Hypertension or high blood pressure is a chronic medical condition in which the blood pressure in the arteries is elevated i.e. 140/90 mmHg systolic /diastolic pressure. High blood pressure has damaging effect on the heart, brain, kidneys and eyes. Drugs used to lower blood pressure is known as antihypertensive drugs. Antihypertensive drug therapy has improved remarkably in the last 50 years. Before 1950, less effective and less tolerated antihypertensive drugs were available. Veratrum and sodium thiocyanate could lower BP, but were toxic and difficult to use. The ganglion blockers that were developed in the 1950s were effective, but inconvenient. Reserpine was a breakthrough, but produced mental depression. The therapeutic potential of hydralazine was not tapped fully because of the marked side effects when it was used alone First choice drug in all grade of essential as well as renovascular hypertension (except renal artery stenosis). This class of medicine works by causing relaxation of blood vessels as well as a decrease in blood volume, which leads to lower blood pressure and decreased oxygen demand from the heart. Most patient require low doses which are well tolerated. Example - Captopril, Enalapril, Lisinopril, Ramipril, Perindopril, Benazepril, Fosinopril, Quinapril, Trandolapril. Large hydrophobic N-heterocyclic ring increase potency. Ring showed contain –COOH group to mimic ACE substrate. The Zn2+binding group may be sulfhydryl (-CH2SH) like captopril Di-carboxylate like in enalapril, lisinopril and quinapril Phosphate like fosinopril Sulfhydryl group shows superior binding to Zn ion and produces side effect like skin rash, taste disturbance etc. Esterification of carboxylate or phosphate produce orally bioactive prodrug. Large heterocyclic ring and hydrophobic ring generally N-containing increase potency and alter pharmacokinetic parameter. Generally pyrrolidine ring is present (E.g. – Captopril, Enalapril) The N-group must contain –COOH group to mimic the C-terminal carboxylate of ACE substrate. X is usually methyl to mimic the side chain of aniline . This type of drug do not require prodrug for oral activity. Drugs are : Losatran, Candesartan, Irbesartan, Valsartan, Telmisartan The most prominent action of angiotensin II is vasoconstriction. The two types of angiotensin II receptors are AT1 and AT2 , most of the action of angiotensin II are mediated by AT1  receptor. Angiotensin receptor blockers do not affect bradykinin production. Oral bioavibility – 33% (1st pass metabolism) It is partially carbonylated in liver to an active metabolism (E3174). All ARB prevent and reverse all known effect of angiotensin-II including slow CNS effect, release of catecholamine, secretion of aldosterone, direct and indirect renal effect. Telmisartan has additional PPAR-ϒ agonistic activity. This activity can help patient with dysglycemia. There are thee functional groups that are the most important part f

1. Anti-Hypertensive Drugs
By – Harshawardhan Rao
M. Pharm
(Pharmaceutical Chemistry)
IGNTU, Amarkantak

2. Content
 Introduction
 History
 Classification
 ACE Inhibitors
 Angiotensin Receptor Blocker
 Direct Renin Inhibitor
 Diuretics
 Calcium Channel Blocker

3. Introduction
 Hypertension or high blood pressure is a chronic medical condition in which the blood pressure
in the arteries is elevated i.e. 140/90 mmHg systolic /diastolic pressure.
 High blood pressure has damaging effect on the heart, brain, kidneys and eyes.
 Drugs used to lower blood pressure is known as antihypertensive drugs.
Blood Pressure Systolic Pressure Diastolic Pressure
Normal < 120 <80
Prehypertension 120-139 80-89
Hypertension stage-I 140-159 90-99
Hypertension stage-I >160 100
Hypertensive Crisis >180 >100

4. History
 Antihypertensive drug therapy has improved remarkably in the last 50 years.
 Before 1950, less effective and less tolerated antihypertensive drugs were available.
 Veratrum and sodium thiocyanate could lower BP, but were toxic and difficult to use.
 The ganglion blockers that were developed in the 1950s were effective, but inconvenient.
 Reserpine was a breakthrough, but produced mental depression.
 The therapeutic potential of hydralazine was not tapped fully because of the marked side
effects when it was used alone

5. CLASS SUB-CLASS DRUGS
Renin angiotensin system inhibitors (RAS)
ACE inhibitors
Captopril, Enalapril, Lisinopril, Ramipril,
Perindopril, Benazepril, Fosinopril, Quinapril, Trandolpril,
Angiotensin receptor
blocker (ARB)
Losartan, Candesartan, Irbesartan,
Valsartan, Telmisartan, Olmesartan
Direct renin inhibitors Aliskerin
Diuretics
Thiazides
Hydrochlorothiazide, Chlorthalidone,
Indapamide
Loop diuretics Furosemide, Bumetanide
K+ Sparing diuretics
Spironolactone, Eplerenone, Triamterene,
Amiloride
Calcium Channel blockers
Phenylalkylamine Verapamil
Benzothiazepine Diltiazem
Dihydropyridines
Nifedipine, Felodipine, Amlodipine,
Nicardipine
Vasodilators
Arterioles Hydralazine, Minoxidil, Diazoxide
Arteriolar + Venous Sodium nitroprusside
Sympathetic inhibitors
ß – Adrenergic blockers Propranolol, Metoprolol, Atenolol (others)
a + ß Adrenergic blockers Labetalol, Carvedilol
a – Adrenergic blockers
Prazosin, Terazosin, Doxazocin,
Phentolamine
Central Sympatholytic Clonidine, Methyldopa
Plasma Kinins Bradykinin and Kallidin

6. ACE Inhibitors
 First choice drug in all grade of essential as well as renovascular
hypertension (except renal artery stenosis).
 This class of medicine works by causing relaxation of blood vessels as
well as a decrease in blood volume, which leads to lower blood pressure
and decreased oxygen demand from the heart.
 Most patient require low doses which are well tolerated.
 Example - Captopril, Enalapril, Lisinopril, Ramipril, Perindopril, Benazepril,
Fosinopril, Quinapril, Trandolapril.

8. Mechanism of ACE Inhibitor

9. Enalapril Lisinopril
Ramipril Captopril

10. Synthesis of Captopril

11. SAR of ACE inhibitors
Sulfhydryl NH with dicarboxylate Phosphonate group

12.  Large hydrophobic N-heterocyclic ring increase potency.
 Ring showed contain –COOH group to mimic ACE substrate.
 The Zn2+binding group may be
 sulfhydryl (-CH2SH) like captopril
 Di-carboxylate like in enalapril, lisinopril and quinapril
 Phosphate like fosinopril
 Sulfhydryl group shows superior binding to Zn ion and produces side
effect like skin rash, taste disturbance etc.
SAR of ACE inhibitors

13.  Esterification of carboxylate or phosphate produce orally bioactive prodrug.
 Large heterocyclic ring and hydrophobic ring generally N-containing increase
potency and alter pharmacokinetic parameter.
 Generally pyrrolidine ring is present (E.g. – Captopril, Enalapril)
 The N-group must contain –COOH group to mimic the C-terminal carboxylate of
ACE substrate.
 X is usually methyl to mimic the side chain of aniline . This type of drug do not
require prodrug for oral activity.
SAR of ACE inhibitors

14. Angiotensin Receptor Blocker
 Drugs are : Losatran, Candesartan, Irbesartan, Valsartan, Telmisartan
 The most prominent action of angiotensin II is vasoconstriction.
 The two types of angiotensin II receptors are AT1 and AT2
, most of the action of angiotensin II are mediated by AT1 receptor.
 Angiotensin receptor blockers do not affect bradykinin production.
 Oral bioavibility – 33% (1st pass metabolism)
It is partially carbonylated in liver to an active metabolism (E3174).

15. Losartan
Candesartan Irbesartan
Telmisartan

16. MOA
 All ARB prevent and reverse all known effect of angiotensin-II
including slow CNS effect, release of catecholamine, secretion
of aldosterone, direct and indirect renal effect.
 Telmisartan has additional PPAR-ϒ agonistic activity. This
activity can help patient with dysglycemia.

17. Synthesis of Losartan

18. SAR
 There are thee functional groups that are the most important
part for bioactivity of ARBs.
 The first one is the imidazole ring.
 The second is bi-phenyl methyl group.
 The third one is the tetrazole group.

19. SAR
0
Imidazole
Ring Bi-Phenyl
Group
Tetrazole
Group

20. SAR
 Most ARBs have same functional groups but the difference in biochemical and
physiological effect is due to its substituents.
 Acidic group (Imidazole) group is thought to mimic either phenol or carboxylate of
angiotensin-II.
 In the bi-phenyl series the tetrazole and carboxylate group must be in ortho
position for optimal activity(the tetrazole group is superior in term of metabolic
stability, lipophilicity and oral bioavibility).
 The n-butyl group provides hydrophobic binding .
 N-butyl group can be replaced with either ethyl ether or an propyl group as seen in
Telmisartan, olmestran.

21. Direct Renin Inhibitor
 Drugs: Aliskiren, Remikiren and Enalkiren.
 Inhibition of function of renin substrate and proposed that inhibition of renin would be
beneficial in treatment of hypertension.
Aliskerin

22. MOA
• Aliskerin directly inhibit renin that stops the formation of
angiotensin-I from angiotensinogen.
• It is a rate limiting step in this pathway.
• Inhibition of renin angiotensin pathway through any of this pathway
shows to cause increase in concentration of renin.

23. Physiochemical properties
 Basic Compound
 log p value of unionized form of Aliskerin is 4.32
 It contains four chiral centres.

24. Uses
 Approved for the treatment of hypertension.
 Used as monotherapy with combination of other anti-hypertensive drugs
like hydrochlorothiazide, amlodipine or valsartan.
 Aliskerin is available alone or in combination with other hypertensive
agent like diuretics, CCBs, and ARBs.

25. Diuretics
 Diuretics are the drugs that induces the urine formation and decrease the
reabsorption.
 Diuresis replace plasma and E.F.C. volume by 5-15% and decrease cardiac
output.

26. Thiazide Diuretics
• Thiazides and thiazide-like diuretics reduce the risk of death, stroke,
heart attack, and heart failure due to hypertension
• Chlorothiazide, hydrochlorothiazide, Bendroflumethiazide,
methyclothiazide etc.

27. MOA
 It increase the elimination of Na+ and H2O
 The blood volume decreases and cardiac output also
decreases.
 Chlorothiazide is the longest acting drug of the class.

28. Synthesis of Chlorothiazide

29. SAR
1 – Sulfonyl group is essential but can be replaced by carbonyl group.
2 - alkyl group form potent drug.
3 – This position decides potency and duration of action. Increased when substituted with
lipophilic group.
4 – Presence of double bond between 3rd and 4th position increases potency.
6 – Substitution with electron withdrawing group like Cl, Br, NO2 are required for activity.
7 – Sulfonyl group is essential for activity. Removal cause decrease in activity.

30. Uses
 Hypertension
 Mild heart failure
 Mild edema

31. Calcium Channel Blockers (CCBs)
 Drugs : Verapamil, Diltiazem, Nifedipine, Amlodipine, Felodipine etc.
 Calcium channel blockers (CCBs) are a group of medicines commonly
prescribed to treat conditions of the heart and blood vessels, such as
hypertension (high blood pressure), angina, some abnormal heart
rhythms.

32. MOA
 Smooth muscle relaxation – Smooth muscle depolarization by inward Ca2+
through L-type voltage gated ion channel and CCBs blocks the L-type
calcium channels.
 Negative chronotropic, Inotropic and dromotropic action on heart.
 They lower the B.P. by decreasing peripheral resistance without
compromising cardiac output.

34. 1,4-dihydropyridine derivatives
Nifedipine Amlodipine
Nicardipine

35. Benzodiazepines Derivative
Dilitazem

36. Di-Phenyl alkyl amine derivatives
Verapamil

37. Synthesis of Nifedipine

38. SAR
• R1 should be unsubstituted.
• Replacement of R2 with a basic amin ethyl ether chain resulting in increasing
potency of drug
• Replacement of R2 with aryl group causes the loss of activity
• R3 and R5 replacement with alkoxy carbonyl group gives more optimum activity.
• Variation in Alkyl component of easter group (ROOC) decrease in activity.
• R4 position substitution must be phenyl ring

39. THANK YOU