Chapter 168: ACE Inhibitors and Angiotensin Receptor Blockers

RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM

Renin, angiotensin, and aldosterone are three peptide hormones which have an important role in the long-term regulation and homeostasis of blood pressure, intravascular volume, and electrolyte composition. The renin–angiotensin–aldosterone (RAA) system essentially involves the kidney, lungs, and adrenal gland. Juxtaglomulerar (JG) cells within the renal afferent arterioles secrete renin in response to systemic (and afferent arteriolar) hypotension, hypovolemia, and sympathetic nervous system activation of beta-1 receptors. Lower pressures in the afferent arteriole decrease glomerular filtration rate (GFR), which increases sodium reabsorption. Macula densa cells within the distal tubules sense the lower NaCl filtrate concentration and lower the filtrate flow rate and respond by stimulating the JG cells to renin release. In the plasma, renin catalyzes the cleavage of the circulating inactive peptide angiotensinogen (synthesized and secreted by the liver) into the new decapeptide angiotensin I. In the lung capillaries, endothelial angiotensin converting enzyme (ACE) further cleaves angiotensin I into the octapeptide angiotensin II.

The new peptide product angiotensin II has several important and potent vasoactive physiologic effects. Angiotensin II has two receptor subtypes (AT1 and AT2), but it is the AT1 receptor that yields its multiple clinical effects, which include:

1. Direct vascular smooth muscle contraction, which rapidly increases the systemic vascular resistance (SVR) and mean arterial pressure (MAP).

2. Enhancement of peripheral sympathetic nervous system synaptic transmission (increases norepinephrine release and decreases its reuptake).

3. Increases sodium reabsorption and water retention in the proximal convoluted tubule.

4. Stimulates antidiuretic hormone (ADH) release from the posterior pituitary, which acts on the distal convoluted tubule to increase water reabsorption.

5. Stimulates central thirst centers, thereby increasing blood volume.

6. Stimulates cardiac and vascular hypertrophy, and remodeling due to increased cardiac afterload and vascular wall tension as well as increased production of growth factors and ECM proteins.

7. Stimulates aldosterone synthesis and secretion from the zona glomerulosa of the adrenal cortex. Aldosterone stimulates the distal renal tubules to increase sodium and water reabsorption (in exchange for potassium excretion) to maintain intravascular volume.

ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are two classes of drugs which act to suppress the function of the RAA system at different sites (Figure 168-1). These forms of drug therapy act on this system for the treatment of hypertension, congestive heart failure, and to decrease post-myocardial infarction (MI) mortality. Both ACEIs and ARBs are used to decrease arterial pressure, afterload, blood volume, and hence ventricular preload, as well as inhibit and reverse cardiac and vascular hypertrophy.

ACE INHIBITORS

1. Commonly used drugs—Lisinopril, benazepril, enalapril.

2. Mechanism—ACEIs affect the RAA system by ...