ANTIHYPERTENSIVE AGENTS, HYPERTENSION, CLASSIFICATION OF ANTIHYPERTENSIVE AGENTS, PRIMARY HYPERTENSION, SECONDARY HYPERTENSION, STRUCTURE, MECHANISM OF ACTION, SAR, SYNTHESIS.

1. ANTIHYPERTENSIVE
AGENTS
Presented by,
ASWINI SASIDHARAN
DEPT. OF PHARMACEUTICAL CHEMISTRY
GRACE COLLEGE OF PHARMACY, PALAKKAD

2. HYPERTENSION
• Physiologic condition where there is an increase in the arterial blood
pressure above the normal.
• Normal B.P – 120/80 mmHg.
• An individual is hypertensive when B.P is >140/90 mmHg.
• Drug that reduces high blood pressure are called ANTIHYPERTENSIVE
AGENTS.

3. CLASSIFICATION
• Primary
• Secondary
PRIMARY HYPERTENSION
Elevation of BP without an identifiable cause.
Also known as Essential hypertension.
It is characterized by:-
• Elevation of diastolic BP
• Normal cardiac output
• An increase in peripheral resistance

4. SECONDARY HYPERTENSION
Elevation of BP with an identifiable cause.
Factors causing secondary hypertension are as follows:
• Acute or chronic renal disease
• Hyperaldosteronism
• Cushing’s syndrome
• Acromegaly
• Pheochromocytoma

5. CLASSIFICATION OFANTIHYPERTENSIVE AGENTS
• Centrally acting adrenergic : Methyl dopa , Clonidine
drugs
• Direct vasodilators : Hydralazine ,Sodium nitroprusside
• Potassium channel openers : Diazoxide , Minoxidil
• Selective α1 adrenergic : Prazosin, Terazosin , Doxazosin
antagonist
• ꞵ - Adrenergic blockers : Propranolol , Atenolol, Metoprolol

6. • Calcium channel blockers
Phenyl alkyl amines : Verapamil
1,4-dihydropyridines : Nifedipine , Amlodipine
Benzothiazepines : Diltiazem
• ACE inhibitors : Captopril , Enalapril , Lisinopril
• Angiotensin receptor : Losartan , Telmisartan , Valsartan
blockers
• Diuretics
Loop diuretics : Frusemide
Thiazide diuretics : Chlorothiazide , hydrochlorothiazide

7. CENTRALLY ACTING ADRENERGIC DRUGS
α – METHYL DOPA CLONIDINE
3(3’,4’-dihydroxy phenyl)-2-methyl-L-alanine 2(2,6-dichloro anilino)-2-imidazoline

8. SYNTHESIS OF α – METHYL DOPA
MECHANISM OF ACTION
Methyldopa α-methyl nor adrenaline stimulate α2 adrenergic
receptors decreased sympathetic outflow decrease cardiac
output fall in BP

9. DIRECT VASODIALATORS
HYDRALAZINE
MECHANISM OF ACTION
• Cause vasodilation by stimulating guanylyl cyclase in arterial
smooth muscle
• The stimulant appears to be nitric oxide [NO].
1-hydrazino phthalazine

11. POTASSIUM CHANNEL OPENERS
DIAZOXIDE
MECHANISM OF ACTION
Activating ATP sensitive K+ channels hyperpolarizes arterial
smooth muscles vasodilation

12. β – ADRENERGIC BLOCKERS
PROPRANOLOL
SYNTHESIS
1- Isopropyl- 3-naphthyloxy-propan-2-ol

13. METOPROLOL
SYNTHESIS
1-(4’- methoxy ethyl)phenoxy -3 –isopropylamino-propan-2-ol

14. SAR OF β - BLOCKERS
• Aryloxy propanol amines
• -O-CH2 group is not essential for antagonistic activity
• These are β-OH substituted carbon must be in ‘S’ absolute
configuration for maximum activity . All are racemic mixtures
• The amino group present must be secondary for maximum activity
• N,N- Di substitution decreases the activity
MECHANISM
• Blocking the effects of epinephrine.
• It cause to beat the heart slowly with less force

15. α- ADRENERGIC BLOCKERS
MECHANISM OF ACTION
Blocking adrenergic receptors causing peripheral vasodilatory action leads
to fall in BP.
TOLAZOLINE
2-benyl-2-imidazoline
PRAZOSIN
4-(2-furoyl)-1-(4-amino-6,7-dimethoxy-2-
quinazoline)piperazine

16. CALCIUM CHANNEL BLOCKERS
Act by preventing the entry of calcium from the cells to heart and
arteries. so it relaxes blood vessals and reduces BP.
a) BENZOTHIAZEPINES
DILTIAZEM
5(2-dimethyl amino ethyl-4-methoxyphenyl-4-oxo-2,3-dihydro1,5-benzothiazepine

17. b) 1,4 – DIHYDRO PYRIDINES
NIFEDIPINE
VERAPAMIL
Dimethyl 2,6-dimethyl- 4(2-nitrophenyl)1,4-
dihydropyridine-3,5-dicarboxylate
c) PHENYLALKYL AMINES

18. RENIN ANGIOTENSIN ALDOSTERONE SYSTEM
[RAAS]
• Hormone dependent system
• Renin , angiotensin, aldosterone are hormones
• Controls BP by maintaining the balance of fluids and electrolytes of
blood plasma
• If it is activated unnecessarily then it leads to hypertension
• RAAS blockers are adequate to control BP
• Angiotensinogen is the precursor and is cleaved by renin

19. ANGIOTENSIN І
ANGIOTENSIN ІІ
ANGIOTENSINOGEN
VASCULAR SMOOTH MUSCLE HYPERTENSION
RENIN
Angiotensin converting enzyme(ACE)
Act on receptors

20. ACE INHIBITORS
ENALAPRIL
LISINOPRIL
N[N(1-ethoxy carbonyl-3-phenyl propyl)L-alanine]L-proline

21. CAPTOPRIL
SYNTHESIS

22. SAR OF ACE INHIBITORS
1. The N ring portion must contain a carboxylic acid
2. Large heterocyclic rings in the N ring increases potency
3. Zinc binding groups can either Sulfhydryl (A), Carboxylate (B),
OR Phosphinate (C)
4. X is usually a methyl group that mimic the side chain of alanine

23. ANGIOTENSIN RECEPTOR BLOCKERS
LOSARTAN VALSARTAN
MECHANISM
Antagonizing the RAAS. It compete with angiotensin II for
binding to the receptors

24. DIURETICS
• These promote increased excretion of electrolytes and water
• Reduce BP by decreasing the sodium and water retention
THIAZIDE DIURETICS
HYDROCHLOROTHIAZIDE
3,4-dihydro-6-chloro-2[H]1,2,4-benzothidiazine-7-sulfonamide-1,1-dioxide

25. MECHANISM OF ACTION
• Inhibit Na+ Cl- symport in luminal membrane of epithelial cells in
DCT
• Antihypertensive action is due to depletion of sodium and decrease in
peripheral resistance

26. SAR OF THIAZIDE DIURETICS
• H atom at the 2nd position is more acidic due to the presence of
neighbouring electron withdrawing S groups
• A free sulfamoyl group at the 7th position is essential for the
activity
• Saturation of double bond btw 3rd and 4th increase the diuretic
activity eg: Hydrochlorothiazide
• Direct substitution at 4th ,5th & 8th with an ethyl group results in
diminished activity
• Substitution of 6th position with an activating group is essential for
the activity eg: Cl, Br,CF3

27. LOOP DIURETICS
MECHANISM OF ACTION
• Inhibit reabsorption of NaCl and KCl by inhibiting Na+ - K+ - 2Cl-
symport in the luminal membrane of thick ascending limp of loop of
Henle
FRUSEMIDE [FUROSEMIDE]
4-chloro-5-sulfamoyl-N-furfuryl anthranilic acid

28. SYNTHESIS OF FRUSEMIDE

29. THANK YOU