2 seconds). This short half-life makes it ideal for the treatment of reentry dysrhythmia where transient interruption can eliminate the dysrhythmia. </div> <div> Finally, no discussion of antiarrhythmics is complete without mentioning the importance of appropriate acid-base and electrolyte balance. It should be clear that electrophysiological effects reflect membrane potential. Electrolyte imbalance can perturb the membrane potential, leading to dysrhythmia generation, as can altered acid-base status, via effects on k <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>concentrations and sympathetic tone. Therapy for dysrhythmia should include correction of acid-base and electrolyte imbalance. Magnesium supplementation should be considered. </div> <bR> <div>  Magnesium deficiency is common in the perioperative period and magnesium administration has been shown to decrease the incidence of post-operative dysrhythmia.</div> <bR> <div> It is difficult to rationally summarize the actions of antidysrhythmic drugs, primarily because of the complexity of their electrophysiological effects and the fact that often it is difficult to see how the particular electrophysiological property translates into an observed clinical effect. The Vaughan Williams classification scheme provides a framework for discussion but is less useful for clinical decision making. In acute management, the selection of specific drugs often is not based so much on the specificity of their electrophysiological effects (since multiple drugs can accomplish the same desired electrophysiological effects) as it is on their suitability for intravenous administration, pharmacokinetics, and effects on ventricular function. The latter two characteristics warrant special emphasis. </div> <div> Drugs that have short effective half-lives after bolus administration, such as adenosine, esmolol, or lidocaine, are preferable in the acute management of dysrhythmia, since the undesirable consequences of their administration, particularly adverse hemodynamic effects, are short-lived. Since many surgical patients with dysrhythmias have depressed myocardial function, it is rational to select drugs for first-line acute therapy that have minimal negative inotrope effects. The first step in clinical management is to determine whether the patient is hemodynamically stable. If not, then electrical cardioversion is almost always indicated. If the patient is hemodynamically stable then intravenous drug therapy is appropriate. </div> <div> Selection of a specific drug depends on the source of the dysrhythmia. If it is supraventricular the priority is to slow the ventricular response. For paroxysmal supraventricular tachycardia the treatment of choice either is adenosine, a drug with a very short half-life, or cardioversion. For atrial fibrillation or flutter in a patient with preserved ventricular function, esmolol is often useful. Although digitalization is important for long-term heart rate control, its onset of action is slow. This agent also has a short half-life. If there are concerns about ventricular function, diltiazem is useful since it has less negative inotropic effects than many antiarrhythmics and has a relatively short duration of action. In some cases it is difficult to determine whether the arrhythmia is ventricular or supraventricular. In this situation, procainamide may be a good choice for intravenous therapy since it is effective against both ventricular and supraventricular arrhythmias. For ventricular arrhythmias, lidocaine remains the first treatment of choice because of its relatively benign hemodynamic effects and its rapid clearance from blood by redistribution. Amiodarone has been used in Europe as an agent for supraventricular tachycardia.</div> <bR> <bR> <div> INOTROPIC AGENTS </div> <div> Biventricular function is commonly depressed with a nadir at approximately 4 hours after cardiac surgery</div> <bR> <div> The etiology is multifactorial: pre-existing disease, incomplete correction of the cardiac pathology, myocardial edema, post-ischemic dysfunction, reperfusion injury, cytokine release and generation of nitric oxide; the dysfunction is usually reversible. Although cardiac output can be altered by exploiting the Starling curve with higher preload, often the ventricular function curve is flattened, and it is necessary to utilize inotropic agents. </div> <div> The interaction of the proteins actin and myosin, in which chemical energy (in the form of ATP) is converted into mechanical energy, provides the molecular basis for cardiac contractility. In the relaxed state (diastole) the interaction of actin and myosin is inhibited by tropomyosin, a protein associated with the actin-myosin complex. With the onset of systole, ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>enters the myocyte (during phase 1 of the action potential). This extracellular influx of ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>triggers the release of much larger amounts of ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>from internal stores in the sarcoplasmic reticulum. The binding of ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>to the C subunit of the protein troponin interrupts the inhibition of the actin-myosin interaction by tropomyosin, facilitating hydrolysis of ATP and generation of mechanical force. With repolarization of the myocyte and completion of systole, ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>is actively taken up into the sarcoplasmic reticulum to allow tropomyosin to inhibit the interaction of actin and myosin and relax the myocyte. Thus, <I>inotropic action is mediated by intracellular </I>ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>.  Although experimental drugs currently under investigation increase the sensitivity of the contractile apparatus to ca </div> <div> positive inotropic agents available for clinical use achieve increased contractility by increasing free ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>concentrations in the sarcoplasma. </div> <div> The first drug to consider is ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>itself. The administration of ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>prior to separation form cardiopulmonary bypass is common practice. However, the inotropic effects are very dependent on the plasma ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>concentration. Calcium plays important roles in cellular function, and the intracellular ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>concentration is highly regulated by membrane ion channels and intracellular organelles.</div> <bR> <div>  If the extracellular ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>concentration is normal, administration of ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>has little effect on the intracellular level and does little to increase the inotropic state. On the other hand, if ionized plasma calcium is low, exogenous calcium administration may increase contractility.</div> <bR> <div>  It should be realized also that even with normal plasma ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>concentrations, administration of ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>may increase vascular tone, leading to increased blood pressure but no change in cardiac output. This increased afterload may be the basis of the observation that ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>administration can blunt the response to epinephrine. </div> <bR> <div> ] Routine use of ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>at the end of bypass should be tempered by the realization that ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>may have little effect on contractile function, although it may increase systemic vascular resistance, which in itself may be important. If there is evidence of myocardial ischemia, ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>administration may be deleterious since it may exacerbate both coronary spasm and the pathways leading to cellular injury.</div> <bR> <bR> <div> Digoxin is not very effective as acute therapy for low cardiac output syndrome in the perioperative period; nevertheless, it serves to illustrate the role of intracellular ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>. Digoxin functions by inhibiting the Na-K-ATPase, which is responsible for the exchange of intracellular na <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>with extracellular k <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>. </div> <bR> <div>  It is responsible for maintaining intracellular/extracellular k <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>and na <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>gradients. When Na-K-ATPase is inhibited, intracellular na <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>levels increase. Increased intracellular na <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>increases the chemical potential for driving the ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>/na <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>exchanger, an ion exchange mechanism in which intracellular na <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>is removed from the cell in exchange for ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>. The net effect is an increase in intracellular ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>and enhancement of inotropy. </div> <div> The beta-adrenergic agonists are the most commonly used positive inotropic agents by far. The beta-1 receptor is part of a complex that is composed of the receptor on the outer surface of the cell membrane, coupled with membrane-spanning G-proteins (so named because they bind GTP). The G-proteins stimulate adenylate cyclase on the inner surface of the membrane, to catalyze formation of cyclic adenosine monophosphate (cyclic AMP). The inotropic state is modulated by cyclic AMP via its catalysis of phosphorylation reactions by protein kinase A. These phosphorylation reactions “open” ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>channels on the cell membrane and lead to greater release and uptake of ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>from the sarcoplasmic reticulum.</div> <bR> <bR> <div> The large number of drugs that stimulate beta-1 receptors and have a positive inotropic effect include epinephrine, norepinephrine, dopamine, isoproterenol, and dobutamine. These are the most commonly used catecholamines in the perioperative period. Although there are differences in binding at the beta-1 receptor, the relative effects of the various catecholamines on alpha and beta-2-adrenergic receptors are more important. In general, alpha stimulation of peripheral vasculature receptors causes vasoconstriction, whereas beta-2 stimulation leads to vasodilation. (See the discussion elsewhere in this chapter.) For some time beta-2 and alpha receptors were thought to be only in peripheral vessels and a few other organs, but not in the myocardium. However, recent investigation has shown that alpha receptors are in the myocardium and mediate a positive inotropic effect.</div> <bR> <div> ] The mechanism for this positive inotropic effect probably is stimulation of phospholipase C to hydrolyse phosphotidyl inositol to diacylglycerol and inositol triphosphate compounds that increase ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>release from the sarcoplasmic reticulum and increase myofilament sensitivity to ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>. It is possible also that alpha-adrenergic agents increase intracellular ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>by prolonging the duration of the action potential by inhibiting outward k <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>currents during repolarization or by activating the Na <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>/H <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>exchange mechanism to increase intracellular pH and myofilament sensitivity to ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>. Because the exact mechanism is uncertain, the exact contribution of alpha-adrenergic stimulation to the inotropic state is unclear; however, it is apparent that onset of the effect is slower than that of beta-1 stimulation. </div> <div> In addition to alpha receptors, beta-2 receptors are present in the myocardium.</div> <bR> <div> The fraction of beta-2 receptors (compared to beta-1 receptors) is increased in chronic heart failure and thus may explain the efficacy of drugs with beta-2 activity for this condition. This phenomenon is part of a general observation that beta-1 receptors are down-regulated (decreased in receptor density) and desensitized (uncoupling of effect from receptor binding) in chronic heart failure. </div> <bR> <div> Interestingly, as demonstrated in a dog model, this same phenomenon occurs with cardiopulmonary bypass. </div> <bR> <div>  Thus, for chronic heart failure a newer class of drugs, the phosphodiesterase inhibitors, may be beneficial. These drugs, typified by the agents available in the United States—amrinone and milrinone—increase cyclic AMP levels independently of the beta receptor by selectively inhibiting phosphodiesterase III, the myocardial enzyme responsible for the breakdown of cyclic AMP. </div> <bR> <div> In clinical use, selection of a particular inotropic agent usually is based more on side effects than on inotropic properties. Of the commonly used catecholamines, norepinephrine has alpha and beta-1 but little beta-2 activity and is both an inotrope and a vasopressor. Epinephrine and dopamine are mixed agonists with alpha, beta-1, and beta-2 activity, and at lower doses are primarily inotropes and not vasopressors; however, at higher doses vasopressor effects become more pronounced. This is especially true for dopamine, the synthetic precursor for norepinephrine in the sympathetic nerve terminal, which achieves vasopressor effects at higher doses by stimulating release of norepinephrine.</div> <bR> <div>  Dobutamine is a more selective beta-1 agonist, in contrast to isoproterenol, which is a mixed beta-1 and -2 agonist. Drug selection depends on the particular hemodynamic problem at hand. For example, depressed myocardial function in the presence of profound vasodilation may require a drug with both positive inotropic and vasopressor effects (e.g., norepinephrine), whereas a patient who is vasoconstricted may benefit from another choice. The initial selection of an inotropic agent is rationally based in the preceding considerations but careful monitoring of the response is necessary and may indicate the addition of or the substitution of another agent to achieve optimal hemodynamic effects. </div> <div> Clinical experience indicates that phosphodiesterase inhibitors can be very effective when catecholamines do not produce an adequate cardiac output.</div> <bR> <div>  There are few differences in the hemodynamic effects of the two cyclic AMP-specific (Type III) agents, amrinone and milrinone. Both agents increase contractility with little effect on heart rate and both produce significant venodilation and arteriodilation. Maintenance of an adequate preload is important for inotropic effectiveness and for minimizing systemic hypotension.</div> <bR> <div>  Milrinone is often preferred to amrinone because of lower cost and less pronounced thrombocytopenia with prolonged administrations.</div> <bR> <div> If amrinone is used, the bolus dose recommended in the product insert, 0.75 mg/mL, is inadequate to maintain therapeutic plasma levels, and a loading dose of 1.5–2.0 mg/mL should be used.</div> <bR> <div>  For both drugs, the loading dose is administered over 5–10 min to ameliorate systemic hypotension. Although both drugs have long half-lives, plasma levels drop quickly after a loading dose as a result of redistribution; therefore, the loading dose should be followed immediately by a continuous infusion. </div> <bR> <div>  Because of long plasma half-lives, infusion rates are relatively difficult to titrate according to effect. </div> <div> Despite common use after cardiac surgery, there are few comparative studies of inotropic agents in the perioperative period. In 1978, Steen et al. reported the hemodynamic effects of epinephrine, dobutamine, and epinephrine immediately after separation from cardiopulmonary bypass.</div> <bR> <div> The largest mean increase in cardiac index was achieved with dopamine at 15 mcg/kg/min. However, the only epinephrine dose studied was 0.04 mcg/kg/min, which is a very small dose. In a later comparison of dopamine and dobutamine, Salomon, Plachetka, and Copeland concluded that dobutamine produced more consistent increases in cardiac index, although the hemodynamic differences were small and all patients had good cardiac indices at the onset of the study. </div> <bR> <div>  Fowler et al. also found insignificant differences in the hemodynamic effects of dobutamine and dopamine, although they reported that coronary blood flow increased more in proportion to myocardial oxygen consumption with dobutamine.</div> <bR> <div>  Although neither of these groups reported significant increases in heart rate for either dopamine or dobutamine, clinical experience shows otherwise, as is documented by a study by Sethna et al., who found that the increase in cardiac index with dobutamine is simply owing to increased heart rate, without change in myocardial oxygen balance. </div> <bR> <div>  In a more recent study, Butterworth et al. showed that epinephrine, which is much cheaper, effectively increases stroke volume without increasing heart rate as much as dobutamine. </div> <bR> <div> VASOPRESSORS </div> <div> Catecholamines also are administered routinely for the treatment of vasodilation. The catecholamines most often given to cardiac surgical patients to increase systemic vascular resistance and blood pressure include phenylephrine, dopamine, and norepinephrine, </div> <bR> <div>  Alpha-1 adrenergic receptor stimulation produces vasoconstriction. As noted earlier, stimulation of these receptors activates membrane phospholipase-C, which in turn hydrolyzes phosphatidylinositol 4,5 diphosphate. This leads to the subsequent generation of two second messengers, including diacylglycerol and inositol triphosphate. Both of these second messengers increase cytosolic ca <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2+ </FONT>by different mechanisms, which include facilitating release of calcium from the sarcoplasmic reticulum, direct effects on calcium flux from extracellular to intracellular sites, and potentially increasing calcium sensitivity of contractile proteins in vascular smooth muscle. </div> <div> Vasodilation following cardiopulmonary bypass, or during anaphylactic or septic shock, is produced by multiple vasoactive mediators that affect both vascular endothelium and vascular smooth muscle. Mediator-induced vasodilation often is poorly responsive to catecholamines, </div> <div> but norepinephrine in high doses and infusion rates usually raises systemic blood pressure. Many clinicians are concerned about renal, hepatic, and mesenteric function during norepinephrine administration. However, in septic patients norepinephrine-induced increases in blood pressure can improve renal perfusion and function,and may improve mesenteric perfusion as well.</div> <div> ] Given the hemodynamic similarities between septic patients and some patients at the end of cardiopulmonary bypass, these observations also may pertain to the cardiac surgical patient; however, no confirmatory study has been done. </div> <bR> <bR> <div> VASODILATORS </div> <div> Different pharmacologic approaches are available to produce vasodilation, including: </div> <bR> <div> (1) blockade of alpha-1 adrenergic receptors, ganglionic transmission, and calcium channel receptors; (2) stimulation of central alpha-2 adrenergic receptors or vascular guanylate cyclase and adenylate cyclase; </div> <div> (3) inhibition of phosphodiesterase enzymes and inhibition of angiotensin-converting enzymes Adenosine in low concentrations also is a potent vasodilator with a short half-life, but the drug primarily is used to inhibit atrioventricular conduction (see antidysrhythmics).</div> <div>  Losartan, a novel angiotensin II antagonist (AII), has just been released for treatment of hypertension but is not available for intravenous use. </div> <div>  <A NAME="subsect1103"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Stimulation of Adenylate Cyclase (Cyclic AMP) </div> <div> Prostacyclin, prostaglandin E1, and isoproterenol increase cyclic nucleotide formation [adenosine-3',5'-monophosphate (cyclic AMP)] in vascular smooth muscle and produce calcium movement out of the muscle. Phosphodiesterase inhibition of the breakdown of cyclic AMP increases it. </div> <bR> <div>  Increasing cyclic AMP in vascular smooth muscle facilitates calcium uptake by intracellular storage sites and decreases calcium available for contraction. The net effect of increasing calcium uptake is to produce vascular smooth muscle relaxation and vasodilation. However, phosphodiesterase inhibitors and most catecholamines with beta-2 adrenergic activity (i.e., isoproterenol) have positive inotropic and other side effects that include tachycardia, glycogenolysis, and kaluresis.</div> <div>  Prostaglandins (prostacyclin and prostaglandin E1) are potent inhibitors of platelet aggregation and activation. Catecholamines with beta-2 adrenergic activity, phosphodiesterase inhibitors, and prostaglandin E1 and prostacyclin also have been used to vasodilate the pulmonary circulation in patients with pulmonary hypertension and right ventricular failure. </div> <div>  Recently, prostacyclin (Glaxo-Wellcome) was approved by the FDA for administration in patients with primary pulmonary hypertension. </div> <div>  <A NAME="subsect1104"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Nitrates and Stimulation of Guanylyl Cyclase (Cyclic GMP) </div> <div> The vascular endothelium modulates vascular relaxation by releasing both nitric oxide and prostacyclin.Inflammatory mediators can also stimulate vascular endothelium to release excessive amounts of endothelium-derived relaxing factor (EDRF or nitric oxide), which activates guanylyl cyclase to generate cyclic GMP. </div> <div>  Nitrates and nitroprusside, however, generate nitric oxide directly independent of vascular endothelium.The active form of any nitrovasodilator is nitric oxide (NO) in which the nitrogen is in a +2 oxidation state. Any nitrovasodilator must be first converted to nitric oxide to be active. In nitroprusside, nitrogen is in a +3 oxidation state and the nitric oxide molecule is bound to the charged iron molecule in an unstable manner; thus nitroprusside readily donates nitric oxide. In nitroglycerin, nitrogen molecules exist in a +5 oxidation state; thus these molecules require significant transformation before conversion to an active molecule. As compared to nitroprusside, nitroglycerin is a relatively select coronary vasodilator and does not produce coronary steal because small intracoronary resistance vessels (less than 100 µm) lack the required transformation pathway to convert nitroglycerin to nitric oxide.</div> <div> Chronic nitrate therapy can produce tolerance through different mechanisms as shown in </div> <div>  Nitroprusside and nitroglycerin produce venodilation, which may contribute to excessive hypotension.</div> <bR> <div> Intravenous volume administration often is required with nitroprusside to correct a relative intravascular hypovolemia. </div> <div>  <A NAME="subsect1105"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Dihydropyridine Calcium Channel Blockers </div> <div> Dihydropyridine calcium channel blockers are direct arterial vasodilators.</div> <div>  Nifedipine was the first dihydropyridine calcium channel blocker, and the newer second generation water-soluble agents that are available in intravenous form include isradipine and nicardipine. Isradipine and nicardipine produce arterial vasodilation without any effects on venous capacitance beds, atrioventricular nodal conduction, or ventricular function (i.e., contractility)</div> <bR> <div> Nicardipine is the first intravenous drug of this class available in the United States and offers a novel and important therapeutic option for perioperative hypertension following cardiac surgery. Because currently available intravenous calcium channel blockers have longer half-lives than nitrovasodilators, rapid loading infusion rates or bolus loading doses are needed to attain therapeutic levels. Bolus nicardipine also can be used to treat acute hypertension during the perioperative period (i.e., intubation, extubation, cardiopulmonary bypass-induced hypertension, aortic cross-clamping). However, slower elimination of nicardipine makes it more difficult to titrate than nitroprusside, and more prolonged vasodilation may be undesirable when hypotension-inducing factors disappear (e.g., recovery from hypothermia) or other vasodilating factors arise (e.g., hypothermia). </div> <div>  <A NAME="subsect1106"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <bR> <bR> <div> Phosphodiesterase Inhibitors </div> <div> The phosphodiesterase inhibitors currently available for use produce both positive inotropic effects and vasodilation.</div> <div> When administered to patients with ventricular dysfunction, they increase cardiac output and decrease pulmonary artery pressure, systemic vascular resistance, and pulmonary vascular resistance. Because the mechanism of vasodilation is unique, phosphodiesterase inhibitors are especially useful for patients with acute pulmonary vasoconstriction and right ventricular dysfunction. Multiple drugs are currently under investigation. The bipyridines (amrinone and milrinone), the imidazolones (enoximone), and the methylxanthines (aminophylline) are the ones most widely available. Papaverine, a benzylisoquinolinium derivative isolated from opium, is a nonspecific phosphodiesterase inhibitor and vasodilator used to dilate the internal mammary artery.</div> <div>  <A NAME="subsect1107"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Angiotensin Converting Enzyme (ACE) Inhibitors </div> <div> Angiotensin converting enzyme (ACE) inhibitors have growing indications for the management of heart failure and more patients now receive these drugs. ACE inhibitors prevent the conversion of angiotensin I to angiotensin II by inhibiting kininase, an enzyme in the pulmonary and systemic vascular endothelium. This enzyme also metabolizes bradykinin, a potent endogenous vasodilator and agonist for release of EDRF. Although little data regarding preoperative management of patients receiving these drugs are available, our clinical practice is to withhold them on the day of surgery because of their potential to produce excessive vasodilation during CPB. However, Tuman was unable to find any difference in blood pressure during CPB in patients who were or were not receiving ACE inhibitors; but contact activation during CPB generates bradykinin, and the vasoconstrictor requirements were increased after bypass in his study. </div> <bR> <bR> <bR> <div> PROCOAGULANTS </div> <div>  <A NAME="subsect1112"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Heparin Reversal </div> <div> Unfractionated heparin sulfate, the mainstay therapy for anticoagulation, is reversed by protamine, the only currently available neutralizing agent. Protamine is a basic polypeptide isolated from salmon sperm, where it functions as a histone to provide structural integrity to DNA. Protamine reverses heparin, an acidic glycosaminoglycan, by a nonspecific acid-base interaction (polyanionic-polycationic interaction). A spectrum of adverse reactions to protamine has been reported that ranges from minimal cardiovascular effects with rapid administration to life-threatening cardiovascular collapse following even small doses. Although multiple immunologic and non-immunologic mechanisms have been reported for the pathophysiology of protamine reactions in humans, animal, and in-vitro models, the life-threatening cardiopulmonary collapse following protamine administration in humans appears to represent true anaphylaxis or allergy, mediated by immunospecific antibodies.</div> <bR> <div>  Allergic mechanisms (i.e., immunospecific antibodies against protamine) are the only logical explanation for the unpredictable cardiovascular effects that occur.</div> <bR> <div>  Although protamine reactions have been classified according to systemic or pulmonary vascular effects, this does not elucidate the underlying pathophysiologic mechanisms. </div> <div> The incidence of reported protamine reactions depends on the high-risk patient groups studied. Stewart first reported a 27 percent incidence of reactions following cardiac catheterization in insulins dependent diabetics who received neutral protamine Hagedorn (NPH) insulin preparations, </div> <div> but subsequent studies in cardiac surgical patients found a low incidence. </div> <div> Levy studied approximately 4,700 patients undergoing cardiac surgery with cardiopulmonary bypass and reported that the incidence of life-threatening reactions ranges from 0.6 to 2 percent in NPH insulin-dependent diabetics as compared to 0.06 percent in non-NPH-insulin-dependent diabetics.</div> <div>  <A NAME="subsect1113"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <bR> <bR> <div> Cardiovascular Manifestations of Protamine Reactions </div> <div> The spectrum of cardiovascular manifestations of protamine reactions in humans range from systemic vasodilation with increases in cardiac output, to acute pulmonary vasoconstriction and right ventricular dysfunction. </div> <div> Morel demonstrated increased levels of C5a and thromboxane in three patients who had acute pulmonary vasoconstriction and suggested that complement activation and release of thromboxane was responsible. </div> <div>  In patients previously exposed to protamine, IgG antibodies may be responsible for complement activation.Lowenstein reported that five patients developed pulmonary hypertension and systemic hypotension after protamine administration, and four had mitral valve disease and increased pulmonary artery pressures</div> <bR> <div> .Patients with otherwise normal pulmonary artery pressures who develop acute pulmonary hypertension may not tolerate the increase in right ventricular afterload as well as patients with prior valvular heart disease and chronically elevated pulmonary artery pressures. </div> <div> Although endothelial activation mediated by anaphylaxis appears to cause excessive vasodilation in protamine reactions, therapy is based on catecholamines with alpha-adrenergic effects, epinephrine, and norepinephrine. In patients who develop acute pulmonary hypertension and right heart failure, therapy attempts to reduce pulmonary artery pressure and maintain systemic pressure and right ventricular contractility.</div> <bR> <div>  Vasodilators such as nitroglycerin and cyclic AMP-specific phosphodiesterase inhibitors (i.e., amrinone, milrinone, enoximone) may be useful. As a third-line therapy, alprostadil (PGE <FONT SIZE="1" COLOR="#000000" FACE="Arial" >1 </FONT>) can be used but often infusion of a catecholamine with alpha-agonist properties (e.g., norepinephrine) through a left atrial catheter is needed. Lock also reported that heparin could reverse protamine-induced pulmonary hypertension by decreasing heparin-protamine complexes and stopping thromboxane release from macrophages, but this has not been confirmed. </div> <bR> <bR> <div>  Pulmonary hypertension and systemic hypotension routinely occur in most animal models when protamine or any other polycation is given by rapid injection.</div> <div>  <A NAME="subsect1114"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Alternatives to Protamine </div> <div> Although alternatives to protamine are under development <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U> </U></FONT>, none are clinically available if a patient develops a reaction or is allergic. </div> <bR> <div> Although reports suggest methylene blue is effective, recent data indicate otherwise.</div> <bR> <div>  Polybrene (hexadimethrine), a polybasic inorganic amine used in the 1960s, is no longer available for clinical use.  Two important potential pharmacologic agents are under development. </div> <bR> <div> Recombinant platelet factor 4, a peptide normally found in platelets, directly combines with heparin. Heparinase, an enzyme produced by certain bacteria, degrades heparin into biologically inert fragments. Heparin reversal filters also have been reported and are briefly described in the following. </div> <div>  <A NAME="subsect1115"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <bR> <bR> <div> Recombinant Platelet Factor 4 </div> <div> Platelet factor 4 (PF4) is a basic polypeptide that has a molecular weight of approximately 7,800 daltons. </div> <bR> <div> The protein is stored in platelet dense granules and has some complex biological effects, but PF4's apparent major role is to neutralize vascular heparans following endothelial injury. A recombinant form of PF4 (rPF4) has been synthesized and studied in vitro, in animals, and in humans as a reversal agent. Levy studied the ability of rPF4 to neutralize heparinized blood from cardiopulmonary bypass circuits that contained heparin concentrations ranging from 2.7 to 4.1 U/mL. </div> <bR> <div> An rPF4 reversal ratio of 3.0: 1 (rPF4: heparin) was the minimum dose required to neutralize heparin. Recombinant PF4 does not interfere with viscoelastic measurements of coagulation or differences in clot lysis, as determined by thromboelastography. </div> <div> Dehmer reported human studies of rPF4 to reverse heparin following cardiac catheterization using doses of 0.5, 1.0, 2.5, or 5.0 mg/kg rPF4 administered over 3 min. </div> <bR> <div>  Recombinant PF4 doses of 2.5 or 5.0 mg/kg were required to decrease the ACT to <200 seconds within 5 min of administration. Activated partial thromboplastin times (aPTT) returned to baseline values within 5 min in 11 of 12 patients. Arterial blood pressure and pulmonary artery pressure did not change from baseline after rPF4. Immuno-specific antibodies as detected by enzyme-linked immunosorbent assays to rPF4 were not found at 7 days. Of all the pharmacologic alternatives for heparin reversal, rPF4 appears to be a most promising agent. </div> <div>  <A NAME="subsect1116"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Heparinase </div> <div> Heparinase is isolated from <I>Flavobacterium heparinum </I>, bacteria that produce an enzyme that metabolizes heparin-like carbohydrates.</div> <div>  Hutt and Kingdon first proposed heparinase to neutralize heparin in in-vitro samples taken for coagulation studies. Heparinase was successfully used for in-vitro studies and currently is in phase 1 and 2 studies. </div> <div> ] Michelsen determined the concentration-response relationship between heparinase and heparin neutralization in blood immediately after cardiopulmonary bypass for clinical heart surgery.</div> <bR> <div> Heparinase at concentrations >0.054 IU/mL successfully decreased heparin concentrations of 3.3 ± 0.3 (mean ± SEM) U/mL, and maximally reduced the ACT, but neutralization took 5 min as compared to an ionic neutralizing agent that produces immediate reversal.</div> <div> In canine studies, heparinase neutralized heparin as effectively as did protamine within 5 to 10 min. In this animal model, heparinase at all doses did not alter hemodynamics. </div> <bR> <div> However, protamine caused severe systemic hypotension and pulmonary hypertension. Heparinase at doses of 0.625 IU/kg to 2.5 IU/kg antagonized heparin doses of either 100 or 300 U/kg in rabbits and returned the ACT to baseline.</div> <bR> <div>  The half-life of heparinase is very short (2.2 ±pm 0.2 min). Additional studies must evaluate its effectiveness and potential side-effects.</div> <div>  <A NAME="subsect1117"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Heparin-Binding Filters </div> <div> Heparin-binding filters are based on the concept of placing a highly basic molecule, either hexadimethrine, polylysine, or protamine, on a matrix that is separated by a membrane.</div> <bR> <div>  After cardiopulmonary bypass (CPB), a two-stage venous cannula is placed into the right atrium. Blood passes over the filter that binds and decreases circulating heparin. Additional human studies will demonstrate the safety and efficacy of the method. </div> <div>  <A NAME="subsect1118"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Pharmacologic Approaches to Decrease Bleeding Following CPB </div> <div> Bleeding following cardiopulmonary bypass (CPB) results from multiple defects in coagulation proteins, platelet function, and activation of the fibrinolytic cascade. Pharmacologic approaches to reduce bleeding and transfusion requirements are based on either preventing or reversing defects produced by CPB. </div> <bR> <div>  Because clinical coagulation requires appropriate platelet-fibrinogen interactions, the goal is to preserve normal coagulation but avoid hypercoagulability. Different pharmacologic agents have been reported to decrease perioperative bleeding, especially following cardiac surgery. In addition, the protease inhibitor, aprotinin, or the lysine analogs, epsilon aminocaproic acid or tranexamic acid, are used to inhibit fibrinolysis. Because platelet function also plays an important role in perioperative hemostasis, desmopressin is reviewed in the following. Although erythropoietin can increase red blood cell production, the time required precludes routine use for most cardiac surgical procedures. </div> <div>  <A NAME="subsect2144"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> DESMOPRESSIN ACETATE </div> <div> Desmopressin acetate (1-deamino-8-D-arginine vasopressin-DDAVP) is a synthetic analogue of vasopressin that increases plasma levels of factor VIII 2- to 20-fold, and also stimulates vascular endothelium to release the larger multimers of von Willebrand factor (vWF).</div> <bR> <div>  Von Willebrand factor mediates platelet adherence to vascular subendothelium by functioning as a bridge between platelet glycoprotein 1b receptors and subendothelial vascular basement membrane proteins.</div> <div> Desmopressin first was reported to decrease 24-hour mediastinal drainage (1317 + 486 mL, mean ± standard deviation) compared to placebo (2210 ± 1415 mL).</div> <bR> <div> Czer administered desmopressin to patients bleeding more than 100 mL/h at least 2 hours after CPB and treated control patients by transfusion.</div> <bR> <div>  Patients who received desmopressin required fewer blood products, including platelets, but the study was not randomized or blinded. In 1988, Rocha reported a randomized, double-blinded trial of desmopressin in 100 patients who had atrial septal defect repair or valvular replacement. </div> <bR> <div> There was no significant difference in overall blood loss between the desmopressin and placebo groups (131 vs 193 mL)</div> <bR> <div>  Hackman reported a double-blind, randomized study comparing the effects of desmopressin or placebo on blood loss in patients undergoing primary coronary artery bypass grafting and/or valvular replacement. </div> <bR> <div>  There was no difference between groups in blood-product transfusion rates or blood loss within the first 24 hours after operation. Mongan reported that patients with a thromboelastogram taken after protamine administration and who have a maximal amplitude less than 50 mm benefit from desmopressin. </div> <bR> <div>  In this study, patients with reduced platelet function bled significantly more than those with near normal TEG. DDAVP was administered to patients with abnormal platelet function (TEG < 50 mm) with a reduction in chest tube output similar to those with normal platelet function. Studies have not shown an advantage for combining DDAVP with a lysine analog fibrinolytic inhibitor (tranexamic acid). </div> <bR> <div> Currently it is unclear which patients may benefit from desmopressin. </div> <div>  <A NAME="subsect2145"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> APROTININ </div> <div> Aprotinin (Trasylol) is a polypeptide serine protease inhibitor isolated from bovine lung that inhibits multiple proteases including trypsin, chymotrypsin, plasmin, tissue plasminogen activator, serum urokinase plasminogen activator, and both tissue and plasma kallikreins.</div> <bR> <div> Aprotinin was used clinically first in the treatment of acute pancreatitis; in the 1960s its ability to diminish the adverse effects of cardiopulmonary bypass on bleeding was studied.</div> <bR> <div> Early reports used aprotinin to treat bleeding following cardiopulmonary bypass and reported low-dose administration with variable results. </div> <div> In the 1980s a prophylactic high-dose technique was first studied.</div> <div> Van Oeveren reported a 47 percent reduction in chest-tube drainage in patients receiving aprotinin during coronary bypass surgery.</div> <bR> <div> Bidstrup and Royston also reported three different groups of patients who received aprotinin, including 22 patients who had reoperative cardiac surgery using bubble oxygenators. </div> <bR> <div>  The original design of this study was to develop a pharmacologic approach to inhibit inflammatory responses to cardiopulmonary bypass by maintaining effective levels of a protease inhibitor of contact activation. They administered aprotinin at a loading dose of 2 million units following intubation and maintained therapeutic levels with a continuous infusion of 500,000 U/h and a pump-prime dose equal to the loading dose of 2 million units. The investigators reported significant reductions in chest-tube drainage from aprotinin patients with mean values of 286 mL as compared to controls who lost 1,509 mL. </div> <bR> <div>  In a subsequent study of 80 patients undergoing primary coronary bypass grafting by the same investigators, patients who received aprotinin bled 46 percent less than controls, and received fewer units of packed red blood cells (13 units vs 75 units, aprotinin group vs placebo). A platelet-preserving effect of aprotinin was suggested because patients who received aprotinin had shorter bleeding times as compared to placebo-treated patients. </div> <div>  These findings led to multiple studies throughout the world to test the theory that aprotinin reduces bleeding and transfusion requirements. </div> <div> Multiple studies have all confirmed decreased chest-tube drainage and the need for allogeneic blood in patients who receive aprotinin at high doses based on the “Hammersmith or high dose regimen”. </div> <bR> <div> ] Aprotinin also reduced blood loss 49–75 percent and allogeneic transfusion requirements from 49–77 percent in three studies of patients who received aspirin.</div> <div> In 171 redo coronary artery surgery patients, Cosgrove reported a reduction in postoperative chest-tube drainage for both full-dose and half-dose aprotinin as compared to placebo-treated patients.</div> <bR> <div> ] Havel reported decreased chest-tube drainage and transfusion requirements in 20 heart-transplant patients after 2,000,000 U administered after intubation and 2,000,000 U added to the CPB circuit; 70 percent of aprotinin-treated patients did not receive allogeneic blood compared to 30 percent of controls. </div> <div> Aprotinin inhibits plasmin formation and activity and kallikrein. By inhibiting plasmin, the active proteolytic enzyme of the fibrinolytic system, aprotinin inhibits fibrinolysis. In addition, by partially inhibiting kallikrein, which helps to amplify and accelerate contact activation of factor XII (Hageman factor) to XIIa, activation of the intrinsic pathway of coagulation is inhibited or attenuated. Despite the use of heparin, contact activation and coagulation changes that occur during extracorporeal circulation lead to thrombin formation. Thrombin is the most important amplification agent for a wide range of coagulation factors and is a powerful platelet activator. By inhibiting kallikrein, aprotinin may decrease thrombin formation and protect platelets from activation. Because kallikrein also activates fibrinolysis, by inhibiting kallikrein aprotinin inhibits fibrinolysis independently of its ability to inhibit plasmin. Although Van Oevren postulates that aprotinin inhibits plasmin-related degradation of the platelet glycoprotein Ib receptor, the precise mechanism by which aprotinin reduces blood loss and transfusion requirements is not clear. Aprotinin preserves platelet function and may preserve platelet glycoprotein IIb/IIIa receptors.</div> <bR> <div> Multiple mechanisms appear to be responsible for aprotinin's efficacy. </div> <div>  <A NAME="subsect325"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Dosing strategies </div> <div> Different dosing regimens have been studied. The pharmacokinetics of aprotinin have been recently well described; the elimination half-life is approximately 5 hours. </div> <bR> <div> Recent studies in repeat cardiac surgical patients using one-half of the full “Hammersmith dose” indicate reduced bleeding and transfusion requirements. Van Oeveren found similar results in patients treated with either low-dose or high-dose aprotinin.</div> <bR> <div> Mohr reported similar results in patients undergoing primary CABG surgery. Schonberger reported that a single dose of aprotinin (2 million units added to the CPB prime) in primary CABG patients also was effective; however, primary CABG patients are not at high risk for bleeding complications.</div> <div> In a study of 171 patients undergoing repeat CABG surgery, Cosgrove found that low-dose aprotinin (half Hammersmith dose) was as effective as high-dose aprotinin (Hammersmith dose) in decreasing blood loss and blood transfusion requirements. </div> <bR> <div> Levy reported four different treatment groups in 287 patients undergoing repeat myocardial revascularization that included high-dose aprotinin, consisting of 2,000,000 KIU aprotinin loading dose, 2,000,000 KIU added to the CPB circuit prime, and a continuous infusion of 500,000 KIU during surgery; low-dose aprotinin consisting of 1,000,000 KIU aprotinin loading dose, 1,000,000 KIU added to the CPB circuit prime, and a continuous infusion of 250,000 KIU/h during surgery; pump-prime aprotinin only, consisting of 2,000,000 KIU aprotinin added to CPB circuit prime; and placebo.</div> <bR> <div>  The number of units of allogeneic packed red blood cells was significantly less in the aprotinin-treated patients compared to placebo (high dose 1.6 units, low dose 1.6 units, pump prime only 2.5 units, placebo 3.4 units). There were even greater reductions in total blood-product exposure in high-dose and half-dose groups compared to placebo or pump prime. There were no differences in treatment groups for the incidence of perioperative myocardial infarction. </div> <div>  <A NAME="subsect326"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Effects of aprotinin on ACT </div> <div> The celite activated ACT is significantly prolonged by aprotinin. </div> <bR> <div>  DeSmet suggested a heparin-sparing effect of aprotinin based on the ACT prolongation. Unfortunately, the ACT can be prolonged without inhibiting thrombin as reported in patients with factor XII deficiency.</div> <bR> <div>  Wang reported that kaolin-activated ACT is less affected by aprotinin.</div> <bR> <div> Kaolin absorbs aprotinin and minimizes its effects on the ACT. ACTs greater than 750 seconds during cardiopulmonary bypass are recommended for celite ACTs.</div> <bR> <div>  Although kaolin activated ACTs are preferred for anticoagulation management, the ACT is a complex test that is affected by different factors independent of anticoagulation. Most clinical studies evaluating aprotinin use heparin-protamine titrations to maintain anticoagulation. Additional doses of 100 U/kg heparin every hour in a fixed dosing scheme after the initial loading dose of heparin is an alternative. Heparin doses should not be reduced in the presence of aprotinin. </div> <div>  <A NAME="subsect327"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Adverse effects of aprotinin </div> <div> Based on the large number of patients that have received aprotinin, only a few adverse effects are reported. However, Cosgrove found a trend towards a higher incidence of myocardial infarction and postoperative increases in serum creatinine levels in aprotinin-treated patients. Further studies to evaluate these procoagulant trends do not support these findings. </div> <bR> <div>  Studies by Bidstrup, Havel, and Lemmer find no statistically significant differences in postoperative graft patency. ] Bidstrup reported no differences in vein graft patency 7 to 12 days postoperatively by magnetic resonance imaging in 90 patients who had primary CABG surgery. </div> <bR> <div> There were no differences between treatment or control groups and 46 evaluated IMA grafts were patent. Using ultra-fast computed tomography, Lemmer reported vein and IMA graft patency 7 to 60 days after primary CABG surgery in 151 patients and repeat CABG surgery in 65 patients and found no statistically significant differences between groups, although there was trend toward lower vein and IMA graft patency rate in aprotinin patients. </div> <bR> <div> There were no significant differences in perioperative myocardial infarction. Levy reported a randomized prospective study of repeat CABG patients to evaluate perioperative myocardial infarction in full-dose, half-dose, and pump-prime-only aprotinin-treated patients. The rate of myocardial infarction was not statistically different in high-dose, low-dose, pump-prime-only, and placebo groups. The incidence of stroke was statistically lower in the aprotinin-treated patients compared to placebo. A large body of literature currently supports the claim that aprotinin does not independently increase the risk for graft thrombosis or perioperative myocardial infarction. </div> <div>  <A NAME="subsect328"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Renal effects </div> <div> Aprotinin is metabolized by the proximal tubules of the kidney, and has the potential to produce renal dysfunction during prolonged used. Increased urine output, osmolar clearance, and fractional sodium excretion are reported in aprotinin-treated patients</div> <bR> <div>  However, creatinine concentrations, electrolytes, and creatinine clearances are not altered. In a review of recent U.S. studies, Lemmer reports no differences in renal function in aprotinin- versus placebo-treated patients. </div> <bR> <div>  In patients undergoing hypothermic arrest, creatinine increases greater than 1.5 times preoperative values were reported and compared to historical controls. The patients who received aprotinin also received significantly lower doses of heparin compared to their historical controls (unpublished data). </div> <div>  <A NAME="subsect329"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Allergic reactions </div> <div> Because aprotinin is a bovine protein, it causes anaphylactic reactions in approximately 0.5 percent of patients. </div> <div>  These reactions will probably become more common with prior exposure. From pooled European data, the incidence of hypersensitivity reactions ranges from 0.3 to 0.6 percent in patients.</div> <bR> <div>  Protamine, a polypeptide with a similar molecular weight, produces anaphylactic reactions in 0.6–2 percent of high-risk, previously sensitized patients.</div> <bR> <div> Therefore, the incidence of anaphylaxis to aprotinin may be similar upon re-exposure. Because antibody titers fall with time, a longer time interval from previous exposure lessens the risk. All patients to receive aprotinin should receive a small intravenous test dose at least 10 minutes before the loading dose. In addition, in patients who undergo repeat exposure, the initial dose should be delayed until cardiopulmonary bypass can be instituted if cardiovascular collapse occurs (i.e., with aortic or femoral artery exposure). The risk:benefit ratio for aprotinin in repeat exposure situations should be weighed carefully. The efficacy of pretreatment with steroids and histamine blockers in preventing complications is not proven. </div> <div>  <A NAME="subsect2146"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <bR> <bR> <div> THE LYSINE ANALOG ANTIFIBRINOLYTIC AGENTS </div> <div> Other drugs inhibit the conversion of plasminogen to plasmin and interfere with lysis of fibrinogen and fibrin. The amino carboxylic acid analogues of lysine bind to plasminogen and plasmin and occupy the binding site for fibrinogen and fibrin.</div> <bR> <div>  Both epsilon-aminocaproic acid (EACA, Amicar) and trans- <I>p </I>aminomethylcyclohexane-carboxylic acid (tranexamic acid) are used to decrease fibrinolysis during cardiac surgery. Because of their similarity to lysine, EACA and tranexamic acid attach to lysine binding sites on plasminogen and plasmin to inhibit binding to fibrinogen and fibrin. Because plasmin and plasminogen cannot bind to fibrin and fibrinogen, fibrinolysis is inhibited. Tranexamic acid is six to ten times more potent than epsilon-aminocaproic acid, probably because of subtle differences in the molecular structure, which mimics lysine. </div> <div> Fibrinolysis occurs routinely during CPB.</div> <bR> <div> Early studies from the 1960s and 1970s reported the use of antifibrinolytic agents but lacked controls, were often retrospective, and were not blinded. Since cardiopulmonary bypass equipment, anticoagulation practices and monitoring, and other factors may have affected these results, only recent studies are reviewed. </div> <div> In 1988 Vander Salm administered either EACA or placebo to primary CABG patients before protamine administration and reported less chest tube drainage in EACA-treated patients in the first 12 postoperative hours (273 vs 332 mL). Data regarding blood-product transfusions were not reported. </div> <bR> <div> In a randomized, blinded study of 350 patients undergoing routine CABG, Del Rossi examined a 5-g loading dose of EACA at the time of skin incision followed by a 1-g/h infusion during the next 6–8 hours, and reported decreased chest tube drainage in the EACA vs. placebo group (617 vs 883 mL) and a reduction in transfusion of packed red blood cells (2.8 vs 4.2 mean units transfused).</div> <bR> <div>  There were no differences between groups in myocardial infarction, cerebrovascular accidents, and graft failures, but the overall complication rate was very low. </div> <div> Horrow subsequently reported several studies of tranexamic acid for primary CABG surgery.</div> <bR> <div> ] In one study, 12-hour chest-tube drainage was 496 mL in the tranexamic acid group compared to 750 mL in the placebo group, but there were no differences in transfusions. </div> <bR> <div> A subsequent study found no increased benefit with the combination of DDAVP and tranexamic acid. Dosing studies in 148 patients (2.5 to 40 mg/kg and one-tenth the loading dose hourly for 12 h) showed no further decrease in bleeding with larger doses when the drug was given at skin incision.</div> <div> Even higher doses of tranexamic acid have been reported. Rousou described 415 consecutive patients who had primary CABG surgery and received a 2-g bolus of transexamic acid before initiation of CPB and subsequently 8 g by infusion during bypass.</div> <bR> <div> Chest-tube drainage decreased from 1,114 mL to 803 mL in treated patients. Small but statistically significant differences in the need for allogeneic red blood cells (1.7–0.69 U/patient), fresh frozen plasma (0.23–0.024 U/patient), and platelets (1.06–0.3 U/patient) were also observed. There were no differences in postoperative complications, but all data were collected retrospectively and the study was not blinded. </div> <div>  <A NAME="subsect330"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <bR> <bR> <div> Adverse effect of lysine analog antifibrinolytic drugs </div> <div> Reports on therapy with lysine-analog antifibrinolytic drugs during cardiac surgery do not indicate differences in the incidence of thrombotic complications, but the design of these studies was not prospective and was not consistent with phase 3 studies sponsored by the FDA (Food and Drug Administration). The incidence of perioperative myocardial infarction and stroke as reported is not different in treatment groups as compared to controls. However, because the incidence of these complications in routine CABG surgery is low, and only small numbers of patients were studied, thepossibility of thrombotic complications is not excluded. Prospective studies to evaluate safety issues, including the risk of perioperative myocardial infarction, graft patency, and renal dysfunction, are needed. Tranexamic acid is approved for use in the United States to prevent bleeding in patients with hereditary angioedema undergoing teeth extraction, but has no FDA indication for use in cardiac surgical patients. </div> <div>  <A NAME="subsect1119"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <bR> <bR> <div> Blood Products </div> <div> Blood products are widely administered in cardiac surgery; this places a major demand on blood banking facilities. Once given empirically, blood products are now given for specific indications </div> <div> . In addition to costs, blood products carry significant risks. Although the risk of viral transmission is low, immunosuppressive effects, transfusion-related acute lung injury, and costs are disadvantages of allogenic blood products. Each institution should develop its own algorithm for blood products in cardiac surgical patients. </div> <bR> <div> <IMG SRC="0fd03c30.gif" border=0 width="515" height="451" ALIGN="BOTTOM" HSPACE="0" VSPACE="0">Indications for blood product administration in the bleeding cardiac surgical patient</div> <bR> <div> <IMG SRC="0fe01750.gif" border=0 width="513" height="117" ALIGN="BOTTOM" HSPACE="0" VSPACE="0">Potential alternatives for heparin neutralization</div> <div> BETA-ADRENERGIC RECEPTOR BLOCKERS </div> <div> Beta-adrenergic receptor blockers are competitive inhibitors; hence, the intensity of blockade is dependent on both the dose of the blocker and receptor concentrations of catecholamines, primarily epinephrine and norepinephrine. This competitive interaction between beta-blocking agents and catecholamines can be demonstrated in normal human volunteers and in isolated tissues. </div> <bR> <div>  The presence of disease and other drugs modify responses to beta-blocking agents observed in patients, but the underlying competitive interaction is still operative. Successful utilization of beta-adrenergic receptor blockers requires titrating the dose to a desired effect. Excessive inhibition can be overcome by (1) administering a catecholamine to compete at the blocked receptors and/or (2) administering other drugs to reduce unopposed, counterbalancing autonomic mechanisms. An example of the latter remedy is propranolol-induced bradycardia, which produces unopposed vagal cholinergic dominance on cardiac nodal tissue. Atropine relieves the excessive bradycardia by blocking cholinergic receptors in the sinus and atrioventricular (AV) nodes. </div> <div> Knowledge of the type, location, and action of beta receptors is fundamental to understanding and predicting effects of beta-adrenergic receptor blocking drugs </div> <bR> <div>  The net effect of stimulating beta receptors depends on several variables. For example, in the heart, increased automaticity and conduction velocity in nodal and conduction tissues is opposed by stimulating cholinergic receptors usually by vagal acetylcholine. Therefore, beta1 blockade decreases heart rate as the vagal actions are unopposed. If both beta1 and cholinergic receptors are blocked completely, the intrinsic heart rate dominates (normally greater than 100 bpm). The increase in automaticity usually is not apparent in the normal heart because the rate of spontaneous depolarization in myofibrils is lower than in nodal and conducting tissues. When these are diseased, increased automaticity in myocardial muscle cells becomes apparent with beta1 receptor stimulation, and beta-blocking agents are needed as antidysrhythmics (see the preceding). Increased automaticity can also occur in myocardial ischemia by interrupting normal conduction pathways that usually produce coordinated myofibril depolarization at a rate faster than spontaneous depolarization of individual myofibrils. </div> <bR> <div> As is evident in </div> <div> , many actions of beta receptor stimulation are opposed by stimulation of alpha-adrenergic or cholinergic receptors in the same tissues. With cholinergic receptors, opposing effects are usually produced by acetylcholine spontaneously released from cholinergic nerves or released by giving a cholinomimetic drug. With adrenergic receptors, norepinephrine and epinephrine are released from sympathetic nerve terminals and from the adrenal medulla. Administration of sympathomimetic drugs with varying preferences for different adrenergic receptors can modify responses to beta receptor stimulation and blockade. </div> <div> Beta-adrenergic receptor antagonists (blockers) include many drugs</div> <div> <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U> </U></FONT>that are typically classified by their relative selectivity for beta1 and beta <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2 </FONT>receptors (i.e., cardioselective and nonselective); the presence or absence of agonistic activity; membrane-stabilizing properties, alpha-receptor blocking efficacy, and various pharmacokinetic features (e.g., lipid solubility, oral bioavailability, elimination half-time).</div> <bR> <bR> <div>  The practitioner must realize that the selectivity of individual drugs for beta1 and2 receptors is relative, not absolute. Although the risk of inducing bronchospasm with a beta1 (cardioselective) adrenergic blocker (e.g., metoprolol) may be relatively less than with a nonselective blocker (e.g., propranolol), the risk is still present. With respect to alpha-adrenergic receptor blocking properties, only labetalol has that action and is used primarily for hypertension. Membrane-stabilizing effects of beta-adrenergic blockers generally occur at much higher doses than those given clinically; therefore, other drugs are usually chosen to produce membrane stabilization (e.g., local anesthetics, antidysrhythmics). The reader is referred to pharmacology textbooks and drug compendia for pharmacokinetic details. </div> <div>  <A NAME="subsect1120"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Clinical Indications </div> <div> The list of clinical indications and uses of beta-adrenergic receptor blockers is long </div> <bR> <div> In some of these clinical uses, the mechanisms principally responsible for the desired effects appear obvious and logical but are, in fact, not always proven. In some instances, there are actions that appear to oppose the desirable ones. In the end, the success of therapy has to be judged in terms of the balance of beneficial and undesirable effects. Some considerations in the use of beta-adrenergic receptor blockers for specific diseases treated by cardiac surgery are discussed in the following. </div> <div>  <A NAME="subsect2147"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <bR> <bR> <div> ANGINA PECTORIS </div> <div> The primary goal of beta-blocking agent therapy is to reduce cardiac responses to sympathetic nervous system activation by exertion, emotion, and other types of stress. Limiting or preventing sympathetically induced increases in heart rate, contractility, and systolic blood pressure minimizes increases in myocardial oxygen demand. Doses required to achieve these goals often reduce resting heart rate. This effect may slightly increase ventricular end-systolic volume and myocardial oxygen demand, but this concern is not a clinically important problem. Also, nonselective beta-blocking agents risk coronary vasospasm owing to unopposed alpha-adrenergic receptor responses, but this too is not a clinically important problem, possibly because of routine use of coronary vasodilators (e.g., nitroglycerin). Side-effects of antianginal therapy with beta-blocking agents are considered in the following, but the most common complaints from chronic ingestion are mental depression, fatigue, limited work capacity, and impotence. </div> <div>  <A NAME="subsect2148"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <bR> <bR> <div> ACUTE MYOCARDIAL INFARCTION </div> <div> Clinical trials of intravenous beta-adrenergic blockers in the early phases of acute myocardial infarction suggest that mortality decreases 10 percent. Following myocardial infarction, chronic oral beta-blocking agents reduce the incidence of recurrent myocardial infarction. The major risk of beta-blocking agents after acute myocardial infarction is congestive heart failure, since the heart may be dependent on sympathetic tone to maintain cardiac output. </div> <div>  <A NAME="subsect2149"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <bR> <bR> <div> SUPRAVENTRICULAR TACHYCARDIAS AND VENTRICULAR DYSRHYTHMIAS </div> <div> Adrenergic beta-blocking agents are Class II antidysrhythmics that primarily block cardiac responses to catecholamines. Beta-blocking agents decrease spontaneous depolarization in the sinus and atrioventricular (AV) nodes, decrease automaticity in Purkinje fibers, increase AV nodal refractoriness, increase the threshold for fibrillation (but not for depolarization), and decrease ventricular slow responses that are dependent on catecholamines. There is evidence that beta-blocking agents also decrease intramyocardial conduction in ischemic tissue and reduce the risks of dysrhythmias, to the extent that they decrease myocardial ischemia. Beta-adrenergic blockers are not particularly effective in controlling dysrhythmias that are not induced or maintained by catecholamines. Membrane stabilizing effects of beta-adrenergic blockers occur at doses much higher than those tolerated by patients. </div> <div>  <A NAME="subsect2150"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <bR> <bR> <div> HYPERTENSION </div> <div> Our understanding of the mechanisms for the antihypertensive effects of beta-adrenergic receptor blockers is incomplete, yet it is clear that these effects are caused by beta blockade. During the early phases of therapy there is a decrease in cardiac output, a rise in systemic vascular resistance (SVR), and relatively little change in mean arterial blood pressure. Within hours to days SVR normalizes and blood pressure declines. In addition, the release of renin from the juxtaglomerular apparatus in the kidney is inhibited (beta <FONT SIZE="1" COLOR="#000000" FACE="Arial" >1 </FONT>blockade). Presumably, beta-blocking agents with intrinsic agonistic activity reduce systemic vascular resistance below pretreatment levels, presumably by activating beta <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2 </FONT>receptors in vascular smooth muscle. In addition, labetalol has the ability to block alpha-adrenergic receptors on vascular smooth muscle. Most often beta-adrenergic receptor blockers are used with other drugs in the treatment of chronic hypertension. When combined with a vasodilator, beta-blocking agents limit reflex tachycardia. When propranolol is combined with intravenous nitroprusside, the beta-blocking agent prevents reflex release of renin and reflex tachycardia induced by the vasodilator. </div> <div>  <A NAME="subsect2151"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <bR> <bR> <div> PHEOCHROMOCYTOMA </div> <div> The presence of catecholamine-secreting cells is tantamount to continuous or intermittent infusion of a varying mixture of norepinephrine and epinephrine. It is absolutely essential that virtually complete alpha-adrenergic receptor blockade be established before beta receptor blocker is given to prevent hypertensive episodes owing to unopposed alpha-adrenergic receptor activity in vascular smooth muscle. </div> <div>  <A NAME="subsect2152"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> ACUTE DISSECTING AORTIC ANEURYSM </div> <div> The primary goal in the management of these patients is to reduce stress on the dissected aortic wall by reducing systolic acceleration of blood flow. Beta receptor blockers reduce cardiac inotropy and acceleration of blood during ventricular ejection. Beta-blocking agents also limit reflex sympathetic responses to vasodilating drugs used to lower systemic arterial pressure. </div> <div>  <A NAME="subsect2153"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> OTHER INDICATIONS </div> <div> Other clinical applications of beta-adrenergic receptor blockers listed in <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>Table 8-8 </U></FONT>are based largely on symptomatic treatment or empiric trials of beta-adrenergic receptor blocking therapy. </div> <div>  <A NAME="subsect1121"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Side Effects and Toxicity </div> <div> The most obvious and immediate evidence of a toxic overdose of a beta-adrenergic receptor blocker is hypotension, bradycardia, decreased AV conduction, and a widened QRS complex on the electrocardiogram. Treatment is aimed at blocking cholinergic receptor responses to vagal nerve activity (e.g., atropine) and administering a sympathomimetic to compete with the beta-blocking agents at adrenergic receptors. Bronchospasm is uncommon in the absence of preexisiting pulmonary disease, and hypoglycemia is rare.</div> <div> Side effects of chronic beta-adrenergic receptor blockade include mental depression, physical fatigue, altered sleep patterns, excessive bradycardia, exacerbation of congestive heart failure, increased symptoms of peripheral vascular disease, exacerbation of bronchospasm in patients with pulmonary disease, masking hypoglycemic episodes in diabetics, delayed recovery from hypoglycemia, sexual dysfunction, and gastrointestinal symptoms that include indigestion, constipation, and diarrhea. </div> <div>  <A NAME="subsect1122"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Drug Interactions </div> <div> Pharmacokinetic drug interactions include reduced gastrointestinal absorption of the beta-blocking agent (aluminum-containing antacids, cholestyramine), increased biotransformation (phenytoin, phenobarbital, rifamtin, smoking), and increased bioavailability caused by decreased biotransformation (e.g., cimetidine, hydralazine). Pharmacodynamic interactions include an additive effect with calcium channel blockers to decrease intracardiac conduction and reduced antihypertensive effect of beta-blocking agents when administered with some nonsteroidal antiinflammatory drugs. </div> <bR> <div> <IMG SRC="0ff02b20.gif" border=0 width="514" height="434" ALIGN="BOTTOM" HSPACE="0" VSPACE="0">Clinical applications of beta-adrenergic receptor blockers</div> <div> <IMG SRC="10002b20.gif" border=0 width="514" height="434" ALIGN="BOTTOM" HSPACE="0" VSPACE="0">Clinical applications of beta-adrenergic receptor blockers</div> <div> <IMG SRC="10103860.gif" border=0 width="515" height="646" ALIGN="BOTTOM" HSPACE="0" VSPACE="0">Beta-adrenergic receptor blockers</div> <div> <IMG SRC="10225910.gif" border=0 width="1061" height="657" ALIGN="BOTTOM" HSPACE="0" VSPACE="0">Location and actions of beta-adrenergic receptors</div> <div> <IMG SRC="10325910.gif" border=0 width="1061" height="657" ALIGN="BOTTOM" HSPACE="0" VSPACE="0">Location and actions of beta-adrenergic receptors</div> <div> DRUGS FOR AIRWAY MANAGEMENT </div> <div> The human airway extends from the external nares and lips to the alveolar capillary membrane. Airway management in the perioperative period is a primary responsibility of the anesthesiologist, but the surgeon becomes involved in the anesthesiologist's absence or in difficult situations. Airway management involves instrumentation and mechanics (not discussed here) and employs drugs to facilitate manipulation and instrumentation of the airway and to overcome pathophysiologic problems that contribute to airway obstruction. Most drugs used for airway management are taken from drug classes that have other important therapeutic applications (e.g., sympathomimetics). </div> <div> There are five major challenges encountered in airway management. Each is described succinctly in the following to facilitate understanding of the role drugs have in airway management. Details of pharmacology such as doses, side-effects, and toxicity are left to standard textbooks of pharmacology and drug compendia. The five challenges are: (1) overcoming airway obstruction; (2) preventing pulmonary aspiration; (3) performing endotracheal intubation; (4) normalizing pulmonary function during intermittent positive pressure ventilation (IPPV); and (5) restoring spontaneous ventilation and airway protective reflexes. </div> <div>  <A NAME="subsect1123"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Airway Obstruction </div> <div> Obstruction to gas flow can occur from a foreign object (including food) or from pathophysiologic processes involving airway structures (e.g., trauma, edema). [<FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>128 </U></FONT>] In the anesthetized or comatose patient, loss of muscle tone can allow the tongue or epiglottis to collapse and cause obstruction. The first therapeutic measure involves manipulation of the head and jaw, insertion of an artificial nasal or oral airway device, and evacuation of obstructing objects and substances (e.g., blood, secretions, food particles). Except for drugs used to facilitate endotracheal intubation (see the following), the only drug useful for improving gas flow through a narrowed airway is a mixture of helium and oxygen (Heliox). This mixture reduces viscosity and resistance to gas flow. </div> <div>  <A NAME="subsect1124"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Aspiration </div> <div> The upper airway (above the larynx/epiglottis) is a shared atrium leading to the lungs (gas exchange) and gastrointestinal tract (fluids and nutrition). Passive regurgitation or active vomiting that accumulate gastric contents in the pharynx places the patient at risk of pulmonary aspiration. This risk is greatly increased when airway reflexes (glottic closure, coughing) and voluntary avoidance maneuvers are suppressed (e.g., anesthesia, coma). Particulate matter obstructs the tracheal bronchial tree and acidic fluid (pH < 2.5) injures lung parenchyma. The resulting pneumonitis causes significant morbidity (e.g., ARDS [acute respiratory distress syndrome]) and mortality. Preoperative restriction of fluids and food (i.e., NPO status) does <I>not </I>guarantee absence of aspiration. Similarly, advance placement of a naso/orogastric tube may reduce intragastric pressure but does not guarantee complete removal of gastric contents. Nevertheless, both NPO orders and insertion of a naso/orogastric tube under some circumstances are worthwhile measures to reduce the risks of pulmonary aspiration. In some circumstances, the deliberate induction of vomiting in a conscious patient may be indicated, but this is rarely done in cardiac patients and almost never involves an emetic drug. More often, antiemetic drugs are employed to reduce the risks of vomiting during airway manipulation and induction of anesthesia. </div> <div> The most widely used measure to minimize the risks of pulmonary aspiration in the anesthetized or comatose patient is endotracheal intubation. Drugs to reduce the risks of pulmonary aspiration focus on decreasing the quantity and acidity of gastric contents and on facilitating endotracheal intubation (see the following). Nonparticulate antacids (e.g., sodium citrate-Bicitra) are used to neutralize gastric acidity. Drugs that reduce gastric acid production include H <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2 </FONT>-receptor blockers (e.g., cimetidine-Tagamet, ranitidine-Zantac) and omeprazole (Prilosec). Metochlopramide (Reglan) enhances gastric emptying and increases gastroesophageal sphincter tone. </div> <div> Antiemetic drugs are used more commonly in the postoperative period and include several different drug classes: anticholinergic (scopolamine), antihistamines (hydroxyzine-Vistaril, promethazine-Pherergan), antidopaminergics (droperidol-Inapsine, prochlorperazine-Compazine), and antiserotoninergics (ondansetron Zofran). The intravenous hypnotic-anesthetic, propofol, has significant antiemetic effect. </div> <div>  <A NAME="subsect1125"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Endotracheal Intubation </div> <div> Drugs are employed for three purposes to facilitate endotracheal intubation: (1) to improve visualization of the larynx during laryngoscopy; (2) to prevent closure of the larynx; and (3) to facilitate manipulation of the head and jaw. [<FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>202 </U></FONT>] </div> <div> Improved visualization of the larynx includes decreasing salivation and tracheal bronchial secretions by an anticholinergic drug (e.g., scopolamine), reducing mucosal swelling by a topical vasoconstrictor (e.g., phenylephrine), and minimizing traumatic bleeding caused by mucosal erosion (e.g., phenylephrine). Steroids may have some delayed benefit in minimizing acute inflammatory responses in the airway, but are not indicated just prior to intubation. </div> <div> Reflex responses to airway manipulation, laryngoscopy, and endotracheal intubation can be suppressed by several different methods, alone or in combination. Topical anesthesia (e.g., 2 or 4% lidocaine spray) anesthetizes the mucosal surfaces of the nose, oral cavity, pharynx, and epiglottis. Atomized inhaled local anesthetics anesthetize mucosa below the vocal cords. The subglottic mucosa can be anesthetized topically by injecting local anesthetic through the cricothyroid membrane into the tracheal lumen (transtracheal block). A bilateral superior laryngeal nerve block eliminates sensory input from mechanical contact or irritation of the larynx above the vocal cords. It must be remembered that mucosal anesthetics obtund airway reflexes, compromise reflex protective mechanisms, and increase the risk of aspiration. </div> <div> Intravenous systemic drugs can obtund the cough reflex. Intravenous lidocaine (1–2 mg/kg) transiently obtunds the cough reflex without significantly affecting spontaneous ventilation. The risks of stimulating the central nervous system and seizure-like activity can be reduced by prior small doses of an intravenous barbiturate or benzodiazepine. Intravenous opioids suppress cough reflexes, but the doses required impair spontaneous ventilation to the point of apnea. A combination of an intravenous opioid with a major tranquilizer (e.g., neuroleptanalgesia) allows tolerance of an endotracheal tube with less opioid and less embarrassment of spontaneous ventilation. Small doses of opioids also obtund airway reflexes during intravenous (e.g., thiopental) or inhaled (e.g., isoflurane) general anesthesia. Opioids not only obtund the cough reflex that closes the larynx, but also limit the autonomic sympathetic response (hypertension, tachycardia) to endotracheal intubation. </div> <div> Skeletal muscle relaxants are most commonly used with a general anesthetic to facilitate manipulation of the head and jaw and to prevent reflex closure of the larynx. Since the patient is apneic, two procedures commonly are used to maintain oxygenation. Pure oxygen by mask while the patient is still awake eliminates nitrogen from the lungs; then, in rapid sequence, an intravenous anesthetic (e.g., thiopental) is followed immediately by a rapid-acting neuromuscular blocker (e.g., succinylcholine). As soon as the maximum effect of the muscle relaxant is apparent (30–90 s) laryngoscopy is performed, an endotracheal tube is inserted, the tracheal tube cuff is inflated, and the position of the tube in the trachea is verified. Alternatively, when the risk of pulmonary aspiration is minimal (presumed empty stomach), the patient is anesthetized and paralyzed while ventilation is supported by intermittent positive pressure delivered by face mask. At the appropriate time, laryngoscopy is performed and the endotracheal tube is inserted. </div> <div>  <A NAME="subsect1126"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Normalizing Pulmonary Function During Intermittent Positive Pressure Ventilation </div> <div> Once an endotracheal tube is in place, general anesthesia and partial muscular paralysis are maintained for the operation (see Chap. 7). Postoperatively, general anesthesia and partial muscular paralysis may be continued if prolonged positive ventilation is anticipated. Alternatively, if the patient is not extubated promptly, low doses of hypnotics and opioids are given to suppress the stimulus of the endotracheal tube until spontaneous ventilation recovers and tracheal extubation is imminent (203). </div> <div> Three other problems are encountered in intubated patients supported by mechanical ventilators: (1) poor ventilatory compliance; (2) bronchoconstriction; and (3) impaired gas exchange. Poor ventilatory compliance can reflect limited compliance of the chest wall and diaphragm and/or limited compliance of the lungs per se. Deepening general anesthesia and a skeletal muscle relaxant can reduce intercostal and diaphragmatic muscle tone, but do not improve chest cavity compliance that is impaired by disease (e.g., scoliosis, emphysema). </div> <div> Poor lung compliance may reflect pulmonary interstitial edema, consolidation, bronchial obstruction (e.g., mucous plugs), bronchoconstriction, or compression of the lung (e.g., pneumothorax, hemothorax, tumor mass). Treatment of these conditions involves drug therapy for heart failure or infection and procedures such as bronchoscopy, thoracentesis, etc. </div> <div> Bronchoconstriction may exist chronically (e.g., asthma, reactive airways disease), and this may be exacerbated by the presence of an endotracheal tube. Tracheal bronchial secretions collect in the airway in the presence of an endotracheal tube that reduces cough effectiveness in clearing the airway. Occasionally bronchoconstriction is induced by an endotracheal tube or other object in an otherwise normal patient. Drug treatment is focused on reducing bronchial smooth muscle tone (beta-2 sympathomimetic, anticholinergic), minimizing tracheal bronchial secretions, and decreasing sensory input from the tracheal bronchial tree (e.g., topical anesthetic, deeper general anesthesia, intravenous lidocaine or an opioid). Acute treatment of bronchoconstriction may involve any combination of the following: (1) aerosolized beta-2 sympathomimetic and/or anticholinergic; (2) systemic intravenous administration of a beta-2 sympathomimetic, a phosphodiesterase inhibitor (e.g., aminophylline), and/or an anticholinergic; (3) intravenous steroids. The latter are indicated in severe bronchoconstriction, especially in the asthmatic patient who benefitted previously. With 100 percent oxygen, blood oxygenation usually is satisfactory, but the progressive development of hypercarbia and air trapping reduces ventilatory compliance and increases intrathoracic pressure that reduces venous return and cardiac output. </div> <div> Impaired alveolar capillary gas exchange may result from alveolar pulmonary edema (treated by diuretics, inotropes, and vasodilators), decreased pulmonary perfusion (treated by inotropes and vasodilators), and lung consolidation (antibiotic therapy for infection). </div> <div>  <A NAME="subsect1127"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Restoration of Spontaneous Ventilation and Airway Protective Mechanisms </div> <div> The anesthesiologist tailors the anesthetic plan according to postoperative expectations. In a relatively healthy patient who will be extubated in the operating room, the goal is to have the patient breathing spontaneously with intact airway reflexes and arousable to command immediately after operation. The challenge is to maintain satisfactory general anesthesia during the surgery but to have the patient recover from anesthetic drugs, including hypnotics and opioids, immediately afterwards. If this is not possible, the patient is transferred to the PACU (post-anesthesia care unit) to allow additional time for eliminating drugs that depress spontaneous ventilation and cough reflexes. Another option is to administer an opioid antagonist (e.g., naloxone) and/or benzodiazepine antagonist (e.g., flumazenil); however, this approach risks sudden awakening, anxiety, pain, uncontrolled autonomic sympathetic activity, and recurrent ventilatory depression because of mismatching antagonists and residual anesthetic drugs. On the other hand, neuromuscular blockers routinely are antagonized by an anti-cholinesterase (e.g., neostigmine) in combination with an anticholinergic (e.g., atropine) to limit the cholinergic side-effects of the anticholinesterase. </div> <div> When the postoperative plan calls for maintenance of mechanical ventilation for some time, tolerance of the endotracheal tube is facilitated by residual anesthetic drugs supplemented by intravenous hypnotics (e.g., propofol) and opioids (e.g., fentanyl, morphine) in low doses. The goals are to prevent pain, limit reflex responses to the endotracheal tube, and allow variable degrees of spontaneous ventilation supplemented by intermittent positive pressure ventilation. When ready for extubation, these sedative and analgesic drugs are reduced in dosage or discontinued to allow satisfactory blood oxygenation and carbon dioxide removal, easy arousal of the patient, and partial restoration of airway reflexes. </div> <bR> <div> DIURETICS </div> <div> Diuretics are drugs that act directly on the kidneys to increase urine volume and to produce a net loss of solute (principally sodium and other electrolytes) and water. </div> <bR> <div> Currently available diuretics have a number of uses in medicine (e.g., treatment of hypertension, glaucoma, increased intracranial pressure) that are not discussed here. The principal indications for intravenous diuretics in the perioperative period are: </div> <bR> <div> (1) to increase urine flow in oliguria; </div> <div> (2) to reduce intravascular volume in patients at risk of acute heart failure from excessive fluid administration; and</div> <div>  (3) to mobilize edema. </div> <bR> <bR> <div> Renal function depends on adequate renal perfusion to maintain the integrity of renal cells and to provide hydrostatic pressure for glomerular filtration. There are no drugs that act directly on the renal glomerulus to affect the glomerular filtration rate (GFR). In an average-size normal adult human, GFR averages 125 mL/min and urine production approximates 1 mL/min. In other words, 99 percent of the glomerular filtrate is reabsorbed. Diuretics act on specific renal tubal segments to alter reabsorption of water and electrolytes, principally sodium. </div> <div> There are two basic mechanisms behind renal tubular reabsorption of sodium. </div> <bR> <div> (1) Sodium is extruded from the tubular cell into peritubular fluid primarily by active transport of the sodium ion by the Na-K-ATPase pump and by the bicarbonate reabsorption mechanism (see the following). This extrusion of sodium creates an electrochemical gradient causing diffusion of sodium from the tubular lumen into the tubular cell. </div> <bR> <div> (2) Sodium also moves from the glomerular filtrate into the peritubular fluid by several different mechanisms. The most important quantitatively is the sodium electrochemical gradient created by active extrusion of sodium from the tubular cell into peritubular fluid. Sodium also is coupled with organic solutes and phosphate ions, exchanged for hydrogen ions diffusing from the tubular cell into the tubular lumen, and coupled to the transfer of a chloride ion or a combination of a potassium and two chloride ions (Na-K-Cl cotransport) from tubular fluid into the tubular cell. Diuretics are classified by their principal site of action in the nephron and by the primary mechanism of their naturetic effect </div> <div>  <A NAME="subsect1128"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Osmotic Diuretics </div> <div> Mannitol is the principal example of this type of diuretic, which is used for two primary indications: </div> <bR> <div> (1) prophylaxis and early treatment of acute renal failure characterized by a decrease in GFR leading to a decreased urine volume and an increase in the concentration of toxic substances in the renal tubular fluid; and (2) to enhance other diuretics by retaining water and solutes in the tubular lumen. </div> <bR> <bR> <div> Normally, 80 percent of the glomerular filtrate is reabsorbed isosmotically in the proximal tubule. By an osmotic effect, mannitol limits reabsorption of water and dilutes proximal tubular fluid. This reduces the electrochemical gradient for sodium and limits its reabsorption so that more reaches the distal nephron. Mannitol produces a prostaglandin-mediated increase in renal blood flow that partially washes out medullary hypertonicity that is essential for the counter current mechanism promoting reabsorption of water in the late distal tubule and collecting system under the influence of antidiuretic hormone. The principal toxicity of mannitol is acute expansion of extracellular fluid volume in patients with compromised cardiac function. The drug also reduces chloride and accompanying sodium ion diffusion from the tubular fluid through the pericellular pathway (in between tubular cells) into the peritubular fluid. </div> <div>  <A NAME="subsect1129"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> <B>High Ceiling (Loop) Diuretics </b></div> <div> Furosemide (Lasix), bumetanide (Bumex), and ethacrynic acid (Edecrin) are three chemically dissimilar compounds that have the same primary diuretic mechanism of action. They act on the tubular epithelial cell in the thick ascending limb of Henle's loop to inhibit the Na-K-2Cl cotransport mechanism. Their peak diuretic effect is far greater than other diuretics currently available. Administered intravenously, these drugs have a rapid onset and relatively short duration of action, owing to both pharmacokinetics and compensatory mechanisms. These three diuretics increase renal blood flow without increasing GFR and redistribute blood flow from the medulla to the cortex and within the renal cortex. These changes in renal blood flow also are short-lived and reflect the reduced extracellular fluid volume that results from diuresis. Carbonic anhydrase inhibition by furosemide and bumetanide and actions on the proximal tubule and on sites distal to the ascending limb remain controversial. All three of the loop diuretics increase release of renin and prostaglandin; indomethacin blunts this release as well as the augmentation of renal blood flow and natruresis. The drugs also produce an acute increase in venous capacitance for a brief time after the first intravenous dose that is blocked by indomethacin. </div> <div> Potassium, magnesium, and calcium excretion are increased in proportion to the increase in sodium excretion. In addition, there is augmentation of titratable acid and ammonia excretion by the distal tubal leading to metabolic alkalosis, which also is produced by contraction of the extracellular volume. Hyperuricemia can occur but is of little physiological significance usually. The nephrotoxicity of cephaloridine, and possibly other cephalorsporins, is increased. A rare but serious side-effect of the loop diuretics is deafness, which may reflect electrolyte changes in the endolymph. </div> <div> Because of their high degree of efficacy, prompt onset, and relatively short duration of action, high ceiling or loop diuretics are favored for intravenous administration in the perioperative period to treat the three principal problems cited above. Dosage requirements vary considerably among patients. Some require only 3–5 mg furosemide IV to produce a good diuresis; others may need only the less potent benzothiazides. </div> <div>  <A NAME="subsect1130"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Benzothiazides </div> <div> Hydrochlorothiazide (HCTZ) is the prototype of more than a dozen currently available diuretics in this class. Although the drugs differ in potency, all act by the same mechanism and have the same maximum efficacy. All are actively secreted into the tubular lumen by tubular cells and act in the early distal tubule to decrease the electroneutral Na-Cl co-transport reabsorption of sodium. Their moderate efficacy probably is because more than 90 percent of filtered sodium is reabsorbed before reaching the distal tubule. Efficacy is enhanced by simultaneous administration of an osmotic diuretic such as mannitol. Benziothiazides increase urine volume and excretion of sodium, chloride, and potassium. Reduced reabsorption of potassium reflects diminished reabsorption time from the higher rate of urine flow through the distal tubule. </div> <div> This class of diuretics produces the least disturbance of extracellular fluid composition. Principal side-effects include hyperuricemia, decreased calcium excretion, and enhanced magnesium loss. Hyperglycemia can occur as a result of multiple variables. With prolonged use and contraction of extracellular fluid volume, urine formation decreases. Also, these agents have a direct effect on renal vasculature to decrease GFR. </div> <div>  <A NAME="subsect1131"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Carbonic Anhydrase Inhibitors </div> <div> Acetazolamide (Diamox) is the only diuretic of this class available for intravenous administration. Its clinical use is primarily directed to alkalinization of urine in the presence of a metabolic alkalosis that develops commonly from prolonged diuretic therapy. Acetazolamine acts in the proximal convoluted tubule to inhibit carbonic anhydrase in the brush border of the tubular epithelium to reduce destruction of bicarbonate ion (i.e., prevents conversion to co <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2 </FONT>). Tubular cellular carbonic anhydrase is also inhibited so that conversion of co <FONT SIZE="1" COLOR="#000000" FACE="Arial" >2 </FONT>to carbonic acid is reduced markedly and fewer hydrogen ions are available for the Na-H exchange mechanism. Reabsorption of both sodium and bicarbonate in the proximal tubule is diminished, but more than half of the bicarbonate is reabsorbed in more distal segments of the nephron, to reduce the overall efficacy of the drug. </div> <div>  <A NAME="subsect1132"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Potassium-Sparing Diuretics </div> <div> Spironolactone (Aldactone) is a competitive antagonist of aldosterone. Spironolactone binds to the cytoplasmic aldosterone receptor and prevents conformational change to the active state. The drug aborts the synthesis of active transport proteins in the late distal tubal and collecting system where the reabsorption of sodium and secretion of potassium are reduced. </div> <div> Triamterene (Dyrenium) and amiloride (Midamar) are potassium-sparing diuretics. They have a moderate naturetic effect that leads to an increased excretion of sodium and chloride with little change or a slight increase in potassium excretion when the latter is low. When potassium secretion is high, the drugs produce a sharp reduction in electrogenic entry of sodium ions into distal tubular cells and thereby reduce the electrical potential that drives potassium secretion. </div> <div> Both types of potassium-sparing diuretics are used primarily in combination with other diuretics to reduce potassium loss. The principal side effect is hyperkalemia. It is appropriate to limit intake of potassium when using this type of diuretic. It is also appropriate to use this type of diuretic cautiously in patients taking ACE (angiotensin conversion enzyme) inhibitors that decrease aldosterone formation and consequently increase serum potassium concentrations. </div> <div>  <A NAME="subsect1133"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div> Other Measures to Enhance Urine Output and Mobilization of Edema Fluid </div> <div> Infusion of albumin (5–25% solutions) or other plasma volume expanders (e.g., hetastarch) is often employed to draw water and electrolytes (i.e., edema fluid) osmotically from tissues into the circulation for delivery to the kidneys for excretion. With a reduced circulating blood volume, this is a logical way to increase circulating blood volume and renal perfusion. Because the osmotic effect of albumin and plasma expanders is transient because of their diffusion into tissues, the diuretic effect is limited and water tends to remain in the interstitial space. The same limitation applies to osmotic diuretics such as mannitol, which also diffuse through the capillary membrane. </div> <div> Dopamine (Intropin) is a catecholamine that has the unique ability to interact with vascular D1-dopaminergic receptors in coronary, mesenteric, and renal vascular beds. By activating adenyl cyclase and raising intracellular concentrations of cyclic-AMP, D1-receptor stimulation leads to vasodilation. Infusion of low doses of dopamine (1–3 µg/kg-1/min-1) causes an increase in glomerular filtration rate, renal blood flow, and na <FONT SIZE="1" COLOR="#000000" FACE="Arial" >+ </FONT>excretion. As a catecholamine and a precursor in the metabolic synthesis of norepinephrine and epinephrine, dopamine has inotropic and chronotropic effects on the heart. The inotropic effect is mediated by beta1-adrenergic receptors and usually requires infusion rates higher than those able to produce enhanced renal perfusion and diuresis. Infusion rates greater than 8–10 µg/kg -1/min-1 lead to vasoconstriction produced by dopamine activation of alpha1-adrenergic receptors in vascular smooth muscle. </div> <bR> <bR> </td> </tr></table></body>