Drugs affecting renin-angiotensin system

Drugs affecting renin-angiotensin system

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  DRUGS AFFECTING RENIN-ANGIOTENSIN SYSTEM(RAS) Dr. D. K. Brahma Associate Professor Department of Pharmacology NEIGRIHMS, Shillong
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  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
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  TYPES – CIRCULATINGRAS 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
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  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
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  THE PATHWAYS  AngII 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
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  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)
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  ANG-II ON CHRONICBASIS – 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
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  HYPERTROPHY - IMAGE
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  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
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  AT-II – PATHOPHYSIOLOGICALROLES 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
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  RAS - PHYSIOLOGY Vasoconstriction Na+& water retention (Adrenal cortex) Kidney Increased Blood Vol. Rise in BP (-) (-)Rate limiting
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  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
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  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
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  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
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  ACE INHIBITORS ANDARBS - DRUGS  ACE Inhibitors: Captopril, enalapril, lisinopril, perindopril, fosinopril, benazepril ramipril and imidapril, Benazepril etc.  ARBs: Losartan, candesartan, irbesartan, valsartan and telmisartan
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  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
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  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)
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  CAPTOPRIL – ADVERSEEFFECTS 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
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  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
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  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
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  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)
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  USES - ACEIAND 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.
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  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)
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  ANGIOTENSIN RECEPTOR BLOCKERS(ARBS)  Losartan  Candesartan  Valsartan  Irbesartan  Eprosartan  Telmisartan
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  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
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  LOSARTAN  Competitive antagonistand 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
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  LOSARTAN  Theoretical superiorityover 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
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  LOSARTAN  Pharmacokinetic:  Absorptionnot 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
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  LOSARTAN/ARBS - USES Samerange 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
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  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
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  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
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  THANK YOU Ace inHeart Diseases Trying to be Healthy ACEIs and ARBs