DRUGS AFFECTINGRENIN-ANGIOTENSIN SYSTEM (RAS)Dr. D. K. BrahmaAssociate Professor Department of PharmacologyNEIGRIHMS, Shillong

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

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

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 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

ACTIONS OF ANGIOTENSIN-II - CVSPowerful 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)

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

HYPERTROPHY - IMAGE

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 ROLES1. Mineraocorticoid secretion – Physiological stimulus of

Aldosterone secretion2. 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

RAS - PHYSIOLOGY

Vasoconstriction

Na+ & water retention

(Adrenal cortex)

Kidney

Increased Blood Vol.

Rise in BP

(-)

(-)Rate limiting

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

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

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

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 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

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)

CAPTOPRIL – ADVERSE EFFECTS1. Cough – persistent brassy cough in 20% cases – inhibition

of bradykinin and substance P breakdown in lungs2. Hypotension – initial sharp fall in BP – diuretics + CHF3. 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 stenosis5. Angioedema: swelling of lips, mouth, nose etc. – 0.5%6. Rashes, urticaria etc. – 1 – 4%7. Dysgeusia: loss or alteration of taste8. Foetopathic: hypoplasia of organs, growth retardation etc.9. Neutripenia and proteinuria10. Acute Renal Failure – in bilateral renal artery stenosis Contraindications: Pregnancy, bilateral renal artery

stenosis, hypersensitivity and hyperkalaemia

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 of AMI 3) reduces the chances of development of nephropathy etc. (1.25, 2.55 … 10 mg caps)

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 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

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

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

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

LOSARTAN/ARBS - USESSame range of clinical utility with ACE inhibitors1. Hypertension: Commonly prescribed now than

ACEIs – better than beta-blockers in reducing stroke2. CHF: Superiority over ACEIs uncertain 3. Myocardial Infarction – ACEIs preferred4. Diabetic Nephropathy5. 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

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

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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ACEIs and ARBs