ANGIOTENSIN INHIBITORS

PHYSIOLOGY OF RAAS
• Renin release from the kidney cortex is stimulated by reduced
renal arterial pressure, sympathetic neural stimulation, and
reduced sodium delivery or increased sodium concentration at the
distal renal tubule
• Renin acts upon angiotensinogen to yield the inactive precursor
decapeptide angiotensin I.
• Angiotensin I is then converted, primarily by endothelial ACE, to
the arterial vasoconstrictor octapeptide angiotensin II which is in
turn converted in the adrenal gland to angiotensin III.
• Angiotensin II has vasoconstrictor and sodium-retaining activity.
• Angiotensin II and III both stimulate aldosterone release.
 Introduction
• Angiotensin may contribute to maintaining high vascular
resistance in hypertensive states associated with high plasma
renin activity, such as
– renal arterial stenosis
– some types of intrinsic renal disease
– malignant hypertension
– essential hypertension after treatment with sodium restriction,
diuretics, or vasodilators.
• even in low-renin hypertensive states, these drugs can lower
blood pressure
• addition, β blockers, as noted earlier, can reduce renin
secretion
 Introduction
• A parallel system for angiotensin generation exists in several other
tissues (eg, heart) and may be responsible for trophic changes such as
cardiac hypertrophy.
• The converting enzyme involved in tissue angiotensin II synthesis is
also inhibited by ACE inhibitors.
• Three classes of drugs act specifically on the renin-angiotensin system:
– ACE inhibitors
– the competitive inhibitors of angiotensin at its receptors, including losartan
and other non peptide antagonists; and
– aliskiren, an orally active renin antagonist
• A fourth group of drugs, the aldosterone receptor inhibitors (eg,
spironolactone, eplerenone), is discussed with the diuretics.
• Beta blcokers can also block renin secretion
• Renin-angiotension system (RAS) participates in
the pathophysiology of hypertension, congestive
heart failure, myocardial infarction, and diabetic
nephropathy.
• Effects of angiotensin include
– i)Increased Peripheral vascular resistance
• Direct vasoconstriction
• Enhancement of peripheral noradrenergic neurotransmission
• Increased sympathetic discharge (CNS
• Release of catecholamine from adrenal medulla
– Ii) Altered renal function
• Direct effect to increase Na+ reabsorption in proximal tubule.
• Release of aldosterone from adrenal cortex (increased Na+
reabsorption and increased K+ excretion in distal nephron)
• Altered renal hemodynamics:
– Direct renal vasoconstriction and increased sympathetic tone
– iii)Altered cardiovascular structure(cardiac remodeling)
– Nonhemodynamically mediated effects:
Increased expression of proto-oncogenes B
Increased production of growth factors C.
Increased synthesis of extracellular matrix proteins II.
– Hemodynamically mediated effects:
Increased afterload (cardiac)
Increased wall tension (vascular)
 ANGIOTENSIN-CONVERTING
ENZYME (ACE) INHIBITORS
• ACE-I inhibit the angiotensin converting enzyme ,peptidyl
dipeptidase that hydrolyzes angiotensin I to angiotensin II and
(under the name plasma kininase) inactivates bradykinin
• Bradykinin works by stimulating release of NO and prostacyclin.
• The ACE inhibitors inhibit the conversion of Ang I to AngII.
• The hypotensive activity of ACE-I results both from an inhibitory
action on the renin-angiotensin system and a stimulating action
on the kallikrein-kinin system
– Inhibition of Ang II production lowers blood pressure and enhances
natriuresis.
– inhibition of the degradation of bradykinin,a potent vasodilator
• ACE inhibitors increase by 5-fold the circulating levels of the
natural stem cell regulator Ac-SDKP, which may also contribute
to the cardioprotective effects of ACE inhibitors
 Classification of ACE-I
• 1.Sulfhydryl-containing ACE inhibitors structurally related to
– captopril
• 2. Dicarboxyl-containing ACE inhibitors structurally related to
enalapril
– lisinopril
– benazepril
– quinapril,
– Moexipril
– ramipril
– trandolapril
– perindopril
• 3. Phosphorus-containing ACE inhibitors structurally related to
– fosinopril
 Pharmacokinetics of ACE-I
• Majority are prodrugs that are 100–1000 times less potent but with better
oral bioavailability than the active molecules.
• Differ in potency, whether ACE inhibition is primarily a direct effect of the
drug itself or the effect of an active metabolite, and pharmacokinetics.
• All ACE inhibitors block the conversion of Ang I to Ang II and have similar
therapeutic indications, adverse-effect profiles, and contraindications.
• With the exceptions of fosinopril, trandolapril, and quinapril (which display
balanced elimination by the liver and kidneys), ACE inhibitors are cleared
predominantly by the kidneys.
• renal impairment significantly diminishes the plasma clearance of most ACE
inhibitors and dose adjustment is necessary
• Elevated PRA renders patients hyperresponsive to ACE –I –induced
hypotension e.g in heart failure hence start at low dose
• ACE inhibitors differ markedly in tissue distribution
• Captopril-The prototype ACE-I
• Enalapril
– is an oral prodrug that is converted by hydrolysis to a converting
enzyme inhibitor, enalaprilat
– Enalaprilat itself is available only for intravenous use, primarily for
hypertensive emergencies.
• Lisinopril
– is a lysine derivative of enalaprilat.
• Benazepril, fosinopril, moexipril, perindopril, quinapril, ramipril,
and trandolapril
– are other longacting members of the class.
– All are prodrugs, like enalapril, and are converted to the active agents
by hydrolysis, primarily in the liver.
 pharmacodynamics
• Angiotensin II inhibitors lower blood pressure
principally by decreasing peripheral vascular resistance.
• Cardiac output and heart rate are not significantly
changed.
• Unlike direct vasodilators, these agents do not result in
reflex sympathetic activation and can be used safely in
persons with ischemic heart disease.
• The absence of reflex tachycardia may be due to
downward resetting of the baroreceptors or to
enhanced parasympathetic activity
 Clinical use
• Effective alone or in combination for hypertension
• ACE inhibitors and chronic kidney disease
– they diminish proteinuria and stabilize renal function
– In diabetes be used in the absence of hypertension
– Renal benefits probably result from improved intrarenal hemodynamics,
with decreased glomerular efferent arteriolar resistance and a resulting
reduction of intraglomerular capillary pressure.
• ACE inhibitors and heart failure
– extremely useful in the treatment of heart failure and as treatment
after myocardial infarction where they reduce
mortality,hospitalisation,myocardial infarction etc
• Patients at high risk of cardiovascular events benefit considerably
from treatment with ACE inhibitors
 Toxicity
• Severe hypotension can occur after initial doses of any
ACE inhibitor in patients who are hypovolemic as a result
of diuretics, salt restriction, or GIT loss.
• acute renal failure (particularly in patients with bilateral
renal artery stenosis or stenosis of the renal artery of a
solitary kidney)
• Hyperkalemia,more likely to occur in patients with renal
insufficiency or diabetes
• dry cough sometimes accompanied by wheezing in 5-
20%,resolve 4 days after stopping .Due to elevated
bradykinin ,prostacyclin,substance P
• Angioedema
– 0.1%–0.5% of patients.
– rapid swelling in the nose, throat, mouth, glottis, larynx,
lips, or tongue.
– Once ACE inhibitors are stopped, angioedema disappears
within hours
– Management by protecting airway, epinephrine, an
antihistamine, or a glucocorticoid should be administered.
– Higher risk in African Americans who have a 4.5 times
greater risk than causassian
– is a class effect,patient should NEVER receive ACE-I
• Fetopathic effects
– ACE inhibitors are contraindicated during the second
and third trimesters of pregnancy because of the risk of
fetal hypotension, anuria, and renal failure, sometimes
associated with fetal malformations or death.
– first trimester exposure to ACE inhibitors has been
linked to increased teratogenic risk.
• Minor toxic effects seen more typically include
altered sense of taste, allergic skin rashes, and drug
fever, which may occur in up to 10% of patient
 Drug interractions
• Important drug interactions include those with
potassium supplements or potassium-sparing diuretics,
which can result in hyperkalemia.
• Nonsteroidal anti-inflammatory drugs may impair the
hypotensive effects of ACE inhibitors by blocking
bradykinin mediated vasodilation, which is at least in
part prostaglandin mediated.
• Antacids may reduce the bioavailability of ACE inhibitor
• ACE inhibitors may increase plasma levels of digoxin and
lithium and hypersensitivity reactions to allopurinol.
 ANGIOTENSIN RECEPTOR-BLOCKING
AGENTS
• The Ang II receptor blockers bind to the AT1 receptor with high affinity
and are more than 10,000-fold selective for the AT1 receptor over the
AT2 receptor.
• binding of ARBs to the AT1 receptor is competitive but the inhibition
by ARBs of biological responses to Ang II often is functionally
insurmountable.
• Insurmountable antagonism has the theoretical advantage of
sustained receptor blockade even with increased levels of endogenous
ligand and with missed doses of drug.
• They have no effect on bradykinin metabolism and are therefore more selective
blockers of angiotensin effects than ACE inhibitors.
• They also have the potential for more complete inhibition of angiotensin action
compared with ACE inhibitors because there are enzymes other than ACE that
are capable of generating angiotensin II.
 ARBs

• ARBs inhibit most of the biological effects of Ang II, which include
AngII-induced
– (1) contraction of vascular smooth muscle
– (2) rapid and slow pressor responses
– (3) thirst
– (4) vasopressin release
– (5) aldosterone secretion
– (6) release of adrenal catecholamines;
– (7) enhancement of noradrenergic neurotransmission
– (8) increases in sympathetic tone
– (9) changes in renal function
– (10) cellular hypertrophy and hyperplasia
 ARBs
• Losartan and valsartan were the first marketed blockers of the
angiotensin II type 1 (AT1) receptor.
• Azilsartan, candesartan, eprosartan, irbesartan, olmesartan, and
telmisartan are also available.
• Angiotensin receptor blockers provide benefits similar to those of ACE
inhibitors in patients with heart failure and chronic kidney disease.
• The adverse effects are similar to those described for ACE inhibitors,
including the hazard of use during pregnancy.
• Cough and angioedema can occur but are uncommon.
• Angiotensin receptor-blocking drugs are most commonly used in
patients who have had adverse reactions to ACE inhibitors.
• Combinations of ACE inhibitors and angiotensin receptor blockers or
aliskiren, are not recommended due to toxicity
 pharmacokinetics
• Oral bioavailability of ARBs generally is low (50%) except azilsartan(60%) and
irbesartan 70%
• Highly protein bound >90%
• Losartan.
– Frist ARB,still commonly used
– ~14% of an oral dose of losartan is converted by CYP2C9 and CYP3A4 to the 5-
carboxylic acid metabolite, EXP 3174, which is more potent than losartan as an AT1
receptor antagonist.
– Peak plasma levels of losartan and EXP 3174 occur about 1–3 h after oral
administration
– plasma half-lives are 2.5 and 6–9 h, respectively.
– The plasma clearances of losartan and EXP 3174 are via the kidney and liver
(metabolism and biliary excretion) and are affected by hepatic but not renal
insufficiency
– is a competitive antagonist of the thromboxane A2 receptor and attenuates
platelet aggregation.
 Pharmacokinetics
• Metabolism and biodisposition
– Predominat hepatic
• valsartan 70%
• Telmisartan 100%
• irbesartan
– Both hepatic and renal
• Olmesrtan
• Azilsartan
• Losartan
• eprosartan
Angiotensin Receptor–Neprilysin Inhibitor.
• A combination of sacubitril and valsartan is the is a first-in-class drug that
combines the AT1 receptor antagonistic moiety of valsartan with the neprilysin
inhibitor moiety of sacubitril.
• The complex (sacubitril, valsartan, Na+, and water [1:1:3:2.5]) dissociates into
sacubitril and valsartan after oral administration.
• Sacubitril bioavailability is about 60%, and it is highly protein bound (94%–
97%).
• Sacubitril is further metabolized by esterases into the active metabolite
LBQ657, which has a t 1/2 of 11 h.
• The neprilysin inhibitor blocks the breakdown of natriuretic peptides ANP,
BNP, and CNP, as well as Ang I and bradykinin.
• The drug combination lowers vascular resistance and increases blood flow.
• In clinical trial, this combination agent was reported to be superior to enalapril
in decreasing the risk of deaths from cardiovascular causes and heart failure by
20%
 AR-NI
• approved for treatment of heart failure with
reduced ejection fraction,
• Because the ACE/neprilysin inhibitor omapatrilat
demonstrated an increased risk of angioedema,
use of this drug is contraindicated in conjunction
with an ACE inhibitor or in patients with a history
of angioedema during ACE inhibitor or ARB use.
• Potential adverse effects discussed for valsartan
also apply to this sacubutrilvalsartan combination
 Therapeutic Uses of ARBs
• All ARBs are approved for the treatment of hypertension.
– The efficacy of ARBs in lowering blood pressure is comparable with that of
ACE and other established antihypertensive drugs, with a favorable adverse-
effect profile inhibitors than other.
– available as fixed-dose combinations with HCTZ or amlodipine
• ARBs are reno protective in type 2 diabetes mellitus, are considered
drugs of choice for renoprotection in diabetic patients
• Heart failure
– shown to reduce cardiovascular mortality in clinically stable patients with left
ventricular failure or left ventricular dysfunction following MI
– Current recommendations are to use ACE inhibitors as first-line agents for the
treatment of heart failure and to reserve ARBs for treatment of heart failure
in patients who cannot tolerate or have an unsatisfactory response to ACE-I
• superior to other agents in reducing stroke risk in hypertensive patients
 Direct Renin Inhibitors
• Angiotensinogen is the only specific substrate for renin.
• DRIs inhibit the cleavage of Ang I from angiotensinogen by
renin, an enzymatic reaction that is the rate-limiting step for
the subsequent generation of Ang II.
• Aliskiren is the only DRI approved for clinical use.
• Aliskiren is a low-molecular-weight non peptide and a potent
competitive inhibitor of renin.
• It binds the active site of renin to block conversion of
angiotensinogen to AngI, thus reducing the consequent
production of AngII.
• Aliskiren has a 10,000-fold higher affinity to renin than to any
other aspartic peptidases
• Aliskiren induces a dose-dependent decrease in
blood pressure, reduces PRA and Ang I and AngII
levels, but increases PRC by 16- to 34-fold due to
the loss of the short-loop negative feedback by
AngII .
• Aliskiren also decreases plasma and urinary
aldosterone levels and enhances natriuresis
• No clear role in clinical practice
• Combination with ACE-I or ARB linked to higher risk
of severe toxicity and shouldn’t be combined
 Pharmacokinetics of Aliskiren
• Aliskiren is recommended as a single oral dose
• Bioavailability of aliskiren is low (~2.5%), but its high affinity and
potency compensate for the low bioavailability.
• The t 1/2 is 20–45 h. Steady state in plasma is achieved in 5–8 days.
• Plasma protein binding is 50% and is independent of concentration.
• Aliskiren is a substrate for P-glycoprotein, which contributes low
bioavailability.
• Fatty meals significantly decrease the absorption of aliskiren.
• Hepatic metabolism by CYP3A4 is minimal.
• Elimination is mostly as unchanged drug in feces.
• About 25% of the absorbed dose appears in the urine as the parent
drug.
 Adverse Effects
• Aliskiren is well tolerated, and adverse events are mild
• mild GI symptoms such as diarrhea at high doses abdominal
pain, dyspepsia, and gastroesophageal reflux
• headache; nasopharyngitis; dizziness; fatigue; upper
respiratory tract infection
• back pain
• angiodema and cough (much less than with ACE-I).
• Other adverse effects include rash, hypotension,
hyperkalemia in diabetics on combination therapy, elevated
uric acid, renal stones, and gout.
• Like other RAS inhibitors,is not recommended in pregnancy