The renin-angiotensin system (RAS) plays a key role in hypertension and other cardiovascular diseases. It involves renin cleaving angiotensinogen to form angiotensin I, which is then cleaved by ACE to form the active peptide angiotensin II. Angiotensin II causes vasoconstriction and sodium retention. RAS inhibitors like ACE inhibitors, ARBs, and direct renin inhibitors are used to treat hypertension and related conditions by blocking the formation or effects of angiotensin II. These drugs effectively lower blood pressure and protect organs but can cause side effects like cough, hypotension, and hyperkalemia.

1. RAAS
APPLIED PHARMACOLOGY

2. • The renin–angiotensin system (RAS)
participates significantly in the
pathophysiology of hypertension, congestive
heart failure, myocardial infarction, and
diabetic nephropathy.

3. History
• In 1898, Tiegerstedt and Bergman found that crude saline
extracts of the kidney contained a pressor substance that
they named renin.

4. • In 1934, Goldblatt and his colleagues
demonstrated that constriction of the renal
arteries produced persistent hypertension in
dogs.
• In 1940, Braun- Menendez and his colleagues in
Argentina and Page and Helmer in the U.S.
reported that renin was an enzyme that acted on
a plasma protein substrate to catalyze the
formation of the actual pressor material, a
peptide, that was named hypertensin by the
former group and angiotonin by the latter

5. • In the mid-1950s, two forms of angiotensin were
recognized, a decapeptide (angiotensin I [AngI]) and an
octapeptide (angiotensin II [AngII]) formed by
proteolytic cleavage of AngI by an enzyme termed
angiotensin- converting enzyme (ACE).
• In the early 1970s, polypeptides were discovered that
either inhibited the formation of AngII or blocked AngII
receptors. These inhibitors revealed important
physiological and pathophysiological roles for the RAS :
the orally active ACE inhibitors.

6. • AngII, the most active angiotensin peptide, is
derived from angiotensinogen in two proteolytic
steps.
• First, renin, an enzyme released from the kidneys,
cleaves the decapeptide AngI from the amino
terminus of angiotensinogen (renin substrate).
• Then, ACE removes the carboxy- terminal
dipeptide of AngI to produce the octapeptide
AngII.

10. • The plasma t ½ of renin is 15 min.
• The biological potency of Ang I is only 1/100
that of Ang II, but it is rapidly converted into
the latter by ACE which is a dipeptidyl
carboxypeptidase, an ectoenzyme located
primarily on the luminal surface of vascular
endothelial cells (especially in lungs).

12. Tissue (local) renin-angiotensin
systems
Extrinsic local RAS
• blood vessels capture circulating
angiotensinogen and renin to
produce Ang II at the surface of
their wall.
• This Ang II diffuses to act locally
on the angiotensin receptors
producing localized responses.
Intrinsic local RAS
• Many tissues, especially heart,
blood vessels, brain, kidneys,
adrenals
• They generate Ang II and III
intracellularly as per
physiological need and
pathological status.
• These regulates organ function,
hypertrophy, apoptosis,
remodeling and fibrosis.

13. Prorenin and (Pro) renin receptor
(PRR)
• Renin is synthesized in juxtaglomerular (JG)
cells of kidney and in tissues expressing local
RAS as a larger peptide pre-prorenin.
• In response to appropriate stimuli both
prorenin and renin are secreted.

16. ACE Activating Pathways
• Ang II dependent pathway : Activation of
prorenin/renin generates Ang I which is
converted to Ang II by ACE. Ang II acts on AT
receptors on the tissue cells to produce effects
on cell growth, inflammation, apoptosis, etc.

17. • Ang II independent pathway: Binding of
prorenin/renin to PRR on cell surface directly
triggers intracellular signalling via activation
of MAP kinase, plasminogen activator-
inhibitor-1 (PAI-1), JAK-STAT pathway,
transcription factors, protooncogenes, etc. to
regulate cell growth, collagen deposition,
fibrosis and apoptosis.

19. • Overactivity of RAS via such signalling
abundantly contributes to pathological
changes and end-organ damage in many
conditions like hypertensive
vascular/ventricular hypertrophy, post-
infarction myocardial fibrosis and remodeling,
congestive heart failure, nephropathy,
retinopathy, etc

21. ACTIONS
• CVS
– The most prominent action of Ang II is
vasoconstriction—produced directly as well as by
enhancing Adr/NA release from adrenal
medulla/adrenergic nerve endings and by increasing
central sympathetic outflow.
– Ang II induced vasoconstriction promotes movement
of fluid from vascular to extravascular compartment.
– Ang II increases force of myocardial contraction by
promoting Ca2+ influx.

23. • Adrenal cortex
– Ang II and Ang III are trophic to the zona
glomerulosa of adrenal cortex.
– They enhance synthesis and release of
aldosterone which acts on distal tubule in kidney
to promote Na+ reabsorption and K+/H+
excretion.
– These effects are exerted at concentrations lower
than those required to cause vasoconstriction.

24. • Kidney
– In addition to exerting indirect effect on kidney
through aldosterone, Ang II promotes Na+/H+
exchange in proximal tubule increased Na+, Cl¯
and HCO3¯ reabsorption.
– Further, Ang II reduces renal blood flow and GFR,
and produces intrarenal haemodynamic effects
which normally result in Na+ and water retention.

25. • CNS
– systemically administered Ang II can gain access to
certain periventricular areas of the brain to induce
drinking behaviour and ADH release—both of
which would be conducive to plasma volume
expansion.

26. • Smooth muscles

27. Inhibition of renin-angiotensin system
1. Sympathetic blockers ( blockers, adrenergic neurone
blockers, central sympatholytics)—decrease renin
release.
2. Direct renin inhibitors (DRIs): block renin action—
interfere with generation of Ang I from
angiotensinogen (rate limiting step).
3. Angiotensin converting enzyme (ACE) inhibitors—
prevent generation of the active principle Ang II.
4. Angiotensin receptor blockers (ARBs)— antagonise
the action of Ang II on target cells.
5. Aldosterone antagonists—block mineralocorticoid
receptors.

30. Drug Dose(mg/d
ay)
Special features
CAPTOPRIL 25–150  It is first ACEIs.
 It is an active metabolite not a prodrug.
 It is administered 1 hour prior to meals because food interferes with its
absorption.
 It has high incidence of adverse effects than other ACEIs.
ENALAPRIL 2.5–40  It is a prodrug.
 ‘Enalaprilat’is the active metabolite of enalapril and it is available as such
also for iv use in emergency control of hypertension.
 It is more potent than captopril and food does not interfere its absorption.
 It has longer duration of action than captopril.
 The adverse reactions are less prominent than captopril.
LISINOPRIL 5–40  It is an active metabolite not a prodrug.
 It is a longer acting derivative of Enalapril.
 Causes decrease in cardiac output, cardiac and venous return.
FOSINOPRIL 10–40  It is a prodrug.
 Metabolized by both renal and hepatic system. Hence, can be given in the
patient with renal impairment.
 The incidence of 1st dose hypotension is more.
PERINDOPRIL 2–8  It is a prodrug.
 Another long acting ACEIs.
 It has slow onset of action.
 The incidence of 1st dose hypotension is low.
RAMIPRIL 1.25–10  It is a prodrug.
 It has wide volume of distribution with triphasic elimination.

31. THERAPEUTIC USES OF ACE
INHIBITORS
• Hypertension: ACE inhibitors are agents of choice in
hypertension associated with LVH, Diabetes mellitus,
IHD and renal disease(except renal artery stenosis).
Addition of a diuretic agent (thiazides and thiazide like)
potentiates their antihypertensive efficacy.
• Congestive cardiac failure: These drugs retard and
reverse cardiac remodeling and hypertrophy.
• Myocardial infarction: These drugs decrease early and
long-term mortality.
• Diabetic nephropathy: These drugs prevent
progression of renal complications and decrease
proteinuria.

32. ADVERSE EFFECTS
• Dry cough : It is a major disadvantage associated with the use
of ACE inhibitors. Due to inhibition of ACE present in the
lungs, the levels of bradykinins rise and produce cough.
Normally, ACE is involved in degradation of bradykinins also.
• Angioedema.
• Rashes and urticaria.
• Hypotension.
• Alteration of taste.
• Teratogenicity.
• Precipitation of Acute renal failure in renal artery stenosis
patients.
• Nausea, headache, dizziness are some other side effects.

33. ANGIOTENSIN (AT1 RECEPTOR)
BLOCKERS (ARBs)
Drug Dose Special features
Losartan 25-50mg OD  It was the first AT1 receptor antagonist.
 10,000 times more selective for AT1 than for
AT2 receptors.
Telmisartan 20-80mgOD  Action starts in 3 hours and lasts for more than 24
hours.
 In liver diseases, dose adjustment is required.
Olmesartan 20-40 mg OD  More potent ARB.
 It is a prodrug.
 No dose adjustment is required in kidney or liver
disease.
Candesartan 8mg OD  Dissociation from AT1 receptors is very slow and
acts for a very longer time.
Irbesartan 150-300mg OD  It has best oral bioavailability amongst all ARBs.
Valsartan 80-160mg OD  It has poor oral bioavailability(23%) and food
interferes with its absorption.

34. ADVERSE EFFECTS
• GIT: Diarrhoea, abdominal pain, nausea and
dry mouth.
• CNS: Headache, dizziness and syncope.
• CVS: Hypotension.
• Others: Upper respiratory tract infections &
mild cough, rash, dry skin, mild angioedema,
teratogenicity and alopecia.

35. Direct renin inhibitor
(Aliskiren, Ramikiren)
• Renin acts in the initial steps of RAAS and
converts angiotensinogen to angiotensin-I. When
,we interfere this step by blocking the renin
(Renin is essential for the formation of
angiotensin-1), the levels of angiotensin-1 & II
fall, which causes fall in BP.
• The hypotensive effects can be equated with that
of ACEIs or ARBs.
• These are recommended as alternative drugs for
the patients not tolerating the other
antihypertensive drugs.

36. • These drugs are given orally and have poor
bioavailability.
• Aliskerin is given in a dose of 150-300 mg OD.
• The hypotensive effect is long lasting and
persists for many days after discontinuation of
therapy.
• The main side effects produced are; headache,
dyspepsia, loose motions etc.
• These agents should be avoided in pregnancy.