Download Inhibitors of angiotensin

Antihypertensive agents
Introduction
• Hypertension is the most common CV disease
• Definition: either a sustained SBP of greater than 140
mm Hg or a sustained DBP of greater than 90 mm Hg
• HTN can lead to cerebrovascular accidents (strokes),
CHF, MI, and renal damage
• The incidence of morbidity and mortality significantly
decreases when HTN is diagnosed early and is
properly treated
JNC 7 Blood Pressure (BP) Classification
BP
Classification
Normal
Systolic BP,
mm Hg*
Diastolic BP,
mm Hg
Lifestyle
Modification
<120
and
<80
Encourage
Prehypertension
120-139
or
80-89
Yes
Stage 1
hypertension
140-159
or
90-99
Yes
Stage 2
hypertension
≥160
or
≥100
Yes
JNC 7 = seventh report of the Joint National Committee on Prevention, Detection, Evaluation,
and Treatment of High Blood Pressure.
*Classification for ages 18 years and older.
JNC 7. JAMA. 2003;289:2560-2572.
Differing influence of hypertension on
absolute and relative risk of stroke and MI
20
5 Year Risk (%)
Normotensives
Hypertensives
15
10
Stroke
MI
5
0
0
20
40
60
80
100
120
140
160
180
200
220
240
260
280
300
Systolic Blood Pressure (mmHg)
Brown, M.J. Lancet 2000; 355: 659 - 660
CV Disease Risk Doubles with
Each 20/10 mm Hg BP Increment*
8
7
6
5
CV
disease 4
3
risk
2
1
0
115/75
135/85
155/95
SBP/DBP (mm Hg)
175/105
*Individuals aged 40-70 years, starting at BP 115/75 mm Hg.
CV, cardiovascular; SBP, systolic blood pressure; DBP, diastolic blood pressure
1. Lewington S, Cardiovascular Issues in Ageing Pilots. et al. Lancet. 2002; 60:1903-1913
2. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, And Treatment of High Blood
Pressure. http://jama.ama-assn.org/cgi/content/full/289.19.2560v1. Assessed 5-1-08
Proportion of deaths attributable to leading
risk factors worldwide (2000)
High mortality, developing region
Lower mortality, developing region
Developed region
0
1
2
3
4
5
6
7
8
Attributable Mortality
(In millions; total 55,861,000)
Ezzati et al. WHO 2000 Report. Lancet. 2002;360:1347-1360.
Etiology of HTN
I.
Essential or primary hypertension
– Accounts for ˃90% of cases
– No single identifiable cause (idiopathic)
– It is usually caused by a combination of several
(multifactorial) abnormalities
– A number of factors increase the risk of developing
essential HTN: age, genetics, environment (e.g.
stress, sodium intake, alcohol), weight, and race
Etiology of HTN
II. Secondary hypertension
– Account for 10-15% of cases
– Secondary to a known organic disease, such as
renovascular disease or pheochromocytoma
– Correction of the underlying may result in a fall in
BP
Normal regulation of blood pressure
• Arterial blood pressure is regulated within a narrow range to
provide adequate perfusion of the tissues without causing
damage to the vascular system, particularly the arterial intima
(endothelium)
• Arterial blood pressure is directly proportional to the product
of the cardiac output and the peripheral vascular resistance
• BP is maintained by moment-to-moment regulation of cardiac
output and peripheral vascular resistance, exerted at four
anatomic sites: arterioles, postcapillary venules (capacitance
vessels), heart, & the kidney
Determinants of Arterial Pressure
Mean Arterial
Pressure
= Cardiac output X Peripheral resistance
Heart
Rate
Contractility
Filling
Pressure
Blood Volume
Venous Tone
Arteriolar
Diameter
Normal regulation of blood pressure
• The function of these four control sites is
controlled/coordinated mainly by two overlapping control
mechanisms:
a) The baroreflexes, which are mediated by the
sympathetic nervous system
b) The renin-angiotensin-aldosterone system
• Regulation of blood pressure in hypertensive patients
differs from healthy patients in that the baroreceptors
and the renal blood volume-pressure control systems
appear to be "set" at a higher level of blood pressure
Activation of
Baroreceptor
Reflexes
 Renal Sympathetic
Nerve Activity
 BLOOD PRESSURE
BLOOD VOLUME
Beta-adrenergic
Stimulation
 RENIN
SECRECTION
 Renal Artery
Pressure
Renal
Baroreceptor
 Plasma
Ang I
 Plasma
Ang II
Systemic
Vasoconstriction
 Aldosterone
Secretion
 BLOOD PRESSURE
BLOOD VOLUME
Ang, angiotensin.
Reid IA. Adv Physiol Edu. 1998;20:S236-S245.
Treatment Aims
• The aim of therapy is straightforward:
1) Reduction of blood pressure to within the
normal range
2) Reduction of CV and renal mortality &
morbidity
Population-Based Strategy
SBP Distributions
After
Intervention
Before
Intervention
Reduction
in BP
Reduction in SBP
mmHg
2
3
5
% Reduction in Mortality
Total CHD Stroke
–3
–4
–7
–4
–5
–9
–6
–8
–14
Antihypertensive agents
• Drugs lower blood pressure by actions on peripheral
resistance, cardiac output, or both
• All antihypertensive agents act at one or more of four
anatomic control (arterioles, postcapillary venules, heart,
& the kidney) and produce their effects by interfering with
normal mechanisms of blood pressure regulation
Antihypertensive agents
• Antihypertensive agents can be categorized according to
the principal regulatory site or mechanism on which they
act:
1. Diuretics
2. Direct vasodilators
3. Sympathoplegic agents
4. Agents that block production or action of
angiotensin
Treatment strategies
• Monotherapy of hypertension (treatment with a single
drug) is desirable because compliance is likely to be
better and cost is lower, and because in some cases
adverse effects are fewer
• Most patients with HTN require two or more drugs
(polypharmacy), if BP is inadequately controlled with a
monotherapy, with the selection based on minimizing the
adverse effects of the combined regimen
Treatment strategies
• It is important to match antihypertensive drugs to the
particular patient
• It is important to enhance compliance by carefully
selecting a drug regimen that both reduces adverse
effects and minimizes the number of doses required
daily
• HTN may coexist with other diseases that can be
aggravated by some of the antihypertensive drugs
JNC 7: Compelling Indications for Individual
Drug Classes
High-Risk Condition
With Compelling
Indication*
Heart failure
Recommended Drugs
Diuretic
x
Post-MI
BetaACE
Blocker Inhibitor
x
x
x
x
ARB
x
x
x
x
Diabetes
x
x
x
x
x
x
Recurrent stroke
prevention
x
Aldo Ant
x
x
High CAD risk
Chronic kidney disease
CCB
x
x
x
MI = myocardial infarction; CAD=coronary artery disease; Aldo Ant = aldosterone antagonist.
*Based on benefits from outcome studies or existing guidelines, the compelling indication is managed in
parallel with the BP.
JNC 7. JAMA. 2003;289:2560-2672.
Treatment strategies
• In
the
general
nonblack
population
initial
antihypertensive treatment should include a thiazide-type
diuretic, CCB, ACEI, or ARB*
• In the general black population initial antihypertensive
treatment should include a thiazide-type diuretic or CCB*
*
I. Diuretics
Diuretics
• Diuretics alone often provide adequate treatment for
mild or moderate essential HTN
• Low-dose diuretic therapy is safe, inexpensive, and
effective in preventing stroke, MI, and CHF, all of
which can cause mortality
• Diuretics are used in combination with sympathoplegic
and vasodilator drugs to reverse Na+ and H2O
retention observed with other antihypertensive agents
Diuretics
• Thiazides are the most frequently used class of
antihypertensive agents
• Thiazide diuretics are appropriate for most patients with
mild or moderate hypertension and normal renal and
cardiac function
• Loop diuretics (e.g. furosemide) are used in moderate,
severe, and malignant hypertension
• K+-sparing duiretics can be employed in conjunction
with other types of diuretics to help alleviate the K+ loss
caused by thiazide and loop diuretics
Diuretics
Mechanism of action
I.
Initially, diuretics lower BP by increasing Na+ and H2O
excretion, causing a decrease in blood volume and
cardiac output
II. With long-term treatment, cardiac output returns toward
normal while peripheral vascular resistance declines.
The explanation for the long-term vasodilation induced
by these drugs is unknow
Na+, H2O
retention
Blood
volume
Perpheral
resistance
Decreased in blood
pressure
Cardiac
output
II. Sympathoplegic agents
Drugs that Alter Sympathetic Nervous System
Function
• Sympathoplegics are drugs that reduce BP by
depressing the function of the sympathetic control of CV
function
• Are subdivided by anatomic site of action:
1. CNS-active agents: they reduce sympathetic outflow
from vasomotor centers in the brainstem and allow
these centers to retain or even increase their sensitivity
to baroreceptor control
2. Ganglionic blocking drugs (e.g. hexamethonium and
trimethophan)
Drugs that Alter Sympathetic Nervous System
Function
3. Postganglionic
sympathetic
nerve
terminal
blockers: either by inhibiting neurotransmitter release
(e.g. guanithidine) or by depleting the stores of
norepinephrine (e.g. reserpine)
4. Adrenoceptor blockers: by antagonizing the actions of
norepinephrine on effector cells
Brain
Brain Stem (Cardiovascular Control Center)
a2 Receptors
Sympathetic
ganglion
b1 Receptors
Heart
b1 Receptors
Kidney
a1 Receptors
Drugs that Alter Sympathetic Nervous System
Function
• All can elicit compensatory effects through mechanisms
that are not dependent on adrenergic nerves
• The antihypertensive effect of any of these agents used
alone may be limited by retention of sodium by the
kidney and expansion of blood volume
• Sympathoplegic antihypertensive drugs are
effective when used concomitantly with a diuretic
most
Centrally acting sympathoplegic drugs
Clonidine
•
It stimulate the α2A subtype of α2 adrenergic receptors
in the brainstem, resulting in a reduction in sympathetic
outflow from the CNS & increase in the
parasympathetic tone
•
Blood pressure lowering results by an effect on both
cardiac output and peripheral resistance
•
Clonidine decreases renal vascular resistance and
maintenance of renal blood flow and, therefore, is
useful in the treatment of HTN complicated by renal
disease
Centrally acting sympathoplegic drugs
Clonidine
• The most common: sedation, dry mouth, and drowsiness
• Severe hypertensive crisis mediated when clonidine is
suddenly withdrawn
• Concomitant treatment with TCA may block the
antihypertensive effect of clonidine
Centrally acting sympathoplegic drugs
α-Methyldopa
•
•
•
•
•
It is now used primarily for HTN during pregnancy
It rapidly enters the brain, where it accumulates in
noradrenergic
nerves,
is
converted
to
αmethylnorepinephrine
(α2
adrenergic
receptors
agonist), and is released
Renal blood flow and GFR are not reduced
The most common undesirable effect of methyldopa is
sedation and drawsiness
Other side effects include hyperprolactinemia
Postganglionic sympathatic nerve terminal blockers
Guanethidine
• Powerful antihypertensive agent
• It exerts its effects at peripheral sympathetic nerve
endings
• Guanethidine is transported across the sympathetic
nerve membrane by the same mechanism that
transports norepinephrine itself (NET, uptake 1), and
uptake is essential for the drug's action
Postganglionic sympathatic nerver terminal blockers
Guanethidine
• Once it has entered the nerve, it is concentrated in
transmitter
vesicles,
where
it
replaces
norepinephrine, causing a gradual depletion of
norepinephrine stores in the nerve ending
• The onset of sympathoplegia is gradual (maximal
effect in 1–2 weeks), and sympathoplegia persists
for a comparable period after cessation of therapy
Postganglionic sympathatic nerver terminal blockers
Guanethidin
• Undesirable effects that are related entirely to
sympathetic blockade: postural hypotension, sexual
dysfunction, and diarrhea
• Drugs that block the catecholamine uptake process
block guanethidine effects: cocaine and TCA
• Sympathomimetic agents, at doses available in OTC
cold preparations, can produce hypertension in patients
taking guanethidine
• Guanethidine can produce
releasing
catecholamines
pheochromocytoma
hypertensive crisis by
in
patients
with
Postganglionic sympathatic nerver terminal blockers
Reserpin
•
Reserpine binds tightly to vesicular membraneassociated transporter (VMAT) in central and
peripheral adrenergic neurons resulting in depletion of
norepinephrine, dopamine, and serotonin
•
SE effects:
– CNS: sedation, severe mental depression, &
extrapyramidal effects resembling Parkinson's
disease
– PNS: nasal congestion, postural hypotension,
diarrhea, bradycardia, increased gastric secretion,
and impotence
Adrenoceptor antagonist
•
Agents: β-blockers and α1-blockers
•
Useful for lowering BP in mild to moderate HTN
•
Especially useful in preventing the reflex
tachycardia that often results from treatment with
direct vasodilators
•
Beta-blockers are recommended first-line drug
therapy for HTN when concomitant disease is
present (e.g. MI and CHF)
III. Vasodilators
Vasodilators
•
All of these agents relax smooth muscle of arterioles,
thereby decreasing systemic vascular resistance
•
The induced vasodilation is associated with powerful
stimulation of the sympathetic nervous system, likely
due to baroreceptor-mediated reflexes
•
Vasodilators act by four major mechanisms:
1) Release of nitric oxide
2) Opening of potassium channels
3) Blockade of calcium channels
4) Activation of D1 dopamine receptors
Sites of action of drugs that relax vascular smooth
muscle
a-Adrenoceptor
antagonists
Prazosin
Terazosin
Activators of the
NO/guanylate cyclase pathway
Hydralazine
Nitroglycerin
Nitroprusside
Ca2+-channel blockers
Dihydropyridines
Verapamil
Ca2+
Diltiazem
NO
K+
Angiotensin II receptor
antagonists
Losartan
Valsartan
K+-channel activators
Minoxidil
Diazoxide
Vasodilators
•
1.
2.
3.
Vasodilators include:
Oral vasodilators (e.g. hydralazine and minoxidil):
used for long-term outpatient therapy of HTN
Parenteral vasodilators (e.g. nitroprusside, diazoxide,
and fenoldopam): used to treat hypertensive
emergencies
Calcium channel blockers (CCBs) (e.g. amlodipine,
diltiazem, felodipine,..etc)
Oral Vasodilators
Hydralazine
• Its actions are largely confined to vascular smooth
muscle and occur predominantly on the arteries &
arteriole
• Hydralazine apparently acts through the release of NO
from endothelial cells
• Its
toxicity
include
compensatory
responses
(tachycardia,
water
and
salt
retention)
and
immunological reactions chiefly in slow acetylator the
drug (arthralgia, myalgia, skin rashes, and fever that
resembles lupus erythematosus)
Oral Vasodilators
Minoxidill
•
Minoxidil sulfate, the active metabolite, activates the
ATP-modulated K+ channel
•
By opening K+ channels in smooth muscle and thereby
permitting K+ efflux, it causes hyperpolarization and
relaxation of smooth muscle
•
The use of minoxidil is associated with severe
compensetary responses (reflex tachycardia, sodium
and fluid retention) and hypertrichosis (hirsutism)
Parenteral Vasodilators
Sodium Nitroprusside
•
Used in treating hypertensive emergencies: its onset of
action is within 30 seconds; the peak hypotensive
effect occurs within 2 minutes
•
Nitroprusside is a nitrovasodilator that acts by
releasing NO, which activates the guanylyl cyclasecyclic GMP-PKG pathway, leading to vasodilation
•
Nitroprusside dilates both arterial and venous vessels,
resulting in reduced peripheral vascular resistance and
venous return
Parenteral Vasodilators
Sodium Nitroprusside
•
•
In the absence of heart failure, blood pressure
decreases, owing to decreased vascular resistance,
whereas cardiac output does not change or decreases
slightly
Sodium nitroprusside is an unstable molecule that
decomposes under strongly alkaline conditions or
when exposed to light. Infusion solutions should be
changed after several hours
Parenteral Vasodilators
Sodium Nitroprusside
1) Excessive hypotension: close monitoring of blood
pressure and the use of a continuous variable-rate
infusion pump will prevent an excessive hemodynamic
response
2) Accumulation of cyanide (metabolic acidosis,
arrhythmias, excessive hypotension): usually occurs
when sodium nitroprusside is infused at a rate greater
than 5 mg/kg per minute. Concomitant administration
of sodium thiosulfate can prevent accumulation of
cyanide
Parenteral Vasodilators
Sodium Nitroprusside
3) Accumulation of thiocyanate (weakness, disorientation,
psychosis, muscle spasms, convulsions, and rarely
hypothroidism) particularly in patients with renal
insufficiency: thiocyanate can be removed readily by
hemodialysis
Parenteral Vasodilators
Diazoxide
•
•
•
•
•
Diazoxide is an effective and relatively long-acting
parenterally administered that is occasionally used to treat
hypertensive emergencies
Its onset of action is within 5 minutes and lasts for 4–12
hours
Diazoxide opens potassium channels, thus hyperpolarizing
and relaxing smooth muscle cells
Diazoxide inhibits insulin release from the pancreas and is
used to treat hypoglycemia secondary to insulinoma
Diazoxide toxicities include has been excessive
hypotension, hyperglycemia, and salt and water retention
Parenteral Vasodilators
Fenoldopam
•
•
•
•
It is a peripheral arteriolar dilator used for hypertensive
emergencies and postoperative hypertension
It acts primarily as an agonist of dopamine D1
receptors, resulting in dilation of peripheral arteries and
natriuresis
Administered by continuous intravenous infusion
The major ADEs are reflex tachycardia, headache,
flushing, and an increase intraocular pressure (avoided
in patients with glaucoma)
Vasodilators
Calcium channel blockers (CCBs)
•
Agents: verapamil, diltiazem, and dihydropyridine
•
Dihydropyridines include: amlodipine, felodipine,
isradipine, nicardipine, nifedipine, and nisoldipine
•
All of the Ca2+ channel blockers lower blood pressure
by relaxing arteriolar smooth muscle and decreasing
peripheral vascular resistance
•
Verapamil and diltiazem have depressant effect on the
heart and may decrease heart rate and cardiac output.
Therefore, tachycardia is typically minimal to absent
with verapamil and diltiazem
Vasodilators
Calcium channel blockers (CCBs)
•
Dihydropyridine agents are more selective as
vasodilators and have less cardiac depressant
effect than verapamil and diltiazem
•
Reflex
sympathetic
activation
with
slight
tachycardia maintains or increases cardiac output
in most patients given dihydropyridines
IV. Inhibitors of angiotensin
Introduction
• The renin–angiotensin system (RAS) is
important for the regulation of vascular smooth
muscle tone, fluid and electrolyte balance, and
the growth of cardiac and vascular smooth
muscle
• It participates significantly in the pathophysiology
of HTN, CHF, MI, diabetic nephropathy, and
atherosclerosis
Introduction
• RAS comprises a series of biochemical steps
leading to the production of a family of structurally
related peptides (e.g., angiotensin II, angiotensin III,
and other smaller peptides with bioactivity)
• Renin is a proteolytic enzyme that is secreted by the
juxtaglomerular apparatus
Angiotensinogen
NH2-Asp-Arg-Val…Pro-Phe-Hist-Leu…COOH
1 2
3
7
8
9 10
Renin
None-ACE
pathways
(eg. Chymase)
Angiotensin I
NH2-Asp-Arg-Val…Pro-Phe-COOH
1 2
3
7
8
9 10
ACE
Angiotensin II
NH2-Asp-Arg-Val…Pro-Phe-COOH
1 2
3
7
8
aminopeptidase
Angiotensin III NH2-Arg-Val…Pro-Phe-COOH
2
Angiotensinases
Peptide fragments
3
7
8
Introduction
• Three generally accepted mechanisms are involved in
the regulation of renin secretion:
1. Reduced renal arterial pressure
2. Sympathetic neural stimulation
3. Reduced Na+ delivery at the distal renal tubule
Blood
Pressure
Rises
Blood Volume
Rises
Blood
Pressure
Falls
-
Renin
Release
+
Na+ Retention
Vasoconstriction
Aldosterone
Secretion
Blood Volume
Falls
Na+ Depletion
Angiotensin
Formation
A schematic portrayal of the homeostatic roles of the renin-angiotensin system
Angiotensin II receptors
• The effects of ang II are exerted through specific G
protein-coupled receptors
• Angiotensin receptors have been classified into two
subtypes: AT1 and AT2
• The major biological functions of ang II (CV regulation)
are mediated through the AT1 receptor
• AT1 is located predominantly in vascular and myocardial
tissue and also in brain, kidney, and adrenal glomerulosa
cells
Angiotensin II receptors
• Effects mediated by AT1 receptors include:
1. Generalized vasoconstriction, especially marked in
efferent arterioles of the kidney
2. Increased release of noradrenaline from sympathetic
nerve terminals, reinforcing vasoconstriction and
increasing the rate and force of contraction of the heart
3. Stimulation of proximal tubular reabsorption of Na+
4. Secretion of aldosterone from the adrenal cortex
5. Cell growth in the heart and in arteries
Inhibitors of angiotensin
• Three classes of drugs act specifically on the reninangiotensin system:
I. Angiotensin-converting enzyme
inhibitors
(ACEI)
II. Angiotensin II receptor antagonists (sartans)
III. Renin inhibitors (e.g. aliskiren)
Inhibitors of angiotensin
Angiotensin-converting enzyme (ACE) inhibitors
• Agents: captopril, enalapril, lisinopril, benazepril,
fosinopril, moexipril, perindopril, quinapril, ramipril,
and trandolapril
• Vasodilatory activity results both from an inhibitory
action on the renin-angiotensin system (lower
vasoconstriction) and a stimulating action on the
kallikrein-kinin system (increased bradykinin)
• ACEIs decrease the secretion of aldosteronem
resulting in decreased sodium and water retention
Angiotensinogen
Bradykinin
Renin
None-ACE
pathways
(eg. Chymase)
Angiotensin I
Bradykinin
ACE
Inactive peptide
Angiotensin II
vasodilation
of vascular
smooth muscles
ACEI
AT2R
AT1R
Aldosterone
Vasoconstriction
↑ sympathatic activity
Sympathatic
output
Na+, H2O
retention
Inhibitors of angiotensin
Angiotensin-converting enzyme (ACE) inhibitors
• ACEIs do not result in reflex sympathetic activation and
can be used safely in persons with IHD
• Because the renal vessels are extremely sensitive to the
vasoconstrictor actions of AngII, ACEIs increase renal
blood flow via vasodilation of the afferent and efferent
arterioles
• The ACE inhibitors appear to confer a special advantage
in the treatment of patients with diabetes, slowing the
development and progression of diabetic glomerulopathy
Inhibitors of angiotensin
ACE inhibitors- ADRs
1) Hypotention: after initial doses of any ACE inhibitor in
patients who are hypovolemic (e.g. diuretics)
2) Dry cough (5% to 20% of patients) due to increased
level of bradykinin in the pulmonary tree
• Thromboxane
antagonism,
aspirin,
and
iron
supplementation reduce cough induced by ACE
inhibitors
• ACE dose reduction or switching to an ARB is
sometimes effective
3) Angioedema (0.1% to 0.5% of patients)
Inhibitors of angiotensin
ACE inhibitors- ADRs
4) Hyperkalemia: patients with renal insufficiency or in
patients taking K+-sparing diuretics, K+ supplements, βblockers, or NSAIDs
5) Acute renal failure: Captopril, particularly when given
in high doses to patients with renal insufficiency, may
cause neutropenia or proteinuria
•
ACEI are contraindicated during the 2nd and 3rd
trimesters of pregnancy because of the risk of fetal
hypotension, anuria, and renal failure, sometimes
associated with fetal malformations or death
Inhibitors of angiotensin
Angiotensin Receptor–Blockers (ARBs)
• Agents: losartan, valsartan, candesartan, eprosartan,
irbesartan, telmisartan, and olmesartan
• Non-peptide competitive
angiotensin II receptor
antagonists
of
the
AT1
• Their pharmacologic effects are similar to those of ACEI
in that they produce vasodilation and block aldosterone
secretion
• More selective blockers of angiotensin effects than ACEI
and have no effect on bradykinin metabolism
Renin
Angiotensinogen
Angiotensin I
ACE
X
X
Aldosterone
secretion
Renal tubular
reabsorption of
sodium and water
Angiotensin II
Non-ACE alternate
pathways (eg, chymase)
ARB
Vasoconstriction
AT1 receptors
Catecholamine
secretion
Antidiuretic hormone
(vasoprressin)
secretion
X
X
X
X
Stimulation of thirst center
 BP
Inhibitors of angiotensin
Angiotensin Receptor–Blocking Agents
• Provide benefits similar to those of ACE inhibitors in
patients with HF and chronic kidney disease
• Their ADEs are simillar to those of ACEI
• Unlike ACE inhibitors, ARBs do not cause cough, and
the incidence of angioedema with ARBs is much less
than with ACE inhibitors
Inhibitors of angiotensin
Selective renin inhibitor: Aliskiren
• Aliskiren functions by blocking the catalytic functions of
this enzyme by binding to the active site of renin, which
inhibits the conversion of angiotensinogen to angiotensin
I and reduces angiotensin II concentrations
• It lowers BP as effectively as ARBs, ACEI, and thiazides
• It can also be combined other antihypertensives, such
diuretics, ACEIs, ARBs, or CCBs
Direct renin inhibitor
Angiotensinogen
Renin
Ang I
Heart
Non ACE pathways
Kidney
ACE
Vessels
ACEIs
Feedback Loop
Vasoconstriction
Remodelling
Ang II
ARBs
AT1 Receptor
ACEI
ARB
Aliskiren
Ang I
Ang II
Renin
PRA
↑
↑
↓
↓
↑
↓
↑
↑
↑
↑
↑
↓
Azizi M et al. 2006; Adapted from: Müller DN & Luft FC. 2006
Inhibitors of angiotensin
Selective renin inhibitor: Aliskiren
• Adverse effects include:
1) Mild GIT symptoms: diarrhea observed at high doses
(600 mg daily), abdominal pain, dyspepsia, and
gastroesophageal reflux
2) Others: headache; nasopharyngitis; dizziness; fatigue;
upper-respiratory tract infection; back pain; angiodema;
cough (cough was much less common than with ACE
inhibitors, rash, hypotension, hyperkalemia in diabetics
on combination therapy, elevated uric acid, renal stones,
and gout
• It is contraindicated during pregnancy