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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
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
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
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
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
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
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
4. Drug Interactions
a. Diuretics – may intensify first dose hypotension
- should be withdrawn 1 week prior to initiating ACE inhibitor
treatment
B. THERAPEUTIC USES
1. Hypertension – all ARBs are approved
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
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
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
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