The document discusses the renin-angiotensin system (RAS) and drugs that affect it. RAS regulates blood pressure and electrolyte balance through the actions of angiotensin II, which is produced from renin and angiotensin converting enzyme. Angiotensin II causes vasoconstriction, sodium retention, and other effects. Drugs like ACE inhibitors and angiotensin receptor blockers inhibit parts of the RAS pathway to lower blood pressure. Captopril is an ACE inhibitor that blocks the conversion of angiotensin I to angiotensin II, reducing vasoconstriction and sodium retention.

1. DRUGS AFFECTING
RENIN-ANGIOTENSIN SYSTEM (RAS)
Dr. D. K. Brahma
Associate Professor
Department of Pharmacology
NEIGRIHMS, Shillong

2. RENIN-ANGIOTENSIN (RAS) SYSTEM –
RECALL PHYSIOLOGY
 Angiotensin – II is an
octapeptide generated in
plasma from precursor
plasma α2 globulin –
involved in electrolyte, blood
volume and pressure
homeostasis
 Enzyme Renin generates
inactive Angiotensin – I from
plasma protein)
 Angiotensin-I is rapidly
converted to Angiotensin-II
(A-II) by Angiotensin
Converting Enzyme (ACE)
(present in luminal surface
of vascular endothelium)
Essentials of Medical pharmacology by KD Tripathi – 7th
Edition, JAYPEE, 2013

3. TYPES – CIRCULATING RAS AND TISSUE RAS
 Circulating RAS: Renin is the rate limiting factor of Ang-II release
 Plasma t1/2 of Renin is 15 minutes
 Ang-I is less potent (1/100th) than of Ang-II
 Ang-I is rapidly converted to Ang-II by ACE (in vascular endothelium- mainly
lungs)
 Ang-II half life is 1 minute only
 Degradation product is Ang-III (heptapeptide) - 2-10 times less potent than
Ang-II
 Both Ang-II and An-III stimulates Aldosterone secretion from Adrenal Cortex
(equipotent)
 Ang-IV – different from all – mainly CNS action via AT4 receptor
 Tissue RAS:
 Blood vessels capture Renin and Angiotensinogen from circulation – produce
Ang-II (Extrinsic local RAS) – on cell surface – local response
 Many tissues also - Heart, brain, kidneys, adrenals capture Renin and
Angiotensinogen to produce intracellularly Ang-II (Intrinsic local RAS) -
Important in these organs – regulates organ function, cell growth/death

4. TISSUE RAS - PRORENIN AND (PRO) RENIN
RECEPTOR
 JG cells and RAS expressing
tissues/organs synthesize pre-
prorenin
 In response to stimuli Prorenin
and renin secreted
 Prorenin activated –
enzymatically (irreversible)
 Also non-enzymatically
(reversible) – binding to (Pro)
renin receptor (PRR) – exposes
catalytic domain of Prorenin -
also binding to PRR Renin
increases its catalytic activity –
ENERGY BOOSTER
 Non enzymatic activation has
major Role in local RAS via
Ang-II – heart, BV, kidneys,
brain, eye and liver
Essentials of Medical pharmacology by KD Tripathi –
7th Edition, JAYPEE, 2013

5. THE PATHWAYS
 Ang II dependent pathway –
activation of prorenin/renin generates
Ang I and then Ang II by ACE
 Ang II independent pathway – binding
of prorenin/renin to PRR on cell
surface – direct activation of MAP
kinase, PAI-1, JAK-STAT pathway,
transcription factor, protooncegenes
etc.
 Alternative pathway: Small amount -
Ang II and Ang II produced by
cathepsin, chymase etc.
 Other angiotensins: Ang IV – acts via
inhibiting AT4 receptor or Insulin
regulated aminopeptidase (IRAP)
 Ang (1-7): Produced from Ang I or
Ang II – by ACE-2 – action opposite
of Ang II ACEIs enhance action
Essentials of Medical pharmacology by KD Tripathi
– 7th Edition, JAYPEE, 2013

6. ACTIONS OF ANGIOTENSIN-II - CVS
Powerful vasoconstrictor particularly arteriolar and
venular
 direct action
 release of Adr/NA release (adrenal and adrenergic nerve
endings)
 increased Central sympathetic outflow
 Promotes movement of fluid from vascular to
extravascular
 Less prominent in cerebral, skeletal, pulmonary and
coronary
 Overall Effect – Pressor effect (Rise in Blood
pressure)
 More potent vasopressor agent than NA –promotes
Na+ and water reabsorption and no tachyphylaxis
Cardiac action:
 Increases myocardial force of contraction (Ca++ influx
promotion)
 Increases heart rate by sympathetic activity - but reflex
bradycardia occurs
 Cardiac output is reduced
 Cardiac work increased (increased Peripheral resistance)

7. ANG-II ON CHRONIC BASIS – ILL EFFECT
 Directly: Induces hypertrophy, hyperplesia and
increased cellular matrix of myocardium and vascular
smooth muscles – by direct cellular effects involving
proto-oncogens and transcription of growth factors
 Indirectly: Volume overload and increased t.p.r in heart
and blood vessels
 Ventricular Hypertrophy and Remodeling (abnormal redistribution
of muscle mass)
 Long standing hypertension – increases vessel wall
thickness and Ventricular hypertrophy
 Myocardial infarction – fibrosis and dilatation in
infarcted area and hypertrophy of non-infarcted area of
ventricles
 CHF – progressive fibrotic changes and myocyte death
 Risk of increased CVS related morbidity and mortality
 ACE inhibitors reverse cardiac and vascular
hypertrophy and remodeling

8. HYPERTROPHY - IMAGE

9. OTHER ACTIONS OF
ANGIOTENSIN-II – CONTD.
 Adrenal cortex: Enhances the synthesis and release of
Aldosterone
 In distal tubule Na+ reabsorption and K+/H+ excretion
 At lower conc. than vasoconstrictor effect
 Kidney: Enhancement of Na+/H+ exchange in proximal
tubule – increased Na+, Cl- and HCO3 reabsorption
 Also reduces renal blood flow and GFR - promotes Na+ and
water retention
 CNS: Drinking behaviour and ADH release
 Peripheral sympathetic action: Stimulates adrenal
medulla to secrete Adr and also releases NA from
autononic ganglia

10. AT-II – PATHOPHYSIOLOGICAL ROLES
1. Mineraocorticoid secretion – Physiological stimulus of
Aldosterone secretion
2. Electrolyte, blood volume and pressure homeostasis: Renin is
released when there is change in blood volume or pressure or
decreased Na+ content:
I. Reduction in tension in afferent gromerulus - Intrarenal Baroreceeptor
Pathway (PG) activation – PG production - Renin release
II. Low Low Na+ and Cl- conc. in tubular fluid – macula densa pathway – COX-2
and nNOS are induced – release of PGE2 and PGI2 – more renin release
III. Baroreceptor stimulation increases sympathetic impulse – via β-1 pathway –
renin release
 Renin release – increased Ang-II production – acute rise in BP
direcytly acting by vasoconstriction and indirectly, increased Na+
and water reabsorption
 Long-loop negative feedback mechanism: Rise in BP – decreased
Renin release
 Short-loop -ve feedback mechanism: A-II also formed locally in the
Kidneys
 Activation of AT1 receptor in JG cells – inhibition of Renin release
 Overall - Long term stabilization of BP – independent of salt and water
intake

11. RAS - PHYSIOLOGY
Vasoconstriction
Na+ & water
retention
(Adrenal cortex)
Kidney
Increased
Blood Vol.
Rise in BP
(-)
(-)
Rate limiting

12. ANG-II ROLES – CONTD.
 Pharmacological implications:
 Drugs Increasing Renin release:
 ACE inhibitors and AT1 receptor antagonists enhance
Renin release
 Vasodilators and diuretics stimulate Renin release
 Loop diuretics increase renin release
 Decrease in Renin release:
 Beta blockers and central sympatholytics
 NSAIDs and selective COX-2 inhibitors decrease Renin
release

13. ROLE OF AT-II – CONTD.
3. Hypertension development
• Renovascular hypertension – PRA activity
• Essential hypertension
• Pre-eclampsia – AT1 receptor agonist antibodies
4. Secondary hyperaldosteronism
Inhibitors of RAS
 Sympathetic blockade
 ACE inhibitors
 AT1 receptor antagonists
 Aldosterone antagonists
 Renin inhibitory peptides and Renin specific antibodies

14. ANGIOTENSIN RECEPTORS
 2 (two) subtypes: AT1 and AT2 (opposite effects)
– most of known Physiologic effects are via AT1
 Both are GPCR
 Utilizes various pathways for different tissues
 PLC-IP3/DAG: AT1 utilizes pathway for vascular
smooth muscles by MLCK
 Membrane Ca++ release: aldosterone synthesis,
cardiac inotropy, CA release - ganglia/adrenal
medulla action etc.
 Adenylyl cyclase: in liver and kidney (AT1)
 Intrarenal homeostatic action: Phospholipase A2

15. ACE INHIBITORS AND ARBS - DRUGS
 ACE Inhibitors:
Captopril, enalapril,
lisinopril, perindopril,
fosinopril, benazepril
ramipril and imidapril,
Benazepril etc.
 ARBs: Losartan,
candesartan,
irbesartan, valsartan
and telmisartan

16. CAPTOPRIL …… TEPROTIDE
 Surrogate of Proline – abolishes only Ang-I actions, not on Ang-II
 ACE – non-specific enzyme– splits off dipeptidyl segment - bradykinin,
substance P, natural stem cell regulating peptide
• Captopril increases plasma kinin levels – potentiate hypotensive action
of bradykinin - overall hypotensive effects
 However, increased kinin level by Captopril - no role on long term regulation of BP –
Kinins play minor role in BP regulation and Kininase I
 But increased kinins – PG synthesis – cough and angioedema
 Rise in stem cell regulator peptide - cardioprotective
 But, BP lowering is not long term - depends on Na+ status and level of
RAS
 In normotensives:
 With normal Na+ level – fall in BP is minimal
 But restriction in salt or diuretics - more fall in BP
 In CHF (increased renin) – marked fall in BP
 Most effective greater fall in BP: Renovascular and malignant
hypertension
 Essential hypertension: 20% hyperactive RAS and 60% normal in RAS
 Contributes to 80% of maintainence of tone – lowers BP

17. CAPTOPRIL – CONTD.
 ACEI – feedback increase in Renin release – but, ACE blocked –
Ang I converted to Ang (1-7) by ACE-2 ---BP lowering
 Actions:
 Decrease in peripheral Resistance
 Arteriolar dilatation and compliance of larger arteries increased
 Fall in Systolic and Diastolic BP - No effect on Cardiac output
 No reflex sympathetic stimulation – Can be used safely in IHD patients
 Little dilatation of capacitance vessels
 Minimal Postural hypotension
 Renal blood flow is maintained – Ang-II constricts them
 Cerebral and coronary blood flow – not affected
 Pharmacokinetics:
• 70% absorbed, partly metabolized and partly excreted unchanged in
urine
• Food interferes absorption
• T1/2 = 2 Hrs (6-12 Hrs)

18. CAPTOPRIL – ADVERSE EFFECTS
1. Cough – persistent brassy cough in 20% cases – inhibition
of bradykinin and substance P breakdown in lungs
2. Hypotension – initial sharp fall in BP – diuretics + CHF
3. Hyperkalemia in renal failure patients with K+ sparing
diuretics, NSAID and beta blockers (routine check of K+
level)
4. Acute renal failure: CHF and bilateral renal artery stenosis
5. Angioedema: swelling of lips, mouth, nose etc. – 0.5%
6. Rashes, urticaria etc. – 1 – 4%
7. Dysgeusia: loss or alteration of taste
8. Foetopathic: hypoplasia of organs, growth retardation etc.
9. Neutripenia and proteinuria
10. Acute Renal Failure – in bilateral renal artery stenosis
 Contraindications: Pregnancy, bilateral renal artery stenosis,
hypersensitivity and hyperkalaemia

19. ACE INHIBITORS - ENALAPRIL
 It’s a prodrug – converted to enalaprilate
 Not used orally – poor absorption
 Advantages over captopril:
 Longer half life – OD (5-20 mg OD)
 Absorption not affected by food
 Rash and loss of taste are less frequent
 Longer onset of action
 Less side effects

20. ACE INHIBITORS – LISINOPRIL
(LIPRIL/LISTRIL)
 It’s a lysine derivative
 Not a prodrug
 Slow oral absorption – less chance of 1st dose
phenomenon
 Absorption not affected by food and not
metabolized – excrete unchanged in urine
 Long duration of action – single daily dose
 Doses: available as 1.25, 2.5, 5, 10 and 20 mg tab
– start with low dose

21. ACE INHIBITORS – RAMIPRIL (CARDACE)
 It’s a popular ACEI now - long acting and extensive
tissue distribution
 It is also a prodrug with long half life
 Tissue specific – Protective of heart and kidney
 Uses: Diabetes with hypertension, CHF, AMI and cardio
protective in angina pectoris
 Blacks in USA are resistant to Ramipril – addition of
diuretics help
 Dose: Start with low dose; 2.5 to 10 mg daily
 EBM Reports: 1) improves mortality rate in early AMI
cases 2) reduces the chance of development of AMI 3)
reduces the chances of development of nephropathy
etc. (1.25, 2.55 … 10 mg caps)

22. USES - ACEI AND HYPERTENSION
 1st line of Drug: advantages renovascular and
resistant
 No postural hypotension or electrolyte imbalance (no
fatigue or weakness)
 Safe in asthmatics and diabetics
 Prevention of secondary hyperaldosteronism and K+
loss (diuretics)
 Renal perfusion well maintained
 Reverse the ventricular hypertrophy and increase in
lumen size of vessel
 No hyperuraecemia or deleterious effect on plasma
lipid profile
 No rebound hypertension
 Minimal worsening of quality of life – general
wellbeing, sleep and work performance etc.

23. ACE INHIBITORS – USES
 Congestive Heart Failure:
 Reduction in preload and afterload
 Some benefits - Reduction in pulmonary artery pressure, right atrial
pressure, systemic vascular resistance
 Improved Renal perfusion (Na+ and water excretion)
 CO and stroke volume increases – with reduced heart rate (less cardiac
work)
 1st line of drug with beta-blocker and diuretics in all cases (digitalis ?)
 Myocardial Infarction: 0 – 6 weeks
 Reduces mortality
 Also reduces recurrent MI
 Extension of therapy – in CHF patients
 Prophylaxis of high CVS risk subjects: Ramipril – post MI,
diabetes etc.
 Diabetic Nephropathy and non-diabetic nephropathy – reduce
albuminuria (both type 1 and 2) – higher creatinine clearance
 Better haemodynamic and prevention of mesangial growth
 Schleroderma crisis: Rise in BP and deteriorating renal function
(Ang –II)

24. ANGIOTENSIN RECEPTOR BLOCKERS (ARBS)
 Losartan
 Candesartan
 Valsartan
 Irbesartan
 Eprosartan
 Telmisartan

25. ANGIOTENSIN RECEPTORS
 2 (two) subtypes: AT1 and AT2 (opposite effects) –
most of known Physiologic effects are via AT1
 Both are GPCR
 AT1 utilizes various pathways for different tissues
 Ang III also activates AT1 and AT2 – but weak
 Also Ang IV and Ang (1-7) – uses AT4 and Mas
 AT2 receptors – expressed in foetus – high quantity
 Also in vascular endothelium, adrenal medulla, kidney and
brain areas
 NO-dependent vasodilatation, apoptosis, myocardial
fibrosis, inhibits cell proliferation and lower BP

26. LOSARTAN
 Competitive antagonist and inverse agonist of AT1
receptor – 10,000 times for AT1
 Does not interfere with other receptors except TXA2
– platelet antiaggregatory
 Blocks all the actions of Ang-II - - - vasoconstriction,
sympathetic stimulation, aldosterone release and
renal actions of salt and water reabsorption, growth
promoting effects in heart and blood vessels and
central action (thurst) etc.
 No inhibition of ACE

27. LOSARTAN
 Theoretical superiority over ACEIs:
 Cough is rare – no interference with bradykinin, Substance
P and other ACE substrates
 Complete inhibition of AT1 – alternative pathway remains
for ACEIs
 Result in indirect activation of AT2 – vasodilatation
 Little increase in Ang (1-7) - vasodilatation
 Clinical benefit of ARBs over ACEIs – not known
 However, losartan decreases BP in hypertensive which is for
long period (24 Hrs) –
 Heart rate remains unchanged and cvs reflxes are not
interfered
 No significant effect in plasma lipid profile, insulin
sensitivity and carbohydrate tolerance etc.
 Mild uricosuric effect

28. LOSARTAN
 Pharmacokinetic:
 Absorption not affected by food but unlike ACEIs its
bioavailability is low (30 – 40%)
 High first pass metabolism
 Carboxylated to active metabolite E3174
 Highly bound to plasma protein
 Do not enter brain
 No dose adjustment in renal insufficiency
 Adverse effects:
 Foetopathic like ACEIs – not to be
administered in pregnancy
 Rare 1st dose effect hypotension & cough
 Low dysgeusia and dry cough
 Lower incidence of angioedema
 Available as 25 and 50 mg tablets

29. LOSARTAN/ARBS - USES
Same range of clinical utility with ACE inhibitors
1. Hypertension: Commonly prescribed now than ACEIs
– better than beta-blockers in reducing stroke
2. CHF: Superiority over ACEIs uncertain
3. Myocardial Infarction – ACEIs preferred
4. Diabetic Nephropathy
5. Combination with ACEIs – theoretical
• ARBs: Ang II generated in local tissues by non-ACE
mechanism with ACEIs - ARBs block
• ACEIs: vasodilatation due to bradykinin & Ang (1-7) – not
produced by ARBs
• Increase in Ang II by ARBs – blocked by ACEIs
• Increase in AT2 action with ARBs can be prevented by
ACEIs

30. DIRECT RENIN INHIBITOR - ALISKIREN
 Nonpeptide – competitive blocker of catalytic site of Renin –
Ang-I not produced from Angiotensinogen
 Concentration of Renin increases, but PRA decreased
 Pharmacological actions:
 Causes fall in BP – Na+ depleted states more
 Plasma aldosterone level decreased – K+ retention occurs
 Equivalent to ACEIs and ARBs in reducing BP – combination of all 3
- greater fall in BP
 Renoprotective – hypertension and DM – being evaluated
 Used as alternative – do not respond/tolerate 1st line
 Kinetics: Orally effective – low bioavailability (p-glycoprotein) –
half life = > 24 hours
 ADRs: Dyspepsia, loose motions, headache, dizziness – lesss
rash, hypotension, hyperkalaemia, cough, angioedema etc.
 Contraindication - Pregnancy

31. MUST KNOW
 Drugs - ACEIs and ARBs
 ACEIs – Pharmacological actions and the common
ADRs
 Therapeutic uses of ACEIs
 Captopril, Ramipril, Losartan
 Role of ACEIs/ARBs in the management of
Hypertension, CHF and MI

32. THANK YOU
Ace in Heart
Diseases
Trying to be
Healthy
ACEIs and ARBs