Antihypertensive Drugs.pptx

ANTIHYPERTENSIVE DRUGS
Dr.ManojR.Kumbhare
Prof. Dr. M.R. Kumbhare

ANTIHYPERTENSIVEDRUGS
Hypertensioncanbedefinedasthe increaseof arterial bloodpressureabovethe limits.
Thischart reflectsbloodpressurecategoriesdefinedbytheAmericanHeart
Association.
3

ANTIHYPERTENSIVEDRUGS
Thereare two typesof hypertension:
Most commontype of hypertension
(a) Primary(Essential) Hypertension
(b) SecondaryHypertension
(90-95%)
Causecannot beidentified
Causecanbe identified
Suchasrenal hypertension(kidney
diseases), Pheochromocytoma

Diuretics
CentrallyActing Sympatholytics
AdrenergicNeuronBlockers
AdrenergicReceptor Blockers
-AdrenergicReceptor Blockers
1-AdrenergicReceptorBlockers
DirectActing Vasodilators
PotassiumChannel Agonists
Renin-Angiotensin SystemInhibitors
CalciumChannel Blockers
Other Drugs
CLASSIFICATIONOFTHEANTIHYPERTENSIVEDRUGS
will bediscussedin a separated section

-ADRENERGICBLOCKERS
Activationof thereceptorsin heart leadsto an increasein rate andforceof
contraction.
-ReceptorBlockers reduce
(a) the heart rate,
(b) contractility
(c)arterial pressure
Dependingupontheseeffects,these
drugsreducethe work andthe oxygen
demandof heart and
improvethe oxygensupply/demand
ratio.

-ReceptorBlockerscanbedividedinto two classdependingonthe receptorselectivity
(a)Nonselective-ReceptorBlockers(1 and2 blockingeffect) (FirstGeneration)
Propranolol,timolol, nadolol, pindolol(someexamplesof this class)
()1-SelectiveAdrenergicBlockers(cardioselective1 blockers)(SecondGeneration)
Acebutolol,atenolol, metoprolol(someexamplesof this class)
Nonselective-ReceptorBlockerswith 1 antagonisticactivity (Third Generation)
labetalol,carvedilol

 adrenergicreceptorblockersare amongthe mostwidely usedantihypertensive
drugsandalsoconsideredfor the first line treatment for glaucoma.
Cardioselective adrenergicreceptor blockershavea greater affinity for the  -
receptorsin heart than for the -receptorsin other tissue.
providestwo important advantages
(next slide please)

Cardioselective adrenergicreceptorblockershavea greater affinity for the  -
receptorsin heart than for the -receptorsin other tissue.
providetwo important advantages
-Blockersdonot haveblocking
effectson-receptorson bronchi
Theycanbeusedsafelyin patients with
bronchitisor bronchial astma
 -Blockersdonot haveblocking
effectsonvascular-receptors
mediatingvasodilation

-ReceptorBlockersare the derivatives of
(a) Aryloxypropanolamine(mostly)or
(b)Arylethanolamine

EXAMPLESOF-ADRENERGICBLOCKERS
LABET
ALOL
It isarylethanolamine type -blockers.
Labetaloliscompetetivenonselective (1 and2) and1-receptor blocker.
Labetalolisclinicallyusefulantihypertensive agent.

LABET
ALOL
Labetalolhastwo asymmetriccenters(seethe formula *).
Twoasymmetriccenterscorrespondto 4 stereoisomers(RR,SS/ RS,SR).
Mixture of 4 stereoisomersisusedin treating hypertension.
However,the different isomerspossessdifferent receptorblocking activities
(seenestslide) .
* *

LABET
ALOL
* *
n:numberof chiral centers
2n: numberof stereoisomers
enantiomers
n:1
Onechiral center 21 stereoisomers
REMINDER
2enantiomers R
n:2
Twochiral center 22 stereoisomers 4 stereoisomers
R,S S,R R,R S,S
S
enantiomers
diastereoisomers

*
*
HO
C
H
N
O NH2
LABET
ALOL
OH
CH3
R R only-blockeractivity
S R -blockeractivity
S S -blockeractivity
R S
Possessinggreater
therapeuticactivity

PHAR406PHARMACEUTICALCHEMISTRYIV
EMU-SPRINGTERM
LABET
ALOL
ethyl
2-hydroxybenzamide
butyl
(salicylamide)
2-Hydroxy-5-[1-hydroxy-2-(4-phenylbutan-2-ylamino)ethyl]benzamide

EXAMPLES-ADRENERGICBLOCKERS
CARVEDILOL
It isAryloxypropanolaminetype-blockers.
Carvediloliscompetetivenonselective (1 and2) and1-receptor blocker. It
alsohasantioxidant andan antiproliferative effect onvascularsmooth cells.
Therefore, it possessesneuroprotectiveeffect andability
H-carbazole-4-yloxy)-3-[2-(2-
hoxyphenoxy)ethylamino]propan-2-ol
1 1-(9
met
carbazole
to providemajor cardiovascularorgan protection
*
4
3
1

CARVEDILOL
Bothenantiomers(R,S)have1-receptor blockingeffects
Only(S)enantiomer has-blocking effect
Carvedilolhasoneasymmetriccenter(seethe formula *).
Oneasymmetriccenterleadsto 2 stereoisomers(enantiomers).
Racemateisusedin therapy.
However,the enantiomerspossessdiferent receptor blockingactivities .

CLASSIFICA
TIONOFTHEANTIHYPERTENSIVEDRUGS
Diuretics
CentrallyActingSympatholytics
1-AdrenergicReceptor Blockers
-AdrenergicReceptorBlockers
Other Drugs

1-ADRENERGICRECEPTORBLOCKERS
Nonselective-adrenergicreceptorblockersare usedin the treatment of catecholamine-
dependent hypertension.
Thesedrugs, asnon-specific–blockingagents, blockboth 1 and2 adrenergicreceptors.
Blockingpresynaptic2 receptorsleadsto cardiacstimulatory effect and tachycardia.
Examplesof nonselectiveadrenergicreceptorblockersare Tolazoline, Phentolamine and
Phenoxybenzamine.

Talozoline
2-benzyl-4,5-dihydro-1H-imidazole
N
H
N
OH
CH3
NONSELECTIVE-ADRENERGICRECEPTORBLOCKERS
N
Phentolamine
3-[(4,5-dihydro-1H-imidazol-2-yl) (p-tolyl) amino]phenol
usedin persistent pulmonaryhypertensionof the newborn
(hasbeenusedto treat Raynaud Syndrome)

N
H
N
OH
CH3
N
Phentolamine
usedto prevent or controlhypertensive episodesin patient
with pheochromocytoma
a neuroendocrinetumor of the medulla of adrenal glands

irreversible nonselective-adrenergic blocker
bindsthe receptorscovalently
2-chloroethyl groupalkylates the receptor
Phenoxybenzamine
N-benzyl-N-(2-chloroethyl)-1-phenoxypropan-2-amine
Singledoseof phenoxybenzaminemay last 3 to 4 days.
It isusedinpheochromocytoma.

Selective1-adrenergicreceptorblockersare usedin the treatment of hypertension.
produce antihpertensive effect by blocking the vasocontricting effect of 1-adrenergic receptor
onsmooth muscle.
Thesedrugsdo not have any effect on 2-adrenergic receptors.
Examplesof selectiveadrenergic receptorblockersare Prazosin,Terazosinand Doxasozin.

PRAZOSİN
İupac:[4-(4-Amino-6,7-dimethoxyquinazolin-
2-yl)piperazin-1-yl]-(furan-2-yl)methanone
N 3
N1
Quinazoline
Benzo[d]pyrimidine
4
7 2
5
6
8
piperazine
1
2 3
4
1
Furan
2
3
4
5
2-Furoicacid
furan-2-carboxylicacid
4-Amino-2-[4-(2-furoyl)piperazin-1-yl]-6,7-dimethoxyquinazoline

SYNTHESISOFPRAZOSİN
Sodiumcyanate
(NaOCN)
2-amino-4,5-dimethoxybenzoic acid
SOCl2
Thionyl chloride

SYNTHESISOFPRAZOSİN(continuing)
NH3
1-(2-furoyl)piperazine

PRAZOSİN
Aminogroupat 4th positionof quinazoline ring
isveryimportant for the 1 receptor affinity
Prazosineisorally usedashydrochloride salt.
Plasmahalf life is2 to 3 hours.
Sideeffectsincludedizziness,orthostatic hypotension (due to lossof reflex vasoconstriction
upon standing).

DOXAZOSİN
2,3-dihydrobenzo[b][1,4]dioxine
Aminogroupat 4th positionof quinazoline ring
28
(2,3-dihydro-1,4-benzodioxin-3-yl)methanone
isveryimportant for the 1 receptor affinity.
Saturatedfuran
(tetrahydrofuran)
[4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]-
[4-(4-amino-6,7-dimethoxyquinazolin-2-
yl)piperazin-1-yl]-(oxolan-2-yl)methanone
TERAZOSİN

AdrenergicNeuronBlockersare comprisedof two different groups:
(a) Reserpineand Derivatives
(b) Guanidine Derivatives
ADRENERGİCNEURONBLOCKERS

RES
ERPINE
Reserpineisan alkaloid isolated from the rootsof Rauwolfia Serpentina.
It affects the storageandreleaseof norepinephrine. It depletescatecholaminesandserotonine
from central andperipheral neuronsbyinterfering with the uptake of theseamines.
Reserpineisthe first effective antihypertensive drugin westernmedicine.
It haslargely beenreplacedbynewer agentswith fewer side effects.

RES
ERPINE
Asindole derivatives, it issensitiveto decompositionbylight andoxidation, especially in
solution.
Reserpineisusedorally or parenterally for the treatment of hypertension.

Guanethidinepreventsthe releaseof norepinepherinefrom the postganglionic
neuronsin responseto sympatheticnervestimulation andcausesdepletionof it in
adrenergicneurons.
İt isusedorally for antihypertensive therapy.
2-[2-(azocan-1-yl)ethyl]guanidine
GUANETHIDINE
Ocane:Suffixes for fully saturated
eight membered ring without nitrogen

CENTRALL
YACTINGSYMP
A
THOL
YTICDRUGS
Centrallyacting sympatholyticdrugsare 2-adrenergicreceptor agonists.
Thesedrugscausea decreasein sympathetic outflow from the central nervoussystem.
Therefore, they decreasethe peripheral vascularresistance, bloodpressureandheart
rate andcontractility.
Clonidine,-methyldopa, guanabenzandguanafacineare examplesof thisclass.

1H-Imidazole
N
H
CENTRALL
YACTINGSYMP
A
THOL
YTICDRUGS
CLONIDINE
Cl
N
H
N
Cl
4 3
1
2
5
NH
N
H
2,3-dihydro-1H-imidazole 4,5-dihydro-1H-imidazole
NH
N
H
Imidazolidine
REMINDER
IndicatedHydrogen
(2-imidazoline)
(4-imidazoline)

1H-Imidazole
2,6-dichloro-N-(2-imidazolin-2-yl)aniline
N
H
N
CENTRALL
YACTINGSYMP
A
THOL
YTICDRUGS
CLONIDINE
Cl
2-[(2,6-dichlorophenyl)amino]-2-imidazoline
4 3
1
2
5
NH
N
H
2,3-dihydro-1H-imidazole 4,5-dihydro-1H-imidazole
N
H
Cl
indicatethe saturated positions
indicatedoublebond’s position
REMINDER
(2-imidazoline)
(4-imidazoline)

What istautomerization ?
Tautomerization isthe processof isomerizationof onetautomer into anothertautomer.
REMINDER
Tautomersare two formsof the samecompoundwhichdiffer bypositionsof a hydrogenatom and a pi bond.The
Equilibriumarrow isusedto showthe tautomerequlibrium.
Forexampleketonesandenolsare tautomers:
ketone enol
N
H
N
H
N
Cl
Cl
N
H
H
N
N
Cl
Cl
Clonidinetautomerscanbedrawnasfollows

H2NCH2CH2NH2
Cl
N C
3
H SCH
NH
Cl
2,6-dichlorophenyl-S-methylisothiourea
-CH3SH
-NH3
N
H
N
H
N
Cl
Cl
CENTRALL
YACTINGSYMP
A
THOL
YTICDRUGS
SYNTHESISOFCLONIDINE
C
L
ONIDINE
CH2
CH2
H
H N
H N
H
+

it existsto a significantextent in the nonionizedform.
Thenonionizedform canpassthe membranesand/ orBBB
(BloodBrainBarrier).
N
H
N
H
N
CENTRALL
YACTINGSYMP
A
THOL
YTICDRUGS
CLONIDINE
Asa centrally actingdrug,at physiologicalpH,
Cl
Cl
Cl
H
N
N
N
H
Cl
Guanidine

it existsto a significantextent in the nonionizedform
Howcanwe explainthisdilemma ?
Guanidine(strongbasic)
(pKa=13.6)
ionizedat physiologicalpH
Clonidinebearsa guanidine moiety
CENTRALL
YACTINGSYMP
A
THOL
YTICDRUGS
CLONIDINE
Cl
N
H
N
N
H
Cl

H
N
CENTRALL
YACTINGSYMP
A
THOL
YTICDRUGS
CLONIDINE
Cl
it existsto a significantextent in the nonionizedform.
N
N
H
Cl
pKaof clonidineismuchmorelower than guanidine’spKa.
Guanidine(strong basic)
(pK
a=13.6)
Clonidine
(pKa=8.0)
Becauseof the inductiveand
resonanseeffectsof dichlorophenyl
ring
Thebasicityof clonidine is
decreased
43

GUANABENZ
2-[(E)-(2,6-dichlorophenyl)methylideneamino]guanidine
CENTRALL
YACTINGSYMP
A
THOL
YTICDRUGS
GUANFACINE
N-(diaminomethylidene)-2-(2,6-dichlorophenyl)acetamide

GUANABENZ GUANFACINE
Guanidine
C
L
ONIDINE
20-25h
C
L
ONIDINE
17h
GUANF
AC
INE
3h
GUANABENZ
> >
Eliminationhalf-life isdecreasing

HO
HO
CH2 COOH
NH2
C*
H
L-DOP
A
Dopa is the precursor of the catecholamines
[dopamine, norepinephrine (noradrenaline)
andepinephrine (adrenaline)].
Alsousedasantiparkinson drug.
Flyingwedgeprojectionof L-Methyldopa
L-Methyldopahas Sconfiguration
CENTRALL
YACTINGSYMP
A
THOL
YTICDRUGS
METHYLDOPA
*
?

FromIUP
ACGoldBook
D/ LCONVENTIONIN STEREOCHEMISTRY
REMINDER
Anarbitrary conventionaccordingto which(+)-glyceraldehydewasnamedD-
glyceraldehyde (with the enantiomer L-glyceraldehydeandits racemate DL-
glyceraldehyde).
D-glyceraldehyde
(R)-2,3-dihydroxypropanal
L-glyceraldehyde

REMINDER
Achemicalnameisconsistedof fourparts in the IUPACNomenclature System
IUPACNOMENCLATURE
PREFIX PARENT LOCANT SUFFIX
indicatethe location
andidentity of substituent(s)
Definesthe main part of the molecule
andindicatethe longestcarbonchain
orthe ring, etc.
identifies the primary functional group
FromFundamentalof Organic
ChemistrybyJ.McMurry
givesthe locationof the
primary functionalgroup

CENTRALL
YACTINGSYMP
A
THOL
YTICDRUGS
METHYLDOPA
1
2
3
4
3 1
2
propanoicacid
2-methyl
2-amino
3-(3,4-dihydroxyphenyl)
* Substituentsare written in alphabeticalorder
Phenylalanine
derivative
2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoicacid

CENTRALL
YACTINGSYMP
A
THOL
YTICDRUGS
METHYLDOPA
It isa prodrug.
.
Methyldopa istransportedactively in the CNSbyan aromatic acid transporter
system.Then,it isconvertedto the metabolite responsiblefrom the activity.
Thisconvertionispresentednext slide.

CENTRALL
YACTINGSYMP
A
THOL
YTICDRUGS
CONVERSIONOFMETHYLDOPATOACTIVEMET
ABOLITE
AADC
(L-AromaticAmino
AcidDecarboxylase)
Methyldopa -Methyldopamine
DBH
(Dopamine--hydroxylase)
(1R,2S)--Methylnorepinephrine
active metabolite of methyldopa
2-agonist

METHYLDOPA
CENTRALL
YACTINGSYMP
A
THOL
YTICDRUGS
HO
HO
Methydopa isused only by oral route, because its zwitterionic character limits its
solubility.
Methyldopa absorptionislimited andrange 8%to 62%.
Its absorption appears to involve an amino acid transport system. Therefore its absorption
isaffected by food and about 40% of absorbed drug isconverted to O-sulfate conjugate by
the intestinalmucosal cells.
CH2
NH3
C COO-
CH3
+

Methyldopa isunstablein the presenceof oxidizingagents(alsoair), alkaline pH and
light.
METHYLDOPA
CENTRALL
YACTINGSYMP
A
THOL
YTICDRUGS
HO
HO
CH2
NH3
C COO-
CH3
+
Catecholisverysusceptibleto oxidation

Theethyl esterof methyldopaisknownasMethyldopate.
Thehydrochloridesalt of methyldopateishighlywater solubleanddeveloped to
makeparenteral solution.
Methyldopate ishydrolyzedto methydopain the bodyby esterases.
METHYLDOPA
CENTRALL
YACTINGSYMP
A
THOL
YTICDRUGS
METHYLDOP
A
TE
Hydrochloridesalt of
METHYLDOP
A
TE

DIRECTV
ASODILA
TORS
TheseDrugsreducearterial smoothmuscletonebydirect action onthe vasculature
without interference from the autonomic innervation.
Theyproducevasodilationandlower the blood tension.
Theycancauseincreasein heart rate andcardiacoutputbyincreasedsympathetic
reflex activity.
Hydralazine, dihydralazineandsodiumnitroprussideare the examplesof this class.

DIRECTV
ASODILA
TORS
HYDRALAZINE
benzene
a
c b
pyridazine
d
4
3
2
5
6
7
8 1
benzo[d]pyridazine
phthalazine
1-hydrazinylphthalazine
hydrazine

Synthesisof Hydralazine
DIRECTV
ASODILA
TORS
C
C
O
H
O
2-formylbenzoic acid
OH
PCl5
phthalazin-1(2H)-one
phthalazin-1-ol
- HCl
- 2H2O
Addedhydrogen

ADDEDHYDROGENINNOMENCLA
TURE
pyridin-2(1H)-one
3
N
1
2
5
6
pyridine
REMINDER
‘’AddedHydrogen’’describeshydrogenatomsaddedto a specificstructureasa consequenceof the
addition of a suffixor a prefix describinga structural modification.
Thistype of indicated hydrogenisnormally citedin parenthesesafter the locant of the additional
feature.
4 4
3
2
5
6 N
H
N
O
1
pyrimidine
pyrimidin-2(1H)-one
FromIUP
ACGoldBook

HYDRALAZINE
Hydralazineactsonvascularsmoothmuscleto causerelaxation.
It isusedorally ashydrochloride salt.
Hydralazineismetabolizedby microsomalenzymesand excretedby kidneys.
DIRECTV
ASODILA
TORS

DIRECTV
ASODILA
TORS
Metabolismof Hydralazine
N
N
NHNH2
OH
Benzylic
Oxidation
Acetylation
Glucuronide Formation

DIHYDRALAZINE
DIRECTV
ASODILA
TORS
N
NHNH2
N
NHNH2
1,4-dihydrazinylphthalazine
SODIUMNITROPRUSSIDE
Na2Fe(CN)5NO Sodiumnitroferricyanide
Thisdrughasshortdurationof action.
Its useislimited to hypertensiveemergencies.
It formsnitric oxide(NO).
Thehypotensiveeffect of the drugisthe resultof nitric oxide.

POTASSIUMCHANNELAGONISTS
Thesedrugsare alsoknownasPotassiumChannelOpeners.
TheseagentsactivateATP-sensitiveK+-channelsin vascularsmoothmuscle.
Openingpotassiumchannelsleadsto a decreaseof intracellularCa+2 andresultsin
hyperpolarizationof the membrane.
Thisprocessproducesaninhibitory influenceonthe membraneexcitation and
causesvasodilation
Minoxidil anddiazoxideare the examplesof thisclass.

7-Chloro-3-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide
2H-1,2,4-thiadiazine
1,2,4-thiadiazine
S
1
4
H
N
N 2
1 2
4
5 3
6 6
5 3
4H-1,2,4-thiadiazine
1,2,4-thiadiazine
benzo thiadiazine
2H-1,2,4-benzothiadiazine
1
2
3
DIAZOXIDE
5 4
6
7
8
IndicatedHydrogen

DIAZOXIDE
Hydrochlorothiazide
C
hlorothiazide
Diuretics
İt wasdevelopedto increasethe antihypertansive action and
to minimize the diuretic effect (without sulfamoyl group!!)
Acidicproton
Sodiumsalt canbeprepared

DIAZOXIDE
It isa rapidly acting antihypertensiveagent for emergencyreductionof blood pressure
in hospitalizedpatient (with accelerated or malignant hypertension)byintravenous
injection.
Water solublesodiumsalt isusedfor injectable formulation.

H2N NH2
N 1
O
6
5
4
2
N 3
MINOXIDIL
piperidine
2,6-diamino-4-(piperidin-1-yl)pyrimidine 1-oxide
N
pyrimidine
N
N
N
H2N NH2
3
OSO-
MinoxidilSulfate
Prodrug
S
ulfotransferase
enzyme
ActiveMetabolite
(in theliver)

MINOXIDIL
N
N
N
H2N NH2
sodiumandwater retention, reflex tachycardia.
Minoxidileisusedfor severehypertensionuncontrolledbyother
drugs.It isthe onlydirect-acting vasodilatorthat requires
metabolicactivation to produceits antihypertensive effect.
It hascharacteristicsideeffectsof directvasodilatoryagentssuchas
O
Minoxidiletopical solutionisusedto treatalopeciaandrogenitica. It isbelievedto
increasecutaneousbloodflow stimulating hair growth.
Male-pattern baldness

SYNTHESISOFMINOXIDIL
N
N
OH
HO
HO
N
N
Cl
Cl
Cl
2,4,6--trichloropyrimidine
POCl3
NH3
Barbituric acid
m-chloroperbenzoic acid
(MCPBA)
2,6-diamino-4-chloropyrimidine 1-oxide 2,6-diamino-4-chloropyrimidine
Next Slide
Please

SYNTHESISOFMINOXIDIL
piperidine
2,6-diamino-4-chloropyrimidine 1-oxide
N
N
N
H2N NH2
O
Minoxidile
NH
- HCl

RENIN-ANGIOTENSIN SYSTEM INHIBITORS
Therenin-angiotensinhormonalsystemplaysa central role in the control of
sodiumexcretionandbodyfluid volume.
It iscloselyconnectedwith sympatheticsystemandaldosteronsecretionin the
regulation of bloodpressure.

SympatheticStimulation
Hypotension
Decreasedsodium extrection
Angiotensinogen Angiotensin I
Kidneys
Aglycoprotein
Synthesizedprimarily in the liver
Renin(an aspartyl protease)
decapeptide

AngiotensinI Angiotensin II
AngiotensionConverting Enzyme
AC
E
decapeptide Octapeptide
a potent vasoconstrictor
Significantregulatory effect onsodiumexcretionbyrenal tubes
Glu-AP
(Glutamyl aminopeptidase)
Angiotensin III
Lesspotent asvasoconstrictor

Renin
Angiotensinogen AngiotensinI AngiotensinII
Cardiacand Vascular
Hypertrophy
Systemic
Vasocontriction
IncreasedBlood
Volume
RenalSodiumand
FluidRetention
Aldosterone
Kidney
ELEV
A
TEDBLOOD
PRESSURE
AngiotensionIII
AC
E Glu-AP

Renin-angiotensinsysteminhibitorscanbeclassifiedasfollows
(a) AngiotensionConvertingEnzyme(ACE)Inhibitors
(b) AngiotensionAntagonists(AngiotensionAT1Receptor Blockers)
(c) ReninInhibitors

A
CEINHIBITORS
Captopril,Lisinopril,Enalapril, Benazepril,Quinapril,Ramipril, Fosinopril and
Trandoprilare the examplesofAngiotensionConvertingEnzyme(ACE)
Inhibitors.
Enalapril, Benazepril,Quinapril,Ramipril, FosinoprilandTrandoprilare
prodrugs.

EMU-SPRINGTERM
A
CEINHIBITORS
Becauseof the importancein regulating kidneyfunction,aldosteronerelease,
electrolyte balanceandbloodvolume,the renin-angiotensionsystemisvery
important drugtarget in the managementof highbloodpressureandhearth
failure.
Theyare usedin hypertensionandhearth failure
Acommonsideeffect ofACEinhibitorsisa drycoughappearingin about 10%
of patients(it appearsto berelated to the elevationin bradykinin).

A
CEINHIBITORS
C
APTOPRIL
*
*
(S)-1-((S)-3-mercapto-2-methylpropanoyl)pyrrolidine-2-carboxylic acid
FirstACEinhibitor usedin therapy
drugs(e.g. Penicillamine)
Sulfhydrylgroupisresponsiblefor the excellentinhibitor activity
It isalsoresponsibletwo commonsideeffectsof captopril:
SkinRashes
Tastedisturbances(metallic taste, lossof taste)
Commonsideeffects ofmercapto-containing

N
C
O
CH3
H
C
S
H
C O
O-
Arg
C
H2N N+
H
H
O
H
Zn++
HYPOTHETICALBINDINGOFCAPTOPRILIN THEACTIVESITEOFA
CE
Activesiteof ACE
Arginineresidue
(cationicsite)
Zincion
Hydrophobicpocket
Hydrogenbond
donorgroup
Prolin

EMU-SPRINGTERM
David W.Cushman,Miguel A. Ondetti, Designof angiotensin converting
enzyme inhibitors, Nature Medicine , Volume 5, Number 10,p.1110-1112,
October 1999.
Proposed binding to the active site of ACEby asubstrate or venom peptide inhibitor with
terminal sequence Phe–Ala–Pro,by succinylamino acids, and by captopril.

EMU-SPRINGTERM
CONCLUSION
Theactivesitemodelthat we describedin our originalstudiesusedsimple
chemicalconceptsguidedbya hypothetical ‘paper andpencil’modelof
substrateandinhibitor bindingto the enzyme.
Thisrational designapproachhasled to a classof structurallysimple
compoundsthat caninhibit the actionof the enzymewith greatpotencyand
specificity,propertiesthat translate in vivointo effective antihypertensive
activity with aremarkablylow level of unwantedsideeffectsor toxicity.
82

ACEINHIBITORS
LISINOPRIL
* *
*
(S)-pyrrolidine-2-carboxylicacid
(R)-6-aminohexanoyl
(S)-1-carboxy-3-phenylpropyl
CAPTOPRIL 83

ACEINHIBITORS
*
84
*
*
(S)-1-((R)-6-amino-2-((S)-1-carboxy-3-phenylpropyl)hexanoyl)pyrrolidine-2-carboxylic acid
LISINOPRIL

PHARMACEUTICALC
EMU-SPRINGTER
ACEINHIBITORS
SYNTHESISOFCAPTOPRIL
+
DCC
3-(acetylthio)-2-methylpropanoic acid butyl pyrrolidine-2-carboxylate
CF3COOH
NH3
butyl 1-(3-(acetylthio)-2-methylpropanoyl)
pyrrolidine-2-carboxylate
CAPTOPRIL
N,N'-Dicyclohexylcarbodiimide
85

ACE INHIBITOR PRODRUGS
Enalapril, Benazepril,Quinapril,Ramipril, FosinoprilandTrandoprilare examples
of thisclass.
Enalaprilisthe first andthe prototype of this class.
Thesedrugsdonot havethiol group(nocommonsideeffects!)
Exceptfosinopril(containingphosphorus),all of them sharethe (S)-2-amino-4-
phenylbutyricacidethyl estermoiety. Whyester formation?
(S)-ethyl 2-amino-4-phenylbutanoate
86

GeneralStructureofACE
InhibitorProdrugs
hydrolysis
Metabolism byliver andintestinal enzymes
Activemetabolite
87

ENALAPRIL
(S)-pyrrolidine-2-carboxylicacid
*
*
*
Propanoyl(propionyl)
((R)-1-ethoxycarbonyl-3-phenypropyl)amino
C
APTOPRIL
88

ENALAPRIL
Long-actingACEinhibitor
Maleate salt isused
(S)-1-[(S)-2-[((R)-1-ethoxycarbonyl-3-phenypropyl)amino]propanoyl]pyrrolidine-2-carboxylic
acid
89

ENALAPRIL
hydrolysis
in vivo
90
ENALAPRILA
T
ActiveMetabolite
Prodrug

ENALAPRILMALEA
TE
Whichnitrogenatom canbeformed maleate salt ?Why?
91

BENAZEPRIL
H
a
N
1H-azepine
b
1H-benzo[b]azepine
1
2
3
4 5
6
7
8
9
C2H5OOC
92
CH2
H2C
C N
H
H N
O
CH2COOH
2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl]acetic
acid
((R)-1-ethoxycarbonyl-3-phenypropyl)amino

BENAZEPRIL
C
C2H5OOC
CH2
H2C
N
H
H N
O
CH2COOH
2-[(S)-3-[((S)-1-ethoxycarbonyl-3-phenylpropyl)amino]-2-oxo-2,3,4,5-tetrahydro-1H-
benzo[b]azepin-1-yl]aceticacid
BENAZAPRILA
T
ActiveMetabolite
93

QUINAPRIL
A
CEINHIBITOR PRODRUGS
((S)-1-ethoxycarbonyl-3-phenylpropyl)amino
1
(S)-propanoyl
1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid
94

QUINAPRIL
(3S)-2-[(S)-2-[((S)-1-ethoxycarbonyl-3-phenylpropyl)amino]propanoyl]-1,2,3,4-
tetrahydroisoquinoline-3-carboxylicacid
QUINAPRILATE
ActiveMetabolite
95

(c) ReninInhibitors
96

ANGIOTENSIN II ANT
AGONIS
TS
97
Thesedrugsare the angiotensionII receptor blockers.
Thereare four subtypesof angiotensionII receptorsidentified to date, namely
AT1, AT2,AT3and AT4
AT1receptors of angiotensionII haveimportancein managingspesific
cardiovasculardiseases.

Stimulation ofAT1receptorsof angiotensionII cause
(a) vasocontriction
(b) increasedaldosteronesynthesisand secretion
(c) increasedvasopressin secretion
(d) decreasedrenal blood flow
(e) increasedrenal tubular sodium reuptake
(f) Other physiological events
98
ANGIOTENSIN II ANT
AGONIS
TS

ANGIOTENSINII ANT
AGONISTS
CompetetiveantagonistsofAT1receptorsof angiotensionII produce
vasodilatory effects.
Thesedrugsare usedin the treatment of hypertensionandheart failure in a
similarmannerasACEinhibitors.
Because they do not inhibit ACE,they do not cause an increase in bradykinin,
which contributes to the some of the side effects of ACEinhibitors (cough and
angioedema).
Losartan, valsartan, candesartan, irbesartan and telmisartan are the
examplesof this class.
99

EMU-SPRINGTERM
General Structurefor Losartan,Valsartan,
Candesartan,Irbesartan and Telmisartan
Prof. Dr.Erçin ERCİY
AS,May 8,2018 104

ANGIOTENSIN II ANT
AGONIS
TS
N
HOH2C C4H9
CH2
N
N
N
HN
L
OS
ART
AN
101
2-butyl-4-chloro-1-[4-[2-(1H-tetrazol-5-yl)phenyl]benzyl]imidazole-5-methanole
1
2
N3
Cl
4
5
Losartanisthe first angiotensionII A
T1receptorantagonist
Potassiumsalt isusedorally. How??Fromwhere canit give
Ksalt?Brandname :Cozaar
Tetrazoleringhasacidiccharacter and
resemblesthe acidicfunctionof
angiotensionII duringreceptor
interaction.

ANGIOTENSIN II ANT
AGONIS
TS
N
N
HOH2C C4H9
CH2
N
N
N
HN
L
OS
ART
AN
Cl
Extensivefirst-pass metabolism
N
N
Cl
C4H9
CH2
N
N
N
HN
HOOC
Thismetabolite isclosely15 times more
potent than the parent compound
oxidation
102

ANGIOTENSIN II ANT
AGONIS
TS
SYNTHESISOFLOSART
AN
NaOCH3
N
N
HOH2C
+
4'-(bromomethyl)-[1,1'-biphenyl]-2-carbonitrile
(2-butyl-4-chloro-1H-imidazol-5-yl)methanol
Cl
C4H9
CH2
NC
NaN3
N
N
HOH2C
Cl
C4H9
CH2
N
N
N
HN
103

ANGIOTENSIN II ANT
AGONIS
TS
V
ALSART
AN
2-[N-[4-[2-(1H-tetrazol-5-yl)phenyl]benzyl]pentanamido]-3-methylbutanoic acid
104

(c) ReninInhibitors
105

RENIN INHIBITORS
Renin
Angiotensinogen AngiotensinI AngiotensinII
Reninisa circulatingenzymesecretedbykidneysin responseto decreased
glomerular filtration rate.
Inhibitorsof renin, byreducingthe biosynthesisof angiotensionII, haveusefulness
in managingcardiovasculardiseasessuchashypertensionandheart failure .
Renininhibitorshavebeeninvestigatedmorethan 30 years;first memberof this
class,Aliskiren,hasbeenintroducedinto therapy in 2007.
AngiotensionIII
AC
E Glu-AP
106

RENININHIBITORS
ALISKIREN
(5S,7S)-N-(3-amino-2,2-dimethyl-3-oxopropyl)-4,5-dihydroxy-2-isopropyl-7-(4-methoxy-
3-(3-methoxypropoxy)benzyl)-8-methylnonanamide
It isthe first renin inhibitor approvedbyFDAashypertensivein2007.
107

CLASSIFICA
TIONOFTHEANTIHYPERTENSIVEDRUGS
Diuretics
CentrallyActingSympatholytics
1-AdrenergicReceptor Blockers
-AdrenergicReceptorBlockers
Other Drugs
108

CALCIUMCHANNELBLOCKERS
CalciumChannelBlockerscanbeclassifiedaccordingto their chemical
structures as follows:
BenzothiazepineDerivatives
Diltiazem
Aralkylamine Derivatives(DiphenylalkylamineDerivatives)
Verapamil
1,4-DihydropyridineDerivatives
Nifedipine,nicardipineamlodipineand others
Theeffects of thesethree classesonmyocardiumandthe arteries vary from
oneclassto the other
Prof. Dr.ErçinERCİY
AS,May 8,2018
109

Benzothiazepines(diltiazem) andAralkylamines(verapamil) affect boththe
hearth and arteriols
Diltiazem
Verapamil
Nifedipine,nicardipine,amlodipineand others
Therefore, benzothiazepines(diltiazem) andAralkylamines(verapamil) are used
clinicallyasantianginal, antiarrhythmicand antihypertensive
114

Dihydropyridines have much less affect on cardiac tissues and higher
specificityfor the arteriols.
Diltiazem
Verapamil
Nifedipine,nicardipine,amlodipineand others
Therefore, Dihydropyridines are used frequently as antianginal and
antihypertensive
111

CLASSIV AGENTS
(CALCIUMCHANNELBLOCKERS)
112
Takenfrom antiarrhythmic drugs section

EMU-SPRINGTERM
VERAPAMIL
C
LAS
S IV
5-((3,4-Dimethoxyphenethyl)(methyl)amino)-2-(3,4-dimethoxyphenyl)-2-
isopropylpentanenitrile
113

EMU-SPRINGTERM
VERAPAMIL
Verapamil works by relaxing the muscles of heart and
blood vessels.
It has been used in the treatment of hypertension,
angina pectoris, cardiac arrhythmia. It has also been
usedasa vasodilator.
114
C
LAS
S IV

EMU-SPRINGTERM
DIL
TIAZEM
C
LAS
S IV
115

EMU-SPRINGTERM
DILTIAZEM
Diltiazem is usedfor treating:
Heart pain (angina),
High blood pressure,
Abnormal heart rhythms.
It is based upon a thiazepinering.
116
C
LAS
S IV

EMU-SPRINGTERM
BEPRIDIL
C
LAS
S IV
It hasinhibitory effectsonboththe slowcalciumandfast sodiuminward
currentsin myocardial andvascularsmooth muscle.
3
117
2
1
1

MISCELLANEOUS
TACHYARRHTHYMİCAGENTS

EMU-SPRINGTERM
ADENOS
INE MISCELLANEOUS
2
119
1
4
5
6 7
9

R1
R2
R3
CH CH NH
OH
R5
BRADYCARDIA
R4
Compound R1 R2 R3 R4 R5
Ephedrine
2-(methylamino)-1-phenylpropan-1-ol
-H -H -H -CH3 -CH3
Isoproterenol (isoprenaline) -OH -OH -H -H -
1-(3,4-Dihydroxyphenyl)-2-
isopropylaminoethanol
CH(CH3)2
Metaproterenol (orciprenaline) -OH -H -OH -H -
1-(3,5-Dihydroxyphenyl)-2-
isopropylaminoethanol
CH(CH3)2
Terbutaline
1-(3,4-Dihydroxyphenyl)-2-tert-
-OH -H -OH -H -C(CH3)3
butylaminoethanol
120

Antihypertensive Drugs.pptx

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