Inhibitors of the Renin-Angiotensin System in Hypertension Therapy

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Inhibitors of the Renin-Angiotensin System in
Hypertension Therapy

• Dr. Thomas Abraham
• PHAR 417 Fall 2005

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The Renin-Angiotensin System in hypertension

• Ø      Approximately 20 of pts. with essential
  hypertension have high plasma renin activity
  while another 20 have low renin activity.
• A significant role for the
  renin-angiotensin system in hypertension appears
  probable and high renin pts. respond well to ACE
  inhibitors and angiotensin II receptor
  antagonists.

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The Renin-Angiotensin System in hypertension
Factors that promote renin release 1. Amount of
NaCl in the glomerular filtrate Ø      Macula
densa cells on the wall of the thick ascending
loop of Henle detect decreased NaCl in the
filtrate and trigger the juxtaglomerular cells to
release renin into the afferent arteriole.

• Increased NaCl in filtrate increases NaCl
  transport into the macula densa cells which
  release adenosine to signal Juxtaglomerular cells
  to decrease renin release.
• Decreased NaCl transport into macula densa
  cells results in release of PGI2 which increases
  renin release by the JG cells.

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The Renin-Angiotensin System in hypertension

• Factors that promote renin release (Cont.)
• 2. Intrarenal baroreceptors
• Ø      Renin release is also influenced by
  intrarenal baroreceptors that detect low pressure
  in the afferent arterioles.
• 3. Sympathetic nervous system activity
• Enhanced sympathetic nerve activity results
  in NE release which stimulates b1-adrenoceptors
  on JG cells to cause renin secretion.

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The Renin-Angiotensin System in hypertension
Factors Promoting Renin Release by the
Juxtaglomerular cells
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The Renin-Angiotensin System in hypertension

• Factors that decrease renin release
• Circulating angiotensin II activates AT1
  receptors on JG cells to decrease renin release
• Vasoconstriction by angiotensin II increases
  systemic blood pressure to decrease renin release
  by
• - Decreasing sympathetic tone to the JG cells
• - Constricting afferent arterioles
• - Decreasing Na reabsorption in the proximal
  tubules

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The Renin-Angiotensin System in hypertension
Consequences of Plasma Renin and ACE actions
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The Renin-Angiotensin System in hypertension

• Physiological Roles of Angiotensin II
• Direct vasoconstrictor of various vascular beds
  to increase TPR
• Enhanced NE release from sympathetic nerve
  endings
• Blunts the baroreceptor-mediated decrease in
  sympathetic nerve activity
• Releases catecholamines from adrenal medulla
• Stimulates aldosterone release from adrenal
  cortex
• Increase/decrease GFR by constriction of
  efferent/afferent arterioles

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The Renin-Angiotensin System in hypertension
Angiotensin II receptors Angiotensin II via the
AT1 receptor produces Phosphoinositide hydrolysis
in vascular smooth muscle cells to cause smooth
muscle contraction and increased PVR
Majority of the physiological effects of
angiotensin II is due to the function of the AT1
receptor. The AT2 receptor may have additional
roles in embryological development and also
regulate apoptosis, decrease cell proliferation
and vasodilation
AT1
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The Renin-Angiotensin System in hypertension

• Role of renin-angiotensin system in
  cardiovascular pathology
• Increased angiotensinogen levels are associated
  with essential hypertension
• Elevated serum ACE levels may be associated with
  increased risk of cardiac ischemia, coronary
  artery spasm, left ventricular hypertrophy and
  hypertension
• Polymorphisms of the AT1 receptor may be
  associated with hypertension, hypertrophic
  cardiomyopathy, aortic stiffness

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The Renin-Angiotensin System in hypertension
 Angiotensin-Converting Enzyme Inhibitors in
Hypertension Therapy Ø      ACE inhibitors were
first isolated from pit viper venom in the 1960s
and shown to increase bradykinin levels and
decrease angiotensin II blood levels to cause
decreases in blood pressure.
Ø      ACE inhibitors decrease circulating levels
of angiotensin II and may also increase levels of
bradykinin (a potent vasodilator) to produce
antihypertensive effects.
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The Renin-Angiotensin System in hypertension
 Ø      All the ACE inhibitors except captopril,
enalaprilat and lisinopril are ester prodrugs
that have to be converted to the active
carboxylic acid derivative. All these agents have
oral bioavailability and all except fosinopril
and spirapril are primarily eliminated by the
kidneys.  benazapril, enalapril, perindopril,
quinapril, ramipril, trandolapril,
moexipril Ø      ACE inhibitors decrease PVR
without affecting cardiac output or causing
baroreceptor reflex increase in sympathetic
activity to the heart. Lack of baroreflex may
be due to resetting of the baroreceptors to a
lower point or blunting sensitivity. Generally
hypertensive pts. show greater lowering of BP
than normotensive subjects and high renin
hypertensives are most susceptible to the effects
of these drugs.
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The Renin-Angiotensin System in hypertension
Ø      Primary therapeutic uses of ACE
inhibitors hypertension, congestive heart
failure, diabetic nephropathy, and
post-myocardial infarction. Ø      Adverse
effects include severe first dose hypotension
(esp. in hypovolemic pts, high renin pts.), acute
renal failure, hyperkalemia, dry cough, wheezing
and angioedema. Other effects observed are
altered taste, skin rash and drug fever. These
agents are contraindicated in the 2nd and 3rd
trimesters due risk of fetal hypotension, anuria,
renal failure and developmental
malformations.  Ø      Drug interactions
include hyperkalemia with K-supplements or
K-sparing diuretics NSAIDS decrease hypotensive
effects by blocking bradykinin-mediated
prostaglandin formation.
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The Renin-Angiotensin System in hypertension
Angiotensin Receptor Antagonists Ø      These
agents appear to be competitive antagonists (e.g.
losartan, eprosartan, candesartan, irbesartan)
but most seem to dissociate very slowly from the
receptor (candesartan, EXP 3174). Potency order
for the AT1 receptor candesartangt irbesartangt
telmisartan valsartan EXP3174gt losartan
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The Renin-Angiotensin System in hypertension

• Ø      These agents are selective for the AT1
  receptor with poor affinity for the AT2 receptor.
  
• These antagonists decrease angiotensin
  II-mediated vasoconstriction, enhanced NE
  release at sympathetic nerve endings, increased
  catecholamines release from the adrenals,
  increased aldosterone synthesis and release.
• May indirectly activate AT2 receptors by
  blocking AT1 receptors and causing elevated
  Angiotensin II levels
• These agents may also have beneficial effects on
  limiting smooth and cardiac muscle hypertrophy
  seen in hypertension and heart failure.
• As with the ACE inhibitors BP is reduced without
  altering cardiac output
• Does not interfere with bradykinin metabolism

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The Renin-Angiotensin System in hypertension

• Ø      Generally these agents show poor to modest
  oral bioavailability (lt50) except for irbesartan
  (70) and tend to be highly bound to plasma
  proteins.
• Most of them undergo extensive hepatic metabolism
  to active and inactive metabolites. Elimination
  of metabolites may be via renal or hepatic route.
  Doses of losartan and valsartan need to be
  reduced in liver failure. 
• Candesartan, irbesartan, eprosartan require
  renal and hepatic elimination. Losartan,
  telmisartan, valsartan have mostly hepatic
  elimination.

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The Renin-Angiotensin System in hypertension
Ø      Primary adverse effects first dose
hypotension acute renal failure and
hyperkalemia are common to ACEI as well risk
to developing fetus prevents its use in
pregnancy dry cough and angioedema seen with
ACEIs is not seen with AT1 antagonists probably
because those affects are due to potentiation of
bradykinin effects following kininnase
inhibition.