FUNCTIONS AND EFFECTS OF RAS AND DRUGS AFFECTING IT

Dr. Jinia GhoshMD PGT (2nd yr)

Dept. of PharmacologyRGKMCH

OVERVIEW•Historical aspects•Components of RAS•Functions and Effects of RAS•Inhibitors of RAS- ACE Inhibitor, ARBs, Direct renin inhibitor.•MOA, individual drugs, therapeutic uses, adverse effects.

HISTORY•1898 - Tiegerstedt and Bergman discovered a pressor substance from kidney that they named renin.

•1934 - Goldblatt demonstrated that constriction of the renal arteries produced hypertension in dogs.

•1940 - Braun-Menéndez in Argentina and Page and Helmer in the U.S. discovered the actual pressor material that was named hypertensin by the former group and angiotonin by the later.

Bergman

Tiegerstedt

•Mid-1950s - 2 forms of angiotensin were recognized, AngI and AngII, formed by angiotensin-converting enzyme (ACE).

•1957 - Schwyzer and Bumpus made AngII available for intensive study.

•Early 1970s - polypeptides were discovered that either inhibited the formation of AngII or blocked AngII receptors.

COMPONENTS1. Renin - Synthesized, stored, and secreted - granular JG cells. Synthesized as a preproenzyme that is processed to prorenin.

Prorenin is proteolytically activated to uncover the active site of renin.

Aspartyl protease Generate AngI from Angiotensinogen

In local (tissue) RAS, prorenin binds to the prorenin/renin receptor, resulting in enhanced catalytic activity of renin.

Also AngII independent signaling event

These signaling pathways are not blocked by ACE inhibitors or ARBs

Control of Renin Secretion –

The secretion of renin from JG cells is controlled predominantly by 3 pathways

• the macula densa pathway• the intrarenal baroreceptor pathway• the β1 adrenergic receptor pathway

2. Angiotensinogen –

•An abundant globular glycoprotein.•Synthesized as preangiotensinogen•Substrate for renin.• Synthesized and secreted - liver. • Synthesis is stimulated by inflammation, insulin, estrogens, glucocorticoids, thyroid hormone and AngII.

3. Angiotensin-Converting Enzyme-

Ectoenzyme and glycoprotein.Nonspecific.Does not degrade AngII.ACE is identical to kininase II, the enzyme that inactivates

bradykinin and other potent vasodilator peptides.

4. Angiotensin-Converting Enzyme 2-

•Converts AngI to Ang(1-9) and AngII to Ang(1-7).•AngII - preferred substrate.• The physiological significance - uncertain; may serve as a counter-regulatory mechanism to oppose the effects of ACE.• Not inhibited by the standard ACE inhibitors and has no effect on bradykinin.

5. Angiotensin Peptides & Receptors

Local (tissue) RAS –

Involved in hypertrophy, inflammation, remodeling, and apoptosis.

Extrinsic local RAS: ACE is present on the luminal face of vascular endothelial cells throughout the circulation, and acts on circulating renin.

Intrinsic local RAS: Brain, pituitary, blood vessels, heart, kidney, and adrenal gland. May influence vascular, cardiac, and renal function and structure.

Alternative Pathways for Angiotensin Biosynthesis –

Functions and Effects of the Renin–Angiotensin System

The main effects of AngII on the cardiovascular system include:• rapid pressor response• slow pressor response• vascular and cardiac hypertrophy and remodeling

INHIBITORS OF THE RENIN–ANGIOTENSIN SYSTEM

• ACE inhibitors (ACEIs)• angiotensin receptor blockers (ARBs)• direct renin inhibitors (DRIs)

Angiotensin-Converting Enzyme InhibitorsMechanism of Action –

• ACE inhibitors increase by 5-fold the circulating levels of the natural stem cell regulator > cardioprotective effects.

ACE inhibition

↑Renin release

↑AngI

↑Ang(1-7)

Vasodilation

Clinical Pharmacology – 3 broad groups based on chemical structure:

(1) sulfhydryl-containing ACE inhibitors structurally related to captopril

(2) dicarboxyl-containing ACE inhibitors structurally related to enalapril (e.g., lisinopril, benazepril, quinapril, moexipril, ramipril, trandolapril, perindopril)

(3) phosphorus-containing ACE inhibitors structurally related to fosinopril.

• Prodrugs, less potent, better oral bioavailability.

• Cleared predominantly by the kidneys except fosinopril and spirapril.

• Elevated PRA renders patients hyperresponsive to ACE inhibitor–induced hypotension

Captopril –

• first ACE inhibitor to be marketed. • oral bioavailability 75%. reduced by 25-30% with food.∼

• t1/2 2 hours. Most of the drug is eliminated in urine.∼

• oral dose of captopril ranges from 6.25-150 mg two to three times daily, with 6.25 mg three times daily or 25 mg twice daily being appropriate for the initiation of therapy for heart failure or hypertension, respectively.

Enalapril -•Prodrug•Metabolized in liver to form active Enalaprilat.•Enalaprilat is not absorbed orally but is available for intravenous administration.•Captopril and enalapril are indistinguishable with regard to efficacy and safety, captopril may have a more favorable effect on quality of life.• t1/2 1.3 hours, but enalaprilat has a plasma t 1/2 of 11 ∼ ∼hours. Eliminated by the kidneys. •The oral dosage ranges from 2.5-40 mg daily, with 2.5 and 5 mg daily for the initiation of therapy for heart failure and hypertension, respectively.

Lisinipril -•itself is active.•slightly more potent than enalaprilat.

Ramipril -• triphasic elimination kinetics with half-lives of 2-4 hours, 9-18 hours, and >50 hours.•it is due to extensive distribution to all tissues (initial t1/2), clearance of free ramiprilat from plasma (intermediate t1/2), and dissociation of ramiprilat from tissue ACE (long terminal t 1/2).

Therapeutic UsesHypertension :

lowers systemic vascular resistance and mean, diastolic, and systolic BP

Not active in primary aldosteronism related htn

Systemic arteriolar dilation, little change with posture & exercise, little/no change in HR

Action potentiated with diuretics

Left ventricular systolic dysfunction -

reverse ventricular remodeling.

prevents or delays the progression of heart failure, decreases the incidence of sudden death and myocardial infarction, decreases hospitalization, and improves quality of life.

AMI –Beneficial effect in hypertensive and diabetic patients.

Should be started immediately. In high-risk patients should be continued long term.

High risk of Cardiovascular Events –

significantly decreased the rate of MI, stroke and death in patients without left ventricular dysfunction but had evidence of vascular disease or diabetes.

DM and Renal Failure – captopril prevents or delays the progression of renal disease. Renoprotection also is observed with lisinopril.ACE inhibitors may decrease retinopathy progression.

Adverse EffectsHypotension – Following the first dose in patients with

elevated PRA.Cough - In 5-20% of patients, dry cough, bradykinin, substanceP, and/or prostaglandins.

Hyperkalemia - Renal insufficiency, diabetes, K+-sparing diuretics, K+ supplements, β receptor blockers, or NSAIDs.

Acute Renal Failure -bilateral renal artery stenosis, heart failure, or volume depletion.Fetopathic Potential - fetal hypotensionSkin RashAngioedemaOther – dysgeusia, neutropenia, glycosuria and hepatotoxicity.

ANGIOTENSIN II RECEPTOR ANTAGONISTS

Pharmacological Effect -Bind to the AT 1 receptor. The rank-order affinity- candesartan = olmesartan >

irbesartan = eprosartan > telmisartan = valsartan =EXP 3174 (the active metabolite of losartan) > losartan.

Competitive inhibitionOften insurmountable.

Difference with ACE inhibitor –

•ARBs block the action of AngII formed by alternative pathway.•ARBs permit activation of AT2 receptor.•ACE inhibitors increase Ang(1-7) level more than ARBs.•ACE inhibitors increase bradykinin.

Therapeutic Uses –HypertensionDiabetic Nephropathy - Irbesartan, LosartanStroke prophylaxis - LosartanHeart failure - Valsartan, Candesartan

Adverse effects -HypotensionARFHyperkalemiaTeratogenecity

DIRECT RENIN INHIBITOR

ALISKIREN – Only approved DRIPharmacological effects -•Competitive inhibitor•Dose dependent decrease in BP•Decrease aldosterone, enhance natriuresisClinical Pharmacology -•Single oral dose daily•Low bioavailability•High affinity & potency•Elimination – mostly feces•Well tolerated

Therapeutic Uses –HypertensionEnd organ damage – Left ventricular hypertrophy Nephropathy