drugsaffectingrenin-angiotensinsystem.pptx

drugsaffectingrenin-angiotensinsystem.pptx

1. D RUGS A FFECTING R ENIN -A NGIOTENSIN S YSTEM (RAS) Dr. MEHERUNISA Associate Professor Department of Pharmacology CIMS, LKO

2. R ENIN -A NGIOTENSIN (RAS) S YSTEM – R ECALL P HYSIOLOGY Angiotensin – II is an octapeptide generated in plasma from precursor plasma α 2 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 – 7 th Edition, JAYPEE, 2013

3. T YPES – C IRCULATING RAS AND T ISSUE 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 (1/100 th ) 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 AT 4 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. T ISSUE RAS - P RORENIN AND (P RO ) 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  N o n e n z y matic activ a tion h a s major Role in local RAS via Ang-II – heart, BV, kidneys, brain, eye and liver Essentials of Medical pharmacology by KD Tripathi – 7 th Edition, JAYPEE, 2013

5. T HE P ATHWAYS Ang II dependent pathway – activation of prorenin/renin generates Ang I and then An g 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 AT 4 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 – 7 th Edition, JAYPEE, 2013

6. A CTIONS OF A NGIOTENSIN -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 ex t ravas c ular Less prominent in cerebral, skeletal, pulmonary and c o rona r y 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 pr o moti o n) Increases heart rate by sympathetic activity - but reflex bradycardia occurs Cardiac output is reduced Cardiac work increased (increased Peripheral resistance)

7. A NG -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. H YPERTROPHY - I MAGE

9. O THER ACTIONS OF A NGIOTENSIN -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 HCO 3 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 – P ATHOPHYSIOLOGICAL R OLES 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 PGE 2 and PGI 2 – more renin release II I. 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 - P HYSIOLOGY V aso c on s trict i on Na+ & water retention K id n e y (Adrenal cortex) Inc r ea s ed Blood Vol. Rise in BP (-) (-) Rate limiting

12. A NG -II R OLES – CONTD . Pharmacological implications: Drugs Increasing Renin release: ACE inhibitors and AT 1 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. R OLE OF A T - I I – CON TD . • • • 3. Hypertension development Renovascular hypertension – PRA activity Essential hypertension Pre-eclampsia – AT 1 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. A NGIOTENSIN R ECEPTORS 2 (two) subtypes: AT 1 and AT 2 (opposite effects) – most of known Physiologic effects are via AT 1  Both are GPCR Utilizes various pathways for different tissues PLC-IP3/DAG: AT 1 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 (AT 1 ) Intrarenal homeostatic action: Phospholipase A2

15. ACE INHIBITORS AND ARB S - D RUGS ACE Inhibitors: Captopril, enalapril, lisinopril, perindopril, fosinopril, benazepril ramipril and imidapril, Benazepril etc. ARBs: Losartan, candesartan, irbesartan, valsartan and telmisartan

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

19. ACE INHIBITORS - E NALAPRIL 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 – L ISINOPRIL (L IPRIL /L ISTRIL ) It’s a lysine derivative Not a prodrug Slow oral absorption – less chance of 1 st 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 – R AMIPRIL (C ARDACE ) 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 ca s es 2) redu c es the c han c e of development of A M I 3) reduces the chances of development of nephropathy etc. (1.25, 2.55 … 10 mg caps)

22. U SES - ACEI AND HYPERTENSION 1 st 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) 1 st 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. A NGIOTENSIN R ECEPTOR B LOCKERS (ARB S ) Losartan Candesartan Valsartan Irbesartan Eprosartan Telmisartan

25. A NGIOTENSIN R ECEPTORS 2 (two) subtypes: AT 1 and AT 2 (opposite effects) – most of known Physiologic effects are via AT 1 Both are GPCR AT1 utilizes various pathways for different tissues Ang III also activates AT 1 and AT 2 – but weak Also Ang IV and Ang (1-7) – uses AT 4 and Mas AT 2 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. L OSARTAN Competitive antagonist and inverse agonist of AT 1 receptor – 10,000 times for AT 1 Does not interfere with other receptors except TXA 2 – 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. L OSARTAN Theoretical superiority over ACEIs: Cough is rare – no interference with bradykinin, Substance P and other ACE substrates Complete inhibition of AT 1 – alternative pathway remains for ACEIs Result in indirect activation of AT 2 – 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. L OSARTAN 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 1 st dose effect hypotension & cough Low dysgeusia and dry cough Lower incidence of angioedema Available as 25 and 50 mg tablets

29. L OSARTAN /ARB S - USES Same range of clinical utility with ACE inhibitors • • • • Hypertension: Commonly prescribed now than ACEIs – better than beta-blockers in reducing stroke CHF: Superiority over ACEIs uncertain Myocardial Infarction – ACEIs preferred Diabetic Nephropathy 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 AT 2 action with ARBs can be prevented by ACEIs

30. D IRECT R ENIN I NHIBITOR - A LISKIREN 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 1 st 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. M UST K NOW 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. T HANK YOU Ace in Heart Diseases Trying to be Healthy ACEIs and ARBs