RAAS Drugs

Question 1

Overview of the Renin-Angiotensin System

Answer 1

Natures way of maintaining blood pressure
When artery perfusion decreases -> RAAS is activated

RAAS -> Increases renal perfusion by increasing intravascular colume and perfussion pressure

NE (efferent sympathetic nerves) -> Stimulate B1 receptors on the juxtoglomerular apparatus -> Secretes renin and contribute to hypertension

Question 2

Where is angiotensinogen produced? What does it do?

Answer 2

Liver

In response to low blood flow, the kidney’s produce renin that act on angiotensinogen to produce angiotensin I.

Question 3

Where is angiotensin-converting enzyme (ACE) produced? What is it’s function?

Answer 3

ACE is produced mainly by the lungs to convert angiotensin I to angiotensin II

Question 4

What is the function of angiotensin II?

Answer 4

After angiotensin I is converted to angiotensin II by ACE, angiotensin II acts on the adrenal glands to increase aldosterone production, causing sodium and water retention.

• Constricts resistance vessels
• Acts on adrenal cortex to release aldosterone
• Stimulates the release of vasopressin (ADH) from the posterior pituitary
• Stimulates thirst centers in the brain
• Facilitates NE release from sympathetics and inhibits NE re-uptake by nerve endings
• Stimulates cardiac hypertrophy and vascular hypertrophy

Question 5

Function of renin inhibitors

Answer 5

Reduce the conversion of angiotensinogen to angiotensin I

Question 6

Function of ACE inhibitors

Answer 6

Block the conversion of angiotensin I to the active peptide angiotensin II and also increase the availability of bradykinin

Question 7

Function of angiotensin-receptor blockers (ARBs)

Answer 7

Selectively antagonize angiotensin II at the AT1 receptors and increase the activation of the AT2 receptors.

Question 8

Function of aldosterone-receptor blockers?

Answer 8

Reduce the metabolic and proliferative effects of aldosterone

Question 9

What are juxtaglomerular cells associated with?

Answer 9

Afferent arteriole entering the renal glomerulus and is the primary site of renin storage and release in the body. B1-adrenoreceptors located on the JG cells respond to sympathetic stimulation by releasing renin.

Question 10

Where is renin primarily produced? What is it’s function?

Answer 10

Kidneys

Stimulates the formation of angiotensin in blood and tissues, which in turn stimulates the release of aldosterone from the adrenal cortex.

It’s release is stimulated by:

• sympathetic nerve activation (B1 activation)
• renal artery hypotension (systemic hypotension or renal artery stenosis)
• decreased sodium delivery to the distal tubules of the kidney

Question 11

How is the renin-angiotensin-aldosterone pathway regulated by the heart?

Answer 11

Through ANP and BNP, natriuretic peptides that act as important counter-regulatory system

Question 12

What conditions/diseases to drugs that affect the RAAS treat?

Answer 12

HF with low EF
MI
CKD with proteinuria
Stable coronary artery disease
Hypertension

Question 13

ACE inhibitors MOA and indications? Adverse effects? Contraindications?

Answer 13

Inhibit the conversion of the relatively inactive angiotensin I to the active angiotensin II

Captopril and Lisinopril

• Increase bradykinin levels, which stimulate prostaglandin synthesis
• Increase in renin release, which leads to increased rate of angiotensin I formation

Indications: left ventricular dysfunction (CHF), myocardial infarction, progressive renal impairment, hypertension, coronary artery disease, systolic heart failure

Adverse effects: hypotension (esp. salt depleted), cough, hyperkalemia, renal effects (usually well tolerated), proteinuria, skin rash, angioedema

Contraindicated: bilateral renal artery stenosis, NSAIDs (can cause afferent vasoconstriction and reduce GFR), pregnancy (fetopathic), hypotensive agents and diuretics, drugs increasing K concentration, antacids, probenecid

Question 14

Ethnic differences in response to ACE inhibitors and ARBs?

Answer 14

Blacks respond better to diuretics and calcium channel blockers

Whites respond better to ACE inhibitors and B-blockers

Question 15

How do prostaglandins respond to changes in blood perfusion?

Answer 15

Prostaglandins act to dilate the arteriole to maximize blood flow into the nephron. Decreasing blood flow from NSAIDs (because of the inhibition of prostaglandin release) can be overcome by addition of ACEI or ARB that will vasodilate the efferent arterial.

Question 16

Angiotensin II receptor antagonists (ARBs) MOA? Adverse effects and uses?

Answer 16

Block binding of angiotensin II to AT1 receptors in membranes of a variety of tissues, no effect on bradykinin

Losartan

Uses: Known to reverse all effects of angiotensin, hypertension, heart failure, renal protective effects (under study), substitute for ACEI only when intolerant due to cough or angiodema

Adverse effects: angiodema, renal effects, hypotension, hyperkalemia

Question 17

Direct renin inhibitor MOA, adverse effects, uses?

Answer 17

Binds to renin and inhibits the conversion of angiotensinogen to angiotensin I, thus decreasing the production of angiotensin I, angiotensin II and aldosterone

Aliskiren (Tekturna)

Uses: modest lowering of blood pressure (comparable to ARBs), may be used in combo with ARB or HCTZ

Adverse effects: angioedema, cough, hyperkalemia, rash, elevated uric acid, gout, renal stones, abdominal pain, dyspepsia and GERD

Contraindications: Pregnancy, interacts with furosemide

Question 18

Comparison of different drugs that block the RAAS pathway

Answer 18