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Drugs Affecting Renin-Angiotensin System

ACE inhibitors and ARBs work by inhibiting the renin-angiotensin-aldosterone system. They block the conversion of angiotensin I to angiotensin II by ACE or block the effects of angiotensin II by antagonizing its receptors. This lowers blood pressure by vasodilation, sodium excretion, and reduced aldosterone levels. Common uses include hypertension, heart failure, myocardial infarction, diabetic nephropathy. Side effects include hypotension, cough, hyperkalemia, and renal dysfunction. ARBs are better tolerated due to less cough and angioedema.

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135 views36 pages

Drugs Affecting Renin-Angiotensin System

ACE inhibitors and ARBs work by inhibiting the renin-angiotensin-aldosterone system. They block the conversion of angiotensin I to angiotensin II by ACE or block the effects of angiotensin II by antagonizing its receptors. This lowers blood pressure by vasodilation, sodium excretion, and reduced aldosterone levels. Common uses include hypertension, heart failure, myocardial infarction, diabetic nephropathy. Side effects include hypotension, cough, hyperkalemia, and renal dysfunction. ARBs are better tolerated due to less cough and angioedema.

Uploaded by

pradeephd
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© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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ACE inhibitors and ARBs

Vasodialators
Renin-Angiotensin-Aldosterone
System

Angiotensinogen
↓ Renin← JG cells
Angiotensin I
↓ ACE
VC← Angiotensin II → Aldosterone
↓
Angiotensin III
Angiotensin II
 Mechanism of Action
– Acts through specific cell surface
receptors in target tissues
ATII2

ATII1
1
Angiotensin II
– Renin-Angiotensin-Aldosterone
System
Blood Pressure regulation (↑ BP)
– Direct vascular smooth muscle
contraction
– ↑ Autonomic ganglia→ ↑ E/NE release
from
adrenal
medulla
– ↑ release /↓ reuptake of NE at adrenergic
nerve terminals
Angiotensin II
 Renin-Angiotensin-Aldosterone
System
– ATII- ↑ Aldosterone release from
adrenal cortex (zona glomerulosa)
– ATII- Renal actions
 ↑ renal VC
 ↑ proximal tubular Na+ reabsorption

 ↓ renin secretion
Angiotensin II
 Renin-Angiotensin-Aldosterone
System
– Effect on cell growth
Mitogenic for cardiac/vascular cells
↑ cardiac/vascular hypertrophy
Angiotensin Converting Enzyme
Inhibitors

 Classification

– Sulfhydryl containing
Captopril, Alacepril, Zofenopril
– Dicarboxyl containing
Lisinopril, Benazepril, Ramipril
– Phosphorus containing
Fosinopril
Angiotensin Converting Enzyme
Inhibitors
 Specific competitive inhibitors of ACE
(peptidyl dipeptidase) that converts ATI to
ATII
Angiotensin I
↓ ACE← ACEI’s
Angiotensin II
 ATII is a potent vasoconstrictor acting via ATII
receptors, viz
– ATII2
– ATII1
Angiotensin Converting Enzyme
Inhibitors
 ACEI’s inhibit vasoconstriction
 ATII stimulates adrenal cortex to
secrete Aldosterone
↓
Promotion of Na+ & H2O retention
 ACEI’s inhibit Na+ & H2O retention
 ACEI’s cause K+ retention
Angiotensin Converting Enzyme
Inhibitors- PK
 Captopril

– Rapidly absorbed after oral


administration
– Food decreases bioavailability
– Peak plasma levels in 1 h
– Renal elimination of 95% dose in
24 h
Angiotensin Converting Enzyme
Inhibitors- PK
 Enalapril
– Rapidly absorbed after oral administration
– Food does not decrease bioavailability
– Prodrug; biotransformed to active Enalaprilic
acid (Enalaprilat)
– More potent w.r.t. Captopril
– Clinical active levels in 2-4 h due to hepatic
conversion & activation
– T(1/2)= 11 h (Enalaprilat)
– DOA = 24 h
Angiotensin Converting Enzyme
Inhibitors- PK
 Lisinopril

– Slower absorption w.r.t. Enalapril


– Slower onset of action w.r.t. Enalapril
 Fosinopril, Spirapril
– Excreted in bile & urine
– Does not require dose adjustment in
renal failure
Angiotensin Converting Enzyme
Inhibitors- PK
 Benazepril, Ramipril
– Excreted in urine
– Require dose adjustment in renal failure

 Quinapril

– Prodrug
– Bioactivation in intestine + liver
Angiotensin Converting Enzyme
Inhibitors- Pharmacological Actions
 Hypertension
– First-line drugs (except in blacks)
– ACEI’s→↓ SBP/↓ DBP/ ↓ MABP
– ACEI’s →↓ ACE/↓ ATII → systemic arteriolar
dilation
↓
↓ BP
– ACEI’s →↓ ACE/↓ ATII → ↓ Aldosterone
↓
↓ BP ← ↓ Na+/H2O
absorption
Angiotensin Converting Enzyme
Inhibitors- Pharmacological Actions
 Left
Ventricular Systolic
Dysfunction/CHF

– ACEI’s→↓ ATII → ↓ VC → ↓ Afterload→ CO

– ACEI’s→↓ ATII → ↓ VC → Renal VD→ RBF

↓
↓ BP ← Natriuresis/Diuresis ← GFR
Angiotensin Converting Enzyme
Inhibitors- Pharmacological Actions
 Left Ventricular Systolic Dysfunction/CHF

– ACEI’s→↓ ATII → ↓ Aldosterone → ↓Na+/H2O


retention
↓
↓ Venous return(↓ Preload)← ↓ PV/venodilation
↓
↓ Pulm artery pressure→ ↓ LV diastolic filling
↓
↓ ventricular dilation← ↓ diastolic wall tension
Angiotensin Converting Enzyme
Inhibitors- Pharmacological Actions
 Left Ventricular Systolic Dysfunction/CHF
– ↓ ventricular dilation→ improved
vent geometry
↓
reversal of ventricular remodelling
↓ ATII-induced myocyte growth
↓ Aldosterone-induced cardiac fibrosis
↓
↓ sudden cardiac death
incidence
Angiotensin Converting Enzyme
Inhibitors- Pharmacological Actions
 Myocardial Infarction

– ACEI’s during peri-infarction period


(16 d post infarction; Treatment
maintained for ≥ 6 wks)
↓
↓ mortality
Angiotensin Converting Enzyme
Inhibitors- Pharmacological Actions
 ProgressiveRenal Impairment/
Diabetic Nephropathy

– BP/DM → Diab Nephropathy→ End stage

renal failure

– Captopril slows progression of Diab


Nephropathy in IDDM patients
Angiotensin Converting Enzyme
Inhibitors- Pharmacological Actions
 ProgressiveRenal Impairment/
Diabetic Nephropathy
– ACEI’s → ↓ ATII → ↓ mesangial growth &
↓ hypertrophy
↓ BP → ↓ GFR
↓ Renal VC (efferent)→ Renal VD
(efferent)
↓
↑ GFR ← ↑
RBF
Angiotensin Converting Enzyme
Inhibitors- Pharmacological Actions

 Scleroderma Renal Crisis


– Captopril decreases mortality
Angiotensin Converting Enzyme
Inhibitors- Adverse Effects
 Hypotension- First dose hypotension
 Cough- due to bradykinin
 ↓ATII → ↓ Aldosterone → K+ retention
 ↓ATII → ↓ Efferent renal arteriole
constriction
↓
↓ GFR → ARF
Angiotensin Converting Enzyme
Inhibitors- Adverse Effects
 Glycosuria/Proteinuria
 Hepatotoxicity
 Brassy cough
 Skin Rash(Captopril)
 Angioneurotic edema
 Dysgeusia (Captopril)
 Neutropenia
 Fetopathy (Teratogenic)
– no effect on 1st trimester organogenesis
– 2nd & 3rd trimester oligohydramnios, etc
Angiotensin II receptor Antagonists
 Enumeration

– Candesartan
– Eprosartan
– Irbesartan
– Losartan
– Telmisartan
– Valsartan
Angiotensin II receptor Antagonists
 More selective blocker of ATII effects
 No effect on bradykinin metabolism

↓
Less incidence of persistent
cough/angioedema w.r.t. ACEIs
Angiotensin II receptor Antagonists
 Losartan

– Orally active
– Metabolized extensively to active
metabolites
– T(1/2) Losartan = 2 h
– T(1/2) Metabolites = 6-9 h
– Dose: 25-100 mg/d
– Side-effects: Similar to ACEIs except
cough/angioedema
vasodilators
 hydralazine
 Directly acting arteriodilator
 Reduces diastolic pressure
 Tolerance
 Used in moderate to severe
hypertention
 Ae: flushing , headadche, angina
may precipitate, postural
hypotention
USES
 Moderate to severe hypertension.
 Avoided in older patients and with
ischaemic heart disease.
 Preferred during pregnancy .
 .Used parenterally in hypertensive
emergencies
minoxidil
 Powerful vasodilator, direct relaxtion,
 Elicit strong compensatory
mechanism
 Also used in alopecia

 Enhanced micro circlation in hair


follicle
Diazoxide:

 K+ channel opener, causes smooth muscle


sympathetic reflexes remain intact.
 Causes marked fluid retention →
expansion of plasma volume.
 Inhibits insulin secretion.

 Causes hyperuricaemia by inhibiting uric


acid excretion.
 Increased hair growth – side effect.
Sodium nitroprusside
 Rapid and consistent
 Con be titrated with infusion
 Endothelial cells split sodium nitroprusside
to generate nitric oxide
 Can produce controlled hypotension in
refractory CHF
 Increase ventricular performance by
decreaseing the pre and after load
 Should not be given for more than 2 days.
 Palpitation, vomiting, perspiration, pain
abdomen, lactic acidosis
SODIUM NITROPRUSSIDE: -
Rapidly and consistently acting vasodilator
Both anterior and venous vasodilator
Short duration of action 2-5 min
Exposure to light.&alkaline ph decomposes it
USE: -
Hypertensive emergencies.
50mg is added to a 500ml bottle
Infusion started at 0.1mg / min x titrated upward
with the response 0.2 to 0.3mg /min.
Bottle should be covered with black paper.
SIDE EFFECTS:
Palpitation, nervousness, vomiting, perspiration,
pain in abdomen, weakness,
Thank You

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