PharmacologyAntiHypertensives

NormalregulationofBP
Normalcontrol

BPmaintainedbyregofCOandPVR(atarterioles,postcapillaryvenules(capacitancevessels),andheart),kidneyregulatesintravascularfluidvolume,localreleaseofvasoactivesubstancesfromvascularendothelium(i.e.
endothelin1constricts,NOdilates);baroreceptors(controlledbyautonomicsandreninsystem)coordinateoverallfunctiontomaintainnmlBP;cHTNthesystemis"set"forahigherpressure

baroreceptorsresponsibleforrapidadjustmentsinBP,sympatheticneuronsinmedullaaretonicallyactive,carotidbaroreceptorsarestimulatedbystretchofthevesselwall2*to BP,baroreceptors mula on

PosturalBaroreflex inhibitscentralsympatheticdischarge(oppositeisalsotrue);whensomeonestands,baroreceptorssensethereductioninBPfrompoolingofbloodintheveins>sympatheticdischargeisdisinhibited sympathetic
outflowtoPVR(constrictsarterioles)andCO(directs mofheartandconstric onofcapacitancevessels)
kidneysresponsibleforlongtermBPcontrol,renalperfusionpressurecausesintrarenalredistribu onofbloodflowandreabsorp onofsaltandwaterreninproduc onangiotensinIIproduc on;
Renalresponseto
angiotensinIIcauses1)directconstrictionsofresistancevessels,2)stimulationofaldosteronesynthesisinadrenalcortex( renalNaabsorp onandintravascularbloodvolume);vasopressinreleasedfromposterior
BP
pituitaryregulateswaterreabsorptionbykidneys
DrugClass
DrugExamples
MOA
ClinicalIndications
AdverseEffects
Contraindications
DrugInteractions/Comorbidities
Sympatholytics
block1A.R.onheart,kidney
Cardioselectiveagents1 HR(nega vechronotrope)
selective:
contrac lity(nega veinotrope)
Atenolol,Metoprolol
CO
renalreninsecre on

Blockers

Vasodilatingagents:
Carvedilol,Labetalol,
Nebivolol
AgentscISA:
Pindolol,Acebutolol,
penbutolol

treatsHTNcthefollowingcomorbidities:
Ischemicheartdisease,nondecomensated
heartfailure,dissectingthoracicaneurysm
(notaseffectiveforelderlyorAA)
insevereHTN,usefultopreventreflex
tachythatresultsfromdirectvasodilators

htn
carvedilolandlabetalol:
pheochromocytoma,HTNemergencies,
andclonidinewithdrawalsyndrome
note:HRandCOlessthanotherbeta
arepartialagonists(blockcsome
blockers(greateragonsitthanantagonist
intrinsicsympathomimeticactivity):BP
activityat2)preferredforpa entscbrady
byPVR

carevilolandlabetalolblockand;
nebivololcoupledcNO(release)and
only

TGsandHDL
bronchospasm:useccautioninCOPD
fatigue,coldextremities,canworsen
Raynaud's,vividdreams,impotence,
hyperglycemia
propranolol(nonselective):willmask
hypoglycemiainDM

arrhythmiasorPVD

Esmolol

shorthalflifemakesitpreferredfor
Beta1selectiveblockerthatisrapidly
intraoperativeandpostoperativeHTN,and
metabolizedviahydrolysisbyRBC
HTNemergenicesassociatedctachycardia

1and2blockers
(phenoxybenzamine,
phentolamine)

relaxvascularsmoothmusclesby
Phenoxybenazomine/phentolamine:dx
preventingNEfrominteractingc1
andtxpheochromocytoma
receptorsandblocks2onpresynaptic Phentolamine:addpropranololtotx
clonidinewithdrawalsyndrome
sympatheticautrecptors

1selectiveblocker
(prazosin,doxazosin,
terazosin)

relaxvascularsmoothmusclesby
preventingNEfrominteractingc1
receptors

Prazosin:uselimitedbyseverepostural
hypotension,usefulonlyasaddontotreat
1stdosehypotension,postural
resistanthypertension
hypotension,urinaryincontinence
Doxazosin:sxofbladderou lowtract
obstructionandBPH

Methyldopa

takenupintoadrenergicnerve
convertedtomethylNEinCNS
where2receptorsarestimulatedto
sympathe cou lowtoperiphery

DOCduringpregnancy
usefulinpatientswhocan'ttolerateother
drugs
PVR(variableinHRandCO)

Clonidine(partialagonist)

BPbyCO2*HRandrelaxa on
ofcapacitancevessels,TPR;also
renalvascularresistanceand
HRandCOmorethanmethyldopa
maintenanceofrenalbloodflow
bindstoimidazolinereceptor
NEreleasecentrally

adrenergicblockers
(systemic)

Centrallyacting2
adrenergicagonist

IndirectlydrugmetabolismbyCO
hepa cbloodflow(egdrugschigh
hepaticextractionratio:lidocaine,
decompensatedheart morphine,sodiumpentothal,ASA,
failure
propranolol)
Additiveeffectscverapamil,lidocaine,&
asthma
othernegativeinotropes(ifverapamil
andBblockergiventogether:canbe
fatal)

reflextachycardia(blocks,1stdose
hypotension,posturalhypotension,
urinaryincontinence

note:ex:doxazosinhaslong1/2life(10
12hrs)

MCsedation(atonsetoftx)depression,hepatitis,immune
hemolyticanemia(positiveCoomb'stest),fever,nightmares,
note:advantageiscausesreduc onin
lactation;longtermtx:persistentmentallassitudeandimpaired renalvascularresistance
concentration

drymouthandsedation
ptsatriskfor
DONOTstopsuddenlywillcauselife
depression,
threateningHTNcrisis2*symph
concomitantcTCAs
activity

causesshortBP(directs mof
peripheralreceptors)prolonged
hypotension(adrenoceptorsinmedulla)

longactingdrugs:
ACEinhibitors
trandolapril,ramipril=qd
(angiotensin
dosing
convertingenzyme)
"pril"
allendin"sartan"
losartan,candesartan,
AngiotensinReceptor
eprosartan,irbesartan,
Blockers(ARBs)
olmesartan,telmisartan,
valsartan
DirectRenin
Inhibitors

Aliskiren(tekturna)

Dihydropyridines(endin
"dipine")
CalciumChannel
Blockers(CCB)
briefhere,morelater verapamil

SodiumNitroprusside

mostlyvasodilationandTPR(blocks
Cachannelsonarteriolarsmooth
muscles);minimalcontrac lity
effectiveinelderlypts,AA,Caribbean
riskofMIandstrokeinptscHTN
slowsAVnodalconduction
atrialflutter(combinedcquinine)
cardiaccontrac lity
angina

generallywelltolerated
shortacting(nifedipinecapsules):
flushing,HA,angina
pedaledema
verapamil:exacerbateheartfailure,
constipation

diltiazem

cardiaccontrac lity
vasodilationandTPR

dilatesbotharterialand
veins

cyanidetoxicitycprolongeduse
undergoesdegradationreleasingNO severehypertensiveemergencies(e.g.
hypertensiveencephalopathy)inICUviaIV metabolicacidosis,arrhythmias,
PVRandvenousreturn
mustbegivencblocker
andsevereheartfailure
hypotension

arteriolesonly,notveins

Hydralazine

IVverapamil:cancause
circulatorycollapsec
concurrentblockers

parenteralvasodilators

activatesK+channelsandrelax
vascularsmoothmusclesrapidin
SVRandBPbutsubstantialtachycardia
andCO

Diazoxide

Minoxidil

Reninangiotensinaldosteronesystemantagonists
preferredfor:whiteyoungorAsian
1stdosehypotension,drycough&
pregnancy(devdefects
hypertensivepatient,plasmarenin
competitiveinhibitorofACEinhibit
beneficialdruginteractions:K+wasting
mortalityin:acuteMI,CHF,riskofCV angioedema(bradykinin),dysgeusia, ifgivenin2nd,3rd)
diuretic(loopdiuretic,thiazidediuretics)
synthesisofangiotensinIIand
anemia(EPO),serumK+,
b/lrenalartery
disease
badinteractions:K+supplements,allK+
accumulationofbradykinin
renalprotectiveinchronickidneydisease hypoglycemia,fxnalrenalfailurechxof stenosis,renalfailure,
sparingdiuretics,NSAIDs,ARBs
circula nglevelsofaldosterone
andchypertensiveptscdiabetic
renalstenosis
angioedema
neuropathy
inhibitsangiotensin2receptors(AT1,
1stdosehypotension(lisinopril)
riskofcough/angioedemaofACE
AT2)
givenighttimedose
sameasabove,effectiveafteracuteMI,
sameasabove
aldosteronelevels
serumK+(<ACEtho),otherwise
heartfailure
plasmavolumeandTPR
sameasabove
noeffectonbradykinin
angioedema,hyperkalemia,
hypotension,diarrhea,GI;hassameAE pregnancyornursing
asaboveaswell
PeripheralvasodilatorsworkbestincombowithdrugthatwillopposecompensatoryCVresponse
cautionwithischemicheartdisease2*toreflextachycardia

excessive

prodrugthatworksviaasulfate
metaboliteac vatesK+channels
andrelaxvascularsmoothmuscles

severerefractoryhypertension
combinecblockerandloopdiuretic

HA,sweating
hypertrichosis,hirsutismand
coarsenessoffacialfeatures(F>M)

unclear,directvasodilatoractionon
vascularsmoothmuscle;
usuallycombinedwithotherdrugs

severehypertensionduringpregnancy
(nifedipineispreferredbysome)

HA,flushing,tachycardia,fluid
retention
longtermtherapycdosesmycause
SLElikesxinsomepts

Oralvasodilators

Fenoldopam
Lifestyle
ChronicalcoholintakecorrelatescHTN,consumptionresistancetoan hypertensivemedssecondarytobioavailabilityofan hypertensivedrugs
transientinBP2*toeectofnico neonautonomicganglia,riskfordevelopingsustainedhypertension,atherogenic
VisceralobesitycorrelatescHTN,if10%idealweightthen10kgweightloss520mmHgdropinsystolicBP,waisttohipra oimportantindex
aerobicexerciseuseful,HRandconcentra oncircula ngcatecholamine's,HDL,ANPrelease
caloricrestrictionandfruitsandvegetablesuseful
stresshormones(cortisol,NE,epi)arereleaseandcouldBP,relaxa onstateusefultoBP
BestUse(inorderLefttoRight)
Generalorderofuse
Diuretics(thiazides)
betablockers

Alcohol
CigaretteSmoking
Weight
RegularExercise
Dietarychoices
Relaxation

1stlineforuncomplicatedHTN
Diabetes
Peripheralneuropathy
Elderly

Thiazides
ACEinhibitors
ACEinhibitors
diuretics

ARBs

CCBs(nondihydropyridine)

thiazide

ACEI

CCBs

noalphaorbetablockers

AfricanAmerican
youngwhite
exertionalangina
prinzmetal'svariant
Pregnancy
dyslipidemia
chronickidney
Migrainecephalgia
BPH
priorMI
heartfailure
Avoids
DrugClass
General

LoopDiuretics
(Highceiling)

Thiazides

DrugExamples

diuretics
betablockers
betablockers
CCB
Methyldopa
alphablockers
ACEI(unlessb/lstenosis)
betablockers
alpha1selectiveblockers
betablockers
ACEI(ARB)
Gout:thiazides
MOA

CCB
ACEI
orCCB(notboth!)
NifedipineorHydralazine
ACEI(ARBs)

ifpreeclampsia:labetalol
CCBs

Indapamide

nondihydropyridineCCBs
ACEI
diuretics
aldosterone
betablockers
Depression:Centralalphaagonists,betablockers
Asthma:betablockers
Diuretics(Naexcre on,rateofurineflow)
ClinicalIndications
AdverseEffects
Contraindications

circulatoryvolume,CO,andmeanarterialpressure;mosteec veinpa entscmildtomoderateHTNwhohavenormalrenalfxn,1015mmHg

inhibitsNa/K/2Cltransporter(TALthick Acutepulmonaryedema,edemaof
Furosemide(lasix),
ascendinglimb)
nephroticsyndrome,HTN(2*tothiazides
Ethacynicacid,Toresmide, reabsorp onofdivalentca ons
insufficiency),CHF,severehypercalcemia
Bumetanide
(Mg,Ca)
(combinecisotonicsaline),urineflowin
SignificantKwasting
drugoverdose

hypokalemia,hypomagnesaemia(
riskforarrhythmias);hypochloremic
metabolicalkalosis(H+,K+depletion)
hyperuricemiagouta acks
ototoxicity(highdosesalter
endolymph)

Hydrochlorothiazide
(HCTZ),chlorothiazide,
chlorthlidone,indapmide

bestinitialtherapyforuncomplicated
HTN,heartfailure,hepaticcirrhosis,
inhibitsNaClsymportintheDCT
nephroticsyndrome,chronicliverfailure,
onlythiazideshavesignificanteffecton
acuteglomerulonephritis,nephrogenic
thissymport
diabetesinsipidus,calciumnephrolithiasis
andosteoporosis

amiloride
triameterene

commonforboth:N/V
amiloride:diarrhea,HA
Usedincombinationwithotherdiureticsto triameterne:legcrampsanddizziness
lumennega vetransepithelial
voltageexcre onrateofK+,H+, curtailK+lossduringtreatmentofedema riskoflifethreatening:contraindicated
associatedwithCHFand/orhypertension inptscrenalfailureortakingACEI,
Ca,Mg
AmilorideblocksLi+transportinthe
antikaliureticactiontooffsetthe
otherK+sparingdiuretic,K+
excretionofK+andH+byK+wasting collectingtubulesandisthereforeusedto supplement,pentamidine,
treatlithiuminducednephrogenic
diuretics
trimethoprim
lowimpactonNa+excretion
Triamtereneisaweakfolicacid
diabetes
antagonistandcanexacerbate
megaloblastosis

K+sparingdiuretics

postmenopausal
osteopenicwomen

hypokalemicmetabolicalkalosisand
hyperuricemia,hyperlipidemia(total
cholesterolandLDL),impaired
carbohydratetolerance,quinidine
inducestorsadesdepointes

Hyperkalemia,Impotence,decrease
libido,hirsutism,gynecomastia,
Inhibitsmineralocorticoidreceptor
Spironolactone:diureticofchoiceinptsc deepeningofthevoiceandmenstrual
Aldosteroneantagonists:
(MR)inepithelialcellsoftheDCTand
hepaticcirrhosis,PrimaryAldosteronism, irregularities;diarrhea,gastritis,gastric patientswithgastric
Eplerenone(Inspra)and
CT
ulcers
bleedingandpepticulcers;
Refractoryedemaassociatedwith
Spironolactone(Aldactone) Conservepotassiumattheexpenseof
Spironolactonemaycauseskinrashand
secondaryhyperaldosteronism
sodium
itsCNSeffectsmayincludedrowsiness,
ataxia,lethargy,confusionandHA

Osmoticdiuretic

Mannitol

waterexcre oninpreferenceto
sodiumexcretion;majoreffectinPCT intracranialhypertension
anddescendinglimbofHenle

DrugInteractions
eec veinAAandelderly(salt
sensitive)
note:generallytoopotentandshortlived
foruseasantihypertensiveagents;but
usefulinptscrenalinsufficiencywhodo
notrespondtootherdiuretics

mostcommonlyuseddiureticinHTN

Amilorideisexcretedintactintheurine
Triamtereneundergoesextensivehepatic
transformationcautioninbothhepatic
andrenalinsufficiency