Introduction, classification, SAR and Mechanism of action

1. ANTIHYPERTENSION
By, Masooma Nafiya.M
1st M.pharm
Department of pharmaceutical chemistry
Al-ameen college of pharmacy

2.  Definition
It is defined as a physiologic condition where there is an
increase in the arterial blood pressure above normal.
 •Normal B.P is 120/80 mm Hg.
 •An individual is hypertensive when B.P is >140/90 mm Hg.
INTRODUCTION

3. Hypertension
Primary hypertension or Secondary hypertension
essential hypertension or malignant hypertension.
INTRODUCTION

4. Primary hypertension:
 Common form of hypertension tension
 Blood pressure becomes above normal
 The precise etiology is not known .
INTRODUCTION
Factors :-
Dietary intake of more sodium and less potassium.
Herediatary.
Advancement of age.
Decreased vascular synthesis of Nitric oxide (No)

5. Secondary hypertension:
 the etiology is known
 system which are responsible of controlling the arterial blood
presssure.
INTRODUCTION
Factors :-
Renal disease.
Adrenal disease.
Muscular disorders.
Renal artery stenosis.
oral contraceptives.
Toxemia of pregnancy.
Encephalitis.
Increased intra cranial
pressure.
Thyrotoxicosis.

6.  The system which are responsible for arterial blood
pressure control are :
1. CNS
2. Sympathetic ganglia
3. Adrenergic nerve ending
4. Vascular smooth muscle
5. Kidney
6. Arterioles
INTRODUCTION

7. Sl no class examples structures
1 β-adrenergic blockers Propranolol
Timolol
2 Angiotensin enzyme
inhibitors
Captopril
Enalapril

8. 3 Diuretics Spironolactone
hydrochlorthiazides
4 Ca²⁺ channel blockers Nifedipine
Amlodipine
NH
S
N
H
OO
Cl
H2NO2S
N
H
O CH3
O
O
O
O
CH3
O
NH2
Cl

9. 5 Peripheral anti-adrenergic drug
/α₁ antagonist
prazosin
6 Centrally acting agent /α₂ agonist Clonidine
Guanithidine

10. 7 Angiotensin ∥ receptor
antagonist
Losartan
Valsartan
8 Direct vasodilator Hydralazime
Minoxydil
9 Ganglionic blocking agent Trimethaphan
camsylate
Mecamylamine
N
N
NH NH2

16. β-adrenoreceptors
Mostly found in cardiac muscles. Mostly found in bronchial and
vascular muscles.
β₁-adrenoreceptors β₂-adrenoreceptors

17. β-adrenergic blockers
Drugs exhibiting same affinity towards Drugs showing higher affinity
β₁ and β₂ adrenoreceptors. towards β₁ adrenoreceptors.
Ex:- propranolol, timolol. Ex:-Atenolol.
Non-selective blockers Selective/cardioselective
blockers

18. Sympathetic nervous system
Catecholamines which in turn activates β-receptors of heart
β-adrenergic receptor blockers reversibly bind with β-adrenergic
Receptive regions and prevent the activation of the receptors ,
β-receptors of the heart
Slow the heart beat
release
Hence
1
MOA

19. Reduce the force of contraction
Reduce cardiac output
Reduced hypertension
These drugs also reduce the plasma levels of angiotensin ∥(a
potent vasoconstrictor)
2

20.  the substitution of two methylene moeities in the side chain,
enhance the metabolic stability and it destroy the activity.
 Replecement (Bioisosteric replacement) of ethereal linkage
with bioisoster like –S-, -NH₃,-CH₂ was found to have less
potent activity.
 Secondary amine is favorable for potent biological activity

21.  Introduction of larger alkyl substituition than isopropyl are
found to be less potent.
 -OH bearing carbon of aryloxypropanol as side chain plays a
vital role in the interaction of the drug with the β receptors.
 Introduction of substitution at para position of aromatic ring in
the absence of meta substitution, converts a nonselective
antagonist to a cardio selective antagonist .
O NH
CH3
CH3OH

22. ➢ Sulfhydryl containing inhibitors.
 eg. Captopril
➢ Dicarboxylate containing inhibitors:
 eg. Enalapril, Lisinopril, Quinapril,
Ramipril, Trandopril, Spirapril,
Moxeipril, Benazepril
➢ Phosphonate containing inhibitor: eg.Fosinopril

23. ACE inhibitors
inhibitor
Blood pressure
A-II blockers - block
angiotensin II from
receptors in blood
vessels, adrenals,
and all other
tissues.
MOA

24.  The zinc binding groups such as sulphydryl group, carboxylic
group or phosphoric groups are essential for the stabilisation
of the binding.
Among these 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.

25.  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

26.  A diuretic is any substance that promotes diuresis, that is, the
increased production of urine.
Thiazide
diuretics
Loop
diuretics
Potassium
sparing
diuretcs
Aldasterone
antagonist
DIURETICS

27. MOA

28. MOA

29. MOA

30. MOA

31. MOA

32.  The position 2 can tolerate the presence of relatively
small alkyl groups such as –CH₃
 Substitution in the 3rd position play a dominant role in
determining the potency and duration of action of
thiazide diurectics.
 Loss of carbon carbon double bond between 3rd and 4th
position of nucleus increases the diuretic potency.
NH
S
N
OO
H2NO2S
R
1
R

33.  Direct substitution of the 4th , 5th , 8th , position with alkyl
goup usually results in diminished diuretic activity.
 Substitution of the 6th position with an activating group is
essential for the diuretic activity
 The sulphamoyl group in the 7th position is essential for the
diuretic property.

35. MOA

36. Calcium ions play a vital role in vascular smooth
muscle contraction
Calcium enters cells through specialized pores in the
membrane wall called calcium chanels
These calcium channels are activated by voltage operated
membrane depolarisation
MOA

37. Calcium channel blocking agents block voltage dependent
calcium channels, especially the calcium channels in cardiac
and smooth muscles by decreasing calcium influx during
action potential
They reduce systolic intracellular calcium concentration and
muscle contactility because of this arteriole vasodialation take
place which ultimately leads to decrease in blood pressure.
MOA

38.  Substitution at 1st position on N reduces the biological activity
 Methyl group substitution is highly designed at 2nd position. It
increases the potency, where as, other alkyl substitution lead to
diminished activity.
 Presence of ester group at 3rd position is very much desired for
the activity. substitution of –NO₂ group at 3rd position may
decrease the activity.
 Presence of phenyl group at 4th position is essential for the
activity as substitution of non-polar alkyl or cyclo alkyl groups
reduces the activity.
 Substitution at R of ester of 5th position by a electron
withrawing groups decreases the activity.
N
H
RCH3
COOR
1
R
11
OOC

39. Α₁-adrenoreceptors act by phospolipase activation which
forms inositol triphosphate.
Inositol triphosphate and diacylglycerol together act as
secondary messenger which tranduce signal to blood vessels
for vasocontriction
Α₁-antagonist lower blood pressure by blocking α₁-
adrenoreceptors by facilitating relaxation of blood vessels
MOA

40.  Example :-

41. These drugs act by stimulation of α₂-andrenoreceptors
α₂-agonists interact with these receptors and supress the
vasomotor entre neurons of medulla oblongata, which causes
reduction of hypothalamus activity ,
This leads to a decline in sympathetic impulses to the vesssels
and the heart, due to which cardiac output and heart rate are
moderately reduced and consequently arterial blood pressure
is reduced

42.  Examples :-
Clonidine :-
Guanithidine :-

43. These drugs compete with Angiotensin ∥ and block the contraction
effect of angiotensin in all vascular smooth muscles
Examples :- Losartan,
Valsartan
MOA

44.  There are three functional groups which are important for
biological activity
 The imidazole ring is essential as it binds to Asn²⁹⁵amine at
the active site of the receptor.
 The biphenyl-methyl group is desired for the activity as it
binds to amino acids like Tri³⁵³ ,His ²⁵⁶ at the active site of the
receptor.
 The tetrazole group binds with Arg¹⁶⁷ and Lys ¹⁹⁹ amino acids
to provide essential bioactivity.

45. Site of Action- vascular smooth muscle nitroprusside
induces nitric oxide
from endothelial
cells (arterioles and
veins
induces nitric
oxide from
endothelial
cells (arterioles
and veins
hydralazine
alters intracellular calcium, increases nitric
oxide in arterioles
Ca++
NO
minoxidil
diazoxide
opens K+ channels on
arteriolar membranes,
stabilizes membrane
K+Na+ Ca++
MOA

46.  These drugs sympathetic ganglia interrupting adrenergic
control of arterioles and results in vasodilatation improved
peripheral blood flow in some vascular beds and a fall in
blood pressure
 Examples :-
Mecamylamine hydrochlore
Trimethaphan camsylate
MOA

47. THANK YOU