4. Control of Renin Secretion
• Macula densa pathway - Low NaCl conc. in
tubular fluid sensed by macula densa --- ↑ renin
secretion
• Intrarenal baroreceptor pathway - ↓BP in
preglomerular vessels → ↑ renin secretion
• β adrenergic receptor pathway - release of NA
from postganglionic sympathetic nerve and
activation of β1 receptor on JG cells → ↑ renin
secretions
5. Major effects of Angiotensin II
• Rapid Pressure Response
• Direct vasoconstriction
• ↑sympathetic discharge
• Enhancement of peripheral noradrenergic
transmission
6. Contd.
• Slow Pressure Response
• Directly increasing Na+ absorption from
proximal tubule
• Release of Aldosterone :↑Na+ reabsorption
& K+ excretion from distal nephron
9. Contd.
• The Renin Angiotensin System (RAS) participates
significantly in the pathophysiology of
• Hypertension
• Congestive heart failure
• Myocardial infarction
• Diabetic nephropathy
10. Receptors for Angiotensin II
• AT1 receptor
• GPCR
• Most effects of A-II mediated by this receptor
• Blockade of this receptor blocks the effects of
A-II
• ARB- Angiotensin II receptor blocker
15. Hypertension
• -1st line drugs
• Large trials have confirmed … cardiovascular morbidity
& mortality ↓ by ACE inhibitors in hypertensive
patients
• Advantages –
• Lack of postural hypotension,
• reversal of cardiac hypertrophy,
• no rebound hypertension on withdrawal ,
• no deleterious effect on lipid profile,
• Safety in asthmatics, diabetics and peripheral vascular
disease patients
16. Contd.
• Renal blood flow is well maintained
• Secondary hyperaldosteronism and K+ loss
due to diuretics is prevented
• Minimum worsening of quality of life
17. Congestive Heart Failure
• 1st line drugs
• ↓pre & afterload → ↓BP
• ↓pulmonary artery pressure
• Salt & water loss due to improved renal
perfusion and ↓ aldosterone secretion
• MOST IMP – reversal of cardiac
remodeling
• PRLONG SURVIVAL of CHF patients
18. Myocardial Infarction (MI)
• ACE inhibitor administered while MI is
evolving (within 24 hrs) & continued for 6
weeks ↓early & long term mortality
• Useful in hypertensive & diabetic patients
19. Prophylactic use in patients who are
at High Risk of Cardiovascular Events
• ACE inhibitors significantly decrease the rate
of myocardial infarction, stroke, and death in
these patients
20. Contd.
Diabetic nephropathy
• ACE inhibitor delay the progress of nephropathy
• Treated patients have higher creatinine
clearance, require less dialysis & longer life
expectancy
• Arrest/partly reverse any degree of albuminuria
• RAS seems to accentuate micro- and
macrovascular complications in diabetics, and
ACE inhibitors have specific organ protective
effect
• Deterioration of retinopathy in diabetics retarded
21. Contd.
• Mechanism
• ↓glomerular capillary pressure,
• attenuate mesangial cell growth and matrix
production
Also useful in non diabetic retinopathy
22. Contd.
• Scleroderma renal crisis
• Malignant hypertension develops and causes
acute renal failure treated by ACE inhibitors
(Scleroderma is a systemic autoimmune
disease)
23. Enalapril
• Prodrug, deesterified in the liver to enalaprilat
• Advantages:
• More potent, effective dose 5–20 mg OD
• Absorption is not affected by food
• Onset of action is slower
• Has a longer duration of action
• Rashes and loss of taste are probably less
frequent
24. Adverse effects of ACE inhibitors
• Hypotension - due to arterial & venodilation
• Cough
– Due to ↑level of bradykinin in lungs
– (Bradykinin is metabolized by ACE & ACE
inhibition results in ↑level of bradykinin)
29. Contd.
• Acute Renal Failure
• AngII, by constricting the efferent arteriole,
helps to maintain adequate glomerular
filtration when renal perfusion pressure is low
(In bilateral renal artery stenosis)
31. Losartan
• competitive antagonist
• 10,000 times more selective for AT1 than for AT2
receptor
ARBs differ from ACE inhibitors in the following ways:
• Not interfere with degradation of bradykinin and other
ACE substrates:No cough
• Result in more complete inhibition of AT1 receptor
activation because :
– responses to Ang II generated via alternative pathways
and consequent AT1 receptor activation are also blocked
32. Contd.
• Result in indirect AT2 receptor activation
• Cause little increase in the level of Ang (1-7)
which is raised by ACE inhibitors
33. Mechanism
• Selectively block AT1 receptor than AT2
• ARBs potently and selectively inhibit most of
the biological effects of AngII
• Pharmacological effects similar to ACE
inhibitors
34. Use of ARBs
• Hypertension – comparable to ACE inhibitors
• CHF - ACE inhibitors 1st choice – ARBs for
patients intolerant to ACE inhibitors
• Diabetic nephropathy - renoprotective
• MI (myocardial infarction)
35. Adverse effects of ARBs
• Cough, Angioedema --incidence less than
ACE inhibitors
Other side effects same as ACE inhibitors –
• Hypotension
• Hyperkalemia
• Fetopathic potential - TO BE AVOIDED IN
PREGNANCY
36. Direct renin inhibitor (DRI) – Aliskiren
• Blocks conversion of angiotensinogen to
angiotensin I
• Useful in hypertension & CHF
• ADR
• Dyspepsia, abdominal pain, loose motions,
headache and dizziness
• Acute hypotension, hyperkalaemia, cough,
angioedema and rashes are much less frequent
than with ACE inhibitors
• Contraindicated in pregnancy