A PowerPoint Presentation on "Drugs affecting renin-angiotensin system" suitable for UG MBBS level students

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