DOC-20240719-WA0002..pdf B pharmacy 3 Rd year

Antihypertensive drugs

1. Antihypertensive Drugs
S. Parasuraman, M.Pharm., Ph.D.,
Senior Lecturer, Faculty of Pharmacy,
AIMST University NISHANT SINGH KATIYAR

2. Etiology of Hypertension
•A specific causeofhypertension establishedinonly
10–15%ofpatients.
•Patientsinwhomnospecificcauseofhypertensionare
saidtohaveessentialorprimaryhypertension.
•Patients with a specific etiology are saidtohave
secondaryhypertension.
•Genetic factors, psychological stress, and
environmental and dietary factorsascontributingto
the developmentofhypertension. The heritabilityof
essentialhypertensionisestimatedtobeabout30%.

3. Classification of hypertension on the
basis of blood pressure
JNC 7;
2003

4. Normal Regulation of Blood Pressure
Accordingtothehydraulicequation,arterialbloodpressure
(BP) is directly proportionatetothe productofthe blood
flow (cardiac output, CO) and the resistancetopassageof
blood through precapillary arterioles (peripheral vascular
resistance,PVR)
•BP=CO×PVR

5. Blood pressure is maintained by
•Moment-to-moment regulationofcardiac output
and peripheral vascular resistance exertedatthree
anatomic sitesarterioles, postcapillary venules
(capacitancevessels),andheart.
•Kidney
•Baroreflexesmediatedbyautonomic nerves
(combination with humoral mechanisms, including
therenin-angiotensin-aldosteronesystem)
•Localreleaseofvasoactivesubstances

6. Antihypertensive agents
•Diuretics
–Thiazides: Hydrochlorothiazide, Chlorthalidone,
Indapamide
–Highceiling:Furosemide,Torsemide,ethacrynicacid.
–K+Sparing:Spironolactone,Amiloride
•ACEinhibitors
–Captopril, Enalapril, Lisinopril, Perindopril, Ramipril,
Fosinopril,etc.
•Angiotensin (AT1 receptor) blockers:Losartan, Candesartan,
Irbesartan,Valsartan,Telmisartan
•Directrenininhibitor:Aliskiren
•βAdrenergicblockers:Propranolol,Metoprolol,Atenolol,etc.

7. Antihypertensive agents
•Calciumchannelblockers
–Verapamil, Diltiazem, Nifedipine, Felodipine, Amlodipine,
Nitrendipine,Lacidipine,etc.
•β+αAdrenergicblockers:Labetalol,Carvedilol
•αAdrenergic blockers:Prazosin, Terazosin, Doxazosin,
Phentolamine,Phenoxybenzamine
•Centralsympatholytics:Clonidine,Methyldopa
•Vasodilators
–Arteriolar:Hydralazine,Minoxidil,Diazoxide
–Arteriolar+venous:Sodiumnitroprusside
•Others:Adrenergic neurone blockers (Reserpine,
Guanethidine,etc.),Ganglionblockers(Pentolinium,etc.)

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

9. Diuretics
•Thiazide diuretics:Thiazide
diuretics, such as
hydrochlorothiazide and
chlorthalidone, lower blood
pressure initiallyby
increasing sodium and
water excretion. Thiazide
diuretics can induce
hypokalemia,hyperuricemia
and,toa lesser extent,
hyperglycemiainsome
patients.

10. Diuretics
•Loopdiuretics:
•Inhibitorsofepithelial sodium transportatthe late
distal and collecting ducts (furosemide,and
ethacrynicacid)orantagonizingaldosteronereceptor
(spironolactone,andeplerenone) and reduce
potassiumlossintheurine.
•Aldosteroneantagonistshavetheadditionalbenefitof
diminishing the cardiac remodeling that occursin
heartfailure.

11. Diuretics
•Loopdiuretics:
•Theloopdiureticsactpromptlybyblockingsodium
and chloride reabsorptioninthe kidneys, evenin
patientswithpoorrenalfunctionorthosewhohave
not respondedtothiazide diuretics. Loop diuretics
cause decreased renal vascular resistance and
increasedrenalbloodflow.

12. Diuretics
•K+Sparing:
•potassium-sparing diuretics (spironolactone,and
eplerenone)arecompetitiveantagoniststhateither
compete with aldosterone,ordirectly block
epithelialsodiumchannel(amiloride).

13. ACE inhibitors
Renin Inhibitors
ACE Inhibitors
Angiotensin
blockers

14. ACE inhibitors
•The ACE inhibitors, are recommendedasfirst-line
treatmentofhypertensioninpatientswithavariety
ofcompelling indications, including high coronary
disease riskorhistoryofdiabetes, stroke, heart
failure, myocardial infarction,orchronic kidney
disease.

15. ACE inhibitors
•ACEisalso responsible for the breakdownof
bradykinin,apeptidethatincreasestheproduction
ofnitricoxideandprostacyclinbythebloodvessels.
Both nitric oxide and prostacyclin are potent
vasodilators.

16. ACE inhibitors
•ACE inhibitors decrease angiotensinIIand increase
bradykininlevels.Vasodilationisresultofdecreased
vasoconstriction (from diminished levelsof
angiotensinII) and enhanced vasodilation (from
increasedbradykinin).
•Byreducing circulating angiotensinIIlevels,ACE
inhibitors also decrease the secretionof
aldosterone, resultingindecreased sodium and
waterretention.
•ACE inhibitorsreduce both cardiac preload and
afterload,therebydecreasingcardiacwork.

17. ACE inhibitors
Comparative features of some ACE inhibitors

18. ACE inhibitors
AdverseeffectsofACEinhibitors:
•The adverse effect profileofall ACE inhibitorsis
similar.Captopriliswelltoleratedbymostpatients,
especiallyifdailydoseiskeptbelow150mg.
•Hypotension:Aninitial sharp fallinBPoccurs
especiallyindiuretictreatedandCHFpatients
•Hyperkalaemia
•Cough
•Rashes,urticaria
•Angioedema

19. ACE inhibitors
AdverseeffectsofACEinhibitors:
•Dysgeusia/parageusia
•Foetopathic
•Headache,dizziness,nauseaandbowelupset
•Granulocytopeniaandproteinuria(rareADR)
•Acuterenalfailure

20. ACE inhibitors
AdvantagesofACEinhibitor:
•Freeofpostural hypotension, electrolyte
disturbances,feelingofweaknessandCNSeffects
•Safetyinasthmatics, diabetics and peripheral
vasculardiseasepatients
•Long-termACEinhibitortherapyhasthepotentialto
reduce incidenceoftype 2 diabetesinhigh risk
subjects
•Noreboundhypertensiononwithdrawal

21. ACE inhibitors
AdvantagesofACEinhibitor:
•Nohyperuricaemia,nodeleteriouseffectonplasma
lipidprofile
•ACE inhibitors are the most effective drugs for
preventingsuddencardiacdeathinpost-infarction
patients.However, they are less effective for
primary prophylaxisofMIand for preventing left
ventricularhypertrophy.

22. Uses of ACE inhibitors
•Hypertension:
–TheACEinhibitorsarefirstlinedrugsinallgrades
ofhypertension, but the angiotensin receptor
blockers (ARBs) have now surpassed themin
popularity.
–Essential hypertension respondtomonotherapy
with ACE inhibitors and majorityofthe restto
theircombinationwithdiureticsorbetablockers.

23. Uses of ACE inhibitors
•CongestiveHeartFailure(CHF):ACEinhibitorscause
both arteriolar and venodilatationinCHFpatients;
reduceafterloadaswellaspreload.
•Myocardial infarction:Long-term ACE inhibitor
therapyreducesrecurrentMI.
•Prophylaxisinhighcardiovascularrisksubjects:ACE
inhibitors are protectiveinhigh cardiovascular risk
subjects even when thereisnoassociated
hypertensionorleft ventricular dysfunction. ACE
inhibitorsmayimprovedendothelialfunction.

24. Uses of ACE inhibitors
•Diabetic nephropathy:Prolonged ACE inhibitor
therapy has been foundtopreventordelay end-
stage renal diseaseintype IaswellastypeII
diabetics.
•Nondiabetic nephropathy:ACE inhibitors reducing
proteinuriabydecreasing pressure gradient across
glomerular capillariesaswellasbyaltering
membranepermeability.
•Scleroderma crisis:The marked riseinBPand
deteriorationofrenalfunctioninsclerodermacrisis
ismediatedbyAngII. ACE inhibitors produce
improvementandarelifesavinginthiscondition.

25. Angiotensin antagonists (ARBs)
•Angiotensin antagonists:losartan, candesartan,
valsartan,telmisartan,olmesartanandirbesartan.
•Their pharmacologic effectsofARBs are similarto
thoseofACEinhibitors.
•ARBs produce arteriolar and venous dilation and
block aldosterone secretion, thus lowering blood
pressureanddecreasingsaltandwaterretention.
•ARBsdonotincreasebradykininlevels.
•ARBs maybeusedasfirst-line agents for the
treatmentofhypertension,especiallyinpatients
with a compelling indicationofdiabetes, heart
failure,orchronickidneydisease.

26. Direct renin inhibitor
•A selective renin inhibitor, aliskiren directly inhibits
renin and, thus,acts earlierinthe renin–
angiotensin–aldosteronesystemthanACEinhibitors
orARBs.
•Itlowers blood pressure aboutaseffectivelyas
ARBs,ACEinhibitors,andthiazides.Aliskirenshould
notberoutinelycombinedwithanACEinhibitoror
ARBs.
•Aliskiren can cause diarrhea, especiallyathigher
doses,andcanalsocausecoughandangioedema,
butprobablylessoftenthanACEinhibitors.
•Aliskirenis contraindicated during pregnancy.

27. β-adrenergic blockers
•β-adrenergicblockersaremildantihypertensivesand
donot significantly lowerBPinnormotensives.In
stage1casesofhypertensivepatients(30-40%),β-
adrenergicblockersareusedalone.

28. β-adrenergic blockers
Propranolol
•Propranololisa firstβblocker showed effectivein
hypertensionandischemicheartdisease.
•Propranolol has now beenlargely replacedby
cardioselectiveβblockers suchasmetoprolol and
atenolol.
•Allβ-adrenoceptor-blocking agents are useful for
lowering blood pressureinmildtomoderate
hypertension.
•Insevere hypertension,βblockers are especially
usefulinpreventingthereflextachycardiathatoften
resultsfromtreatmentwithdirectvasodilators.

29. β-adrenergic blockers
Metoprolol & Atenolol
•Metoprolol and atenolol, which arecardioselective,
arethemostwidelyusedβblockersinthetreatment
ofhypertension.
•Metoprololisatenololisinhibiting stimulationofβ1
adrenoceptors.
•Sustained-releasemetoprololiseffectiveinreducing
mortalityfromheartfailureandisparticularlyuseful
inpatientswithhypertensionandheartfailure.
•Atenololisreportedtobeless effective than
metoprololinpreventing the complicationsof
hypertension.

30. β-adrenergic blockers
Other beta blockers
•Nadolol and carteolol, nonselectiveβ-receptor
antagonists
•Betaxololandbisoprololareβ1-selectiveblockers
•Pindolol, acebutolol, and penbutolol are partial
agonists,ie,βblockers with someintrinsic
sympathomimetic activity. These drugs are
particularly beneficial for patients with
bradyarrhythmiasorperipheralvasculardisease.

31. β-adrenergic blockers
Other beta blockers
•Nadolol and carteolol, nonselectiveβ-receptor
antagonists
•Betaxololandbisoprololareβ1-selectiveblockers
•Pindolol, acebutolol, and penbutolol are partial
agonists,ie,βblockers with someintrinsic
sympathomimetic activity. These drugs are
particularly beneficial for patients with
bradyarrhythmiasorperipheralvasculardisease.

32. β-adrenergic blockers
Other beta blockers
•Labetalol, Carvedilol, & Nebivolol have bothβ-
blockingandvasodilatingeffects.
•Esmololisaβ1-selective blockerthatisrapidly
metabolizedviahydrolysisbyredbloodcellesterases.
Esmololisused for managementofintraoperative
andpostoperativehypertension,andsometimesfor
hypertensive emergencies, particularly when
hypertensionisassociatedwithtachycardiaorwhen
thereisconcern about toxicity suchasaggravation
ofsevereheartfailure.

33. α-Adrenergic blockers
Prazosin, terazosin, and doxazosin
•Prazosinisaprototypeα
1-adrenergicblockingagent.
•Terazosinanddoxazosinarelong-actingcongenersof
prazosin
•Alpha blockers reduce arterial pressurebydilating
bothresistanceandcapacitancevessels.
Other alpha-adrenoceptorblockingagents
•phentolamine (reversible nonselectiveα-adrenergic
antagonist) and phenoxybenzamine (non-selective,
irreversible alpha blocker)areusefulindiagnosis and
treatmentofpheochromocytoma.

34. Centrally acting adrenergic drugs
Clonidine
•Clonidine acts centrallyas anα
2agonisttoproduce
inhibitionofsympathetic vasomotor centers, decreasing
sympathetic outflowtothe periphery. This leadsto
reduced total peripheral resistance and decreased blood
pressure.Atpresent,itisoccasionallyusedincombination
withadiuretic.
Methyldopa
•Itisanα
2agonist thatisconvertedto
methylnorepinephrine centrallytodiminish adrenergic
outflowfromtheCNS.Itismainlyusedformanagement
ofhypertensioninpregnancy, whereithas a recordof
safety.

35. Vasodilators
•Hydralazine/Dihydralazineandminoxidilnotusedas
primary drugstotreat hypertension. These
vasodilatorsactbyproducing relaxationofvascular
smooth muscle, primarilyinarteries and arterioles.
Thisresultsindecreasedperipheralresistance.
•Bothagents produce reflexstimulationoftheheart,
resultinginthe competing reflexesofincreased
myocardial contractility, heart rate, and oxygen
consumption.
•Hydralazineisanaccepted medication for controlling
bloodpressureinpregnancyinducedhypertension.This
drugisusedtopicallytotreatmalepatternbaldness.

36. Treatment of hypertension
•Hypertensive emergency:Itisrare but life-
threatening condition (systolicBP>180mmHgor
diastolicBP>120mmHgwithevidenceofimpending
orprogressive target organ damage suchasstroke,
myocardialinfarction).
•A varietyofmedications are used, including calcium
channel blockers (nicardipine and clevidipine),nitric
oxide vasodilators (nitroprusside and nitroglycerin),
adrenergic receptor antagonists (phentolamine,
esmolol, and labetalol), the vasodilator hydralazine,
andthedopamineagonistfenoldopam.

37. Treatment of hypertension
•Resistant hypertension:Itisdefinedasblood
pressure that remains elevated despite
administrationofanoptimalthree-drugregimenthat
includes a diuretic. The most common causesof
resistanthypertension
–poorcompliance
–excessiveethanolintake
–concomitant conditions (diabetes, obesity, sleep apnea,
hyperaldosteronism,highsaltintake,metabolicsyndrome)
–concomitant medications (sympathomimetics,
nonsteroidal anti-inflammatory drugs,orantidepressant
medications)
–insufficientdose/drug

38. Treatment of hypertension
•SummaryofWHO-ISHand British Hypertension
Society(BHS)2004,guidelines
–Except for stageIIhypertension, start with a single most
appropriatedrug
–Follow A B C D rule(A—ACE inhibitor/ARB; B—βblocker;
C—CCB, D—diuretic). While A and (insome cases) B are
preferredinyounger patients(<55years), C and D are
preferredinthe older(> 55years) for the step Ior
monotherapy.
–Initiate therapyatlow dose;ifneeded increase dose
moderately.
–Ifonly partial responseisobtained, add a drug from
another complimentary classorchangetolow dose
combination

39. Treatment of hypertension
•SummaryofWHO-ISHand British Hypertension
Society(BHS)2004,guidelines
–Ifnoresponse,changetoadrugfromanotherclass,orlow
dosecombinationfromotherclasses
–Incaseofside effecttotheinitially chosen drug, either
substitutewithdrugofanotherclassorreducedose
–MajorityofstageIIhypertensives are startedona 2 drug
combination

40. Treatment of hypertension in patients with
concomitant diseases

41. Combinations to be avoided
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
haemodynamicaction
Verapamil or diltiazem with β
blocker
bradycardia, A-V block can
Methyldopa with clonidine or any two drugs of the same class

42. Antihypertensives& pregnancy
Antihypertensivesto be avoided
during pregnancy
Antihypertensivesfound safer
during pregnancy
ACE inhibitors, ARBs: Risk of foetal
damage, growth retardation.
Hydralazine
Methyldopa
Diuretics: increase risk of foetal
wastage, placental infarcts,
miscarriage, stillbirth.
DihydropyridineCCBs: if used, they
should be discontinued before
labouras they weaken uterine
contractions.
Nonselective β blockers: Propranolol
cause low birth weight, decreased
placental size, neonatal bradycardia
and hypoglycaemia.
Cardioselectiveβ lokers 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.

43. Possible combinationofantihypertensive drugs:Continuous green line
(preferential combinations);dotted green line (acceptable combinations); 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.

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