This document provides an overview of the renin-angiotensin system (RAS), including its history, components, functions, and inhibitors. It describes renin, angiotensinogen, angiotensin-converting enzyme, angiotensin-converting enzyme 2, local RAS, and alternative pathways for angiotensin biosynthesis. It also discusses the main effects of angiotensin II and therapeutic uses, mechanisms of action, pharmacology, and adverse effects of ACE inhibitors, ARBs, and the direct renin inhibitor aliskiren.

1. Dr. Jinia Ghosh
MD PGT (2nd yr)
Dept. of Pharmacology
RGKMCH

2. OVERVIEW
•Historical aspects
•Components of RAS
•Functions and Effects of RAS
•Inhibitors of RAS- ACE Inhibitor, ARBs, Direct renin
inhibitor.
•MOA, individual drugs, therapeutic uses, adverse effects.

3. HISTORY
•1898 - Tiegerstedt and Bergman
discovered a pressor substance from
kidney that they named renin.
•1934 - Goldblatt demonstrated that
constriction of the renal arteries produced
hypertension in dogs.
•1940 - Braun-Menéndez in Argentina
and Page and Helmer in the U.S.
discovered the actual pressor material that
was named hypertensin by the former
group and angiotonin by the later.
Bergman
Tiegerstedt

4. •Mid-1950s - 2 forms of angiotensin were recognized,
AngI and AngII, formed by angiotensin-converting
enzyme (ACE).
•1957 - Schwyzer and Bumpus made AngII available for
intensive study.
•Early 1970s - polypeptides were discovered that either
inhibited the formation of AngII or blocked AngII
receptors.

5. 1. Renin -
 Synthesized, stored, and secreted - granular JG cells.
 Synthesized as a preproenzyme that is processed to prorenin.
Prorenin is proteolytically activated to uncover the active
site of renin.
 Aspartyl protease
 Generate AngI from Angiotensinogen

6. In local (tissue) RAS,
prorenin binds to the
prorenin/renin receptor,
resulting in enhanced
catalytic activity of
renin.
 Also AngII
independent signaling
event
These signaling
pathways are not
blocked by ACE
inhibitors or ARBs

7. Control of Renin Secretion –
The secretion of renin from JG cells is controlled predominantly
by 3 pathways
• the macula densa pathway
• the intrarenal baroreceptor pathway
• the β1 adrenergic receptor pathway

9. 2. Angiotensinogen –
•An abundant globular glycoprotein.
•Synthesized as preangiotensinogen
•Substrate for renin.
• Synthesized and secreted - liver.
• Synthesis is stimulated by inflammation, insulin, estrogens,
glucocorticoids, thyroid hormone and AngII.

10. 3. Angiotensin-Converting Enzyme-
 Ectoenzyme and glycoprotein.
 Nonspecific.
 Does not degrade AngII.
 ACE is identical to kininase II, the enzyme that inactivates
bradykinin and other potent vasodilator peptides.

11. 4. Angiotensin-Converting Enzyme 2-
•Converts AngI to Ang(1-9) and AngII to Ang(1-7).
•AngII - preferred substrate.
• The physiological significance - uncertain; may serve as a
counter-regulatory mechanism to oppose the effects of ACE.
• Not inhibited by the standard ACE inhibitors and has no
effect on bradykinin.

13. Local (tissue) RAS –
Involved in hypertrophy, inflammation, remodeling, and
apoptosis.
Extrinsic local RAS: ACE is present on the luminal face of
vascular endothelial cells throughout the circulation, and acts
on circulating renin.
Intrinsic local RAS: Brain, pituitary, blood vessels, heart,
kidney, and adrenal gland. May influence vascular, cardiac,
and renal function and structure.

14. Alternative Pathways for Angiotensin Biosynthesis –

15. The main effects of AngII on the cardiovascular system include:
• rapid pressor response
• slow pressor response
• vascular and cardiac hypertrophy and remodeling

17. • ACE inhibitors (ACEIs)
• angiotensin receptor blockers (ARBs)
• direct renin inhibitors (DRIs)

18. Angiotensin-Converting Enzyme Inhibitors
Mechanism of Action –

19. • ACE inhibitors increase by 5-fold the circulating levels of the
natural stem cell regulator > cardioprotective effects.
ACE
inhibition
↑Renin
release
↑AngI
↑Ang(1-
7)
Vasodilation

20. Clinical Pharmacology –
3 broad groups based on chemical structure:
(1) sulfhydryl-containing ACE inhibitors structurally related to
captopril
(2) dicarboxyl-containing ACE inhibitors structurally related to
enalapril (e.g., lisinopril, benazepril, quinapril, moexipril, ramipril,
trandolapril, perindopril)
(3) phosphorus-containing ACE inhibitors structurally related
to fosinopril.

21. • Prodrugs, less potent, better oral bioavailability.
• Cleared predominantly by the kidneys except fosinopril and
spirapril.
• Elevated PRA renders patients hyperresponsive to ACE inhibitor–
induced hypotension

22. Captopril –
• first ACE inhibitor to be marketed.
• oral bioavailability ∼75%. reduced by 25-30% with food.
• t1/2 ∼2 hours. Most of the drug is eliminated in urine.
• oral dose of captopril ranges from 6.25-150 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 for heart
failure or hypertension, respectively.

23. Enalapril -
•Prodrug
•Metabolized in liver to form active Enalaprilat.
•Enalaprilat is not absorbed orally but is available for
intravenous administration.
•Captopril and enalapril are indistinguishable with regard to
efficacy and safety, captopril may have a more favorable
effect on quality of life.
• t1/2 ∼1.3 hours, but enalaprilat has a plasma t 1/2 of ∼11
hours. Eliminated by the kidneys.
•The oral dosage ranges from 2.5-40 mg daily, with 2.5 and 5
mg daily for the initiation of therapy for heart failure and
hypertension, respectively.

24. Lisinipril -
•itself is active.
•slightly more potent than enalaprilat.
Ramipril -
• triphasic elimination kinetics with half-lives of 2-4 hours, 9-
18 hours, and >50 hours.
•it is due to extensive distribution to all tissues (initial t1/2),
clearance of free ramiprilat from plasma (intermediate t1/2),
and dissociation of ramiprilat from tissue ACE (long terminal t
1/2).

25. Therapeutic Uses
Hypertension :
 lowers systemic vascular resistance and mean, diastolic, and
systolic BP
 Not active in primary aldosteronism related htn
 Systemic arteriolar dilation, little change with posture &
exercise, little/no change in HR
 Action potentiated with diuretics

26. Left ventricular systolic dysfunction -

27. reverse ventricular remodeling.
prevents or delays the progression of heart failure, decreases
the incidence of sudden death and myocardial infarction,
decreases hospitalization, and improves quality of life.
AMI –
Beneficial effect in hypertensive and diabetic patients.
Should be started immediately.
In high-risk patients should be continued long term.

28. High risk of Cardiovascular Events –
significantly decreased the rate of MI, stroke and death in
patients without left ventricular dysfunction but had evidence
of vascular disease or diabetes.
DM and Renal Failure –
 captopril prevents or delays the progression of renal
disease.
 Renoprotection also is observed with lisinopril.
ACE inhibitors may decrease retinopathy progression.

29. Adverse Effects
Hypotension –
Following the first dose in patients with
elevated PRA.
Cough -
In 5-20% of patients, dry cough,
bradykinin, substanceP, and/or prostaglandins.
Hyperkalemia -
Renal insufficiency, diabetes, K+-
sparing diuretics, K+ supplements, β receptor blockers, or
NSAIDs.

30. Acute Renal Failure -
bilateral renal artery stenosis, heart failure, or volume
depletion.
Fetopathic Potential - fetal hypotension
Skin Rash
Angioedema
Other – dysgeusia, neutropenia, glycosuria and
hepatotoxicity.

31. ANGIOTENSIN II RECEPTOR
ANTAGONISTS
Pharmacological Effect -
 Bind to the AT 1 receptor.
 The rank-order affinity- candesartan = olmesartan >
irbesartan = eprosartan > telmisartan = valsartan =EXP
3174 (the active metabolite of losartan) > losartan.
 Competitive inhibition
 Often insurmountable.

32. Difference with ACE inhibitor –
•ARBs block the action of AngII formed by alternative
pathway.
•ARBs permit activation of AT2 receptor.
•ACE inhibitors increase Ang(1-7) level more than ARBs.
•ACE inhibitors increase bradykinin.

33. Therapeutic Uses –
Hypertension
Diabetic Nephropathy - Irbesartan, Losartan
Stroke prophylaxis - Losartan
Heart failure - Valsartan, Candesartan
Adverse effects -
Hypotension
ARF
Hyperkalemia
Teratogenecity

34. ALISKIREN – Only approved DRI
Pharmacological effects -
•Competitive inhibitor
•Dose dependent decrease in BP
•Decrease aldosterone, enhance natriuresis
Clinical Pharmacology -
•Single oral dose daily
•Low bioavailability
•High affinity & potency
•Elimination – mostly feces
•Well tolerated

35. Therapeutic Uses –
Hypertension
End organ damage –
Left ventricular hypertrophy
Nephropathy