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Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5200_Библиотеки_им_академика_М_И_Перельмана

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increasedpotassiumandbicarbonateexcretionanddecreasedcalciumexcretion.Theymaybehelpfulin patientswithosteoporosisastheycanslowdemineralization.Additionally,theycauseuricacidretention, socautionshouldbeusedinpatientswithahistoryofgout.
TABLE18.4
ThiazidesandThiazide-likeDiuretics
Agent InitialDose Maximum
Total
DailyDose Clinical
Pearls
Chlorothiazide(Diuril) 500mgPO
dailyorBID
2,000mg
Hydrochlorothiazide (oftenabbreviatedas HCTZ)
12.5-25mg POdaily
50mg Dosesabove25mgoftenresultinincreasedadverse
effectswithminimaladdedbenefit
Chlorthalidone 12.5-25mg
POdaily
100mg
Indapamide 1.25mgPO
daily
5mg Titrateevery4weeks;
GivewithfoodormilktodecreaseGIsideeffects
Metolazone 2.5mgdaily 20mg Otherthiazidesareusuallypreferred;Maybeaddedto
loopdiureticsinhospitalizedpatientstoaugmenteffect
GI,gastrointestinal.
Contraindications
Thiazide diuretics are contraindicated in those who are anuric or are hypersensitive to thiazides or sulfonamides.Theyare notrecommendedinpatientswithacreatinineclearance(CrCl)oflessthan30 mL/minbecausetheyareineffective.
AdverseEvents
Sideeffectsincludehypokalemia,hypomagnesemia,hyper-calcemia,hyperuricemia,andhyperglycemia. As a result of drug-induceddiuresis, hypokalemia occurs in15% to 20%ofpatientstaking low-dose thiazide diuretics; therefore, potassium supplements can be utilized by some patients. Combination therapywiththiazideandpotassium-sparingdiuretics(e.g.,hydrochlorothiazideandtriamterene)maybe prudentwhenthepotassium levelislessthan4.0mEq/Landthepatientistakingathiazidediureticor when a low potassium level may potentiate drug toxicity, as in patients concurrently taking digoxin. MonitortheSCr,sodium,andpotassiumwithin7to10daysafterinitiationordosetitration.
Othersideeffectsincludetinnitus,paresthesia,abdominalcramps,nausea,vomiting,diarrhea,muscle cramps,weakness,andsexualdysfunction.Thiazidescanalsoworsengoutduetoanincreaseinserum uricacid.Diuretic-inducedhyperuricemiamayproducegoutyarthritisoruricacidstones.Thereisalsoa greater risk of developing diabetes with thiazides than with ACE inhibitors (ACEIs), angiotensin II receptorblockers(ARBs),orcalciumchannelblockers(CCBs)(Table18.5).
TABLE18.5
LoopDiuretics
TABLE18.6
Potassium-SparingDiureticsandAldosteroneReceptorAntagonists
LoopDiuretics
MechanismofAction
Loopdiureticsare indicatedinthepresenceofedemaassociatedwithcongestiveheartfailure,hepatic cirrhosis, andrenal disease. Thisdrugclass isusefulwhengreater diuresis is desired compared with thiazidediuretics. In general, loopdiuretics should be reserved for hypertensive patientswithchronic renalinsufficiencyand/ortheneedformoreseverediuresis.
Furosemideandethacrynicacidinhibitthereabsorptionofsodiumandchloride,notonlyinproximal and distal tubules but also in the loop of Henle. In contrast, bumetanide is more chloruretic than natriureticandmayhaveanadditionalactionintheproximaltubule.
LoopdiureticsareespeciallyusefulinpatientswithheartfailureandCKDusingtwicedailydosing.
Contraindications
Loop diuretics are contraindicated in patients whoare anuric and in patients withhepatic coma or in states of severe electrolyte depletion. Ethacrynic acid is contraindicated in infants. Furosemide, bumetanide,andtorsemidearesulfonamide-basedloopdiureticsthatshouldnotbeusedinpatientswith hypersensitivitytosulfonylureas;ethacrynic acidis generallyreserved for thispatientpopulationas it doesnotcontainasulfamoiety.
AdverseEvents
Loop diuretics may cause the same side effects as thiazides, although the effects onserumlipids and glucosearenotassignificant,andhypocalcemiamayoccurinstead.Themetabolicabnormalities,suchas hyperlipidemia andhyperglycemia, usually occur with high doses of diuretics and can be avoided by usinglowdosesofthedrug.
Loopdiureticsmayleadtoelectrolyteandvolumedepletionmorereadilythanthiazides;theyhavea shortdurationofaction,butthethiazidediureticsaremoreeffectivethanloopdiureticsinreducingBPin patientswithnormalrenalfunction.Therefore,loopdiureticsshouldbereservedforhypertensivepatients withrenaldysfunction(SCr>2.5mg/dL).MonitorSCr,sodium,andpotassiumwithin7to10daysafter initiationordosetitration.
Loopdiureticsmayalsocauseototoxicity.Thisismorelikelytooccurwithhighdoses,duringrapidIV administration,orwithsevererenalimpairment.Itismorecommonwithethacrynicacid(Table18.6).
Potassium-SparingDiureticsandAldosteroneReceptorAntagonists
MechanismofAction
Inthekidney,potassiumisfilteredattheglomerulusandthenabsorbedparalleltosodiumthroughoutthe proximaltubuleandthethickascendinglimboftheloopofHenle,sothatonlyminoramountsreachthe distal convoluted tubule. As a result,potassium appearinginurineis secretedat the distal tubule and collectingduct.Thepotassium-sparingdiureticsinterferewithsodiumreabsorptionatthedistal tubule, thusdecreasingpotassiumsecretion.ThesedrugscanbeusedasapossibleagentforHTN;however,their truebenefitisinpatients withheartfailure.IntheRandomizedSpironolactoneEvaluationStudy, low­dose spironolactonewas showntoimprove morbidityandmortalityratesinpatientswithsevereheart failure(Pittetal.,1999).
Aldosterone receptor antagonists inhibit the effect of aldosterone by competitively binding to aldosteronereceptorsinthecorticalcollectingduct.Thisresultsindecreasedreabsorptionofsodiumand water,whiledecreasingpotassiumsecretion.TheyaretypicallyusedinpatientswithrefractoryHTN.
Thesediureticshavethepotentialforcausinghyperkalemiaandhyponatremia,inparticular,inpatients withrenalinsufficiencyordiabetesandinpatientsreceivingconcurrenttreatmentwithanACEIinhibitor, NSAIDs,orpotassiumsupplements.
Contraindications
Potassium-sparingdiureticsarecontraindicatedinpatientswithhyperkalemia,Addisondisease, anuria, orpatientstakingeplerenone.
AdverseEvents
Side effectsincludegynecomastia,hirsutism,andmenstrualirregularities. Asymptomatic hyperuricemia mayoccur,andgoutmaybeprecipitated.Potassium-sparingdiureticsshouldbeavoidedinpatientswith CrClbelow10mL/min,andaldosteroneantagonistsshouldnotbeusedinpatientswithCrClbelow30 mL/min.MonitorSCrandpotassiumwithin7to10daysafterinitiationortitrationofpotassium-sparing diuretics.SCrandpotassiumshouldbemonitoredin3daysandin7daysandmonthlyfor3monthsafter initiationortitrationofaldosteroneantagonists(Table18.7).
Beta-AdrenergicBlockers
MechanismofAction
Beta-1receptors,located predominantlyintheheartandkidney,regulateheartrate,reninrelease, and cardiaccontractility.Beta-2receptors,locatedinthelungs,liver,pancreas,andarteriolarsmoothmuscle, regulatebronchodilationandvasodilation.Betablockers reduceBPbyblockingcentral andperipheral betareceptors,whichresultsindecreasedcardiacoutputandsympatheticoutflow.
Betablockershavebeenincludedinclinicalguidelinessincethe1980sandremainamainstayofHTN treatment.Despiteseveralpharmacologicdifferencesintheavailablebetablockers,theyarealleffective intreatingHTN.Betablockers thatmostlybindtobeta-1 receptors arereferredtoas cardio-selective becausetheydonotsignificantlyblockbeta-2receptorsandaretypicallyusedfortreatingHTN.These agentsincludemetoprololtartrate,metoprololsuccinate,atenolol,nebivolol,andbisoprolol.Thesemay besaferthannonselectivebetablockersforpatientswithasthma,chronicobstructivepulmonarydisease, andperipheralvasculardisease.Athigherdoses,however,selectivebetablockerslosecardioselectivity andmayaggravateapreexistingcondition.
Drugs with beta-1 and alpha-1 receptor blockade are more effective in lowering blood pressure comparedtodrugswithsinglereceptorblockade.Agentswithdualreceptorblockadeincludecarvedilol andlabetalol.
Somebeta blockers possess intrinsic sympathomimetic activity (ISA);these agentsare partial beta­receptoragoniststhatreduceheartrateandcontractilityduringexcessivesympatheticoutflow.Inresting states,heartrateandcontractilityaremaintained.Typicalmedicationsincludepindololandacebutolol.
TABLE18.7
Beta-AdrenergicBlockers
Studiessuggestthatbetablockersmaydecreasesympatheticactivityinvolvedwiththeprogressionof heart failure (see Chapter 21, “Heart Failure”). For example, carvedilol and metoprolol succinate decreased mortality rates in patients with heart failure and decreased ventricular remodeling (which resultsinLVH).Betablockersshouldbeusedonlyinpatientswithstablecongestiveheartfailureandbe temporarilydiscontinuedifthepatienthasanacutedecompensation.Practitionersshouldreferanypatient withheartfailuretoacardiologistforevaluationoftherapy.
Patientsshouldbecautionednottodiscontinuetherapyabruptly.Thedoseofbetablockersshouldbe taperedgraduallyover14daystopreventwithdrawalsymptoms,whichincludeunstableangina,MI,or evendeath in patients with underlyingCVD. Patients withoutcoronaryartery disease mayexperience sinustachycardia,palpitations,increasedsweating,andfatigue.
Contraindications
Betablockers arecontraindicatedinpatientswithsinoatrialor atrioventricular(AV)nodedysfunction, decompensated heart failure, and severe bronchospastic disease. They should be used with caution, especially at higher doses, in patients with asthma or chronic obstructive pulmonary disease due to blockade of pulmonary beta receptors. Beta blockers should be avoided in patients who have sinus bradycardia,second-orthird-degreeheartblock,orovertcardiacfailure.
Non-ISA betablockersarethepreferredagentsfortreatingHTNinpatientwithcoexistingcoronary arterydiseaseandespeciallyinpatientsafterMI.
Betablockersshouldbeusedcautiously,butnotavoided,inpatientswithrestingischemiaorsevere claudicationsecondarytoperipheralvasculardisease,reactiveairwaydisease,systoliccongestiveheart failure,diabetesmellitus,ordepression.
AdverseEvents
Themostcommonsideeffectsofbetablockersarefatigue,drowsiness,dizziness,bronchospasm,nausea, and vomiting. Serious side effects include bradycardia, AV conduction abnormalities, and the development of congestive heart failure. The dose should be adjusted in patients who develop symptomaticbradycardiaorgreaterthanfirst-degreeheartblock.
Inpatientswithdiabetes,betablockerscanmaskallsymptomsofhypoglycemia,exceptforsweating. Betablockersmayalsocausedepression.Similar tothethiazides, there isa higherriskofdeveloping diabeteswithbetablockersthanwith ACEIs,ARBs,orCCBs.
Someoftheseadverseeffectscanbebeneficialforcertainpatients.Forexample,betablockersmaybe favorable intreatingpatientswith atrialfibrillation,tachyarrhythmias, angina, migraines, andessential tremor(Table18.8).
TABLE18.8
Angiotensin-ConvertingEnzymeInhibitors
Angiotensin-ConvertingEnzymeInhibitors
MechanismofAction
ACEIs, such as lisinopril, enalapril, captopril, ramipril, and trandolapril (see Table 18.5). exert an antihypertensiveeffectbypreventingtheconversionofangiotensinItoangiotensinII,whichisa potent vasoconstrictor.ACEIsalsoinhibitthedegradationofbradykininandincrease thesynthesis ofvasodi­latingprostaglandins.ACEIsdecreasemorbidityandmortalityinpatientswithcongestiveheartfailure, post-MI,andsystolicdysfunction.
Contraindications
ACEIsarecontraindicatedinpatientswithbilateralrenalarterystenosisbecauseoftheriskofacuterenal failure.Theyarealsocontraindicatedinpregnancyduetotheirteratogeniceffects,soconsideravoiding their use in women of child-bearing age. Additionally, ACEIs are contraindicated in patients with a historyofangioedema.
AdverseEvents
ThemostcommonsideeffectsassociatedwithACEIsincludechronicdrycough,rashes(mostcommon withcaptopril),anddizziness.Hyperkalemiacanoccurbutisahigherriskinpatientswithrenaldisease, withdiabetes,ortakingconcomitantpotassium-sparingdrugsorpotassiumsupplements.Angioedemaisa rare but dangerous side effect that occurs 2 to 4 times more frequently in African Americans; it is reversible upon discontinuation of the agent. Laryngeal edema, another rare adverse effect, is life threateningandrequiresimmediatemedicalattention.ACEIscanalsocauseariseinSCr;amodestrise ofupto30%frombaselineisacceptableandshouldbeconsideredthenewbaseline.
ACEIsarenotrecommendedtobeusedincombinationwithanARBorarenininhibitorbecauseallof theseagentsaffecttheRAASsystem,therebyincreasingtheincidenceofsideeffects.Wheninitiatingor titratingthedoseofanACEI,thepotassiumandSCrshouldbecheckedwithin1to2weeks(Table18.9).
TABLE18.9
AngiotensinReceptorBlockers
AngiotensinIIReceptorBlockers
MechanismofAction
ARBs block the vasoconstriction and aldosterone-secreting effects of angiotensin II by selectively blockingthebindingofangiotensinIItotheangiotensinIIreceptorfoundinmanytissues(seeTable18.6). ThisreducesendorganresponsestoangiotensinIIandresultsindecreasedafterloadandpreload.They are indicated for patients with HTN,nephropathy in type 2 diabetes, andheart failure and those who cannottoleratethesideeffectsassociatedwithACEIs.
TheresultsoftheLosartanInterventionforEndpointReductioninHTNstudysuggestthatlosartanis more effective thanatenolol in reducingcardiovascular morbidity and mortality in patients who have diabetes,HTN,andLVH(Dahlöfetal.,2002).Theincidenceofcoughandhyperkalemiaassociatedwith thisclassofdrugsislowerthanwithACEIsbutmaystilloccur.
Contraindications
LiketheACEIs,ARBsarecontraindicatedinpatientswithbilateralrenalarterystenosisandpregnancy. AngioedemacanbeseenwithARBtherapybutwithmuchlessfrequencythanwithACEIs.Thereshould be some justification(heartfailure or proteinuric nephropathy) for theuse ofARBsinpatients having experienced ACEI-related angioedema. Combination with ACEI and/or renin inhibitors is not recommended.Cautionshouldbeusedinpatientswithrenalandhepaticfunctionimpairment.
TABLE18.10
ReninInhibitor
AdverseEvents
Adversereactionsincludedizziness,upperrespiratorytractinfections,viralinfection,fatigue,diarrhea, pain,sinusitis, pharyngitis,andrhinitis. LikeACEIs,thereisa riskofhyper-kalemia inpatientstaking
another potassium-sparing medicationor potassiumsupplements. ARBs canalso elevate the SCr; like ACEIs,amodestriseof30%abovebaselineisacceptableandshouldbeconsideredthenewbaseline. WheninitiatingortitratingthedoseofanARB,thepotassiumandSCrshouldbecheckedwithin7to10 days(Table18.10).
ReninInhibitorsMechanismofAction
Renin inhibitors block the conversion of angiotensinogen to angiotensin I. Angiotensin I suppression decreases the formation of angiotensin II. Angiotensin II functions within the RAAS as a negative inhibitoryfeedbackmediatorwithintherenal parenchymatosuppress the furtherrelease of renin.The reductioninangiotensinIIlevelssuppressesthisfeedbackloop,leadingtofurtherincreasedplasmarenin concentrationsandsubsequentlowplasmareninactivity.Aliskirenisthefirstrenininhibitorapprovedby theU.S.Food and Drug Administration,inMarch 2007. It is currently the onlyrenin inhibitor on the marketintheUnitedStates.AliskirenlowersBPbyadegreecomparabletomostotheragents.Thereare no clinical trial data of aliskiren monotherapy on outcomes in HTN. The Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints, which compared aliskiren added to an ACEI or ARB with placebo, was terminated early due to an increase in adverse events and lack of apparentbenefit.It is also important tonotethatpatientswithrenal insufficiencywereexcludedfrom clinicaltrials.
Contraindications
ThisdrugisnotrecommendedincombinationwithACEIandARBtherapyduetosimilarmechanismsof action. It is contraindicated for use with an ACEI or ARB in patients with diabetes. Aliskiren is contraindicatedduringpregnancybecauseitdirectlyactsontherenin-angiotensinsystemandcancause fetalandneonatalmorbidity.
AdverseEvents
Significantadverseeventsincludedose-related diarrhea,hyper-kalemiawhenused withanACEI,and angioedema(rare)(Table18.1.).
CalciumChannelBlockersMechanismofAction
CCBssharetheabilitytoinhibitthemovementofcalciumionsacrossthecellmembrane.Theeffecton the cardiovascular system is muscle relaxation and vasodilation. Non-dihydropyridines, such as verapamil and diltiazem, decrease heart rate and slow cardiac conduction at the AV node. The dihydropyridines(amlodipine,felodipine,nifedipine,nicardipine,nisoldipine,andisradipine)arepotent vasodilators.CCBsareeffectiveas mono-therapyandareespeciallyeffective inblackpatients.CCBs are similar in antihypertensive effectiveness but differ in other phar-macodynamic effects. The non­dihydropyridinesaretypicallyusedinpatientswithatrialfibrillationorstableangina.
TABLE18.11
CalciumChannelBlockers
Contraindications
Thenon-dihydropyridines(verapamilanddiltiazem)arecontraindicatedinpatientswithheartblockor sicksinus syndrome.Theymayaccelerate theprogressionofcongestiveheartfailure ina patientwith cardiac dysfunction;therefore, these agents are not first line.Diltiazem andverapamil should also be avoided inpatientswithleftventricular(systolic)dysfunctionwhentheejectionfractionmeasures less than40%.
Short-acting nifedipine should not be used for treating essential HTN or hypertensive emergencies becauseofitsassociationwithcausinginconsistentfluctuationsinBPandreflextachycardia.
AdverseEvents
Diltiazemandverapamilcancausegastrointestinal(GI)upset,peripheraledema,andhypotension.Rare side effects include bradycardia, AV block, and congestive heart failure. Verapamil can cause constipationinolderadults.Thesemedicationsare alsopotentCYP450inhibitors;therefore,theyhave thepotentialforsevere drug—druginteractions.Theyshouldalsobeusedwithcautioninpatientsalso takingabetablocker.
The dihydropyridine agents (nifedipine, nicardipine, isradipine, felodipine, nisoldipine, and amlodipine) produce symptomsofvasodilation,such as headache,flushing,palpations,andperipheral edema. Other side effects of nifedipine include dizziness, gingival hyperplasia, mood changes, and various GI complaints. Nifedipine may cause reflex tachycardia as a result of stimulating the baroreceptorsinresponsetoanacutedropinBP(Table18.12).
PeripheralAlpha-1ReceptorBlockers
MechanismofAction
Doxazosin,prazosin,andterazosinare selectivealpha-1receptorblockersthatareeffectiveinpatients
withbenignprostatic hypertrophyandarenotusuallyprescribed solelyfor HTNtreatment.Peripheral alpha-1 receptor blockers act byinhibitingtheactionof adrenaline onsmoothmuscle inbloodvessel walls,dilatingbotharteriolesandveins,causingrelaxationofsmoothmuscle.
Inthepresenceof CVD,alpha-1 receptor blockers should be avoided, as theAntihypertensive and Lipid-LoweringTreatmenttoPreventHeartAttack(ALLHAT)studyshowedthat thesepatientshadan increaseinmortality(Papademetriouetal., 2003). Alpha-1blockers are generallyviewedas fourth-or fifth-lineagents.Thesedrugsaretypicallyreservedformalepatientswithbenignprostatichyperplasia.
Contraindications
Theuseoftadalafil,sildenafil,andvardenafilisnotrecommendedwithalpha-1receptorblockersdueto anincreasedriskofsymptomatichypotension.Ifbothagentsareprescribed,awashoutwindowofatleast 4to6hoursisrecommended.
AdverseEvents
Themostcommonsideeffectassociatedwiththisclassofantihypertensivemedicationsisthefirst-dose phenomenon,whichconsists ofdizzinessor faintness, palpitations,orsyncope.Orthostatichypotension may also occur. These agents should be administered initially at bedtime, and the dosage should be adjustedslowly.Withchronicadministration,evenatlowdoses,fluidandsodiumaccumulate,requiring concurrentdiuretictherapy.Othersideeffectsincludevividdreamsanddepression(Table18.13).
CentralAlpha-2ReceptorAgonists
MechanismofAction
Central alpha-2 agonists stimulate alpha-2 adrenergic receptors in the brain, resulting in decreased sympathetic outflow,cardiacoutput,andperipheral resistance.Theseagentsmaycausefluid retention, andinmostcases,combinationwithadiureticcanbeconsidered.Clonidine,methyldopa,andguanfacine shouldnotbeusedas initial monotherapy. Abruptcessationofalpha-2 agonisttherapymayresultina compensatoryincreaseinthenorepinephrinelevel,therebyincreasingBP.
TABLE18.12
PeripheralAlpha-1ReceptorBlockers
TABLE18.13
CentralAlpha-2ReceptorAntagonists
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