Renin Angiotensin Aldosterone System and its applications

1. Renin Angiotensin System
&
Its Applications
DR. SAHIL KUMAR

2. OUTLINE
• History
• Overview
• Components
• Angiotensin Receptors
• Effects of Renin Angiotensin System
• Drugs Acting on RAS
• Inhibitors of RAS – ACEi, ARBs, Direct Renin Inhibitors,
Vasopeptidase inhibitors
• Aldosterone Antagonists & RAS
• Conclusion

3. HISTORY
• 1898 : Tigerstedt and Bergman : Saline
extracts of Rabbit kidney.
• 1934 : Harry Goldblatt.
• 1940 : Two groups –
Eduardo Braun Menéndez, Irvine Page
• Leonard Skegg et al

5. COMPONENTS OF RAS
Renin :
• Synthesized, stored, secreted by JG cells.
• Proconvertase 1/ Cathepsin B enzymes.
• t1/2 15 min
• Rate at which renin released, primary
determinant of RAS activity.

7. • Short loop negative feedback.
• Long loop negative feedback.
Control of Renin Release
Renin
Release
Macula Densa Pathway
– ATP, Adenosine, PGI2.
Intrarenal
Baroreceptor
Pathway. β-Adrenergic
receptor
Pathway.

8. Angiotensinogen:
• Circulating α2 globulin.
• Synthesized, secreted primarily by liver.
• ↑ by inflam., insulin, estrogens, glucocorticoids, thyroid hormone.
Pregnancy.
• BP influenced by changes in levels.
Angiotensin I:
• (Ang 1-10)
• No biological activity per se. 1% as potent as Ang II.

9. AngII:
• (Ang 1-8)
• Principal active local hormone. Prominent actions.
• Very brief plasma half life (35-40 sec).
AngIII:
• (Ang 2-8)1/4th as potent as Ang II in elevating BP.
• Equipotent to Ang II in Aldosterone secretion.

10. AngIV:
• (Ang 3-8) AT4 receptors, secretes PAI-1.
• AT4 R identified as IRAPs.
• Effects on memory & cognition.
• Renal vasodiln, neuronal diffn, hypertrophy, ECM remodeling.
Ang (1-7):
• Anti-angiogenic, anti-proliferative,
anti-thrombotic: cardioprotective.
• Mas Receptor.
• Counterbalances actions of Ang II.

11. ACE/ Dipeptidyl Carboxypeptidase:
• Zn-containing membrane bound enz on luminal
surface of vascular endothelium.
• Preferred substrates – proline must not be
penultimate AA.
• Kininase II.
• Lung.

12. ACE 2:
• Donoghue et al, Tipnis et al independently discovered. (2000)
• Forms Ang (1-9), Ang (1-7)
• Ang II is preferred substrate. (x400)
• Physiological role unclear, may serve to oppose effects of ACE.
• Not inhibited by ACEi, no effect on bradykinin.
• Reduced expression, overexpression.

13. Local (tissue) RAS:
• Kidneys, adrenals, heart, brain, blood vessels.
• Express mRNAs - renin, angiotensinogen, and/or ACE.
• Exists independently of Renal/Hepatic based system.
• Maybe involved in specific functions in these organs.
• Alternative Pathways for Ang Biosyn.
(Pro)Renin Receptor – PRR:
• Binds prorenin and induces non-proteolytic activation.
• Abundant in heart, brain, eye, adrenals, placenta, adipose tissue,
liver, kidneys.

14. Organ damage- fibrosis, inflam., nephropathy,
retinopathy
PAI-1, TGF-β
Local Ang II Prodn
Non-proteolytic
Activation
Ang II Independent effects
Activation of
intracellular signalling

15. ANGIOTENSIN RECEPTORS
AT1 AT2
Vascular Smooth Muscle,
Myocardium, Plasma membrane of
several target cells
Foetus – Widely distributed
Adults - Adr medulla, vasc. endo, brain
PLC/IP3/DAG- Ca2+ Release,
Ca2+ Channels
PKC, Gene Transn (Jak-Stat)
Membrane NADH/NADPH Oxidase
Gi,
Inhibition of Ca2+ Channels
Activation of K+ Channels, tyrosine
phosphatases and NO Production.
Vasodilatation, Anti-proliferative,
Apoptosis, Foetal tissue development
Agonist - Ang II, Ang III Ang II, Ang III
Antag. – Losartan, Val, Irbe, Cande Antagonist – PD123177

16. Mas receptor:
• Ang (1-7)
• Vasodilation and anti-proliferation.
• Heart, kidney.
AT4 Receptor:
• Ang IV
• IRAP.
• Heart, vasculature, adrenal cortex, brain.

17. Effects of Angiotensin II
I. Direct
vasoconstriction.
II. ↑of peripheral
NA neurotransn.
III. ↑symp dis
(CNS).
IV. R/o
catecholamines
from adr. medulla.
I. Direct effect to
↑ Na+ reabs. in
PCT.
II. R/o aldosterone
from adr. cortex.
III. Altered renal
hemodynamics.
I. Non-
hemodynamically
mediated effects.
II.
Hemodynamically
mediated effects.

18. DRUGS AFFECTING RAS
Directly affecting:
• ACE inhibitors
• ARBs
• Direct Renin inhibitors
• Vasopeptidase inhibitors
• Aldosterone antagonists
Indirectly affecting:
Stimulating renin release
• Diuretics
• Phosphodiesterase Θ
Inhibiting renin release
• Beta blockers
• Centrally acting
sympatholytics
• NSAIDs

19. ACE INHIBITORS
• Brazilian pit viper venom. (Sérgio Ferreira)
• Captopril – First ACEi to be marketed.
• MOA
• Currently 11 ACEi available for clinical use.
• Most are prodrugs converted to active metabolites.

20. ACEi Chemistry Activity BA DOA Dosing Elim.
Captopril SH Active 75% 8-12 hrs 25-50 mg BD R
Enalapril Ester Pro 60% <24 hrs 2.5-40 mg OD R
Lisinopril Carboxy Active 30% 24 hrs 5-40 mg R
Benazepril Ester Pro 37% >24 hrs 5-80 mg R
Fosinopril Phosphinate Pro 36% >24 hrs 10-80 mg R & H
Trandolapril Ester Pro 10% >24 hrs 1-8 mg R
Quinapril Ester Pro 60% >24 hrs 5-80 mg R
Ramipril Ester Pro 60% >24 hrs 1.25-20 mg R
Perindopril Ester Pro 75% >24 hrs 2-16 mg R
Moexipril Ester Pro 20% >24 hrs 7.5-30 mg R
Imidapril Ester Pro 40% >24 hrs 5-10 mg R

21. THERAPEUTIC USES
• HYPERTENSION
↓ sys. vascular resistance, SBP, DBP, Mean BP.
↑ RBF.
Alone – redn 50%, Combination – redn 90%.
• LEFT VENTRICULAR SYSTOLIC DYSFUNCTION
Given to all pts whether or not HF symptoms present.
Delay progression of HF.
Prevent ventricular remodeling.

22. • ACUTE MYOCARDIAL INFARCTION
Started immediately during acute phase of MI (unless C/I).
• PATIENTS WITH HIGH RISK OF CV EVENTS
HOPE Study, EUROPA Trial.
• DIABETES MELLITUS & RENAL FAILURE
Mechanism of renoprotection.
• SCLERODERMA RENAL CRISIS

23. A/E, INTERACTIONS
• Hypotension
• Cough
• Hyperkalemia
• Acute Renal Failure
• Fetopathic
• Rash
• Angioedema
• Dyguesia, Neutropenia, Glycosuria,
Hepatotoxicity
• Interactions – Antacids, NSAIDs,
Diuretics, Capsaicin

24. NON-PEPTIDE ANGIOTENSIN RECEPTOR ANTAGONISTS
(ARBs)
• Saralasin (1970s) – peptide analog.
• 1980s – Breakthrough - (Losartan), since then 6 additional
approved.
• High Affinity to AT1 receptors.
• Rank order of affinity:
Cande = Olme > Irbe = Epro > Telmi = Val = EXP3174 > Losartan
• Binding competitive, but insurmountable.
• ARBs inhibit most biological effects of Ang-II.

25. ARBs BA Pl. hf life (h) Plasma Clearance Dosage
Losartan 33 2.5-3 Renal/Hepatic 50 mg OD
(EXP 3174) - 6-8 Renal/Hepatic -
Eprosartan 13 5-8 Renal/Biliary 400 mg – 800 mg
OD/BD
Valsartan 25 9 Liver (70%) 80 - 300 mg OD
Candesartan
Cilexetil
42 9 Renal (30%) & Bil (70%) 8 mg OD
Irbesartan 70 11-15 Biliary (80%) 150–300 mg OD
Telmisartan 50 24 Biliary (90%) 40 – 80 mg OD
Olmesartan
Medoxomil
26 13 Biliary 20 – 40 mg OD

26. HOW ARE ARBs DIFFERENT FROM ACEi ?
• More effective ↓ in AT1 receptor activation.
• ARBs permit AT2 receptor activation.
• ACEi may ↑ Ang (1-7) more than ARBs.
• ACEi ↑ levels of bradykinin. ARBs do not.

27. THERAPEUTIC USES
• HYPERTENSION
• CONGESTIVE HEART FAILURE
• CLINICALLY STABLE WITH LV DYSFUNCTION POST – MI
• STROKE PROPHYLAXIS (Losartan)
• DIABETIC NEPHROPATHY (Irbesartan and Losartan)

28. ADVERSE EFFECTS
Like ACEi :
• Foetal toxicity.
• Precipitate Renal Failure in b/l Renal Artery Stenosis.
• Hyperkalemia
• Hypotension
• Unlike ACEi : No Cough, Angioedema, Dysguesia.
• Rare reports : Anaphylaxis, hepatitis, leukopenia, urticaria,
vasculitis (HSP)

29. USE IN COMBINATION (ACEi + ARBs)
• Rationale : ‘Dual blockade' may be more effective (as Ang II also
generated via non-ACE pathways).
• CHARM-Added trial (McMurray JJ et al. Lancet, 2003, 362: 767–771.),
ValHeFt (Cohn JN et al. N Engl J Med, 2001, 345:1667–1675).
• VALIANT (Pfeffer MA, McMurray JJ et al. New Engl J Med, 2003, 349:1893–1906),
ONTARGET (Telmisartan, ramipril, or both in patients at high risk for vascular events. N
Engl J Med, 2008, 358:1547–1559).
• Reversed the proteinuria(Luno J et al. Current pharmaceutical design 2005, 11 (10):
1291–300).

30. TRIALS ON COMBINATIONS WITH OTHER
AGENTS
• GEMINI Trial: β-blocker + ACEi /ARB therapy. (Wright JT Jr et al. J Clin
Hypertens Greenwich) 2007;9:842–849).
• ACCOMPLISH Trial: Compared ACEi + CCB comb with ACEi +
Thiazide comb. (New Engl J of Med. 2008. 359(23):2417-2428).
• ARB + Thiazide - greater reduction. (Croxtall JD et al. Drugs 2008 ;68:1465–
1472).
• ARB + CCB - (77%) reduction of blood pressure. (Littlejohn TW III et
al. Postgrad Med 2009;12 1:5–14).

31. DIRECT RENIN INHIBITORS
• 1st gen DRIs – Enalkiren, Zankiren, Remikiren
• 2nd gen DRI – Aliskiren (2007)
• MOA : Potent competitive inhibitor of Renin.
• Dose dependent ↓ BP, ↓ PRA ↓ Ang I & Ang II, ↓Aldo (↑ Natriuresis)
• ↑ PRC
• PK : BA is low ≈2.5% (P-gp, Fatty meals), t1/2 = 20-45 hrs.

32. THERAPEUTIC USES
IN HYPERTENSION:
As effective as ACEi (Rami), ARBs (Losartan, Irbe, Val) and HCTZ in
mild-mod HTN.
(Oparil et al., Lancet, 2007, 370: 221–229); (Sanoski CA et al., Pharmacotherapy, 2009, 29:193–212)
• Aliskiren + ACEi (Rami)/ARB (Irbe, Val) /HCTZ additive,
cardioprotective, renoprotective in lowering BP.
• FDC of Aliskiren + HCTZ marketed for anti-HT Therapy.
• Intolerant or for further blood pressure control.

33. • ? END-ORGAN DAMAGE:
• Studies ongoing. (eg ATMOSPHERE Trial)
• ALLAY (Aliskiren in LVH) Trial (2009) : Aliskiren = Losartan in LVH,
Combi – no additional redn.
• ALOFT (Aliskiren Observation of HF t/t) (2008) : Aliskiren beneficial
when added to ACEi in HF.
• AVOID (Aliskiren in evaluation of proteinuria in Diabetes) Trial
(2008) : Renoprotective in HTN with Ty2 DM.
• ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal
Endpoints) Study (2009) : no benefit after adding Aliskiren. (C/I)

34. ADVERSE EVENTS, INTERACTIONS
• GI Side effects : Diarrhea, Abd pain, dyspepsia, Gastro-eso reflux.
• Headache, dizziness
• Nasopharyngitis
• Dizziness
• Fatigue
• Back pain
• Angioedema and Cough
• In Combination Therapy : Hyperkalemia, Hypotension, elevated UA.
• Interactions : Furosemide, Ketoconazole, Atorvastatin, Cyclosporine.

35. VASOPEPTIDASE INHIBITORS
• Agents that simultaneously inhibit enzymes ACE, Neutral
Endopeptidases.

36. • Most developed Vasopeptidase inhibitor - Omapatrilat.
• Others - Fasidotrilat, Sampatrilat, Ilepatrilat.
• Developed for possible uses in HTN and CHF.
• More cases of Angioedema, cough, dizziness.

37. ALDOSTERONE ANTAGONISTS & RAS
• Spironolactone, Eplerenone, Canrenone.
• MOA : Competes with Aldo. in cells of DT and CT for cytosolic MRs.
• PK : Spironolactone : t1/2 = 1.6 hrs, prolonged by enterohepatic circ.
• A/E :
Hyperkalemia, delayed healing of peptic ulcers, GI disturbances,
Rashes, gynecomastia, menstrual irregularities.
• Interactions : Potassium Supplements, ACEi, CYP3A4 Inhibitors.

38. Therapeutic Uses with respect to RAS :
HYPERTENSION :
• Used in comb. with Thiazide/Loop diuretics
• Particularly useful for resistant HTN in 1◦ Hyperaldosteronism.
CHF :
When added to std therapy, substantially ↓ morbidity & mortality.
• RALES, EPHESUS trials.
AHA Guideline:
• Aldo. Antag. recommended if NYHA class II-IV, LVEF ≤35%.
• Aldo. Antag. recommended after MI if LVEF ≤40% with HF symptoms
or DM.

39. CONCLUSION

40. THANK YOU