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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2804_Библиотеки_им_академика_М_И_Перельмана
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Telmisartan 40mgPOdaily 20–80
Valsartan 80mgPOdaily 80–320
DirectReninInhibitor
c
Aliskiren 150mgPOdaily 150–300
AngiotensinReceptor–NeprilysinInhibitor
c
Sacubitril/valsartan
b
24/26mgPOBID 24/26–97/103
Diuretics
c
Chlorthalidone Thiazidediuretic 25mgPOdaily 12.5–50
Hydrochlorothiazide Thiazidediuretic 12.5mgPOdaily 12.5–50
HydroflumethiazidebThiazidediuretic 50mgPOdaily 50–100
Indapamide Thiazidediuretic 1.25mgPOdaily 2.5–5
Methyclothiazide Thiazidediuretic 2.5mgPOdaily 2.5–5
Metolazone Thiazidediuretic 2.5mgPOdaily 1.25–5
Bumetanide Loopdiuretic 0.5mgPOdaily(orIV) 0.5–5
Ethacrynicacid Loopdiuretic 50mgPOdaily(orIV) 25–100
Furosemide Loopdiuretic 20mgPOdaily(orIV) 20–320
Torsemide Loopdiuretic 5mgPOdaily(orIV) 5–10
Amiloride Potassium-sparing
diuretic
5mgPOdaily 5–10
Triamterene Potassium-sparing
diuretic
50mgPObid 50–200
Eplerenone Aldosteroneantagonist 25mgPOdaily 25–100
Spironolactone Aldosteroneantagonist 25mgPOdaily 25–100
α-AdrenergicAntagonists
Doxazosin 1mgPOdaily 1–16
Prazosin 1mgPObid–tid 1–20
Terazosin 1mgPOatbedtime 1–20
CentrallyActingAdrenergicAgents
Clonidine 0.1mgPObid 0.1–1.2
Clonidinepatch TTS1/wk(equivalentto
0.1mg/drelease)
0.1–0.3
Guanfacine 1mgPOdaily 1–3
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Guanabenz 4mgPObid 4–64
Methyldopa
a
250mgPObid–tid 250–2000
Direct-ActingVasodilators
Hydralazine
a
10mgPOqid 50–300
Minoxidil 5mgPOdaily 2.5–100
Miscellaneous
Reserpine 0.5mgPOdaily 0.1–0.25
DHP,dihydropyridine;ISA,intrinsicsympathomimeticactivity;TTS,transdermaltherapeuticsystem.
a
Adjustedinrenalfailure.
b
Availableonlyinbrandname.Assumealldrugsareavailableingenericformunlessotherwisedenotedbysuperscript“b.”
c
Renalfunctionshouldbeconsideredbeforeinitiation.
Thiazideor thiazide-likediuretics,calciumchannelblockers (CCBs), angiotensin-converting enzyme
(ACE)inhibitors,andangiotensinreceptorblockers(ARBs)shouldbeconsideredasfirst-linetherapy
for the general population (except for those from African descent), including those with diabetes.
Multiple large randomized controlled trials have shown comparable effects on decreasing overall
cardiovascularandcerebrovascularmortalityforallfourdrugclasses.
5
InpatientsfromAfricandescent, includingthosewithdiabetes,athiazideorthiazide-likediureticor
CCB can be considered for first-line therapy. Data from the ALLHAT trial have shown decreased
cardiovascularandcerebrovascularmorbidityandmortalitywiththeuseofthiazidediureticsorCCB
overanACEinhibitor.
26
In patients with chronic kidney disease (CKD) stage 3 or higher, or CKD with albuminuria (>300
mg/d),initialorcombinationtherapywithanACEinhibitororARBisrecommended.
1
Additionaltherapy: When a seconddrug is needed, it should generally be chosen from among the
otherfirst-lineagents.
Adjustments of a therapeutic regimen: Before considering a modification of therapy because of
inadequateresponsetothecurrentregimen,otherpossiblecontributingfactorsshouldbeinvestigated.
Poor patientcompliance,use ofantagonistic drugs(examples provided above), inappropriatelyhigh
sodium intake, or increased alcohol consumption may be the cause of inadequate BP response.
Secondarycausesofhypertensionshouldbeconsideredwhenapreviouslyeffectiveregimenbecomes
inadequateandotherconfoundingfactorsareabsent.
Diuretics(see Table3-4)are effectiveagentsinthe therapyofhypertensionandhavebeenshownto
reducetheincidenceofstrokeandcardiovascularevents.Several classes ofdiuretics areavailable,
generallycategorizedbytheirsiteofactioninthekidney.
Thiazides and thiazide-like diuretics (e.g., hydrochlorothiazide, chlorthalidone) block sodium
reabsorption predominantly in the distal convoluted tubule by inhibition of the thiazide-sensitive
sodium/chloride(Na/Cl)cotransporter.Thiazidediureticscancauseweakness,musclecramps,and
impotence. Metabolic side effects include hypokalemia, hypomagnesemia, hyperlipidemia
(increased in low-density lipoproteins [LDLs] and triglyceride levels), hypercalcemia,
hyperglycemia,hyperuricemia,hyponatremia,andrarelyazotemia.Thiazide-inducedpancreatitishas
also been reported. Metabolic side effects may be limitedwhen thiazides are used inlow doses
(e.g.,hydrochlorothiazide, 12.5–25 mg/d). Chlorthalidone andindapamide, thiazide-like diuretics,
are often the preferred diuretics for management of hypertension due to their longer duration of
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action. Thiazide-like diuretics are particularly useful in patients with osteoporosis, edema, and
calciumnephrolithiasiswithhypercalcemia.Itshouldbenotedthatchlorthalidoneisassociatedwith
greater risks of hypokalemia, glucose intolerance, and new-onset diabetes than
hydrochlorothiazide.
27
Loop diuretics (e.g., furosemide, bumetanide, ethacrynic acid, torsemide) block sodium
reabsorption inthe thick ascending limb of the loop of Henle through inhibitionofthe Na/K/2Cl
cotransporter and are the most effective agents in patients with renal insufficiency (estimated
glomerular filtration rate [GFR] <35 mL/min/1.73 m2). Loop diuretics can cause electrolyte
abnormalities such as hypomagnesemia, hypocalcemia, and hypokalemia and can also produce
irreversibleototoxicity(usuallydoserelatedandmorecommonwithparenteraluse).
Spironolactone and eplerenone, potassium-sparing agents, act by competitively inhibiting the
actionsof aldosteroneon the kidney. Triamterene and amiloride are potassium-sparing drugsthat
inhibittheepithelialNa+channelinthedistalnephrontoinhibitreabsorptionofNa+andsecretionof
potassiumions.Potassium-sparing diuretics areweakagentswhenusedalone;thus, they areoften
combinedwithathiazideforaddedpotency.Aldosteroneantagonistsreducemorbidityandmortality
inHFwith reducedejectionfractionandmay haveanadditional benefitinimproving myocardial
function;thiseffectmaybeindependentofitseffectonrenaltransportmechanisms.Spironolactone
or eplerenone are recommended for BP control in patients with resistant hypertension.
1,13
Spironolactoneandeplerenonecanproducehyperkalemia.Thegynecomastiathatmayoccurinmen
andbreasttendernessinwomenarenot seenwitheplerenone.Triamterene(usuallyincombination
with hydrochlorothiazide) can cause renal tubular damage and renal calculi. Unlike thiazides,
potassium-sparing and loop diuretics do not cause adverse lipid effects. Of note finerenone is a
nonsteroidal mineralocorticoid receptor antagonist recently approved for HF management but not
indicatedforhypertension.
Calciumchannel antagonists (see Table 3-4) generally have no significantcentral nervous system
(CNS)sideeffectsandcanbeusedtotreatcoexistingdiseases,suchasanginapectoris.Short-acting
dihydropyridinecalciumchannelantagonistsmayincreasethenumberofischemiccardiacevents,
andthereforearenotindicatedforhypertensionmanagement28;long-actingagentsareconsidered
safeinthemanagementofhypertension.
29,30
Classes of calcium channel antagonists include diphenylalkylamines (e.g., verapamil),
benzothiazepines (e.g., diltiazem), and dihydropyridines (e.g., nifedipine). The dihydropyridines
include many newer second-generation drugs (e.g., amlodipine, felodipine, isradipine, and
nicardipine), which are more vasoselective and have longer plasma half-lives than nifedipine.
Verapamilanddiltiazemhavenegativecardiac inotropicandchronotropiceffects.Nifedipinealso
has a negativeinotropic effect,but inclinicaluse,this effectis muchless pronounced thanthatof
verapamil or diltiazem because of peripheral vasodilation and reflex tachycardia. The second-
generation dihydropyridines have observed less negative inotropic effects. All calcium channel
antagonistsaremetabolizedintheliver;thus,inpatientswithcirrhosis,thedosingintervalshouldbe
adjustedaccordingly.Some ofthesedrugsalso inhibitthemetabolismofotherhepaticallycleared
medications(e.g.,cyclosporine). Verapamil anddiltiazem should be used with cautioninpatients
with cardiac conduction abnormalities, and they can worsen HF in patients with decreased left
ventricularfunction.
Side effects of verapamil include constipation, nausea, headache, and orthostatic hypotension.
Diltiazemcancausenausea,headache,andrash.Dihydropyridinescancauselowerextremityedema,
flushing,headache,andrash.Calciumchannelantagonistscanalsocausegingivalhyperplasia.They
havenosignificanteffectsonglucosetolerance,electrolytes,orlipidprofiles.
Inhibitorsoftherenin–angiotensinsystem(see Table3-4) includeACEinhibitors, ARBs,a direct
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renininhibitor,andanangiotensinreceptor-neprilysininhibitor(ARNI).
ACEinhibitorshavebeneficialeffectsinpatientswithconcomitantHForkidneydisease.Onestudy
hasalsosuggestedthatACEinhibitors(ramipril)maysignificantlyreducetherateofdeath,MI,and
strokeinpatientswithoutHForlowejectionfraction.31Additionally,theycanreducehypokalemia,
hypercholesterolemia, hyperglycemia, and hyperuricemia caused by diuretic therapy and are
particularlyeffectiveinstatesofhypertensionassociatedwitha highrenin state(e.g.,scleroderma
renalcrisis).SideeffectsassociatedwiththeuseofACEinhibitorsareinfrequent.Theycancausea
dry cough (up to 20% of patients), angioneurotic edema, and hypotension, but they do not affect
levelsoflipids,glucose,oruricacid.ACEinhibitorsthatcontainasulfhydrylgroup(e.g.,captopril)
maycausetastedisturbance,leukopenia,andaglomerulopathywithproteinuria.Patientswhohave
decreasedrenalperfusionorpreexistingsevererenalinsufficiencymayendupwithworseningrenal
function because ACE inhibitors cause preferential vasodilation of the efferent arteriole in the
kidney.ACEinhibitors cancausehyperkalemiaandshould be usedwithcautioninpatientswitha
decreased GFR who are taking potassium supplements or who are receiving potassium-sparing
diuretics.
ARBsareaclassofantihypertensivedrugsthatareeffectiveindiversepatientpopulations.32ARBs
areusefulalternativesinpatientswithHFwhoareunabletotolerateACEinhibitors.33Sideeffects
ofARBs occurrarelybut includeangioedema, allergic reaction, and rash.Patientsshould notbe
prescribedbothanACEinhibitorandanARBasthisputspatientsathighriskofvasculareventsor
renaldysfunction.
Thedirectrenininhibitorclassconsistsofasingleagent,aliskiren,whichisindicatedsolelyforthe
treatmentofhypertension(seeTable3-4).Itmaybeusedincombinationwithotherantihypertensive
agents; however, combined use with ACE inhibitors or ARBs is contraindicated in patientswith
diabetes and increases the risk of hyperkalemia
34,35
(Food and Drug Administration [FDA] Drug
SafetyCommunication,April2012).
ARNI(sacubitril–valsartan)isadrugcombinationofaneprilysininhibitorplusanARB.ARNIact
bybothblockingeffectsoftherenin–angiotensin–aldosteronesystemandraisinglevelsofpotentially
beneficial endogenous vasoactive peptides. ARNI is particularly useful in patients with HF, as
sacubitril–valsartan reduces all-cause mortality as well as cardiovascular mortality and
hospitalizationrateforHFcomparedwithenalapril(ACEinhibitor).36ARNItherapyalsolikelyhas
beneficialeffectsonrenalfunctionandglucosecontrol,basedonrecentemergingdata.
37-39
Patients
areoftentransitionedfromanACEinhibitororARBtoanARNI.ARNIsshouldnotbeadministered
within36 hours of switching to or from an ACE inhibitor. ARNIs also should not be used with
aliskireninpatientswithdiabetesorreducedrenalfunction(eGFR<60mL/min/1.73m2).
β-Adrenergic antagonists (see Table 3-4) are part of medical regimens that have been proven to
decreasetheincidenceofstroke,MI,andHF.β-Adrenergicantagonistsworkviacompetitiveinhibition
of the effects of catecholamines at β-adrenergic receptors, which decreases heart rate and cardiac
output. These agents also decrease plasmareninandcause a resetting ofbaroreceptors to accept a
lower level of BP. β-Adrenergic antagonists cause release of vasodilatory prostaglandins, decrease
plasmavolume,andmayalsohaveaCNS-mediatedantihypertensiveeffect.
Classes of β-adrenergicantagonists canbe subdivided intothose that are cardioselective, with
primarilyβ1-blocking effects,andthose thatare nonselective,withβ1- and β2-blocking effects. At
low doses, the cardioselective agents can be given with caution to patients with mild chronic
obstructive pulmonary disease, diabetes, or peripheral vascular disease. At higher doses, these
agents lose their β1 selectivity and may cause unwanted effects in these patients. β-Adrenergic
antagonists can also be categorized according to the presence or absence of partial agonist or
intrinsicsympathomimeticactivity(ISA).β-AdrenergicantagonistswithISAcauselessbradycardia
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thando thosewithoutit. In addition,there areagentswith mixed properties having bothα-andβadrenergic antagonist actions (labetalol and carvedilol). Nebivolol is a highly selective βadrenergicantagonistthathasvasodilatorypropertiesthroughanunclearmechanism.
Sideeffectsincludehigh-degreeatrioventricularblock,HF, Raynaudphenomenon,andimpotence.
Lipophilic β-adrenergic antagonists, such as propranolol, have a higher incidence of CNS side
effects including insomnia and depression. Propranolol can also cause nasal congestion. βAdrenergic antagonists can cause adverse effects on the lipid profile; increased triglyceride and
decreased high-density lipoprotein (HDL) levels occur mainly with nonselective β-adrenergic
antagonistsbutgenerallydonotoccurwhenβ-adrenergicantagonistswithISAareused.Pindolol,a
selectiveβ-adrenergicantagonistwithISA,mayincreaseHDLandnominallyincreasetriglycerides.
Sideeffectsoflabetalolincludehepatocellulardamage,posturalhypotension,apositiveantinuclear
antibody (ANA) test, a lupus-like syndrome, tremors, and potential hypotension in the setting of
halothaneanesthesia.Carvedilolappearstohaveasimilarsideeffectprofiletootherβ-adrenergic
antagonists. Both labetalol and carvedilol have negligible effects on lipids. Rarely, reflex
tachycardia may occur due to the initial vasodilatory effect of labetalol andcarvedilol. Since βreceptor density is increased with chronic antagonism, abrupt withdrawal of these agents can
precipitate angina pectoris, increases in BP, and other effects attributable to an increase in
adrenergictone.
Selective α-adrenergic antagonists such as prazosin, terazosin, and doxazosin have replaced
nonselective α-adrenergic antagonists such as phenoxybenzamine (see Table 3-4) inthe treatmentof
essential hypertension. Based on the ALLHAT trial, these drugs appear to be less efficacious than
diuretics, CCBs, and ACE inhibitors in reducing primary end points of CVD when used as
monotherapy.26Sideeffectsoftheseagentsincludea“first-doseeffect,”whichresultsfromagreater
decreaseinBPwiththefirstdosethanwithsubsequentdoses.Selectiveα1-adrenergicantagonistscan
cause syncope, orthostatic hypotension, dizziness, headache, and drowsiness. In most cases, side
effects are self-limited and do not recurwith continued therapy. Selective α1-adrenergic antagonists
mayimprovelipidprofilesbydecreasingtotalcholesterolandtriglyceridelevelsandincreasingHDL
levels. Additionally, these agents can improve the negative effects on lipids induced by thiazide
diureticsandβ-adrenergicantagonists.Doxazosinspecificallymaybe lesseffectiveatloweringSBP
than thiazide diuretics and may be associated with a higher risk of HF and stroke in patients with
hypertensionandatleastoneadditionalriskfactorforcoronaryarterydisease(CAD).
26
Centrallyactingadrenergicagents(seeTable3-4)arepotentantihypertensiveagents.Inadditionto
itsoraldosageforms,clonidineisavailableasatransdermalpatchthatisappliedweekly.Sideeffects
may include bradycardia, drowsiness, dry mouth, orthostatic hypotension, galactorrhea, and sexual
dysfunction.Transdermalclonidinecausesarashinupto20%ofpatients.Theseagentscanprecipitate
HFinpatientswithdecreased leftventricular function,andabruptcessationcanprecipitateanacute
withdrawal syndrome (AWS) of elevated BP, tachycardia, and diaphoresis. Methyldopa produces a
positive directantibody (Coombs) testin upto25% of patients, butsignificanthemolytic anemia is
much less common. If hemolytic anemia develops secondary to methyldopa, the drug should be
withdrawn.Severecasesofhemolyticanemiamayrequiretreatmentwithglucocorticoids.Methyldopa
alsocausespositiveANAtestresultsinapproximately10%ofpatientsandcancauseaninflammatory
reaction in the liver that is indistinguishable from viral hepatitis; fatal hepatitis has been reported.
Guanabenz andguanfacinedecreasetotal cholesterol levels,andguanfacinecanalso decrease serum
triglyceridelevels.
Direct-acting vasodilators are potent antihypertensive agents (see Table 3-4) now reserved for
refractoryhypertensionorspecificcircumstancessuchastheuseofhydralazineinpregnancy.
Hydralazineincombinationwithnitratesisusefulintreatingpatientswithhypertensionandspecific
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subsets of patients with HF with reduced ejection fraction (see Chapter 5, Heart Failure and
Cardiomyopathy). Side effects of hydralazine therapy may include headache, nausea, emesis,
tachycardia,andposturalhypotension.AsymptomaticpatientsmayhaveapositiveANAtestresult,
and a hydralazine-induced systemic lupus-like syndrome may develop in approximately 10% of
patients. Patients at greater risk for the latter complication include those treated with excessive
doses (e.g., >400 mg/d), those with impaired renal or cardiac function, and those with the slow
acetylation phenotype. Hydralazine should be discontinued if clinical evidence of a lupus-like
syndromedevelopsanda positiveANAtestresultis present.Thesyndromeusuallyresolveswith
discontinuationofthedrug,leavingnoadverselong-termeffects.
Side effects of minoxidil include weight gain, hypertrichosis, hirsutism, ECG abnormalities, and
pericardialeffusions.
Reserpine, guanethidine, and guanadrel (see Table 3-4) were among the first effective
antihypertensive agents available. Currently, these drugs are not regarded as first- or second-line
therapybecauseoftheirsignificantsideeffects.Sideeffectsofreserpineincludeseveredepressionin
approximately 2% of patients. Sedation and nasal stuffiness also are potential side effects.
Guanethidinecancausesevereposturalhypotensionthroughadecreaseincardiacoutput,adecreasein
peripheral resistance,andvenous pooling inthe extremities.Patientswhoare receiving guanethidine
with orthostatic hypotension should be cautioned to arise slowly and to wear support hose.
Guanethidinecanalsocauseejaculatoryfailureanddiarrhea.
ParenteralantihypertensiveagentsareindicatedfortheimmediatereductionofBPinpatientswith
hypertensive emergencies. Judicious administration of these agents (Table 3-5) may also be
appropriateinpatientswithhypertensioncomplicatedbyHForMI.Thesedrugsarealsoindicatedfor
individualswhohaveperioperativeseverehypertensionorneedanemergencysurgery.Ifpossible,an
accurate baseline BP should be determined before the initiation of therapy. In the setting of
hypertensiveemergency,thepatientshould beadmittedtoanintensivecareunitforclosemonitoring,
andanintra-arterialmonitorshouldbeusedwhenavailable.Althoughparenteralagentsareindicated
asafirst-linetreatmentinhypertensiveemergencies,oralagentsmayalsobeeffectiveinthisgroup;the
choice of drug and route of administration must be individualized. If parenteral agents are used
initially, oral medicationsshould be administered shortly thereafter tofacilitate rapid weaning from
parenteraltherapy.
Sodiumnitroprusside,adirect-actingarterialandvenousvasodilator,isthedrugofchoiceformost
hypertensive emergencies (see Table 3-5). It reduces BP rapidly and is easily titratable, and its
action is short lived when discontinued. Patients should be monitored very closely to avoid an
exaggeratedhypotensiveresponse.Therapyformorethan48–72hourswithahighcumulativedose
or renal insufficiency may cause accumulation of thiocyanate, a toxic metabolite. Thiocyanate
toxicitymay cause paresthesias, tinnitus, blurred vision, delirium, or seizures. Serum thiocyanate
levels shouldbe kept at <10 mg/dL. Patientsonhigh doses (>2–3 µg/kg/min) or those with renal
dysfunctionshouldhaveserumlevelsofthiocyanatedrawnafter48–72hoursoftherapy.Inpatients
with normal renal function or those receiving lower doses, levels can be drawn after 5–7 days.
Hepatic dysfunction may result in accumulation of cyanide, which can cause lactic acidosis,
dyspnea, vomiting, dizziness, ataxia, and syncope. Hemodialysis should be considered for
thiocyanate poisoning. Nitrites and thiosulfate can be administered intravenously for cyanide
poisoning.
TABLE3-5
PARENTERALANTIHYPERTENSIVEDRUGPREPARATIONS
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Drug Administration Onset Duration
of
Action
Dosage AdverseEffectsand
Comments
Fenoldopam IVinfusion <5min 30min 0.1–
0.3µg/kg/min
Tachycardia,nausea,
vomiting
Sodium
nitroprusside
IVinfusion Immediate 2–3min 0.5–
10µg/kg/min
(initialdose,
0.25µg/kg/min
foreclampsia
andrenal
insufficiency)
Hypotension,nausea,
vomiting,
apprehension;riskof
thiocyanateand
cyanidetoxicityis
increasedinrenaland
hepaticinsufficiency,
respectively;levels
shouldbemonitored;
mustshieldfromlight
Diazoxide IVbolus 15min 6–12h 50–100mg
q5–10min,up
to600mg
Hypotension,
tachycardia,nausea,
vomiting,fluid
retention,
hyperglycemia;may
exacerbatemyocardial
ischemia,heartfailure,
oraorticdissection
Labetalol IVbolus 5–10min 3–6h 20–80mgq5–
10min,upto
300mg
Hypotension,heart
block,heartfailure,
bronchospasm,
nausea,vomiting,scalp
tingling,paradoxical
pressorresponse;may
notbeeffectivein
patientsreceivingα-or
β-antagonists
IVinfusion 0.5–2mg/min
Nitroglycerin IVinfusion 1–2min 3–5min 5–250µg/min Headache,nausea,
vomiting.Tolerance
maydevelopwith
prolongeduse
Esmolol IVbolus 1–5min 10min 500µg/kg/min
forfirst1min
Hypotension,heart
block,heartfailure,
bronchospasm
IVinfusion 50–
300µg/kg/min
Phentolamine IVbolus 1–2min 3–10min 5–10mgq5–
15min
Hypotension,
tachycardia,headache,
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angina,paradoxical
pressorresponse
Hydralazine
(for
treatmentof
eclampsia)
IVbolus 10–20min 3–6h 10–20mg
q20min(ifno
effectafter
20mg,try
anotheragent)
Hypotension,fetal
distress,tachycardia,
headache,nausea,
vomiting,local
thrombophlebitis.
Infusionsiteshouldbe
changedafter12h
Methyldopate
(for
treatmentof
eclampsia)
IVbolus 30–60min 10–16h 250–500mg Hypotension
Nicardipine IVinfusion 1–5min 3–6h 5mg/h,
increasedby
1–2.5mg/h
q15min,upto
15mg/h
Hypotension,
headache,tachycardia,
nausea,vomiting
Clevidipine IVinfusion 2–4min 5–15min 1–2mg/h,
doubledose
every90sup
to16mg/h
Hypotension,reflex
tachycardia
Enalaprilat IVbolus 5–15min 1–6h 0.6255mg
q6h
Hypotension
NitroglyceringivenasacontinuousIVinfusion(seeTable3-5)maybeappropriateinsituationsin
whichsodium nitroprussideisrelativelycontraindicated,suchas inpatientswith severe coronary
insufficiency or advanced renal or hepatic disease. It is the preferred agent for patients with
moderate hypertension in the setting of acute coronary ischemia or after coronary artery bypass
surgerybecauseofits more favorable effects onpulmonary gasexchange andcollateral coronary
bloodflow.InpatientswithseverelyelevatedBP,sodiumnitroprussideremainstheagentofchoice.
Nitroglycerinreducespreload more thanafterload andshould be used withcautionor avoided in
patientswhohaveinferiorMIwithrightventricularinfarctionandareoftendependentonpreloadto
maintaincardiacoutput.
Labetalolcanbeadministeredparenterally(seeTable3-5) inhypertensive crisis,eveninpatients
intheearlyphaseofanacuteMI,andisthedrugofchoiceinhypertensive emergenciesthatoccur
duringpregnancy.Whengivenintravenously,theβ-adrenergicantagonisteffectisgreaterthantheαadrenergicantagonisteffect.Nevertheless,symptomaticposturalhypotensionmayoccurwithIVuse;
thus,patientsshouldbetreatedinasupineposition.Labetalolmaybeparticularlybeneficialduring
adrenergic excess(e.g.,clonidinewithdrawal,pheochromocytoma, post–coronarybypassgrafting).
Becausethehalf-lifeoflabetalolis5–8hours,intermittentIVbolusdosingmaybepreferabletoIV
infusion.IVinfusioncanbediscontinuedbeforeorallabetalolisbegun.WhenthesupineDBPbegins
to rise, oral dosing can be initiatedat 200 mgPO, followed in 6–12 hours by 200–400 mg PO,
dependingontheBPresponse.
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Esmololis a parenteral, short-acting, cardioselective β-adrenergic antagonist (see Table 3-5) that
canbeusedinthetreatmentofhypertensiveemergenciesinpatientsinwhomβ-blockerintolerance
isaconcern.Esmololisalsousefulforthetreatmentofaorticdissection.β-Adrenergicantagonists
may be ineffective when used as monotherapy in the treatment of severe hypertension and are
frequently combined with other agents (e.g., with sodium nitroprusside in the treatment of aortic
dissection).
NicardipineisaneffectiveIVcalciumchannelantagonistpreparation(seeTable3-5). Sideeffects
include headache, flushing, reflex tachycardia, and venous irritation. Nicardipine should be
administeredviaacentralvenousline.Ifitisgivenperipherally,theIVsiteshouldbechangedq12h.
Fifty percentofthe peakeffect is seenwithinthe first 30 minutes, but the full peakeffect is not
achieveduntilafter48hoursofadministration.Clevidipine,anIVcalciumchannelantagonist,hasa
quickeronsetofactionandshorterhalf-lifethannicardipine.
Enalaprilatis the active de-esterified form of enalapril (see Table3-5) that results from hepatic
conversion after an oral dose. Enalaprilat (as well as other ACE inhibitors) has been used
effectively in cases of severe and malignant hypertension. However, variable and unpredictable
results have also been reported. ACE inhibition can cause rapid BP reduction in hypertensive
patientswith high reninstatessuchas renovascular hypertension,concomitantuseofvasodilators,
and scleroderma renal crisis; thus, enalaprilat should be used cautiously to avoid precipitating
hypotension.TherapycanbechangedtoanoralpreparationwhenIVtherapyisnolongernecessary.
Diazoxide and hydralazine are only rarely used in hypertensive crises and offer little or no
advantage to the agents discussed previously. It should be noted, however, that hydralazine is a
usefulagentinpregnancy-relatedhypertensiveemergenciesbecauseofitsestablishedsafetyprofile.
Fenoldopamisaselectiveagonisttoperipheraldopamine-1receptors,anditproducesvasodilation,
increases renalperfusion,andenhancesnatriuresis.Fenoldopamhasashortdurationofaction;the
eliminationhalf-life is <10 minutes. The drughas importantapplicationas parenteral therapy for
high-risk hypertensive surgical patients and the perioperative management of patients undergoing
organtransplantation.
SPECIALCONSIDERATIONS
Hypertensive emergency and severe asymptomatic hypertension: In hypertensive emergency,
control of acute or ongoing end-organ damage is more important than the absolute level of BP.
Appropriate treatment of hypertensive emergency lowers blood pressure to prevent continued endorgan damage butdoes soslowlyandgraduallytoprevent ischemicdamage.Meanarterial pressure
should be reduced by 10%–20% in the first hour and a further 5%–15% over the next 23 hours.
Exceptionstogradualbloodpressureloweringincludeacuteischemicstroke,acuteaorticdissection,
andintracerebralhemorrhage.
6-8
AprecipitousfallinBPmayoccurinpatientswhoareelderly,volume
depleted,orreceivingotherantihypertensive agents.BPcontrol insevere asymptomatic hypertension
without evidence of end-organ damage can be accomplished more slowly and with use of oral
antihypertensives. Excessive or rapid decreases in BP should be avoided to minimize the risk of
cerebral hypoperfusionor coronaryinsufficiency.Normal BP canbeattained gradually over several
daysastoleratedbytheindividualpatientasthereisnoprovenbenefitfromrapidreductionofblood
pressureinpatientswithsevereasymptomatichypertension.
6,9-11
Aorticdissection
All patients with aortic dissection, including those treated surgically, require acute and chronic
antihypertensive therapy to provide initial stabilization and to prevent complications (e.g.,aortic
rupture, continued dissection). Medical therapy of chronic stable aortic dissection should seekto
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maintain SBP ≤120 mm Hg and heart rate <60 bpm if tolerated.40 Antihypertensive agents with
negative inotropic properties, including calcium channel antagonists, β-adrenergic antagonists,
methyldopa,clonidine,andreserpine,arepreferredformanagementinthepost–acutephase.
β-Blockers are considered the initial drug of choice and should precede vasodilator therapy. βBlockers are effective in lowering the heart rate and counteracting the reflex tachycardia and
increasedinotropyseenwithvasodilatortherapy.IVlabetalolhasbeenusedsuccessfullyasasingle
agentinthetreatment ofacuteaorticdissection.Labetalolproducesadose-relateddecreaseinBP
andlowerscontractility.Ithastheadvantageofallowingfororaladministrationafterthesuccessful
acute stage of dissection management. Esmolol, a cardioselective class intravenous β-adrenergic
antagonist with a very short duration of action, may be preferable, especially in patients with
relative contraindications to β-antagonists. If esmolol is tolerated, a longer-acting β-adrenergic
antagonist should be used. Inpatients who are β-blockade-intolerant,CCBssuchas diltiazem and
verapamilmaybeused.
Vasodilatortherapyincombinationwithβ-blockadeallowsformoreeffectiveandrapidreduction
in BP. Sodium nitroprusside is considered the initial vasodilator drug of choice because of the
predictabilityofresponseandabsenceoftachyphylaxis. Nitroprusside alonecausesanincreasein
left ventricular contractility and subsequent arterial shearing forces, which contribute to ongoing
intimal dissection. Thus, when using sodium nitroprusside, adequate simultaneous β-adrenergic
antagonist therapy is essential. Nicardipine, clevidipine, nitroglycerin, enalaprilat, and
fenoldopammayalsobeused.
The elderlyhypertensive patient(age>65years) is generallycharacterizedby increased vascular
resistance, decreased plasmarenin activity, andgreater LVH than inyounger patients.Often, elderly
hypertensive patients have coexisting medical problems that must be considered when initiating
antihypertensive therapy. SBP <140 mm Hg has been associated with decreased major adverse
cardiovascular events.
41,42
Drug doses should be increased slowly to avoid adverse effects and
hypotension.Diureticsasinitialtherapyhavebeenshowntodecreasetheincidenceofstroke,fatalMI,
andoverall mortality inthis age group.43 Calcium channel antagonists decrease vascular resistance,
havenoadverseeffectsonlipidlevels,andarealsogoodchoicesforelderlypatients.ACEinhibitors
andARBsmaybeeffectiveagentsinthispopulation.
HypertensivepatientsofAfricandescentgenerallyhavealowerplasmareninlevel,higherplasma
volume,andhigher vascularresistancethandoCaucasianpatients.Thus,patients ofAfricandescent
respondwelltodiuretics,particularlythiazidesorthiazide-likediuretics,aloneorincombinationwith
calcium channel antagonists. ACE inhibitors, ARBs, and β-adrenergic antagonists are also effective
agentsinthispopulation,particularlywhencombinedwithadiuretic.
The hypertensive patient with obesity is characterized by more modest elevations in vascular
resistance, higher cardiacoutput,expandedintravascularvolume, andlower plasmareninactivity at
anygivenlevelofarterialpressure.Weightreductionistheprimarygoaloftherapyandiseffectivein
reducingBPandcausingregressionofLVH.
Thediabeticpatientwithnephropathymayhavesignificantproteinuriaandrenalinsufficiency,which
cancomplicate management (see Chapter13, Renal Diseases). Control of BP is the most important
interventionshowntoslowdownadditionallossofrenalfunction.Inthesettingofproteinuria,ACE
inhibitors shouldbe usedasfirst-linetherapybecausetheyhavebeenshowntodecrease proteinuria
and to slow down progressive loss of renal function independent of their antihypertensive effects.
Hyperkalemiaisacommonsideeffectindiabetic patientstreatedwithACEinhibitors, especiallyin
thosewithmoderatetosevere renalimpairment.ARBsare alsoeffectiveantihypertensiveagentsand
have been shownto slow downthe rate ofprogression to ESRD,thussupporting a renal protective
effect.
44
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