Antihypertensive Drugs

Lecture-Pharm D
Medicinal Chemistry
DR.P.Valentina,M.Pharm,Ph.D.,
Professor& Head,
Dept of Pharmaceutical Chemistry,
SRM College of Pharmacy
 HYPERTENSION
y Hypertension is not a disease
y It is an arbitrarily defined disorder to
which both environmental and genetic
factors contribute
y Hypertension - An inc. in BP such that
systolic is > 140 mm/Hg & diastolic > 90
mm/Hg on 2 or more occasions after
initial screening
y
™Essential Hypertension= most 
common. About 90% of clients.
* Exact Origin unknown.Contributing
Factors ‐ family hx,  hyperlipidemia, 
diabetes, obesity, aging, stress, excessive 
ETOH & smoking.
™Secondary Hypertension is about 10% , 
related to endocrine or renal disorders
 Stages Of Hypertension
Stage Systolic Diastolic Range
Range (mm/Hg)
(mm/Hg)
High 85-89 130-139
Normal
Stage-1 90-99 140-159
Stage-2 100-109 160-179
Stage-3 >109 >179
 CLASSIFICATION
1) Sympatholytic drugs
- Centrally acting antiadrenergic agents.
- Adrenergic neuron blocking agents.
- Alpha adrenergic blockers.
- Beta adrenergic blockers.
- Alpha-beta adrenergic blockers.
2) Vasodilators
- Nitric oxide releasers.
- Potassium channel openers.
- Calcium channel blockers.
3) Diuretics
- Thiazides and congeners.
- Loop diuretics.
- Potassium-sparing diuretics
4) Angiotensin inhibitors and
antagonists.
- Angiotensin Converting Enzyme
(ACE) inhibitors.
- Angiotensin receptor antagonists.
 Central Sympatholytics (α-2 Agonists)
Drugs: clonidine (Catapres), methyldopa (Aldomet)
1. Site of Action
CNS medullary
cardiovascular centers
clonidine; direct α-2 agonist
methyldopa: “false neurotrans.”
2. Mechanism of Action
Stimulate Alpha-2 receptors Æ dec. sympathetic
activityÆ dec. epi., norepi. & dec.renin release Æ dec.
peripheral vascular resistance
|Clonidine (Catapres)
Cl Cl
H H
N N

R N R N
H
N N
H
Cl Cl

Name R
Clonidine H
4-Hydroxyclonidine OH
Apra Clonidine NH2

Clonidine is an example of phenyl imino imidazoline derivative that

possesses selective a2 - adrenergic receptor.
 Synthesis
Cl Cl Cl
S SH
NH 4 SCN
NH 2 NH . C - NH NH . C = NH
2
NH 3

Cl Cl
Cl

- HI CH 3 I

Cl Cl
H NH 2 NH
N 2 SCH 3

H 2C CH 2 NH . C = NH
NH
- CH 3 SH
N - NH 3
Cl
Cl

ADR: Dry mouth, drowsiness, headache and constipation.

Dose: 50-100 μg tid.
Use: Selective a2 - adrenergic receptor. It is used as
antihypertensive agent. It possess sedative property and used for
withdrawal syndrome of opioid analgesic.
 Methyldopa (Aldomet)

ADR: Peripheral oedema, mental depression, anxiety and nightmares.

Dose: 250mg bid - tid for 2 days. Maximum dose is 3g daily.

Use: It is drug of choice for treating hypertension during pregnancy.

CH 3

HO CH 2 - C - NH 2

COOH

HO

L – a – methyl – 3, 4 - dihydroxy
phenyl alanine.
BETA-ADRENERGIC ANTAGONISTS

´ All these agents block the effects of endogenous and

exogenous catecholamine. These drugs slow the heart
rate and decrease the force of contraction.
β-Blockers are classified into two main types:
i) Aryl ethanol amines: eg. Isoproterenol, Dichloro
isoproterenol, Pronethalol.
ii) Aryloxy propanol amines: eg. Propranolol, Nodolol,
Practolol, Metaprolol.
´ Therapeutic uses of β-blockers: Used in the treatment
hypertension, coronary artery disease, arrhythmiasis
and open angle glaucoma.
 Structure Activity Relationship

´ β - blockers are structurally similar to β - agonist. The

catechol ring can be replaced by a variety of ring system
without loss of antagonistic activity.
´ Replacement of catechol hydroxyl group with chlorine or
phenyl ring system retains β-blocking activity. eg.
Pronethalol, Dichloro isoproterenol.
´ N, N - disubstitution decreases β-blocking activity.
Activity is maintained when phenyl ethyl, hydroxy phenyl
ethyl or methoxy phenyl ethyl groups are added to amine
as a part of the molecule.
Aryloxy Propanolamines O
Ar OH
NH R

A r = a ro m a tic rin g s tru c tu re

R = b u lk y a lk yl g ro u p (is o p ro p yl o r te rt-b u tyl)

Name Ar R

Metoprolol – CH (CH3)2
CH 3 - O (CH 2 ) 2

Atenolol – CH (CH3)2

Acebutolol NH2 - CO . CH 2
– CH (CH3)2

CH3 - (CH2)2 CO . NH
Propranolol – CH (CH3)2
COCH3
 General Method Of Preparation of Aryloxy propyl amine

Ar . OH + H2C CH CH2 Cl Ar . O . CH2 . CH . CH2 Ar.O.H2C - HC CH CH2 Cl

- HCl
O OH Cl
O
Chlorhydrin Epoxide

Aminolysis
RNH2 - HCl

Ar . O . CH2 . CH - CH2 . NH . R

OH

Mechanism of action:
a) in heart (they reduce cardiac contractility and CO).
b) in kidney (they reduce renin release by sympathetic nerves)
- Na loss by kidney (leading to BV reduction)
- vascular relaxation in some vascular beds.
c) in the CNS (controversial)
Side-effects
´ Bronchoconstriction (minimized by using beta-1 selective
drug; bad for asthmatics)
´ Increase in LDL/HDL ratio (bad for atherosclerosis)

´ Depression, loss of energy (CNS effect)

´ Increase AV node refractoriness (good for SVTs but could be

bad if abnormal SA or AV nodes)
´ Decreased cardiac contractility (good for angina, good or bad
for CHF)
.Propranolol (Betacap, Ciplar)

OH

O - CH2 . CH - CH2 - NH . CH (CH3)2

1-(Isopropyl amino) -3- (1-naphthyloxy)-2- propanol

ADR: Cold extremities, insomnia, fatigue and dizziness.

Dose: Initially, 40-80 mg bid, usual range is 160-320mg daily.

Use: Effective antihypertensive agent. It is also used to treat

arrhythmiasis, angina pectoris, post myocardial infarction, migraine
prophylaxis and essential tremor.
Atenolol (Hipres, Manoten)

OH

O . CH2 . CH - CH2 . NH . CH (CH3)2

CH2 CONH2

4-{2-Hydroxy - 3 - [(1-methylethyl) amino] propoxy} - benzeneacetamide.

ADR: Bronchospasm, cold extremities, fatigue and

dizziness.
Dose: 25 - 100mg daily as a single dose.
Use: It is a b1 - selective drug with low lipid solubility.
Mainly used in the treatment of essential hypertension
Mixed a and b - adrenergic blockers
A. Labetolol (Labesol, Normadate)
OH

CH - CH2 . NH . CH . CH2 . CH2

CH3

HO

CONH2

5-{1-Hydroxy -2- [(1-methyl -3-phenylpropyl) amino} ethyl] salicylamide

Competitive inhibitor of β1, β2 and α1 adrenergic receptor. It is
optically active because it has two optically active centers.1R, 1'R
isomer possess β-antagonistic activity and 1S,1'R isomer possess α -
antagonistic activity
ADR: Orthostatic hypotension, dizziness and fatigue Dose: initially
100mg bid, increase gradually according to patient response to 200-
400mg bid.
Use: It is used to treat chronic hypertension of pheochromocytoma and
hypertensive crisis.
B. Carvedilol (Carvil, Caslot)

OCH3

O - CH2 - CH CH2 . NH . CH2 . CH2O

OH

N
H
1-(9H-Carbazol-4-yloxy) -3- [2-(2-methoxy phenoxy) ethyl amino] - 2 -
propanol.

Both β and α- adrenergic blocking agent. Only S isomer is

β- blocking and both enantiomers have α- blocking activity.
Synthesis

OCH2 HC CH2
OCH3
O CH2CH2NH2

4-(2,3-Epoxy-1-propoxy) carbazole 2-(2-Methoxy phenoxy) ethylamine

OCH3

O - CH2 - CH CH2 . NH . CH2 . CH2O

OH

N
H
Carvedilol
ADR: Bradycardia, atrio ventricular block, angina
pectoris and hypervolaemia.

Dose: Initially, 12.5mg once daily increased to 25mg

once daily after 2 days. If necessary may increase to
50mg once daily or in divided dose.

Use: It is used to treat hypertension and congestive

heart failure.
Α– ADRENERGIC BLOCKING AGENTS
Mechanism of Action
Competitive antagonist at α−1 receptors
on vascular smooth muscle.

Site of Action- peripheral arterioles,

smooth muscle

Blocking α-receptors on vascular smooth

muscle allows
muscle relaxation, dilation of vessel, and
reduced resistance
 O
A c yl
Q u in a z o lin e r in g m o ie ty
N R
H 3 CO N N

N P ip e r a z in e r in g
H 3 CO
NH 2

P r a z o s in : R =
(M in ip r e s ) O

T e r a z o s in : R =
(H y tr in ) O
O
D o x a z o s in : R =
(C a r d u r a )
O

Quinazoline derivative and possesses quinazoline, piperazine and

acyl moieties.
The presence of 4th amino group and hetero moiety at 2nd position is
essential for α1 receptor antagonistic activity
Prazosin (Minipress, Prazopress)

H3CO N O
N N - CO

N
H3CO
NH2

1-(4-Amino-6, 7 - dimethoxy-2-quinazolinyl)-4- (2-furanyl carbonyl) - piperazine.

ADR: Postural hypotension, syncope, palpitations and lack of energy.

Dose: Initially, 500 μg bid - tid for 3-7 days, increased to 1mg bid
- tid for the next 3 - 7 days. Maximum dose is 20mg daily.
Use: It lowers blood pressure by blocking a1 – adrenoreceptors.
 Vasodilators
Drugs: hydralazine (Apresoline); minoxidil (Loniten);
nitroprusside (Nipride); diazoxide (Hyperstat I.V.);
fenoldopam (Corlopam)
1. Site of Action- vascular smooth muscle
2. Mechanism of action nitroprusside
induces nitric oxide
from endothelial
fenoldopam cells (arterioles
and veins
Activates dopamine(D1)
receptors on VSM
NO
(arterioles)
1. Low doses
dopamine stimulates
DA

↓↓↑
primarily dopamine
receptors-Vasodilation
2. Higher doses-
stimulates B1 receptors-
positive inotropic effect
Increases CO
Also releases NE from
vascular nerve terminals-- Na+ Ca++ K+ minoxidil
vasoconstriction
diazoxide
Ca++ opens K+ channels on
hydralazine arteriolar membranes,
alters intracellular calcium, increases nitric stabilizes membrane
oxide in arterioles
Classification
The vasodilators may be classified as follows.
¾Drugs with predominant venodilatory effect.
Nitrates which reduces preload.
¾Drugs with predominant arteriolar dilating
effect.
Hydralazine, Minoxidil which reduces
after-load.
¾ Mixed arteriolar and venodilator:
ACE inhibitors, Angiotensin
antagonists,Sodium nitroprusside which
reduces both preload and after-load.
Hydralazine (Apresoline)

NH. NH 2

Synthesis 1 - H y d r a z in o p h th a la z in e
O OH

COOH
NH N
+ NH 2 - NH 2
N N
CHO Hydrazine
2-Formyl POCl 3
benzoic acid

NH. NH 2 Cl

N NH 2.NH 2 HCl N

N - HCl N

Hydralazine
 Angiotensin converting enzyme (ACE) inhibitors.
ACE inhibitors
inhibitor
Blood pressure

A-II blockers -
block angiotensin II
from receptors in
blood vessels,
adrenals, and all
other tissues.
 Angiotensin converting enzyme
(ACE) inhibitors
¾ Sulfhydryl containing inhibitors.
eg. Captopril
¾ Dicarboxylate containing inhibitors:
eg. Enalapril, Lisinopril, Quinapril, Ramipril,
Trandopril, Spirapril, Moxeipril, Benazepril
¾ Phosphonate containing inhibitor: eg. Fosinopril

Angiotensin
antagonists
Losartan, Irbesartan, Candesartan,
Telmisartan,Valsartan.
Angiotensin converting enzyme is a zinc containing glycoprotein
The important binding sites of ACE are cationic
site to attract carboxylate ion
Zinc ion that can polarize the carbonyl group
of amide function to make it more susceptible to hydrolysis.

(CH2)n Zn + +
binding C
group
N Ring

X
Zn + +
binding groups: - CH2 SH, Sulfhydryl group
- CH - NH - Carboxylate group

COOH

P OH Phosphate group
O
Fig. 20.2. Active site of ACE inhibitors
 Among the three zinc binding group, sulfhydryl group is
superior, but they form disulfide which may result in shorter
duration of action.
9N - ring must contain a carboxylic acid group to mimic the C -
terminal carboxylate of ACE substrate.
9Larger hydrophilic heterocyclic in the N - ring increase the
potency and alter pharmacokinetic properties.
9X - is usually a methyl group, which mimic the side chain alanine
of the ACE substrate.
9When the stereochemistry of inhibitor is consistent optimum
activity occurs with L-amino acid.
 Sulfhydryl Containing Inhibitors
CH3

HS.CH2 - CH - CO

Captopril (Aceten, Capotril) N COOH

H
Synthesis
1-[(2S) -3- Mercapto - 2 - methyl - 1- oxo propionyl] proline

H
COOH COOH COCl N
COOH
HCl SOCl2
CH2 = C - CH3 Cl. CH2.CH - CH3 Cl. CH2.CH - CH3 +
Addition
2- Methyl -2- reaction 2- Methyl -3- chloro
propenoic acid propanoic acid Pyrrolidine -2-
carboxylic acid

- HCl

CH3 CH3
NH4SH / CH3OH
HSCH2 - CH - CO CO CH - CH2 Cl

N
N COOH COOH

Captopril

ADR: Hypotension, tachycardia, chest pain and palpitation.

Dose: Initially, 12.5 mg bid or 6.25mg bid in combination with diuretics.
Use: It is used in condition such as post myocardial infarction, congestive
heart failure and preservation of kidney function in diabetic nephropathy.
Dicarboxylate containing ACE inhibitors

Enalapril (Invoril, Enamate)

COOH
COOC2H5 CH3

CH2 CH2. CH - NH - CH - CO N

1- [N(S) -1-Carboxy -3- phenyl propyl] -L- alanyl] -L- proline -1' - ethylester

Enalapril is a prodrug of Enalaprilate.

It is devoid of side effects of rash and loss of taste seen in Captopril.
It is hydrolyzed in the liver by esterase to active dicarboxylic acid
Enalaprilate.
ADR: Initial hypotension may be severe and prolonged. Dizziness,
headache and fatigue.
Dose: 5mg at bed time. Increased up to 40mg in divided doses.
Use: A prodrug of Enalaprilate, longer acting ACE inhibitor used in the
treatment of reno vascular, essential and malignant hypertension and
congestive heart failure.

Lisinopril (Dilace, Linvas)

COOH (CH2)4.NH2

CH2. CH2 - CH - NH - CH - CO

N
COOH

1-[N2 - (S) -1-carboxy -3- phenyl propyl] -L- lysyl] - L proline dihydrate

It is a lysine analogue of Enalaprilate.

ADR: Dizziness, headache, fatigue and cough.
Dose: 5 -10mg daily given at bed time
Use: It is an ACE inhibitor used in the treatment of reno vascular
essential and malignant hypertension and also for ventricular
congestive heart failure.
 Phosphonate Containing ACE inhibitor
Fosinopril (Fovas)

O O

(CH 2 ) 4 P CH 2 C N
COOH
O H

(CH 3 ) 2 CH - CH.OCOC 2H 5

(4S) - 4- cyclohexyl - 1- {[[(RS) - 1- hydroxy - 2- methyl propoxyl] -4-(phenyl

-butyl) phosphinyl] acetyl} -L- proline propionate

It serve as a prodrug, it is hydrolyzed to active diacid

Fosinoprilate.
ADR: Dizziness, orthostatic hypotension, palpitation and
headache.
Dose: Initially, 10mg once daily at bedtime. Maintenance dose
of 10-40mg.
Use: It is used for the treatment of hypertension and some types
of chronic heart failure
 ANTIHYPERTENSIVE AGENTS

´ Angiotensin II receptor Antagonists (Blockers) - A - II

Blockers
Losartan (Cozaar)
- Newer drugs similar to ACE inhibitors + prevent release
of aldosterone (Na+ retaining hormone)
- Act on renin - angiotensin system
- Diff between ACE &AII is A-II blockers block angiotensin
from angiotensin I receptors found in many tissues -
blocks at receptor site.
- A-II blockers cause vasodilation & dec. peripheral
resistance
Losartan (Resilo, Covance, Cosart)

CH2OH Cl

CH2 N

N
N NH (CH2)3CH3

N N
2- Butyl -4- chloro -5- hydroxy methyl -1- {[2'(1H -
tetrazol - 5- yl) - biphenyl -4 - yl] methyl} imidazole

It was the first non – peptide imidazole to be introduced as an orally active

angiotensin-II antagonist. It inhibits competitively angiotensin-II to
produce vasodilator effect.
ADR: Headache, dizziness, back pain and myalgia.
Dose: 50mg once daily, increased to 100mg daily as a single dose or in 2
divided doses if needed.
Use: It is used as antihypertensive agent and also in the treatment of heart
failure.
 Calcium Channel Blockers

- Free calcium muscle contractility, peripheral resistance &

BP .
So, Calcium blockers
- Dec. calcium levels & promote vasodilation
- SE. Flushing, HA, dizzyness, ankle edema, bradycardia, AV node
block,

™ 1, 4 - Dihydro pyridine

™ Benzothiazepine derivatives
1, 4 - Dihydro pyridine

Following structural feature is important for activity

R1
4 COO R3
R2 OOC
5 3
6
H3C 1N 2 CH3
H

ð A phenyl ring substitution at 4th position optimizes activity.

Substitution at para or unsubstituted phenyl ring decreases the
activity.
ð 1, 4 - Dihydro pyridine ring is essential for activity. Substitution at
N, or oxidation or reduction of the ring decreases or abolishes the
activity.
ð The 3rd and 5th position ester group optimizes activity. Any other
electron withdrawing substitution results in agonist activity.
ð When the ester at C3 and C5 are non - identical the C4 become
chiral and stereoselectivity is observed. S- enantiomers have proved
to be more effective.
 X

4
R 2 OOC 5 COOR 3
3

R1 6 2 CH 3
N 1
H

Compounds R1 R2 R3 X

Amlodipine – CH2 O (CH2)2 NH2 – C2H5 – CH3 2 -Cl

Felodipine – CH3 – C2H5 – CH3 2,3 - Cl2

Nifedipine – CH3 – CH3 – CH3 2 - NO2

Nitrendipine – CH3 – CH3 – C2H5 3 - NO2

Nimodipine – CH3 – CH2 CH2 O CH3 – CH (CH3)2 3 - NO2

Nisoldipine – CH3 – CH2 CH (CH3)2 – CH3 2 - NO2

 Amlodipine (Amlibon, Stamlo, Vamlo)

HO CHCOOC 2H 5
O CH 2 COOC 2H 5 O CH 2 COOC 2H 5
C
HOH 2 CH 2 C-N + C Condensation C
CH 2 -O CH 2 .CH 2 .N
- HCl CH 2 -OCH 2 .CH 2 .N
(CH 2 C 6 H 5 ) 2 CH 2 Cl
(CH 2 C 6 H 5 ) 2
N,N' - Dibenzyl Ethyl chloro aceto (CH 2 C 6 H 5 ) 2
Enol form
ethanol amine acetate Keto form

+
H COOCH 3

C
Cl Cyclisation +
H 5 C 2 OOC COOCH 3
- 2H 2 O C
Cl
H 2N CH 3
CHO
Methyl -2- amino -2-
(C 6 H 5 CH 2 ) 2 NCH 2 CH 2 OH 2 C N CH 3 butenoate o- Chloro
H benzaldehyde

Debenzylation -2 C 6 H 5 CH 2 OH
HCl /

Cl
H 5 C 2 OOC COOCH 3

NH 2 CH 2 CH 2 OH 2 C N CH 3
H

Amlodipine
 Nifedipine (Nifedine, Angiblock)

Step – I + CH 3 CO. CH 2 COOCH 3

- H 2O
NO 2 Methyl aceto acetate
NO 2
CHO CH = C - COCH 3
2- Nitro benzaldehyde
COOCH 3

Methyl - [2-acetyl - 3-(2-nitrophenyl)] -2-

propenoate
Step – II

CH 3 COCH 2 COOCH 3 CH 3 - C = CH - COOCH 3 + NH 3 CH 3 - C = CH - COOCH 3

- H 2O
Ethyl aceto acetate OH NH 2
(keto form) Ethyl aceto acetate Methyl -3- amino -2- butenoate
(Enol form)

Step – III: Condensation of steps I and II products

NO2 H NO2
COOCH3
H3COOC C H3COOC COOCH3
H Cyclisation
+
C - H2O
C
H3C N CH3
H3C O H2N CH3 H
Methyl - [2- acetyl -3- (2- Methyl -3- amino -2- Nifedipine
nitro phenyl)] -2- propenoate butenoate
Phenyl Alkylamine Derivative
Verapamil (Calaptin, Vasopten)
H3CO OCH3
CH (CH3)2 CH3

H3CO C (CH2)3. N.(CH2)2 OCH3

CN
5-(3,4-Dimethoxy phenethyl) methyl amino] -2- (3,4 - diemethoxy
phenyl) -2- isopropylvaleronitrile

H3CO OCH3
CH (CH3)2 CH3

H3CO CH.CN + Cl (CH 2)3.N.(CH2)2 OCH3

- HCl
3,4-Dimethoxy phenyl ethyl - N - methyl
3,4- Dimethoxy -2- -3-chloro propyl amine
isopropyl valeronitrile
H3CO OCH3
CH (CH3)2 CH3

H3CO C (CH2)3. N.(CH 2)2 OCH3

CN
Verapamil
Benzothiazepine derivatives
Diltiazem (Coriem XL, Dilgard)
OCH3

O CO CH3

N
O
CH2 CH2. N (CH3)2

(+) - Cis -3- (acetyloxy) -5- [(2 -dimethyl amino) ethyl] - 2,3- dihydro
-2- (4 -methoxy phenyl) 1,5 - benzothiazepin - 4 (5 H) one.