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Angiotensin II plays a crucial role in electrolyte balance, blood volume, and pressure regulation within the Renin-Angiotensin System (RAS). This system involves the generation of Angiotensin I by Renin, which is subsequently converted to Angiotensin II by Angiotensin Converting Enzyme (ACE). The RAS exists in both circulating and tissue forms, with intricate mechanisms involving different peptides and receptors contributing to its physiological effects. The Tissue Renin-Angiotensin System, specifically involving Prorenin and its receptor, further elaborates on the local regulatory processes in various organs.
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D DRUGS RUGS A AFFECTING R RENIN ENIN- -A ANGIOTENSIN NGIOTENSIN S SYSTEM (RAS) (RAS) Dr. MEHERUNISA FFECTING YSTEM Associate Professor Department of Pharmacology CIMS, LKO
RENIN-ANGIOTENSIN (RAS) SYSTEM RECALL PHYSIOLOGY Angiotensin II is an octapeptide generated in plasma from precursor plasma 2 globulin involved in electrolyte, blood volume and pressure homeostasis Enzyme Renin generates inactive Angiotensin Ifrom 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
TYPES CIRCULATING RAS AND TISSUE RAS Circulating RAS: Renin is the rate limiting factor of Ang-IIrelease Plasma t1/2 of Renin is 15 minutes Ang-I is less potent (1/100th) than ofAng-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 fromAdrenal Cortex (equipotent) Ang-IV different from all mainly CNS action via AT4receptor 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
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
THE PATHWAYS Ang II dependent pathway activation of prorenin/renin generates Ang I and then Ang II byACE 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 actsvia inhibiting AT4 receptor or Insulin regulated aminopeptidase (IRAP) Ang (1-7): Produced from Ang I or Ang II by ACE-2 actionopposite of Ang II ACEIs enhanceaction Essentials of Medical pharmacology by KD Tripathi 7th Edition, JAYPEE,2013
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 vascularto extravascular Less prominent in cerebral, skeletal, pulmonaryand 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)
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
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
AT-II PATHOPHYSIOLOGICAL ROLES Mineraocorticoid secretion Physiological stimulus of Aldosterone secretion Electrolyte, blood volume and pressure homeostasis: Renin is released when there is change in blood volume or pressureor 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 reninrelease III. Baroreceptor stimulation increases sympathetic impulse via -1 pathway renin release Renin release increased Ang-II production acute rise inBP direcytly acting by vasoconstriction and indirectly, increasedNa+ 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 1. 2.
RAS - PHYSIOLOGY Increased BloodVol. (-) Rise inBP (-) Rate limiting Vasoconstriction Na+ &water retention Kidney (Adrenal cortex)
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 decreaseRenin release
ROLE OF AT-II CONTD. Hypertension development Renovascular hypertension PRA activity Essential hypertension Pre-eclampsia AT1 receptor agonist antibodies 3. Secondary hyperaldosteronism 4. Inhibitors of RAS Sympathetic blockade ACE inhibitors AT1 receptor antagonists Aldosterone antagonists Renin inhibitory peptides and Renin specific antibodies
ANGIOTENSIN RECEPTORS 2 (two) subtypes: AT1 and AT2 (oppositeeffects) most of known Physiologic effects are viaAT1 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
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
CAPTOPRIL TEPROTIDE Surrogate of Proline abolishes only Ang-I actions, not onAng-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 KininaseI But increased kinins PG synthesis cough andangioedema 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 isminimal But restriction in salt or diuretics - more fall inBP In CHF (increased renin) marked fall inBP 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
CAPTOPRIL CONTD. ACEI feedback increase in Renin release but, ACE blocked Ang I converted to Ang (1-7)byACE-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)
CAPTOPRIL ADVERSE EFFECTS Cough persistent brassy cough in 20% cases inhibition of bradykinin and substance P breakdown inlungs Hypotension initial sharp fall in BP diuretics +CHF Hyperkalemia in renal failure patients with K+ sparing diuretics, NSAID and beta blockers (routine check ofK+ level) Acute renal failure: CHF and bilateral renal arterystenosis 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 retardationetc. Neutripenia and proteinuria Acute Renal Failure in bilateral renal artery stenosis Contraindications: Pregnancy, bilateral renal arterystenosis, hypersensitivity and hyperkalaemia 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
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
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
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 ofAMI reduces the chances of development of nephropathy etc. (1.25, 2.55 10 mg caps) 3)
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.
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)
ANGIOTENSIN RECEPTOR BLOCKERS (ARBS) Losartan Candesartan Valsartan Irbesartan Eprosartan Telmisartan
ANGIOTENSIN RECEPTORS 2 (two) subtypes: AT1 and AT2 (opposite effects) most of known Physiologic effects are viaAT1 Both are GPCR AT1 utilizes various pathways for different tissues Ang III also activates AT1 and AT2 butweak Also Ang IV and Ang (1-7) usesAT4 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
LOSARTAN Competitive antagonist and inverse agonist ofAT1 receptor 10,000 times forAT1 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 ofACE
LOSARTAN Theoretical superiority overACEIs: Cough is rare no interference with bradykinin,Substance P and other ACEsubstrates Complete inhibition of AT1 alternative pathway remains forACEIs Result in indirect activation of AT2 vasodilatation Little increase in Ang (1-7) -vasodilatation Clinical benefit of ARBs over ACEIs notknown However, losartan decreases BP in hypertensive which is for long period (24 Hrs) Heart rate remains unchanged and cvs reflxes arenot interfered No significant effect in plasma lipid profile, insulin sensitivity and carbohydrate tolerance etc. Mild uricosuric effect
LOSARTAN Pharmacokinetic: Absorption not affected by food but unlike ACEIsits 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 tobe 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
LOSARTAN/ARBS - 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 AT2 action with ARBs can be prevented by ACEIs 1. 2. 3. 4. 5.
DIRECT RENIN INHIBITOR - ALISKIREN Nonpeptide competitive blocker of catalytic site of Renin Ang-I not produced fromAngiotensinogen 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 1stline 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
MUST KNOW Drugs - ACEIs andARBs ACEIs Pharmacological actions and the common ADRs Therapeutic uses ofACEIs Captopril, Ramipril, Losartan Role ofACEIs/ARBs in the management of Hypertension, CHF and MI
THANK YOU Trying to be Healthy Ace in Heart Diseases ACEIs andARBs
