Renin-Angiotensin-Aldosterone System

RAAS is important in maintaining homeostasis. This system plays an important role in the development of hypertension. In most of the cases of hypertension, PRA is seen to be raised.

The long term effects of persistently active PRA leads to cardiac hypertrophy (ventricular) and remodeling and also coronary artery hypertrophy and remodeling. Therefore by blocking of hypertension can be controlled by blocking of ACE practically in most of the hypertensive cases.

Renin is a proteolytic enzyme and also called angiotensinogenase
It is produced by juxtaglomerular cells of the kidney

It is secreted in response to:

• A decrease in arterial blood pressure
• Decrease Na+ in macula densa
• Increased sympathetic nervous activity

Renin acts on a plasma protein known as angiotensinogen which is a glycoprotein synthesized and secreted into the bloodstream by the liver. It cleaves it to produce a decapeptide Angiotensin-I

Angiotensin-I which is then rapidly converted to Angiotensin-II (octapeptide) by ACE (present in the luminal surface of vascular endothelium).

Furthermore, degradation of Angiotensin-II by peptidases produces Angiotensin-III.
Both Angiotensin-II and Angiotensin-III stimulate Aldosterone secretion from Adrenal Cortex (equipotent).

Angiotensin-II has a very short half-life of about 1 minute.

What are the Actions of Angiotensin II?

• Angiotensin II is a powerful vasoconstrictor particularly arteriolar as a result of direct action and release of Adrenaline and noradrenaline.
  1. It promotes movement of fluid from vascular to extravascular compartment.
  2. It is a more potent vasopressor agent than noradrenaline and promotes sodium and water
  3. reabsorption.
  4. It increases the myocardial force of contraction by promoting calcium ion influx and increases heart rate by sympathetic activity, but reflex bradycardia occurs.
  5. Cardiac output is reduced and cardiac work increases.
• It stimulates aldosterone secretion leading to retention of sodium ions in the body.
• Angiotensin II causes vasoconstriction of renal arterioles resulting in a rise in IGP and glomerular damage.
• It decreases nitric oxide release.
• Decreases Fibrinolysis in blood.
• Induces drinking behavior and ADH release by acting in CNS to increase thirst.
• It has a mitogenic effect that promotes cell proliferation.

What are the ill effects on chronic conversion of Angiotensin I to Angiotensin II?

There will be volume overload and increased t.p.r( total peripheral resistance) which results in:

• Cardiac hypertrophy and remodeling.
• Coronary vascular damage and remodeling.

Hypertension results. A long-standing will cause ventricular hypertrophy.

Myocardial infarction and hypertrophy of the non-infarcted area of ventricles.

Renal damage

Risk of increased CVS related morbidity and mortality.

Angiotensin-converting enzyme inhibitors reverse cardiac and vascular hypertrophy and remodeling

Mode of Action of Angiotensin-Converting Enzyme Inhibitors

Angiotensin-converting Enzyme inhibitors work by inhibiting the conversion of angiotensin I to angiotensin II in circulation.

This reduces the vasoconstricting effect of angiotensin II and by inhibiting the release of aldosterone, causes less Na+ retention. The overall effect is a fall in blood pressure as a result of a decrease in peripheral resistance and blood volume.

Examples of drugs under this category are :

• Captopril
• Enalapril
• Perindopril
• Ramipril
• Fosinopril

Captopril

Captopril is Sulfhydryl containing dipeptide and abolishes pressor action of Angiotensin-I and not Angiotensin-II and does not block AT receptors.

Pharmacokinetics:

Available only orally, 70% - 75% is absorbed.
Partly absorbed and partly excreted unchanged in the urine.

Food interferes with its absorption.
It has a half-life of 2 Hrs, but the action stays for 6-12 hours.

Pharmacological Actions

In Normal cases : 
- Its action depends on sodium status and lowers BP marginally on a single dose.
-When there is sodium depletion it causes marked lowering of blood pressure.

In hypertensive cases:
Captopril lowers peripheral vascular resistance and thereby mean, systolic and diastolic blood pressure.
RAAS is overactive in 80% of hypertensive cases and contributes to the maintenance of vascular tone – inhibition causes lowering of blood pressure.

Initially correlates with renin-angiotensin status but chronic administration is independent of renin activity.

Captopril decreases total peripheral resistance on long term use by causing dilation of arterioles and eventual fall in systolic and diastolic blood pressure.

It has no effect on Cardiac output.
Postural hypotension is not a problem because reflex sympathetic stimulation does not occur.
Renal blood flow is maintained – greater dilatation of vessels.

Side Effects of Captopril

• Cough – persistent brassy cough in 20% cases – inhibition of bradykinin and substance P breakdown in lungs.
• Hyperkalemia in renal failure patients with K+ sparing diuretics, NSAID and beta-blockers.
• Hypotension – sharp fall may occur – 1st dose
• Acute renal failure: Congestive heart failure and bilateral renal artery stenosis
• Angioedema: swelling of lips, mouth, nose, etc.
• Rashes, urticaria, etc
• Dysgeusia: loss or alteration of taste
• Foetopathic: hypoplasia of organs, growth retardation, etc
• Neutropenia

Contraindications:

• Pregnancy,
• bilateral renal artery stenosis,
• hypersensitivity and
• hyperkalemia

Enalapril

Enalapril is a prodrug that is converted to enalaprilat.
It has several advantages over captopril in that:

It has a longer half-life that makes it suitable for once-daily dosing (5-20 mg OD).

Absorption not affected by food.

Rash and loss of taste are less frequent.

The longer onset of action.

Fewer side effects.

Ramipril

It’s a popular angiotensin-converting enzyme inhibitor now.
It is also a prodrug with long half-life.

Ramipril is tissue-specific making it protective of heart and kidney.

It is used in:
Diabetes with hypertension,
Congestive heart failure,
Acute myocardial infarction and
cardioprotective in angina pectoris

Dosing:

Start with a low dose of 2.5 to 10 mg daily

Lisinopril

Lisinopril is a lysine derivative.
Unlike others, Lisinopril is not a prodrug.
It has a slow oral absorption and less chance of 1st dose phenomenon.

Absorption not affected by food and not metabolized.

Its excreted unchanged in the urine.

A long duration of action making it suitable for a single daily dose.

Doses:

Its available as 1.25, 2.5, 5, 10 1nd 20 mg tab. Start with a low dose

To sum up, Angiotensin-converting enzyme inhibitors have many indications apart from hypertension such as;

• Hypertension
• Congestive Heart Failure
• Myocardial Infarction
• Prophylaxis of high CVS risk subjects
• Diabetic Nephropathy
• Scleroderma crisis

They are the first line of an agent now in most of the cases of hypertension especially in young persons and persons with ventricular hypertrophy.

In practice, they are used as first-line agents as monotherapy or in combination with diuretics and beta-blockers.

The advantages of Angiotensin-converting enzyme inhibitors are

• No postural hypotension or electrolyte imbalance (no fatigue or weakness)
• Safe in asthmatics and diabetics
• Prevention of secondary hyperaldosteronism and K+ loss
• Renal perfusion well maintained
• Reverse the ventricular hypertrophy and increase in lumen size of vessel
• No hyperuricemia or deleterious effect on plasma lipid profile
• No rebound hypertension
• Minimal worsening of quality of life – general wellbeing, sleep and work performance, etc.

References