CHAPTER 42 DRUGS ACTING ON RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM

3 families of drugs: angiotensin-converting enzyme (ACE)

- ACE inhibitors have roles in treatment of hypertension, heart
failure, and diabetic
nephropathy
- ACE inhibitors are indicated for myocardial infarction and
prevention of cardiovascular
events in patients at risk
angiotensin II receptor blockers (ARBs)
- indications are limited to hypertension, heart failure, and
diabetic nephropathy
selective aldosterone receptor blockers
- eplerenone (only one available) is approved only for
hypertension

I. PHYSIOLOGY OF RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM

- plays an important role in regulating blood pressure, blood volume, and
fluid and electrolyte
balance
- appears to mediate certain pathophysiologic changes associated with
hypertension, heart failure, and
myocardial infarction
- exerts its effects in large part through angiotensin II

A. TYPES OFANGIOTENSIN
- consists of: angiotensin I – precursor of angiotensin II, has very little
biologic activity
angiotensin II – has very high biologic activity
angiotensin III – formed by degradation of angiotensin II, has
moderate biologic activity
- small polypeptides

B. ACTIONS OF ANGIOTENSIN II
- mediates essentially all of the effects of RAAS
- most prominent actions are vasoconstriction and stimulation of
aldosterone release
- actions serve to raise blood pressure
- can act on the heart and blood vessels to alter their morphology

1. Vasoconstriction – angiotensin II acts directly on vascular smooth muscle

(VSM) to cause contraction
- vasoconstriction is prominent in arterioles and less so in veins
- a result of induced vasoconstriction is raising blood pressure
- can cause vasoconstriction indirectly by acting on:
• sympathetic neurons to promote norepinephrine release
• adrenal medulla to promote epinephrine release
 • central nervous system to increase sympathetic outflow to
blood vessels

2. Release of Aldosterone – angiotensin II acts on the adrenal cortex to

promote synthesis and secretion
of aldosterone
- aldosterone acts on the kidney to cause retention of sodium and
excretion of potassium and
hydrogen
- aldosterone increases plasma volume, increasing blood pressure
- adrenal cortex is highly sensitive to angiotensin II and can be
stimulated to release
aldosterone even when angiotensin II levels are too low to
induce vasoconstriction
- aldosterone secretion is enhanced when sodium levels are low and
when potassium levels are
high

3. Alteration of Cardiac and Vascular Structure – angiotensin II may

cause pathologic structure
changes in the heart and blood vessels
- thought to cause both hypertrophy (increased mass of a structure)
and remodeling
(redistribution of mass within a structure)
- in hypertension, may be responsible for increasing the thickness of
blood vessel walls
- in atherosclerosis, may be responsible for thickening intimal
surface of blood vessels
- in heart failure and myocardial infarction, may be responsible for
causing cardiac hypertrophy
and fibrosis

Known effects:
• increased migration, proliferation, and hypertrophy of VSM
cells
• increased production of extracellular matrix by VSM cells
• hypertrophy of cardiac myocytes
• increased production of extracellular matrix by cardiac
fibroblasts

C. FORMATION OF ANGIOTENSIN II BY RENIN AND ANGIOTENSIN-CONVERTING ENZYME

- angiotensin II is formed through two sequential reactions: 1st – catalyzed
by rennin
2nd – catalyzed by ACE

1. Renin – catalyzes the formation of angiotensin I from angiotensinogen

- rate-limiting step in angiotensin II formation
- produced by juxtaglomerular cells of the kidney
 - undergoes controlled release into the bloodstream, converting
angiotensinogen into
angiotensin I

a. Regulation of Renin Release – factors that regulate renin release

regulate the rate of
angiotensin II formation
- regulated by classic negative feedback loop

Renin Release Triggers:

• release increases in response to decline in blood
pressure, blood volume,
plasma sodium content, or renal perfusion
pressure
• reduced renal perfusion pressure (especially important
stimulant) can occur in
response to: stenosis of the renal arteries
reduced systemic blood pressure
reduced plasma volume (brought on by
dehydration,
hemorrhage, or chronic sodium
depletion)
• sympathetic nervous system increase secretion by
stimulation of beta1
adrenergic receptors on juxtaglomerular cells

Renin Suppression Factors:

• inhibited by elevation of blood pressure, blood volume,
and plasma sodium content

2. Angiotensin-Converting Enzyme (Kinase II)

- ACE catalyzes the conversion of angiotensin I (inactive) into
angiotensin II (highly active)
- ACE is located on the luminal surface of all blood vessels,
vasculature of the lungs being
especially rich in the enzyme

- because ACE is abundant, conversion of angiotensin I into

angiotensin II occurs
almost instantaneously
- ACE is a relatively nonspecific enzyme that can act on a
variety of additional
substrates
- substrate as angiotensin I = referred to as ACE
- enzyme acting on other substrates = different names
- substrate as hormone bradykinin = referred to as
Kinase II

D. REGULATION OF BLOOD PRESSURE BY RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM

 - RAAS is poised to help regulate blood pressure: factors that lower blood
pressure turn the system on,
factors that raise blood pressure turn the system off
- RAAS role in normovolemic, sodium-replete individuals is only modest
- RAAS is a major factor in maintaining blood pressure in the presence of
hemorrhage, dehydration, or
sodium depletion

Basic Processes (through Angiotensin II):

Vasoconstriction – raises blood pressure by increasing total peripheral
resistance
- occurs within minutes to hours of activating the system, raising the
blood pressure quickly

Retention of Water and Sodium – raises blood pressure by increasing blood

volume
- requires days, weeks, or even months to raise blood pressure

Promotion of Renal Retention of Water:

1st – constricting renal blood vessels, angiotensin II reduces renal blood
flow, reducing glomerular
filtration
2 – stimulates release of aldosterone from the adrenal cortex
nd

- aldosterone then acts on the kidney to promote retention of sodium

and water and excretion of
potassium

E. TISSUE (LOCAL) ANGIOTENSIN II PRODUCTION

- can be produced in individual tissues, permitting discrete, local effects of
angiotensin II independent of
the main system
- interference with local production may underlie some effect of the ACE
inhibitors
- some angiotensin II is produced by pathways that do NOT involve ACE - -
as a result drugs that inhibit
ACE cannot completely block angiotensin II production

II. ANGIOTENSIN-CONVERTING ENZYME INHIBITORS

- drug names end in “il”
- ACE inhibitors are important drugs for treating hypertension, heart
failure, diabetic nephropathy, and
myocardial infarction (MI)
- also used to prevent adverse cardiovascular events in patients at
risk
- most prominent adverse effects are cough, first-dose hypotension,
and hyperkalemia
- beneficial effects result largely from suppressing formation of
angiotensin II
 - similarities are much more striking than their differences

A. MECHANISM OF ACTION AND OVERVIEW OF PHARMACOLOGIC EFFECTS

- beneficial effects derive from:
reducing levels of angiotensin II (through inhibition of ACE)
- inhibitors can dilate blood vessels (primarily arterioles and to
a lesser extent veins)
increasing levels of bradykinin (through inhibition of Kinase II)
- promoting vasodilation by stimulating production of
prostaglandins and nitric oxide

- adverse effects result from inhibiting:

ACE – possibly causing hypotension, hyperkalemia, renal failure and
fetal injury
Kinase II – with resultant accumulation of bradykinin, possibly
causing cough and angioedema

1. Pharmacokinetics
a. Nearly all ACE inhibitors are administered orally with the exception
of enalaprilat (active form of
enalapril) which is given IV
b. Except for captopril and moexipril, all oral ACE inhibitors can be
administered with food
c. With exception of captopril, all ACE inhibitors have prolonged half-
lives and can be
administered just once or twice a day
- captopril is administered 2 or 3 times a day
d. With exception of lisinopril, all ACE inhibitors are prodrugs that must
undergo conversion to
their active form in the small intestine and liver
- lisinopril is active as given
e. All ACE inhibitors are excreted by the kidneys
- as a result, nearly all can accumulate to dangerous levels in
patients with kidney
disease
- dosages must be reduced in these patients
-fosinopril does not require dosage reduction

2. Therapeutic Uses
- no single ACE inhibitor is approved for all of these conditions

a. Hypertension – especially effective against malignant hypertension

and hypertension secondary
to renal arterial stenosis
- also useful against essential hypertension of mild to
moderate intensity with maximum
benefits possibly taking several weeks to develop
- in hypertension, the mechanism underlying blood pressure
reduction is not fully
 understood
- initial responses are proportional to circulating
angiotensin II levels and are
clearly related to reduced formation of that
compound
- in prolonged therapy, blood pressure often undergoes
additional decline
- no correspondence between reductions in blood
pressure and
circulating angiotensin II
- delayed response may be due to reductions in
local angiotensin II
levels which are not revealed by measuring
levels in the blood

Advantages: do not interfere with cardiovascular reflexes

- exercise capacity is not impaired and
orthostatic
hypotension is minimal
can be used safely in patients with bronchial
asthma
do not promote hypokalemia, hyperuricemia or
hyperglycemia – side
effects seen with thiazide diuretics
do not induce lethargy, weakness, or sexual
dysfunction
reduce the risk of cardiovascular mortality caused
by hypertension

b. Heart Failure
- by lowering arteriolar tone – improve regional blood flow
- by reducing cardiac afterload – increase cardiac output
- by causing venous dilation – reduce pulmonary congestion
and peripheral edema
- by dilating blood vessels in the kidneys – increase renal blood
flow, promoting
excretion of sodium and water
- beneficial effects from this loss of fluid: helps reduce
edema
by lowering blood volume,
decreases
venous return to the
heart,
reducing right heart
size
- by reducing local production of angiotensin II in the heart –
may suppress growth of
 myocytes, possibly preventing pathologic thickening of
the ventricular wall

c. Myocardial Infarction – ACE inhibitors can reduce mortality following

acute MI (heart attack)
- decrease the chance of developing overt heart failure
- captopril, lisinopril, and trandolapril are approved for patients
with MI

d. Diabetic and Nondiabetic Nephropathy – ACE inhibitors can slow

progression of renal disease
- can delay onset of overt nephropathy
- principal protective mechanism appears to be reduction of
glomerular filtration
pressure
- ACE inhibitors lower filtration pressure by reducing
levels of angiotensin II
1st – angiotensin II raises systemic blood pressure,
raising pressure in
the afferent arteriole of the glomerulus
2 – it constricts the efferent arteriole, generating
nd

backpressure in the
glomerulus
- resultant increase in filtration pressure promotes injury
- reducing levels of angiotensin II, ACE inhibitors lower
glomerular filtration
pressure, slowing development of renal injury
- captopril is only ACE inhibitor approved for
nephropathy

e. Prevention of MI, Stroke, and Death in Patients at High

Cardiovascular Risk
- ramipril [Altace] is the only ACE inhibitor approved for
reducing this risk
- high risk being defined by a major cardiovascular event:
• history of stroke, coronary artery disease, peripheral
vascular disease or diabetes combined with
• at least one other risk factor, such as hypertension, high
LDL cholesterol, low HDL cholesterol, or cigarette
smoking
- possible mechanisms underlying benefits include reduced
vascular resistance and
protection of the heart, blood vessels, and kidneys from
the damaging that
angiotensin Ii and aldosterone can cause over time

3. Adverse Effects
- ACE inhibitors are generally well tolerated
 - some adverse effects (first dose hypotension, hyperkalemia) are
due to reduction in
angiotensin II
- other adverse effects (cough, angioedema) are due to elevation of
bradykinin

a. First Dose Hypotension – caused by widespread vasodilation

secondary to abrupt lowering of
angiotensin II levels
- most likely in:
• patients with severe hypertension – blood pressure
should be monitored for
several hours following first captopril dose
- if hypertension develops, patient should assume
a supine position
- blood pressure can be raised with an infusion of
normal saline
• patients taking diuretics – diuretics should be
temporarily discontinued,
starting 2 – 3 days before initial therapy with an
ACE inhibitor
• patients who are sodium depleted or volume depleted
- initial dose should be low to minimize first dose effect

b. Cough – persistent, dry, irritating, nonproductive cough can develop

with all ACE inhibitors
- most common reason for discontinuing therapy
- more troublesome when patient is supine
- occurs more in women than in men
- begins to subside 3 days after discontinuing ACE inhibitor
and gone within 10 days
- caused by accumulation of bradykinin secondary to inhibition
of kinase II

c. Hyperkalemia – aldosterone release (secondary to inhibition of

angiotensin II production) can
cause potassium retention by the kidney
- significant potassium accumulation is limited to patients
taking potassium
supplements or a potassium sparing diuretic
- rare

d. Renal Failure – most likely in patients with bilateral renal artery

stenosis or stenosis in the artery
to a single remaining kidney
- in renal artery stenosis, kidneys release large amounts of
rennin, resulting in high
 levels of angiotensin II serving to maintain glomerular
filtration by: 1) elevating
blood pressure and 2) constricting efferent glomerular
arterioles
- when angiotensin II levels falls, mechanisms that support
glomerular filtration fail,
causing urine production to drop precipitously

e. Fetal Injury – use of ACE inhibitors during the 2nd and 3rd trimesters
can cause harm
- specific effects include hypotension, hyperkalemia, skull
hypoplasia, anuria, renal
failure (reversible and irreversible) and death
- should discontinue treatment as soon as possible
- should be closely monitored for hypotension, oliguria, and
hyperkalemia

d. Angioedema – rare and potentially fatal reaction caused by

accumulation of bradykinin (owing
to inhibition of Kinase II)
- symptoms, resulting from increased capillary permeability,
include giant wheals and
edema of the tongue, glottis, and pharynx
- severe reactions should be treated with subcutaneous
epinephrine
- discontinue and never use ACE inhibitors again if
angioedema develops

4. Drug Interactions
a. Diuretics – may intensify first dose hypotension
- should be withdrawn 1 week prior to initiating ACE inhibitor
treatment

b. Antihypertensive Agents – hypotensive effects are often additive

with those of other
antihypertensive drugs
- dosage of other drugs may require reduction

c. Drugs that Raise Potassium Levels – increased risk caused by

potassium supplements and
potassium sparing diuretics
- increased because, by suppressing aldosterone secretion,
ACE inhibitors can reduce
excretion of potassium and potassium sparing diuretics
should be employed
only when clearly indicated

5. Preparations, Dosage and Administration

- all ACE inhibitors are administered PO, except enalaprilat
 - all oral products are available in single drug formulations - - most
are also available in fixed
dose combinations with hydrochlorothiazide (a thiazide
diuretic)
- all oral formulations may be administered without regard to meals,
except captopril and
moexipril which should be administered 1 hour before meals
- dosages for all ACE inhibitors, except fosinopril, should be reduced
in patients with renal
impairment

III. ANGIOTENSIN II RECEPTOR BLOCKERS (ARBS)

- initially used only for patients with hypertension
- today, approved for patients with heart failure and diabetic nephropathy,
also
- decrease the influence of angiotensin II
- ARBs block angiotensin II actions vs. ACE inhibitors blocking
angiotensin II production
- ARBs do not cause cough or hyperkalemia vs. ACE inhibitors that
do cause it

A. MECHANISM OF ACTION AND OVERVIEW OF PHARMACOLOGIC EFFECTS

- ARBs block access of angiotensin II to its receptors in blood vessels,
adrenals, and all other tissues
- blockage on blood vessels, causes dilation of arterioles and veins
- blockage in the heart, can prevent angiotensin II from inducing
pathologic changes in cardiac
structure
- blockage in adrenals, decrease release of aldosterone and can
increase renal excretion of
sodium and water
- sodium and water excretion is further increased through
dilation of renal blood vessels
- in contrast to ACE inhibitors, ARBs do not increase levels of bradykinin
(because ARBs do not inhibit
Kinase II), therefore, ARBs do not promote cough
- ARBs are better at preventing the effects of angiotensin II than ACE
inhibitors because angiotensin II
can be produced by pathways that do not involve ACE, hence ACE
inhibitors cannot completely
block angiotensin II production and actions - -ARBs block angiotensin
II at its receptors,
completely eliminating its influences

B. THERAPEUTIC USES
1. Hypertension – all ARBs are approved

2. Heart Failure – only valsartan is approved

 - the drug reduces symptoms, deceased hospitalizations, improved
functional capacity, and
increased left ventricular ejection fraction
- most importantly, it prolonged survival
- reserved for patients who cannot tolerate ACE inhibitors (because
of cough)
3. Diabetic Nephropathy – irbesartan and losartan are approved for managing
nephropathy in hypertensive
patients with Type 2 diabetes
- these drugs delay development of overt nephropathy and slow
progression of established
renal disease
- benefits are due in part to reduction in blood pressure and in part
to mechanisms that have not
been determined

C. ADVERSE EFFECTS
- all ARBs are well tolerated
- ARBs do not cause clinically significant hyperkalemia
- ARBs do not promote accumulation of bradykinin, therefore, do not cause
cough

1. Angioedema – even though ARBs do not increase bradykinin, they can

cause angioedema
- if angioedema occurs, ARBs should be withdrawn immediately and
never used again
- severe reaction are treated with subcutaneous epinephrine

2. Fetal Harm – can injury developing fetus if taken during the 2nd or 3rd
trimester

3. Renal Failure – ARBs can cause renal failure in patients with bilateral
renal artery stenosis or stenosis
in the artery to a single remaining kidney

D. DRUG INTERACTIONS
- hypotensive effects of ARBs are additive with those of other
antihypertensive drugs - - dosages of the
other drugs may require reduction

E. PREPARATIONS, DOSAGE, AND ADMINISTRATION

- all ARBs are administered PO
- all may be taken with or without food
- all are available in single drug formulations
- all, except olmesartan, are also available in fixed dose combinations with
hydrochlorothiazide (thiazide
diuretic)
III. SELECTIVE ALDOSTERONE RECEPTOR BLOCKER: EPLERENONE
- trade name Inspra
- spironolactone (trade name Aldactone) also blocks aldosterone receptors,
but is less selective than
eplerenone
- eplerenone is more selective than aldosterone, therefore may cause
fewer side effects

A. THERAPEUTIC USE
- only approved for hypertension
- may be used alone or in combination with other antihypertensive agents
- reduces blood pressure levels equal to those produced by spironolactone,
superior to those produced
by losartan (an ARB)
- in combination with an ACE inhibitor or ARB produces a further reduction
in blood pressure
- should be reserved for patients who have not responded to traditional
antihypertensive drugs

B. MECHANISM OF ACTION
- produces selective blockade of aldosterone receptors, having little or no
effect on receptors for other
steroid hormones
- in the kidney, activation of aldosterone receptors promotes excretion of
potassium and retention of
sodium and water
- in receptor blockade, retention of potassium and increased excretion of
sodium and water (which
reduces blood pressure)
- at normal sites, blockade of aldosterone receptors may also contribute to
beneficial effects

C. PHARMACOKINETICS
- administered orally
- absorption is not affected by food
- plasma level peak about 1.5 hours after ingestion
- elimination half-life is 4 – 6 hours

D. ADVERSE EFFECTS
- well tolerated
- slight effects: diarrhea, abdominal pain, cough, fatigue, gynecomastia,
flu-like syndrome

1. Hyperkalemia – can occur secondary to potassium retention

- combined use with ACE inhibitors or ARBs is permissible but should
be done with caution
 - contraindicated for patients with high serum potassium and
patients with either impaired renal
function or Type 2 diabetes with microalbuminuria

E. DRUG INTERACTIONS
- inhibitors of CYP3A4 (isozyme of cytochrome P450) can increase levels of
eplerenone, posing a risk of
toxicity
- weak inhibitors can double eplerenone levels (dosage reduction may be
required)
- strong inhibitors can increase levels 5-fold; eplerenone should not be
combined with these agents
- drugs that raise potassium levels can increase the risk of hyperkalemia
- should not be combined with potassium supplements or potassium
sparing diuretics
- combining with ACE inhibitors or ARBs should be done with caution
- drugs similar to eplerenone are known to increase levels of lithium

F. PREPARATIONS, DOSAGE AND ADMINISTRATION

- available in tablets taken orally
- can be administered with or without food