Detail study on the following topic contain their drugs and all the metabolism and MOA as well as synthesis

1. Agents affecting renin angiotensin
aldosterone system (RAAS)
Ravish Yadav

2. Agents acting on RAAS
• ACEIs are drugs that competitively inhibit angiotensin converting
enzyme (ACE) OR PEPTIDYL-DIPEPTIDASE.
• Thus inhibiting the production of angiotensin II.
• ↓ TPR, hence BP
• ↓ aldosterone
• ↓ Na retetion
• ↓ H2O retention
2
Angiotensin converting enzyme inhibitors (ACEIs)
Angiotensin receptor blockers (ARBs)
Aldosterone receptor antagonists.
Renin Inhibitors

3. EXAMPLES
• Captopril
• Enalapril
• Lisinopril
• Fosinopril
• Quinapril
• Trandolapril
• Benazepril
CLASSIFICATION OF ACEIs
(Based on Zn+2 binding moeity)
• Sulfhydryl-containing agents: Captopril (Active drug), the
first ACE inhibitor, Zofenopril,
Alacepril and Moveltipril.
• Dicarboxylate-containing agents: This is the largest group,
including: Enalapril, Ramipril,
Quinapril, Perindopril, Lisinopril (Active drug), Benazepril,
Cilazapril, Delapril and
Spirapril
• Phosphonate-containing agents: Fosinopril and SQ 29852
• Naturally occuring ACEIs; Casokinins and lactokinins,
breakdown products of casein and whey, occur naturally
after ingestion of milk products, especially cultured milk.
Their role in blood pressure control is uncertain (Fitzgerald
et al, 2004).
3

4. MOA
• Binding to ACE
• Inhibition of angiotensin II synthesis leading to decreased blood pressure +
cardiovascular protection from hemodynamically mediated effects of
angiotensis II on cardiac cells.
• cardiopretective action from angiotensinII effects on the heart.
4

5. RATIONALE FOR THE USE OF ACEIs IN MI –
THE RAAS
5

6. RAAS
• The renin-angiotensin-aldosterone system (RAAS) is a signaling
pathway responsible for regulating the body's blood pressure.
• Stimulated by low blood pressure or certain nerve impulses (e.g. in
stressful situations), the kidneys release an enzyme called renin.
This triggers a signal transduction pathway: renin splits the protein
angiotensinogen, producing angiotensin I. This is converted by
another enzyme, the angiotensin-converting enzyme (ACE), into
angiotensin II.
• Angiotensin II not only causes blood vessels to narrow
(vasoconstriction), it also simultaneously stimulates the secretion of
the water-retaining hormone vasopressin (also called AVP) in the
pituitary gland (hypophysis) as well as the release of adrenaline,
noradrenaline and aldosterone in the adrenal gland.
6

7. SAR OF ACEIs
7

8. SAR Contd…
1. The N-ring must contain a carboxylic acid to mimic the C-
terminal carboxylate of ACE substrates.
2. Large hydrophobic heterocyclic rings (i.e., the N-ring)
increase potency and alter pharmacokinetic parameters.
3. The zinc binding groups can be either sulfhydryl (A), a
carboxylic acid (B), or a phosphinic acid (C).
4. The sulfhydryl group shows superior binding to zinc (the side
chain mimicking Phe in carboxylate and phosphinic acid
compounds compensates for the lack of a sulfhydryl group)
8

9. SAR Contd….
5. Sulfhydryl-containing compounds produce high incidence of
skin rash and taste disturbances.
6. Sulfhydryl-containing compounds can form dimers and
disulfides which may shorten duration of action.
7. Compounds which bind to zinc through either a carboxylate or
phosphinate mimic the peptide hydrolysis transition state.
8. Esterification of the carboxylate or phosphinate produces an
orally bioavailable prodrug.
9

10. SAR Contd…
9. X is usually methyl to mimic the side chain of alanine. Within
the dicarboxylate series, when X equals n-butylamine (lysine
side chain) this produces a compound which does not
require prodrug for oral activity.
10. Optimum activity occurs when stereochemistry of inhibitor is
consistent with L-amino acid stereochemistry present in
normal substrates.
10

11. Structure of angiotensin I
11

12. From: Are all angiotensin-converting enzyme inhibitors
interchangeable?
The chemical structures of the 10 ACE inhibitors currently available in the U.S. The term “proven” refers to ACE inhibitors shown to improve survival or
reduce morbidity. ACEI = angiotensin-converting enzyme inhibitor.
Figure Legend:

13. 13
CAPTOPRIL
IUPAC: (2S)-1-[(2S)-2-methyl-3-sulfanylpropanoyl]pyrrolidine-2-carboxylic acid

14. CAPTOPRIL (CAPOTEN)
• Captopril was the first potent inhibitor for clinical trial.
• According to the mechanism proposed by Ondetti and colleagues, captopril
interacts with the enzyme through several bonds, i.e. electrostatic,
hydrogenic and lipophilic connections.
• Among these, a co-ordinance bond formed between the free thiol group of
captopril and zinc ion in the active site of ACE.
• It is the only ACE inhibitor approved for use in the United States that
contains a sulfhydryl moiety.
• Given orally, captopril is absorbed rapidly and has a bioavailability of about
75%.
• Peak concentrations in plasma occur within an hour, and the drug is cleared
rapidly with a half-life of approximately 2 hours
14

15. • INTERRACTION OF CAPTOPRIL WITH ACE BINDING SITES
15

16. 16
CAPTOPRIL METABOLISM

17. Angiotensinogen
Angiotensin I
Angiotensin II
Renin
ACEX
MOA OF ACEI
Aldoserone
Na reabsorption
Blood volume
Cardiac output
BP
ACEI
Aldoserone
Na reabsorption
Blood volume
Cardiac output
BP

18. Captopril contd
• Most of the drug is eliminated in urine, 40% to 50% as captopril and the rest
as captopril disulfide dimers and captopril-cysteine disulfide.
• The oral dose of captopril ranges from 6.25 to 150 mg two to three times
daily, with 6.25 mg three times daily or 25 mg twice daily being appropriate
for the initiation of therapy.
• Most patients should not receive daily doses in excess of 150 mg. Since food
reduces the oral bioavailability of captopril by 25% to 30%, the drug should
be given 1 hour before meals
18

19. 19
Synthesis of Captopril

20. 20
ENALAPRIL
As a prodrug, enalapril is converted by de-esterification into its active
form enalaprilat. Enalaprilat competitively binds to and inhibits ACE, thereby
blocking the conversion of angiotensin I to angiotensin II. This prevents the potent
vasoconstrictive actions of angiotensin II and results in vasodilation. Enalapril also
decreases angiotensin II-induced aldosterone secretion by the adrenal cortex, which
leads to an increase in sodium excretion and subsequently increases water outflow.
Enalapril is used to treat hypertension, symptomatic heart failure, and
asymptomatic left ventricular dysfunction. It has been proven to protect the
function of the kidneys in hypertension, heart failure, and diabetes, and may be
used in the absence of hypertension for its kidney protective effects.
IUPAC: (2S)-1-[(2S)-2-[[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-
yl]amino]propanoyl]pyrrolidine-2-carboxylic acid
Contraindications: Pregnancy
and breastfeeding

21. 21
BENAZEPRIL
Benazepril HCl is the hydrochloride salt of benazepril, a carboxyl-containing ACE
inhibitor with antihypertensive activity.
As a prodrug, benazepril is metabolized to its active
form benazeprilat. Benazeprilat competitively binds to and inhibits ACE, thereby
blocking the conversion of angiotensin I to angiotensin II. This prevents the potent
vasoconstrictive actions of angiotensin II, resulting in vasodilation.
Benazeprilat also decreases angiotensin II-induced aldosterone secretion by the
adrenal cortex, which leads to an increase in sodium excretion and subsequently
increases water outflow.
IUPAC: 2-[(3S)-3-[[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-yl]amino]-2-oxo-4,5-
dihydro-3H-1-benzazepin-1-yl]acetic acid; hydrochloride

22. 22
BENAZEPRIL METABOLISM

23. 23
RAMIPRIL
Ramipril is a prodrug and nonsulfhydryl, long-acting ACE inhibitor
with antihypertensive activity. Ramipril is converted in the liver by de-
esterification into its active form ramiprilat, which inhibits ACE,
thereby blocking the conversion of angiotensin I to angiotensin II. This
abolishes the potent vasoconstrictive actions of angiotensin II and
leads to vasodilatation. This agent also causes an increase
in bradykinin levels and a decrease in angiotensin II-
induced aldosterone secretion by the adrenal cortex, thereby
promoting diuresis and natriuresis.
IUPAC:(2S,3aS,6aS)-1-[(2S)-2-[[(2S)-1-ethoxy-1-oxo-4-phenylbutan-2-
yl]amino]propanoyl]-3,3a,4,5,6,6a-hexahydro-2H-cyclopenta[b]pyrrole-2-carboxylic
acid

24. 24
RAMIPRIL METABOLISM

25. LISINOPRIL
Lisinopril, a synthetic peptide derivative, competitively binds to and
inhibits ACE, thereby blocking the conversion of angiotensin
I to angiotensin II. This prevents the potent vasoconstrictive actions
of angiotensin II and results in vasodilation.
Lisinopril also decreases angiotensin II-
induced aldosterone secretion by the adrenal cortex, which leads to
an increase in sodium excretion and subsequently
increases water outflow.
IUPAC:(2S)-1-[(2S)-6-amino-2-[[(1S)-1-carboxy-3-
phenylpropyl]amino]hexanoyl]pyrrolidine-2-carboxylic acid.

26. Lisinopril contd
• Lisinopril does not accumulate in tissues.
• The oral dosage of lisinopril ranges from 5 to 40 mg daily (single or divided
dosage), with 5 and 10 mg daily being appropriate for the initiation of
therapy.
• A daily dose of 2.5 mg is recommended for patients with heart failure who
are hyponatremic or have renal impairment
26

27. 27
CAPTOPRIL
ENALAPRIL
BENAZEPRIL
RAMIPRIL
LISINOPRIL
ACE
INHIBITORS

28. ACEI DRUG INTERRACTIONS
28

29. Interractions contd
29

30. Common side effects of ACEIs
• Angioedema
• Fetotoxicity
• Skin rashes (esp. Captopril due to sulfhydryl group)
• Acute renal failure
• Dry cough
• Headache
• Nausea
• Dizziness
• Fatigue
30

31. Losartan
Valsartan
Candesartan
Telmisartan
31
2. Angiotensin-II Receptor Blockers (ARBS)
MOA: Angiotensin II receptor blockers (ARBs) act differently from ACE inhibitors.
These drugs block the angiotensin-II binding to its receptor,
Aldoserone
Production
Na reabsorption
Blood volume
Cardiac output
BP

32. 32

33. Angiotensin II receptor blockers can be used to treat coronary artery
disease,
heart failure,high blood pressure, kidney disease.
33
Side effects
 Chest pain
 Back pain
 Peripheral edema
 Facial edema
 Dry cough (less common)

34. 34
LOSARTAN
Losartan is an angiotensin-receptor blocker (ARB) that may be used
alone or with other agents to treat hypertension. Losartan and its longer
acting metabolite, E-3174, lower blood pressure by antagonizing the
renin-angiotensin-aldosterone system (RAAS); they compatitively
inhibit with angiotensin II for binding to the type-1 angiotensin II
receptor (AT1) subtype and prevents the blood pressure increasing
effects of angiotensin II. Unlike angiotensin-converting enzyme (ACE)
inhibitors, ARBs do not have the adverse effect of dry cough.
IUPAC: 2-N-Butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-
5-yl)biphenyl-4-yl)methyl] imidazole

35. 35
LOSARTAN METABOLISM

36. 36
VALSARTAN
IUPAC: (2S)-3-methyl-2-[pentanoyl-[[4-[2-(2H-tetrazol-5-
yl)phenyl]phenyl]methyl]amino]butanoic acid
Valsartan is an orally active nonpeptide triazole-derived antagonist of
angiotensin (AT) II with antihypertensive properties. Valsartan selectively
and competitively blocks the binding of angiotensin II to the AT1 subtype
receptor in vascular smooth muscle and the adrenal gland, preventing AT
II-mediated vasoconstriction, aldosterone synthesis and secretion, and
renal reabsorption of sodium, and resulting in vasodilation, increased
excretion of sodium and water, a reduction in plasma volume, and a
reduction in blood pressure.

37. 37
CANDESARTAN
Candesartan is a synthetic, benzimidazole-derived angiotensin II receptor antagonist
prodrug with antihypertensive activity. Candesartan selectively competes
with angiotensin II for the binding of the angiotensin II receptor subtype 1 (AT1) in
vascular smooth muscle, blocking angiotensin II-mediated vasoconstriction and
inducing vasodilatation. In addition, antagonism of AT1 in the adrenal gland
inhibits angiotensin II-stimulated aldosterone synthesis and secretion by the adrenal
cortex; sodium and water excretion increase, followed by a reduction in plasma
volume and blood pressure.
IUPAC: 2-ethoxy-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]benzimidazole-4-
carboxylic acid.

38. 38
TELMISARTAN
Telmisartan is a benzimidazole derivative and a non-peptide angiotensin
II receptor antagonist with antihypertensive
property. Telmisartan selectively antagonizes angiotensin II binding to the
AT1 subtype receptor, located in vascular smooth muscle and adrenal gland.
The antagonism results in vasodilation and inhibits the angiotensin II-
mediated aldosterone production, which in turn leading to a decrease
in sodium and water as well as an increase in potassium excretion leading to
a subsequent reduction in blood pressure.
IUPAC: 4'-((1,4'-Dimethyl-2'-propyl(2,6'-bi-1H-benzimidazol)-
1'-yl)methyl)-(1,1'-biphenyl)-2-carboxylic acid

39. 39
Angiotensin II receptor
blockers
LOSARTAN
VALSARTAN
CANDESARTAN TELMISARTAN

40. 40
RENIN INHIBITORS

41. 41
Renin inhibitors are one of four classes of compounds that affect
the renin-angiotensin-aldosterone system, the other three
being angiotensin converting enzyme inhibitors
(ACEIs), angiotensin receptor blockers (ARBs) and aldosterone
receptor antagonists.
Renin inhibitors are a group of pharmaceutical drugs used
primarily in treatment of essential hypertension (high blood
pressure).
These drugs inhibit the first and rate-limiting step of the renin–
angiotensin–aldosterone system (RAAS), namely the conversion
of angiotensinogen to angiotensin I. This leads to a totality in
absence of Angiotensin II based on the rationale that renin only acts
to inhibit this step unlike Angiotensin Converting Enzyme which is
also involved in other biochemical reactions.

42. 42
ALISKIREN
IUPAC: (2S,4S,5S,7S)-5-amino-N-(2-carbamoyl-2,2-dimethylethyl)-4-hydroxy-
7-{[4-methoxy-3-(3-methoxypropoxy)phenyl]methyl}-8-methyl-2-(propan-2-
yl)nonanamide
Aliskiren is a direct renin inhibitor, decreasing plasma renin activity (PRA) and
inhibiting the conversion of angiotensinogen to Ang I. Whether aliskiren affects
other RAAS components, e.g., ACE or non‐ACE pathways, is not known. All
agents that inhibit the RAAS, including renin inhibitors, suppress the negative
feedback loop, leading to a compensatory rise in plasma renin concentration.
When this rise occurs during treatment with ACEIs and ARBs, the result is
increased levels of PRA. During treatment with aliskiren, however, the effect of
increased renin levels is blocked so that PRA, Ang I and Ang II are all reduced,
whether aliskiren is used as monotherapy or in combination with other
antihypertensive agents.