we look at different classes, m.o.a, clinical uses and adverse effects.

1. Lecture-Pharm D
Medicinal Chemistry
DR.P.Valentina,M.Pharm,Ph.D.,
Professor& Head,
Dept of Pharmaceutical Chemistry,
SRM College of Pharmacy
Antihypertensive Drugs

2. HYPERTENSION
Hypertension is not a disease
It is an arbitrarily defined disorder to
which both environmental and genetic
factors contribute
Hypertension - An inc. in BP such that
systolic is > 140 mm/Hg & diastolic > 90
mm/Hg on 2 or more occasions after
initial screening

3. 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

4. Stages Of Hypertension
Stage Systolic
Range
(mm/Hg)
Diastolic Range
(mm/Hg)
High
Normal
85-89 130-139
Stage-1 90-99 140-159
Stage-2 100-109 160-179
Stage-3 >109 >179

6. 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.

7. 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 dec. sympathetic
activity dec. epi., norepi. & dec.renin release dec.
peripheral vascular resistance

8. |Clonidine (Catapres)
Name R
Clonidine H
4-Hydroxyclonidine OH
Apra Clonidine NH2
N
Cl
Cl
R
H
N
N
H
N
H
Cl
Cl
R
H
N
N
Clonidine is an example of phenyl imino imidazoline derivative that
possesses selective a2 - adrenergic receptor.

9. 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.
NH 2
Cl
Cl
NH 3
NH 4 SCN
NH . C - NH 2
Cl
Cl
S
- CH 3 SH
- NH 3
CH 3 I
NH 2 NH 2
H2C CH 2
NH . C = NH
Cl
Cl
SH
NH . C = NH
Cl
Cl
SCH 3
- HI
N
H
N
NH
HCl
Cl
Synthesis

10. Methyldopa (Aldomet)
HO
HO
CH2 - C - NH2
CH3
COOH
L – a – methyl – 3, 4 - dihydroxy
phenyl alanine.
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.

11. 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.
BETA-ADRENERGIC ANTAGONISTS

12. 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.
Structure Activity Relationship

13. Name Ar R
Metoprolol – CH (CH3)2
Atenolol – CH (CH3)2
Acebutolol – CH (CH3)2
Propranolol – CH (CH3)2
CH3 - O (CH 2)2
NH2 - CO . CH2
CH3 - (CH2)2 CO . NH
COCH3
Ar
O NH R
O H
Ar = arom atic ring structure
R = bulky alkyl group (isopropyl or tert-butyl)
Aryloxy Propanolamines

14. General Method Of Preparation of Aryloxy propyl amine
Chlorhydrin
- HCl
Ar . O . CH2 . CH - CH2 . NH . R
OH
Aminolysis
Epoxide
O
CH CH2 ClH2C+Ar . OH Ar . O . CH2 . CH . CH2
OH Cl
O
CH CH2 ClAr.O.H2C - HC
- HClRNH2
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)

15. 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)

16. .Propranolol (Betacap, Ciplar)
O - CH2 . CH - CH2 - NH . CH (CH3)2
OH
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.

17. Atenolol (Hipres, Manoten)
O . CH2 . CH - CH2 . NH . CH (CH3)2
CH2 CONH2
OH
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

18. Mixed a and b - adrenergic blockers
A. Labetolol (Labesol, Normadate)
CH - CH2 . NH . CH . CH2 . CH2
OH
HO
CONH2
CH3
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
5-{1-Hydroxy -2- [(1-methyl -3-phenylpropyl) amino} ethyl] salicylamide
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.

19. B. Carvedilol (Carvil, Caslot)
N
H
O - CH2 - CH CH2 . NH . CH2 . CH2O
OH
OCH3
Both β and α- adrenergic blocking agent. Only S isomer is
β- blocking and both enantiomers have α- blocking activity.
1-(9H-Carbazol-4-yloxy) -3- [2-(2-methoxy phenoxy) ethyl amino] - 2 -
propanol.

20. OCH2 CH2HC
O
+
OCH3
N
H
O - CH2 - CH CH2 . NH . CH2 . CH2O
OH
OCH3
4-(2,3-Epoxy-1-propoxy) carbazole 2-(2-Methoxy phenoxy) ethylamine
CH2CH2NH2
Carvedilol
Synthesis

21. 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.

22. Α– ADRENERGIC BLOCKING AGENTS
Site of Action- peripheral arterioles,
smooth muscle
Blocking α-receptors on vascular smooth
muscle allows
muscle relaxation, dilation of vessel, and
reduced resistance
Mechanism of Action
Competitive antagonist at α−1 receptors
on vascular smooth muscle.

23. N
NH 3 CO
H 3 CO
NH 2
N
N R
O
O
O
O
O
P ra zo s in : R =
T e ra zo s in : R =
D o x a zo s in : R =
Q u in a zo lin e rin g
P ip e ra zin e rin g
A c yl
m o ie ty
(M in ip re s )
(H ytrin )
(C a rd u ra )
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

24. Prazosin (Minipress, Prazopress)
N N - CO
O
NH2
H3CO
N
N
H3CO
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.

25. 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
minoxidil
diazoxide
hydralazine
fenoldopam
NO
nitroprusside
Ca++
Ca++Na+ K+
↑↓↓
DA
alters intracellular calcium, increases nitric
oxide in arterioles
opens K+ channels on
arteriolar membranes,
stabilizes membrane
induces nitric oxide
from endothelial
cells (arterioles
and veins
Activates dopamine(D1)
receptors on VSM
(arterioles)
1. Low doses
dopamine stimulates
primarily dopamine
receptors-Vasodilation
2. Higher doses-
stimulates B1 receptors-
positive inotropic effect
Increases CO
Also releases NE from
vascular nerve terminals--
vasoconstriction

26. Classification
The vasodilators may be classified as follows.
Drugs with predominant venodilatory effect.
Nitrates which reduces preload.
Drugs with predominant arteriolar dilating
effect.
Hydralazine, Minoxidil which reduces
after-load.
Mixed arteriolar and venodilator:
ACE inhibitors, Angiotensin
antagonists,Sodium nitroprusside which
reduces both preload and after-load.

27. N
N
NH. NH 2
1 - H yd ra zin o p h th a la zin e
CHO
COOH
+ NH2 - NH2
N
NH
N
N
OHO
N
N
NH. NH 2
N
N
Cl
2-Formyl
benzoic acid
Hydrazine
POCl 3
NH2.NH2 HCl
- HCl
Hydralazine
Hydralazine (Apresoline)
Synthesis

28. Angiotensin converting enzyme (ACE) inhibitors.
Blood pressure
ACE inhibitors
inhibitor
A-II blockers -
block angiotensin II
from receptors in
blood vessels,
adrenals, and all
other tissues.

29. Sulfhydryl containing inhibitors.
eg. Captopril
Dicarboxylate containing inhibitors:
eg. Enalapril, Lisinopril, Quinapril, Ramipril,
Trandopril, Spirapril, Moxeipril, Benazepril
Phosphonate containing inhibitor: eg. Fosinopril
Angiotensin converting enzyme
(ACE) inhibitors
Losartan, Irbesartan, Candesartan,
Telmisartan,Valsartan.
Angiotensin
antagonists

30. 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
group
C
O
N Ring
X
Zn + +
binding groups: - CH2 SH,
- CH - NH -
COOH
P OH
O
Sulfhydryl group
Carboxylate group
Phosphate group
Fig. 20.2. Active site of ACE inhibitors

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

32. 1-[(2S) -3- Mercapto - 2 - methyl - 1- oxo propionyl] proline
N COOH
HS.CH2 - CH - CO
CH3
H
CH2 = C - CH3
COOH
Cl. CH2.CH - CH3
COOH
HCl SOCl2
Cl. CH2.CH - CH3
COCl
+
H
N
COOH
N COOH
HSCH2 - CH - CO
CH3
NH4SH / CH3OH
Addition
reaction
- HCl
N
COOH
CO CH - CH2 Cl
CH3
2- Methyl -2-
propenoic acid
Captopril
2- Methyl -3- chloro
propanoic acid Pyrrolidine -2-
carboxylic acid
Sulfhydryl Containing Inhibitors
Captopril (Aceten, Capotril)
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.
Synthesis

33. Dicarboxylate containing ACE inhibitors
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.
CH2 CH2. CH - NH - CH - CO N
COOH
COOC2H5 CH3
1- [N(S) -1-Carboxy -3- phenyl propyl] -L- alanyl] -L- proline -1' - ethylester
Enalapril (Invoril, Enamate)

34. 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.
1-[N2 - (S) -1-carboxy -3- phenyl propyl] -L- lysyl] - L proline dihydrate
CH2. CH2 - CH - NH - CH - CO
COOH (CH2)4.NH2
N
COOH
Lisinopril (Dilace, Linvas)
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.

35. Phosphonate Containing ACE inhibitor
Fosinopril (Fovas)
(CH 2)4 P CH 2 C N
H
COOH
O
(CH 3)2 CH - CH.OCOC 2H5
(4S) - 4- cyclohexyl - 1- {[[(RS) - 1- hydroxy - 2- methyl propoxyl] -4-(phenyl
-butyl) phosphinyl] acetyl} -L- proline propionate
O O
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

36. 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

37. N
N N
NH
CH2
N
N
Cl
(CH2)3CH3
CH2OH
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.
Losartan (Resilo, Covance, Cosart)

38. - 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
Calcium Channel Blockers

39. N
H
R1
COO R3R2 OOC
H3C CH31 2
3
4
5
6
1, 4 - Dihydro pyridine
Following structural feature is important for activity
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.

40. 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
N
H
R 2 OOC
R 1
COOR 3
CH 3
1
2
3
4
5
6
X

41. Amlodipine (Amlibon, Stamlo,Vamlo)
HOH 2CH 2C-N +
(CH 2C6H5)2
N,N' - Dibenzyl
ethanol amine
Ethyl chloro aceto
acetate
- HCl
C
CH 2-OCH 2.CH 2.N
CH 2COOC 2H5O
(CH 2C6H5)2
C
C
H2N CH 3
COOCH 3
Methyl -2- amino -2-
butenoate
+
CHO
Cl
o- Chloro
benzaldehyde
C
CH 2-O CH 2.CH 2.N
CHCOOC 2H5
(CH 2C6H5)2
Enol form
- 2H2O
N
H
COOCH 3
CH 3
H5C2OOC
Cl
Debenzylation -2 C 6H5CH 2OH
N
H
COOCH 3H5C2OOC
Cl
Amlodipine
Keto form
+
HO
H
(C 6H5CH 2)2NCH 2CH 2OH 2C
NH 2CH 2CH 2OH 2C CH 3
C
CH 2Cl
CH 2COOC 2H5O
Condensation
Cyclisation
HCl /

42. Nifedipine (Nifedine, Angiblock)
CH 3 CO. CH 2 COOCH 3
NO 2
+
NO 2
CH = C - COCH 3
2- Nitro benzaldehyde
Methyl aceto acetate
CHO
- H 2O
Methyl - [2-acetyl - 3-(2-nitrophenyl)] -2-
propenoate
COOCH 3
CH3 COCH 2 COOCH 3 CH3 - C = CH - COOCH 3
NH2
- H2O
CH3 - C = CH - COOCH 3
OH
(Enol form)
+ NH 3
Ethyl aceto acetate
(keto form) Ethyl aceto acetate Methyl -3- amino -2- butenoate
C
H3COOC
H
H3C
+
C
C
CH3H2N
COOCH3H
N
H
NO2
H3COOC COOCH3
CH3
O
NO2
H3C
- H2O
NifedipineMethyl -3- amino -2-
butenoate
Methyl - [2- acetyl -3- (2-
nitro phenyl)] -2- propenoate
Cyclisation
Step – III: Condensation of steps I and II products
Step – I
Step – II

43. Phenyl Alkylamine Derivative
Verapamil (Calaptin, Vasopten)
CH3
CH3CO
CH (CH3)2
CN
(CH2)3. N.(CH2)2
OCH3
OCH3
H3CO
5-(3,4-Dimethoxy phenethyl) methyl amino] -2- (3,4 - diemethoxy
phenyl) -2- isopropylvaleronitrile
CH3
CH.CNH3CO
CH (CH3)2
+ Cl (CH2)3.N.(CH2)2
OCH3
CH3CO
CH (CH3)2
CN
(CH2)3. N.(CH2)2
OCH3
OCH3
H3CO
CH3
H3CO
Verapamil
3,4-Dimethoxy phenyl ethyl - N - methyl
-3-chloro propyl amine
- HCl
3,4- Dimethoxy -2-
isopropyl valeronitrile
OCH3

44. O CO CH3
OCH3
CH2 CH2. N (CH3)2
N
S
O
(+) - Cis -3- (acetyloxy) -5- [(2 -dimethyl amino) ethyl] - 2,3- dihydro
-2- (4 -methoxy phenyl) 1,5 - benzothiazepin - 4 (5 H) one.
Benzothiazepine derivatives
Diltiazem (Coriem XL, Dilgard)