Contains nomenclature, classification, MOA and SAR

1. ANTIHYPERTENSIVE DRUGS
Dr. R. S. Chavan
PDEA’s Seth Govind Raghunath Sable
College of Pharmacy, Saswad

2. Hypertension
• Blood pressure- resistance to blood flow by
peripheral blood vessels
• Etiology
• Hypertension
Mild : 90-104 mm Hg (diastolic pressure)
Moderate : 105-114 mm Hg
Severe : above 115 mm Hg

3. Hypertension
• Primary (Essential)
• Renal
• Pheochromocytoma

4. Blood perfusion
in tissue
pressure / resistance
Central mechanism
Cardiac output
Renin angiotensin
aldosterone system
Viscosity
Baro and
chemo receptors
Vascular factors
Blood volume
Peripheral adrenergic
activation
Mosaic theory of blood perfusion in tissue

5. Renin release
Angiotensinogenin
Angiotensin I Angiotensin II Angiotensin III
ACE
Vasoconstriction Aldosterone secretion
Sod & Fluid retention
Increased cardiac outputIncreased peripheral resistance
Elevated blood pressure
Reduced Blood pressure Lower sod excretion

6. Effect of adrenergic neurotransmitter on CVS
Sympathetic nerves
Adrenal gland Norepinephrine
Adrenaline
Constriction of blood vessels
(response)
Dilatation of
blood vessels
( response)
Increased heart rate
Increased heart force

7. Effect of sustained hypertension on heart
Sustained hypertension
Cardiac overwork
Increased myocardial
oxygen demand
Angina PectorisHeart Failure
Left ventricular
hypertrophy

8. ETIOLOGY OF HYPERTENSION
• Neural factors
• Hormonal factors
• Electrolyte factors
• Vessel wall factors
• Genetic factors

9. Antihypertensive agents-classification
1] Drugs affecting sympathetic tone
a) Ganglionic blockers
b) α-blockers
c) β-blockers
2] Vasodilators
a) Direct vasodilators
b) Ca++ channel blockers
3] Agents acting on Renin Angiotensin system
4] Diuretics
5] Central depressants
6] Endothelin Receptor Antagonist
7] Phosphodiesterase Type 5 Inhibitors

10. SYMPATHOLYTIC DRUGS
• Centrally acting drugs e.g. Methyldopa,
Clonidine, Guanabenz, Guanafacine
• Adrenergic neuron blockers e.g. Reserpine,
Guanethidine, Guanadrel
• Ganglionic blockers e.g. Trimethaphan
• Selective α– adrenergic blockers e.g.
Prazocin, Terazocin, Doxazocin, Phentolamine
• Selective β-adrenergic blockers e.g.
Propranolol, Atenolol

11. Adrenergic inhibition can be achieved
by
a) Depleting the stores of neurotransmitter
b) Reducing the number of impulses traveling
in sympathetic nerves
c) Antagonizing the actions of
neurotransmitter on the effector cells
d) Inhibiting neurotransmitter release

12. Centrally acting adrenergic drugs
• Act by stimulating α2 - receptors which in CNS
reduces sympathetic outflow to CVS and
produce hypotensive effect.
OH
OH
H2CC
NH2
HOOC
CH3
(L)-2-amino-3-(3,4-dihydroxyphenyl)
-2-methylpropanoic acid
-METHYLDOPA HCl

13. N
H
H
N
N
H
Cl
Cl
2,6-dichloro-N-(imidazolidin-2-ylidene)benzenaminium
CLONIDINE HCl
C
H
N
Cl
Cl
GUANABENZ ACETATE
HNC
NH
H2N
2-(2,6-dichlorobenzylidene)hydrazinecarboximidamide

14. H2
CC
Cl
Cl
GUANAFACINE HCl
HNC
NH
H2N
O
N-carbamimidoyl-2-(2,6-dichlorophenyl)acetamide

15. Adrenergic Neuron Blockers
• Act by depleting the stores of
neurotransmitters
N
H
N
O
H3COOC OCH3
H3CO
C
O
OCH3
OCH3
OCH3
RESERPINE

16. N CH2 CH2 NH C NH
NH2
1-(2-(azocan-1-yl)ethyl)guanidine
GUANETHIDINE

17. N NH
C
H2N NH
Liver microsomes
H
N NH
C
H2N NH
C
O
OH
2-(6-carboxyhexylamino)-
ethylguanidine
Guanethidine
Liver microsomes
N NH
C
H2N NH
O
Guanethidine N-oxide
[metabolite 1]
[metabolite 2]
Metabolism of guanethidine

18. O
O
CH2 NH C NH
NH2
1-(1,4-dioxaspiro[4.5]decan-2-ylmethyl)guanidine
GUANADREL

19. Ganglionic Blockers
(+)-1,3-Dibenzyldecahydro-2-oxoimidazo[4,5-c]thieno[1,2-a]-thiolium-2-oxo-10-
bornanesulfonate
HC
N
CH
CH
N
CH2
C
O
S
H2C
H2C CH2
CH2H2C
Trimethaphan camsylate

20. α– adrenergic blockers
• Act by α1-adrenergic blockade (indirect
Vasodilation )
N
NH3CO
H3CO
NH2
N
N
C
O
O
(4-(4-amino-6,7-dimethoxyquinazolin-2-yl)
piperazin-1-yl)(furan-2-yl)methanone
PRAZOCIN HCl

21. N
NH3CO
H3CO
NH2
N
N
C
O
O
TERAZOCIN HCl
(4-(4-amino-6,7-dimethoxyquinazolin-2-yl)
piperazin-1-yl)(tetrahydrofuran-2-yl)methanone

22. N
NH3CO
H3CO
NH2
N
N
C
O
DOXAZOCIN O
O
(4-(4-amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl)
(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanone

23. N
CH2
N NH
HO
CH3
3-(((4,5-dihydro-1H-imidazol-2-yl)methyl)(p-tolyl)amino)phenol
PHENTOLAMINE
CH2
N NH
TOLAZOLINE
2-benzyl-4,5-dihydro-1H-imidazole

24. β-adrenergic blockers
O
N
H
OH
1-(isopropylamino)-3-(naphthalen-1-yloxy)propan-2-ol
PROPRANOLOL
Nonselective β blocker

25. Cl
Cl
NHCH(CH3)2
OH
DICHLOROISOPROTERENOL (DCI)
NHCH(CH3)2
OH
PRONETHALOL
PROPRANOLO

26. Nonselective β-blockers
• Carteolol
• Levobunolol
• Nadolol
• Pindolol
• Timolol
• Satalol
• Penbutolol
• Metipranolol

27. O NHCH(CH3)2
OH
NHCOCH3
PRACTOLOL
First cardioselective β1-blockers

28. Cardioselective β1-blockers
• More hydrophilic in nature
• Bind through hydrogen bonding with receptor
• Para substitution of sufficient size is required for
selectivity
• Absence of meta substitution
• Aryl gr affects absorption, excretion & metabolism
• Ter butyl or isopropyl gr is found on amino function
of aryoxypropanolamine chain
• Sec amine essential for activity
• Aromatic ring substitutions determines antagonist
activity.

29. Selective β1-blockers
• Atenolol
• Bisoprolol
• Metoprolol
• Esmolol
• Betaxolol
• Acebutolol
O
CH2CONH2
NHCH(CH3)2
OH
2-(4-(2-hydroxy-3-(isopropylamino)
propoxy)phenyl)acetamide
ATENOLOL

30. Adrenergic Antagonists
• alpha-Adrenoreceptors
– α1/ α 2 : Phentolamine
– α1 only: Prazosin
– α2 only: Yohimbine
• beta-Adrenoreceptors
– β1/ β 2: Propranolol
– β1 only: Metoprolol; atenolol
– β2 only: no clinically-useful agents
• alpha- and beta-Adrenoreceptors
– α1/ β 1/ β 2 : Labetolol, Carvedilol

31. HO
CONH2
H
N
OH
2-hydroxy-5-(1-hydroxy-2-(4-phenylbutan-2-ylamino)ethyl)benzamide
LABETALOL
N
H
O N
H
O
OCH3
OH
1-(9H-carbazol-4-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol
CARVEDILOL

32. VASODILATORS
A] Direct vasodilators
i) Arterial vasodilators e.g. Hydralazine
ii) Arterial & Venous vasodilators e.g.
Sodium nitroprusside
B] Indirect vasodilators
e.g α1-adrenoreceptor blockers
C] Calcium channel blockers e.g. Nifedipine
D] Potassium channel agonists e.g.
Minoxidil, Diazoxide

33. N
N
NHNH2
1-hydrazinylphthalazine
HYDRALAZINE
Fe
CN
CN
CN
NO
NC
CN
2Na+
SODIUM NITROPRUSSIDE

34. N
N
NHNH2
METABOLISM OF HYDRALAZINE
Benzylic
oxidation
NH
N
NHNH2
O
Acetylation
NH
N
NHNHC
O
O
CH3
N
N
NHNHC
O
O
CH3
Glucuronic acid
Glucuronidation

35. N
N
N
H2N NH2
O
MINOXIDIL
2,4-diamino-6-piperidino
pyrimidine-3-oxide
N
N
N
H2N NH2
OSO3
minoxidil sulfate
Sulfotransferase

36. S
NH
N
OO
CH3
Cl
7-chloro-3-methyl-2H-1,2,4-
benzothiadiazine1,1-dioxide
DIAZOXIDE
N
N
CONH2
NHNH2
6-hydrazinylpyridazine
-3-carboxamide
HYDRACARBAZINE

37. DRUGS ACTING ON RENIN
ANGIOTENSIN SYSTEM
I] Renin inhibitors e.g. Enalkiren, Zankiren
II] Angiotensin Converting Enzyme Inhibitor
e.g. Captopril, Lisinopril, Enalapril,
Quinapril, Benazepril, Ramipril, Fosinopril,
Trandolapril
III Angiotensin II blockers e.g. Saralasin
Losartan, Candesartan, Irbesartan,
Telmisartan, Valsartan
IV] Aldosterone antagonists e.g.
Spironolactone

38. Renin release
Angiotensinogenin
Angiotensin I Angiotensin II Angiotensin III
ACE
Vasoconstriction Aldosterone secretion
Sod & Fluid retention
Increased cardiac outputIncreased peripheral resistance
Elevated blood pressure
Reduced Blood pressure Lower sod excretion

39. Renin inhibitors
NH
HN
H3CO
H2N
O
O
NH
O
N
NH
OH
OH
3-amino-N-((S)-1-((S)-1-((2S,3R,4S)-1-cyclohexyl-3,4-dihydroxy
-6-methylheptan-2-ylamino)-3-(1H-imidazol-5-yl)-1-oxopropan-2-ylamino)
-3-(4-methoxyphenyl)-1-oxopropan-2-yl)-3-methylbutanamide
ENALKIREN

40. NH
S
N
O
O
NH
O
N
S
OH
OH
O
N
(S)-2-benzyl-N-((S)-1-((2S,3R,4S)-1-cyclohexyl-3,4-dihydroxy
-6-methylheptan-2-ylamino)-1-oxo-3-(thiazol-5-yl)propan-2-yl)-3-
(4-methylpiperazin-1-ylsulfonyl)propanamide
ZANKIREN

41. Angiotensin Converting Enzyme
Inhibitor (ACE inhibitor)
N
C
COOH
H
O
HSH2C
(S)-1-(3-mercapto-2,2-dimethylpropanoyl)
pyrrolidine-2-carboxylic acid
CAPTOPRIL
ASP-ARG-VAL-TYR-ILE-HIS-PRO-PHE-HIS-LEU
(Angiotensin I )
ASP-ARG-VAL-TYR-ILE-HIS-PRO-PHE HIS-LEU
ACE
(Angiotensin II)
ACE not only produces a potent vasoconstrictor but
also inactivates a potent vasodilator (bradykinin)

42. C
H2
S CH
CH3
C
N
O
C O
O
C
NH2
H2N
Arg
Zn++
Accommodation of Captopril to active site of ACE

43. (NH2 end) ASP-ARG-VAL-TYR-ILE-HIS-PRO-PHE-HIS-LEU-VAL-ILE-HIS-R (COOH end)
Renin
(Angiotensinogen)
ASP-ARG-VAL-TYR-ILE-HIS-PRO-PHE-HIS-LEU
ACE
(Angitensin I)
ASP-ARG-VAL-TYR-ILE-HIS-PRO-PHE
Aminopeptidase
(Angitensin II)
Angiotensinases
ARG-VAL-TYR-ILE-HIS-PRO-PHE
(Angiotensin III)
Inactive products

44. N
H
C
H
(CH2)4NH2
H
C O
N COOH
H
O
OC2H5
(S)-1-((S)-6-amino-2-((S)-1-ethoxy-1-oxo-4-phenylbutan
-2-ylamino)hexanoyl)pyrrolidine-2-carboxylic acid
LISINOPRIL

45. NH
H
C OC2H5
O
H
CH3
C
N
O
COOH
H
ENALAPRIL
(S)-1-((S)-2-((S)-1-ethoxy-1-oxo-4-phenylbutan-2-
ylamino)propanoyl)pyrrolidine-2-carboxylic acid

46. (CH2)4 P
O
CH2
O
CHOCCH2CH3
O
C N
O
H
H COONa
FOSINOPRIL

47. N
CH2COOH
O
H
N
CH
C
CH2CH2
O
OCH2CH3
(3S)-3-[[(1S)-1-carbethoxy-3-phenylpropyl]amino]]-2,3,4,5-tetrahydro
-2-oxo-1H-1-benzazepine-1-acetic acid 3-ethyl ester
BENAZEPRIL HCl

48. N
C
H
COOH
O
C
CH3
H
NH
C
C
H
CH2CH2
O
OC2H5
QUINAPRIL

49. C
H
NH C
H3C
H
C2H3O
O
O
N
H
H
H
COOH
RAMIPRIL

50. N
O
OH
O
N
H
O
O
1-[2-(1-ethoxycarbonyl-3-phenylpropylamino)
propionyl]octahydroindole-2-carboxylic acid
TRANDOLAPRIL

51. Angiotensin Antagonist e.g. Saralasin
Sar-Arg-Val-Tyr-Val-His-Pro-Ala
-Substituted analogue of Angiotensin II
-Acts by competitively blocking the
angiotensin receptor site.
-Phenylalanine is repalced by alanine &
sarcosyl is substituted at –NH2 terminal
-does not cross BBB

52. Angiotensin II blockers
N
N N
NH
N N
HOH2C
Cl
(1-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-
butyl-4-chloro-1H-imidazol-5-yl)methanol
LOSARTAN

53. N
N N
NH N
N
O
O
O
O
O
OC2H5
1-(cyclohexyloxycarbonyloxy)ethyl 1-((2'-(1H-tetrazol-5-yl)
biphenyl-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate
CANDESARTAN

54. N
N N
NH N
N
9-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-8-butyl
-10-methylene-7,9-diazaspiro[4.5]dec-7-ene
IRBESARTAN

55. COOH
N
N
N
NN
4'-((5-(1-methyl-1H-benzo[d]imidazol-2-yl)-2-propyl-3H-imidazo
[4,5-b]pyridin-3-yl)methyl)biphenyl-2-carboxylic acid
TELMISARTAN

56. N
N N
NH N
O
COOH
2-(N-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)
pentanamido)-3-methylbutanoic acid
VALSARTAN

57. Aldosterone antagonists
O
O
OH OHO
H H
H
ALDOSTERONE

58. O
O
HO
CH3
CH3
H
S C
O
CH3
SPIRONOLACTONE

59. Endothelin Receptor Antagonist
• ETA and ETB receptor subtypes
• Produce vasoconstriction in vascular
smooth muscles by activation of Gq
receptors and formation of IP3
• Endothelin receptor antagonists are
useful in hypertension, heart failure and
coronary vasospasm
• Pulmonary arterial hypertension (PAH)

60. • Ambrisentan
H3CO
COOH
O
N
N

61. • Bosentan
O
N
N
HN
O
OH
S
N
N
O
O

62. • Sitaxsentan
N
O
Cl
N
H
S
S
O
O
O
O
O

63. Phosphodiesterase type 5 inhibitors
• Sildenafil
• Vardenafil
• Tadalafil
Used in erectile dysfunction and PAH

64. Synthesis of Methyldopa

68. Synthesis of Propranolol

69. Synthesis of Atenolol

71. Synthesis of Prazocin

72. Synthesis of Guanethidine

73. Synthesis of Captopril

76. Synthesis of Hydralazine

77. Synthesis of Losartan