Antihypertensive drugs

Pharmacology of antihypertensive drugs

1. AntihypertensiveDrugs
Dr. Ajay Kumar, M.Pharm., Ph.D.,

2. Etiology ofHypertension
•Aspecificcauseofhypertensionestablishedin
only 10–15% of patients.
•Patients in whom no specific cause of hypertension are
said to have essential or primary hypertension.
•Patients with a specific etiology are said to have
secondary hypertension.
•Geneticfactors,psychologicalstress,and
environmentalanddietaryfactorsascontributingto
thedevelopmentofhypertension.Theheritabilityof
essentialhypertensionisestimatedtobeabout30%.

3. Classification of hypertension on the
basis of blood pressure

4. Normal Regulation of BloodPressure
Accordingtothehydraulicequation,arterialbloodpressure
(BP)isdirectlyproportionatetotheproductoftheblood
flow(cardiacoutput,CO)andtheresistancetopassageof
bloodthroughprecapillaryarterioles(peripheralvascular
resistance,PVR)
•BP = CO ×PVR

5. Blood pressure is maintainedby
•Moment-to-moment regulationofcardiacoutput
andperipheralvascularresistanceexertedatthree
anatomicsitesarterioles,postcapillary
(capacitance vessels), andheart.
KidneyBaroreflexesmediated by autonomic
nerves
•(combinationwithhumoralmechanisms, including
the renin-angiotensinaldosteronesystem)
•Local release of vasoactivesubstances

6. Antihypertensiveagents
•Diuretics
–Thiazides: Hydrochlorothiazide, Chlorthalidone,
Indapamide
–High ceiling: Furosemide, Torsemide, ethacrynic acid.
–K+ Sparing: Spironolactone, Amiloride
•ACE inhibitors
–Captopril,Enalapril,Lisinopril,Perindopril,
Ramipril, Fosinopril, etc.
•Angiotensin (AT1 receptor) blockers: Losartan, Candesartan,
Irbesartan, Valsartan, Telmisartan
•Direct renin inhibitor: Aliskiren
•β Adrenergic blockers: Propranolol, Metoprolol, Atenolol,
etc.

7. Antihypertensiveagents
•Calcium channel blockers
–Verapamil, Diltiazem, Nifedipine, Felodipine, Amlodipine, Nitrendipine,
Lacidipine, etc.
blockers: Prazosin, Terazosin, Doxazosin
•β + α Adrenergic blockers: Labetalol, Carvedilol
•α-Adrenergic
Phentolamine, Phenoxybenzamine
•Central sympatholytics: Clonidine, Methyldopa
•Vasodilators
–Arteriolar: Hydralazine, Minoxidil, Diazoxide
–Arteriolar + venous: Sodium nitroprusside
•Others:Adrenergic neuroneblockers(Reserpine,
Guanethidine, etc.), Ganglion blockers (Pentolinium, etc.)

8. Sites of action of the major
classes of antihypertensive
drugs

9. Diuretics
•Thiazidediuretics:

10. Diuretics
•Loopdiuretics:
•Inhibitorsofepithelialsodiumtransportatthelate
distalandcollectingducts(furosemide,and
ethacrynicacid)orantagonizingaldosteronereceptor
(spironolactone,andeplerenone)andreduce
potassiumlossintheurine.
•Aldosteroneantagonistshavetheadditionalbenefitof
diminishingthecardiacremodelingthatoccursin
heartfailure.

11. Diuretics
•Loopdiuretics:
•Theloopdiureticsactpromptlybyblockingsodium
andchloridereabsorptioninthekidneys,evenin
patientswithpoorrenalfunctionorthosewhohave
notrespondedtothiazidediuretics.Loopdiuretics
causedecreasedrenalvascularresistanceand
increasedrenalbloodflow.

12. Diuretics
•K+Sparing:
•potassium-sparingdiuretics(spironolactone,and
eplerenone)arecompetitiveantagoniststhateither
competewithaldosterone,ordirectlyblock
epithelialsodiumchannel(amiloride).

13. ACEinhibitors
Renin
Inhibitors
ACE
Inhibitors
Angiotensin
blockers

14. ACEinhibitors
•TheACEinhibitors,arerecommendedasfirst-line
treatmentofhypertensioninpatientswithavariety
ofcompellingindications,includinghighcoronary
diseaseriskorhistoryofdiabetes,stroke,heart
failure,myocardialinfarction,orchronickidney
disease.

15. ACEinhibitors
•ACEisalsoresponsibleforthebreakdownof
bradykinin,apeptidethatincreasesthe
productionofnitricoxideandprostacyclinby
thebloodvessels.Bothnitricoxideand
prostacyclinarepotentvasodilators.

16. ACEinhibitors
•ACEinhibitorsdecreaseangiotensinIIandincrease
bradykininlevels.Vasodilationisresultofdecreased
vasoconstriction(fromdiminishedlevelsof
angiotensinII)andenhancedvasodilation(from
increasedbradykinin).Inhibitorsalsodecrease
thesecretionofaldosterone,resultingin
decreasedsodium.
•ByreducingcirculatingangiotensinIIlevels,ACE
water retention.
•ACE inhibitorsreduce bothcardia
preload and afterload, thereby decreasing cardiac
work.

17. ACEinhibitors
Comparative features of some ACEinhibitors

18. ACEinhibitors
AdverseeffectsofACEinhibitors:
•TheadverseeffectprofileofallACEinhibitorsis
similar.Captopriliswelltoleratedbymostpatients,
especiallyifdailydoseiskeptbelow150mg.
•Hypotension:AninitialsharpfallinBPoccurs
especiallyindiuretictreatedandCHFpatients
•Hyperkalaemia
•Cough
•Rashes,urticaria
•Angioedema

19. ACEinhibitors
Adverse effects of ACEinhibitors:
•Dysgeusia/parageusia
•Foetopathic
•Headache, dizziness, nausea and bowelupset
•Granulocytopenia and proteinuria (rareADR)
•Acute renalfailure

20. ACEinhibitors
Advantages of ACEinhibitor:
•Freeofpostural hypotension
•Electrolytes disturbances, feeling of weakness and
CNS effects
•Safetyinasthmatics,diabeticsandperipheral
vasculardiseasepatients
•Long-termACEinhibitortherapyhasthepotential
toreduceincidenceoftype2diabetesinhighrisk
subjects
•No rebound hypertension on withdrawal

21. ACEinhibitors
AdvantagesofACEinhibitor:
•Nohyperuricaemia,nodeleteriouseffectonplasma
lipidprofile
•ACEinhibitorsarethemosteffectivedrugsfor
preventingsuddencardiacdeathinpost-infarction
patients.However,theyarelesseffectivefor
primaryprophylaxisofMIandforpreventingleft
ventricularhypertrophy.

22. Uses of ACEinhibitors
•Hypertension:TheACEinhibitorsarefirstlinedrugsinall
gradesofhypertension,buttheangiotensinreceptorblockers
(ARBs)havenowsurpassedtheminpopularity.
•CongestiveHeartFailure(CHF):ACEinhibitorscause
botharteriolarandvenodilatationinCHFpatients;reduce
afterloadaswellaspreload.
•Myocardialinfarction:Long-termACEinhibitortherapy
reducesrecurrentMI.
•Prophylaxisinhighcardiovascularrisksubjects:ACE
inhibitorsareprotectiveinhighcardiovascularrisksubjects
evenwhenthereisnoassociatedhypertensionorleft
ventriculardysfunction.ACEinhibitorsmayimproved
endothelialfunction.

23. Uses of ACEinhibitors
•Diabeticnephropathy:ProlongedACEinhibitor
therapyhasbeenfoundtopreventordelayend-
stagerenaldiseaseintypeIaswellastypeII
diabetics.
•Nondiabeticnephropathy:ACEinhibitorsreducing
proteinuriabydecreasingpressuregradientacross
glomerularcapillariesaswellasbyaltering
membranepermeability.
•Sclerodermacrisis:ThemarkedriseinBPand
deteriorationofrenalfunctioninsclerodermacrisis
ismediatedbyAngII.ACEinhibitorsproduce
improvementandarelifesavinginthiscondition.

24. Angiotensin antagonists(ARBs)
•Angiotensinantagonists:losartan,candesartan,
valsartan,telmisartan,olmesartanandirbesartan.
•TheirpharmacologicaresimilartothoseofACE
inhibitors.
•ARBsproducearteriolarandvenousdilationand
blockaldosteronesecretion,thusloweringblood
pressureanddecreasingsaltandwaterretention.
•ARBsdonotincreasebradykininlevels.
•ARBsmaybeusedasfirst-lineagentsforthe
treatmentofhypertension,especiallyinpatients
withacompellingindicationofdiabetes,heart
failure,orchronickidneydisease.

25. Direct renininhibitor
•Aselectiverenininhibitor,aliskirendirectlyinhibits
reninand,thus,actsearlierintherenin–
angiotensin–aldosteronesystemthanACEinhibitors
orARBs.
•Itlowersbloodpressureaboutaseffectivelyas
ARBs,ACEinhibitors,andthiazides.Aliskiren
shouldnotberoutinelycombinedwithanACE
inhibitororARBs.
•Aliskirencancausediarrhea,especiallyathigher
doses,andcanalsocausecoughandangioedema,
butprobablylessoftenthanACEinhibitors.
•Aliskireniscontraindicatedduringpregnancy.

26. β-adrenergicblockers
•β-adrenergicblockersaremildantihypertensivesand
donotsignificantlylowerBPinnormotensives.In
stage1casesofhypertensivepatients(30-40%),β-
adrenergicblockersareusedalone.

27. β-adrenergicblockers
Propranolol
•Propranololisafirstβblockershowedeffectivein
hypertensionandischemicheartdisease.
•Propranololhasnowbeenlargelyreplacedby
cardioselectiveβblockerssuchasmetoprololand
atenolol.
•Allβ-adrenoceptor-blockingagentsareusedlowering
bloodpressureinmildtomoderatehypertension.
•Inseverehypertension,βblockersusefulinpreventing
thereflextachycardiathatoftenresultsfromtreatment
withdirectvasodilators.

28. β-adrenergicblockers
Metoprolol&Atenolol
•Metoprololandatenolol,whicharecardioselective,arethemost
widelyusedβblockersinthetreatmentofhypertension.
•Metoprololisatenololisinhibitingstimulationofβ1
adrenoceptors.
•Sustained-releasemetoprololiseffectiveinreducing
mortalityfromheartfailureandisparticularlyusefulin
patientswithhypertensionandheartfailure.
•Atenololisreportedmetoprololintobelesseffectivethan
preventingthecomplicationsofhypertension.

29. α-Adrenergicblockers
Prazosin,terazosin,anddoxazosin
•Prazosin is a prototype α
1-adrenergic blocking agent.
•Terazosinanddoxazosinarelong-actingcongenersof
prazosin
•Alphablockersreducearterialpressurebydilatingboth
resistanceandcapacitancevessels.
Otheralpha-adrenoceptorblockingagents
•phentolamine(reversiblenonselectiveα-adrenergic
antagonist)andphenoxybenzamine(non-selective,
irreversiblealphablocker)areusefulindiagnosisand
treatmentofpheochromocytoma.

30. Centrally acting adrenergicdrugs
Clonidine
•Clonidineactscentrallyasanα
2agonisttoproduce
inhibitionofsympatheticvasomotorcenters,decreasing
sympatheticoutflowtotheperiphery.Thisleadstoreduced
totalperipheralresistanceanddecreasedbloodpressure.At
present,itisoccasionallyusedincombinationwithadiuretic.
Methyldopa
•Itisanα
2agonistthatisconvertedtomethylnorepinephrine
centrallytodiminishadrenergicoutflowfromtheCNS.Itis
mainlyusedformanagement ofhypertensionin
pregnancy,whereithasarecordofsafety.

31. Vasodilators
•Hydralazine/Dihydralazineandminoxidilnotused
asprimarydrugstotreathypertension.These
vasodilatorsactbyproducingrelaxationofvascular
smoothmuscle,primarilyinarteriesandarterioles.
Thisresultsindecreasedperipheralresistance.
•Bothagentsproducereflexstimulationoftheheart,
resultinginthecompetingreflexesofincreased
myocardialcontractility,heartrate,andoxygen
consumption.
•Hydralazineisanacceptedmedicationforcontrolling
bloodpressureinpregnancyinducedhypertension.
Thisdrugisusedtopicallytotreatmalepatternbaldness.

32. Treatment ofhypertension
•Hypertensiveemergency:
•Itis rarebutlife-threateningcondition(systolic
BP>180mmHgordiastolicBP>120mmHgwithevidence
ofimpendingorprogressivetargetorgandamagesuchas
stroke,myocardialinfarction).
•Avarietyofmedicationsareused,includingcalciumchannel
blockers(nicardipineandclevidipine),nitricoxidevasodilators
(nitroprussideandnitroglycerin),adrenergicreceptor
antagonists(phentolamine,esmolol,andlabetalol),the
vasodilatorhydralazine,andthedopamineagonist
fenoldopam.

33. Treatment ofhypertension
•Resistant hypertension:
It is define das blood pressure thatremains elevated
despite administration of an optimal three-drug
regimen that includes a diuretic.
•The most common causes of resistant hypertension
poor compliance
excessive ethanol intake
concomitant conditions (diabetes, obesity, sleep
apnea, hyperaldosteronism, high salt intake, metabolic
syndrome)

34. Treatment ofhypertension
•SummaryofWHO-ISHandBritishHypertension
Society(BHS)2004,guidelines
–ExceptforstageIIhypertension,startwithasinglemost
appropriatedrug
–FollowABCDrule(A—ACEinhibitor/ARB;B—β
blocker;C—CCB,D—diuretic).WhileAand(insome
cases)Barepreferredinyoungerpatients(<55years),C
andDarepreferredintheolder(>55years)forthestep
Iormonotherapy.
–Initiatetherapyatlowdose;ifneededincreasedose
moderately.
–Ifonlypartialresponseisobtained,addadrugfrom
anothercomplimentaryclassorchangetolowdose
combination

35. Treatment ofhypertension
•SummaryofWHO-ISHandBritishHypertension
Society (BHS) 2004, guidelines
–If no response, change to a drug from another
class, or low dose combination from other classes
–In case of side effect to the initially chosen drug,
either substitute with drug of another class or
reduce dose
–Majority of stage II hypertensives are started on a 2
drug combination

36. Treatment of hypertension in patients with
concomitant diseases

37. Combinations to beavoided
Combination Possible effects
An α or β adrenergic blocker
with clonidine
Apparent antagonism of
clonidine action has been
observed.
Hydralazine with a
dihydropyridine (DHP) or
prazosin
haemodynamic action
Verapamil or diltiazem with β
blocker
bradycardia, A-V block can
Methyldopa with clonidine or any two drugs of the same class

38. Antihypertensives &pregnancy
Antihypertensives to be avoided
during pregnancy
Antihypertensives found safer
during pregnancy
ACE inhibitors, ARBs: Risk of foetal
damage, growth retardation.
Hydralazine Methyldopa
Diuretics: increase risk of foetal
wastage, placental infarcts,
miscarriage, stillbirth.
Dihydropyridine CCBs: if used,
they should be discontinued before
labour as they weaken uterine
contractions.
Nonselective β blockers: Propranolol
cause low birth weight, decreased
placental size, neonatal bradycardia
and hypoglycaemia.
Cardioselective β blockers and those
with ISA, e.g. atenolol, metoprolol,
pindolol, acebutolol: may be used if
no other choice.
Sod. nitroprusside: Contraindicated
in eclampsia.
Prazosin and clonidine-provided that
postural hypotension can be avoided.

39. Possiblecombinationofantihypertensivedrugs:Continuousgreenline
(preferentialcombinations);dottedgreenline(acceptablecombinations);dotted
blackline(lessusualcombinations);redline(unusualcombinations).
Ref: Póvoa R, Barroso WS, Brandão AA, et al. I brazilian position paper on
antihypertensive drug combination. Arq Bras Cardiol. 2014;102(3):203-10.

40. Thank
you