‫اعداد الصيدالني‬
‫علي محسن هاشم‬
Antihypertensive drugs
Hypertension
Systolic BP more than 140mmHg &/or diastolic BP
more than 90mmHg.
Classification of BP
Category
• Normal
• High normal
Hypertension
• Stage 1
• Stage 2
• Stage 3
• Stage 4
Systolic
<130
<139
Diastolic
<85
<89
140-159
160-179
180-209
>210
90-99
100-109
110-119
>120
Arterial blood pressure (BP) is determined by cardiac output
(CO) and peripheral vascular resistance (PVR).
BP = CO x PVR
Cardiac output may be
increased in children or
young adults during the
earliest stages of essential
hypertension
Peripheral
resistance
is
determined by the caliber and total
cross-sectional area of the resistance
vessels (small arteries and arterioles)
in the various tissues.
- Influence of predisposing factors
Ways of Lowering Blood
Pressure
• Reduce cardiac output (ßblockers, Ca2+ channel
blockers)
• Reduce plasma volume
(diuretics)
• Reduce peripheral
vascular resistance
(vasodilators)
BP = CO X T PVR
Hypertension
Essential (primary)
- most (90-95 %) patients with
persistent arterial hypertension
- genesis of hypertension unknown
- predisposing factors:
susceptive
(obesity, stress, salt intake, lack of
Mg2+, K+, Ca2+, ethanol  dose,
smoking)
non-susceptive
(positive family history, insulin
resistance, age, sex, defect of
local vasomotoric regualtion)
Secondary
- is secondary to some
distinct disease:
-Renal artery stenosis
-Cushing´s syndrome
-phaeochromocytoma
-Mechanical defect
(coarctation of aorta)
-Hypertension in pregnancy
-Drug-induced hypertension
(sympatomimetics,
glucocorticoids)
-Conn`s syndrome
THERAPY OF HYPERTENSION
A. Non-pharmacological - lifestyle
- decrease of salt intake
- reduction of body weight
- restriction of smoking and drinking excessive
amounts of alcohol
- regular physical activity and relaxation, lack of stress
- increased intake of fruit, vegetables
Drug treatment of hypertension
The choice of antihypertensive drug will depend on the
relevant indications or contra-indications for the individual
patient:
1. Drugs influencing sympathetic
nerves
2. Angiotensin-converting enzyme
inhibitors
(ACEI), blockers of AT1 receptor
3. Calcium-channel blockers
4. Direct vasodilators
5. Diuretics
1. Drugs influencing sympathetic nerves
a) b -adrenoreceptor antagonists
Mechanism of action:
- decrease myocardial contractility
-the fall in cardiac output   BP
- they reduce renin secretion
Possible mechanisms include:
b-adrenoceptors located on sympathetic nerve terminals can promote
noradrenaline release, and this is prevented by b-receptor
antagonists
local generation of angiotensin II within vascular tissues is stimulated
by b2-agonists.
1. Drugs influencing sympathetic nerves
b-adrenoreceptor antagonists
cardio-selective:
b1 blockers
b1 blockers with ISA
b1,2 + a1 blockers
cardio non-selective:
b1 + b2 blockers
b1 + b2 blockers with ISA
atenolol, metoprolol
acebutol
labetalol, carvedilol
nadolol, propranolol,
pindolol, oxprenolol
Note: Partial agonist activity (intrinsic sympathomimetic activity – ISA) - may be
an advantage in treating patients with asthma because these drugs will cause
bronchodilation; they have moderate (lower) effect on lipid metabolism, cause
lesser vasospasms and negative inotropic effect.
Attractive properties
-cardioselectivity ( acebutolol,atenolol,bisoprolol,metoprolol ).
-positive data in heart failure ( carvedilol,metoprolol,bisoprolol ).
-or postinfarct ( carvedilol,metoprolol,timolol ).
-lipid insolubility&no hepatic metabolism (atenolol,nadolol ,
sotalol ).
-long acting (nadolol).
-ISA in selected patients to help avoid bradycardia ( pindolol ,
acebutolol ).
-added a blockade to achieve more arterial dilation(carvedilol).
-well studied antiarrhythmic properties (sotalol).
1. Drugs influencing sympathetic nerves
Adverse effects
Cardiovascular adverse effects, which are extension of the beta
blockade, include:
- bradycardia
- antrioventricular blockade
- congestive heart failure (unstable)
- asthmatic attacks (in patients with airway disease)
- premonitory symptoms of hypoglycemia from insulin overdosage
(eg, tachycardia, tremor and anxiety, may be marked)
- CNS adverse effects - sedation, fatigue, and sleep alterations.
Overdose of betablockade treated by atropine (1-2mg),if serious,temporary
transvenous pacing may be required when an infusion is required,glucagon
(2.5-7.5mg/hour)is drug of choice,dobutamine is given in high dose.
Beta blocker should be avoided
in
1.Asthma
2.IDDM
3.Peripheral vascular disease
4.Hyperlipidemia
5.2nd &3rd degree heart block
1. Drugs influencing sympathetic nerves
b) a -adrenoreceptor antagonists
Mechanism of action:
- vasodilatation (reduce vascular resistence) and decreased blood
pressure by antagonizing of tonic action of noradrenaline on a1
receptors (vascular smooth muscle)
competitive with:
a. short-term action:
a non-selective - phentolamine
a1 selective - prazosin
b. long-acting
a1 antagonists - doxazosin, terazosin
non-competitive with long-term action, non-selective phenoxybenzamin
1. Drugs influencing sympathetic nerves
SE :- the main manifestations are:
- drowsiness, weakness, orthostatic hypotension (first dose –
bedtime administration) - and for the nonselective agents, reflex
tachycardia - in patients with coronary disease, angina may be
precipitated by the tachycardia (less frequent in selective alpha1blockers)
- oral administration of any of these drugs can cause
nausea, vomiting, diarrhoea
- urinary incontinece
- priapism, nasal congestion
1. Drugs influencing sympathetic nerves
c) Centrally acting drugs
a2-agonist actions
Methyldopa
Central a2 agonist ,false transmitter
Clonidine, Moxonidine,Guanabenz,Guanfacine.
direct a2-agonist
- limited use in the treatment of hypertension.
- methyldopa  hypertension during pregnancy
- methyldopa causes symptoms of drowsiness and fatigue that are
intolerable to many adult patients in long-term use
- they are seldom used to treat essential hypertension
- clonidine is potent but poorly tolerated (rebound hypertension, if it is
discontinued abruptly, is an uncommon but severe problem)
1. Drugs influencing sympathetic nerves
Adverse effects:
- drowsiness, fatigue (esp. methyldopa), depression, nightmares
(methyldopa - rarely extrapyramidal features) – driving!!
- nasal congestion, anticholinergic symptoms (constipation, bradycardia)
– clonidine
- dry mouth
- hepatitis, drug fever (with methyldopa)
- sexual dysfunction, salt and water retention
- hypertensive rebound associated with anxiety, sweating, tachycardia
and extrasystoles (rarely hypertensive crisis)
2. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc.
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS (ACEI)
Captopril, enalapril, quinapril, lisinopril, perindopril, ramipril,
cilazapril
Indications
- hypertension where thiazide diuretics and beta-blockers are
contraindicated
- useful in hypertensive patients with heart failure (beneficial effect)
- can limit the size of myocardial infarction
- diabetic nephropathy
2. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc.
Mechanism of action
- ACEI regulates balance between bradykinin (vasodilatation,
natriuresis) and angiotensin II (vasoconstriction, Na+-retention)
- AT1 receptors - widely distributed in the body (lung - huge surface
area of endothelial cells, heart, kidney, striated muscle and brain) and
present on the luminal surface of vascular endothelial cells
Angiotensin II
- vasoconstriction
- noradrenaline release from sympathetic nerve terminals
- stimulate aldosterone secretion from the zona glomerulosa of the adrenal
cortex
2. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc.
Angiotensin I
(inactive)
ACE
inhibitors
Bradykinin
(active vasodilator)
angiotensinconverting
enzyme
Angiotensin II
(active vasoconstrictor)
Inactive metabolites
angiotensinogen
renin
angiotensin I
chymase
CAGE
ACE
angiotensin II
nonrenin proteases
cathepsin
t-PA
2. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc.
Mechanism of action:
Converting enzyme inhibitors lower blood pressure by reducing
angiotensin II, and also by increasing vasodilator peptides
such as bradykinin.
Dilatation of arteriol  reduction of peripheral vascular
resistance, blood pressure and afterload
Increase of Na+ and decrease of K+ excretion in kidney
Decrease noradrenaline release  reduction of sympathetic
activity (use is not associated with reflex tachycardia
despite causing arterioral and venous dilatation)
Inhibition of aldosterone secretion from the zona glomerulosa
contributes to the antihypertensive effects of ACEI
Influence on the arteriolar and left ventricular remodelling that are
believed to be important in the pathogenesis of human essential
hypertension and post-infarction state
2. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc.
Pharmacokinetics:
- active when administered orally
- most of ACEIs are highly polar, eliminated in the urine, without CNS
penetration
fosinopril - metabolized by the liver
enalapril, quinapril - prodrugs  require metabolic conversion to
active metabolites
enalapril, quinapril and lisinopril - given once daily
captopril - administered twice daily
However, ACE inhibitors are effective in many patients with low renin as
well as those with high renin hypertension and there is only a poor
correlation between inhibition of plasma-converting enzyme and chronic
antihypertensive effect, possibly because of the importance of
converting enzyme in various key tissues rather than in the plasma.
2. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc.
ACE inhibitors
Drug
Duration of
effect (hours)
Short-acting:
captopril
Medially-acting:
enalapril
6-8
12
quinapril
perindopril
Long-acting:
lisinopril
spirapril
ramipril
24
2. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc.
Adverse effects and contraindications of ACEI:
-are generally well tolerated. Adverse effects include:
First dose hypotension - particularly in those receiving diuretic
therapy; the first dose should preferably be given at bedtime.
Dry cough
- the most frequent (5-30%) symptom; could be reduced by treatment
with sulindac (inhibits prostaglandin biosynthesis)
Urticaria and angioneurotic edema
-  kinin concentrations  urticarial reactions and angioneurotic
edema)
Functional renal failure
- occurs predictably in patients with hemodynamically bilateral renal
artery stenosis, and in patients with renal artery stenosis in the vessel
supplying a single functional kidney (though they protect the diabetic
kidney) - !!! renovascular disease !!!
Fetal injury
- results in craniofacial malformations
- contraindication in pregnancy
2. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc.
Hyperkalemia – monitor !!
- ACEIs cause a modest increase in plasma potassium as a
result of reduced aldosterone secretion. This may usefully
counter the small reduction in potassium ion concentration
caused by thiazide diuretics.
Potassium accumulation may be marked, especially if the
patient is consuming high-potassium diet and/or potasssiumsparing diuretics. Under these circumstances, potassium
concentrations may reach toxic levels (hazardous in patients
with renal impairment).
Therapeutic combination:
- useful interaction ACEIs with diuretics: Converting enzyme inhibitors interrupt
by diuretics increased plasma renin activity (and the consequent activation of
angiotensin II and aldosterone) and enhance the antihypertensive efficacy of
diuretics, as well as reducing thiazide-induced hypokalemia.
- adverse interaction ACE inhibitors with potassium-sparing diuretics and
potassium supplements, leading to hyperkalemia especially in patients with renal
impairment.
2. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc.
B) BLOCKERS OF AT1 RECEPTOR
telmisartan,losartan, valosartan, irbesartan,
candesartan,eprosartan
- the receptor blockers - competitively inhibit angiotensin II at its AT1
receptor site



most of the effects of angiotensin II - including vasoconstriction
and aldosterone release - are mediated by the AT1 receptor
AT1-blockers do not block AT2 receptor, which is exposed to
high concentration of angiotensin II during treatment with AT1blockers
they influence RAS more effective because of selective blockade
(angiotensin II synthesis in tissue is not completely dependent only
on renin release, e.g. in heart, but could be promote by serinprotease - stronger influence on the myocardial remodelling)
3. Direct vasodilators
DIRECT VASODILATOR include
minoxidil, diazoxide, sodium nitroprusside, hydralazine
Minoxidil
- therapy of severe hypertension resistant to other drugs
- prodrug  its metabolite (minoxidil sulfate) is a potassium channel
opener ( repolarization + relaxation of vascular smooth muscle)
- more effect on arterioles than on veins
- orally active
- Adverse: Na+ and water retention → coadministration with betablocker and diuretic is mandatory for this drug, oedemas,
hypertrichosis, breast tenderness
3.Direct vasodilators
Diazoxide
- given by rapid iv. injection (less than 30 seconds)* in hypertensive
emergencies
- potassium channel opener
- glucose intolerance  due to reduced insulin secretion (used in
patients with inoperable insulinoma)
- adverse: Na+ and water retention, hyperglycaemia, hirsutism
Hydralazine
- rapidly and fairly absorbed after oral administration
-  arteriolar resistance
- useful for hypertensive crisis during pregnancy
- AE: Na+ and water retention,headache,systemic lupus erythematosus
– suspected if there is unexplained weight loss, arthritis,reflex
tachycardia
3. Direct vasodilators
Sodium nitroprusside
- short-acting agent (few minutes)  administrated by infusion in
hypertensive emergencies (hypertensive encephalopathy, shock,
cardiac dysfunction) for max 24 hours (risk of cumulation of
cyanide  toxicity)
- Releases NO
+ NO
- the stock solution should be
diluted and covered with foil to
CN
prevent photodeactivation
CN
++
Fe
- adverse effects: too rapid
reduction of BP, nausea,
-
CN
-
CN
palpitation, dizziness
cyanide metabolite accumulation –
tachycardia, hyperventilation
CN
-
-
4.Calcium channel blocker
CALCIUM CHANNEL-BLOCKING AGENTS include1. dihydropyridine (nifedipine, nicardipine,nimodipine,
amlodipine,isradipine,felodipine)
2. non dihydropyridine (diltiazem, verapamil)
- they block voltage-dependent calcium channels  relaxation
of smooth muscle  vasodilation  reduce peripheral vascular
resistance  reduction of BP
- negatively inotropic drugs
- they differ in selectivity for calcium channels in vascular smooth
muscles and cardiac tissues
- orally active  suitable for long-term use
4. Calcium channel blocker
DIHYDROPYRIDINES (nifedipine, nicardipine)
- evoke vasodilatation resulting in sympathetic reflex activation,
- relatively selective for vascular smooth muscle (arterial)
amlodipine, lacidipine, isradipine, felodipine – 2nd generation
- longer duration of action – once daily
- do not reduce myocardial contractility – do not produce clinical
deterioration in heart failure
nimodipine – preferentially acts on cerebral arteries – prevention of
vascular spasm following aneurysmal subarachnoid haemorrhage
Indication: all grades of essential hypertension
- (nifedipine, amlodipine) in patients with mild hypertension for patients in
whom thiazide diuretics and b-blockers are contraindicated
- angina (with beta-blockers).
-Peripheral vascular disease
4. Calcium channel blocker
verapamil, diltiazem
- effects on the voltage-dependent channels in cardiac conducting
tissue
- vasodilatation
- it also blocks Ca2+ entry in gastrointestinal smooth muscle and
consequently causes constipation.
-verapamil is drug of second choice in the Tx of SVT.
-verapamil is contraindicated in patient with 2nd or 3rd degree heart
block,also patient with WPW syndrome
-oral verapamil not given to patient taking i.v b blocker & the reverse
is true.
4. Calcium channel blocker
Adverse effects of calcium channel-blocking agents
Drug
Effect on
heart rate
Adverse effects
Nifedipine

Headache, flushing, ankle swelling,
gum hypertrophy
Amlodipine

Ankle swelling
Nimodipine
±
Flushing, headache
Diltiazem
±
Generally mild
Verapamil

Constipation, marked negative
inotropic action
Calcium channel blockers do not affect concentrations of plasma cholesterol
or triglycerides, or extracellular calcium homeostasis.
5. DIURETICS
- drugs of first choice for treating patients with mild hypertension
- often combined with another drug in treatment of more severe
hypertension
THIAZIDES &related drugs:hydrochlorothiazide,chlorthiazide, hydrflumethiazide
bendroflumethiazide, chlorthalidone,clopamid,xipamide,
indapamid,metipamid,metolazone
- preferable (to loop diuretics) for the treatment of
uncomplicated hypertension
- given by mouth as a single morning dose
- begin to act within 1-2 hours and work for 12-24 hours
- treatment should be started using a low dose
-clinical uses: hypertion, idiopathic hypercalciuria,oedema
state,diabetes insipidus.
Lumen –
urine
Thiazides
Distal
convoluted
tubule
Interstitium blood
Mechanism of action:
-lower blood pressure by reduction of blood volume and by direct
vascular effect
- inhibition of sodium chloride transport in the early segment of the
distal convoluted tubule  natriuresis, decrease in preload and
cardiac output - renal effect
- slow decrease of total peripheral resistance (raised initially) during
chronic treatment, suggesting an action on resistance vessels extrarenal effects
compensatory responses to pressor agents including angiotensin II and
noradrenaline are reduced during chronic treatment with thiazides
- used with loop diuretic - synergistic effect occurs
Adverse effects:
- Idiosyncratic reactions (rashes - may be photosensitiv)
- Increased plasma renin (which limits the magnitude of their effect on BP)
- Metabolic and electrolyte changes
Hyponatremia
Hypokalemia
(combine with potassium-sparing diuretics)
Hypomagnesemia
Hyperuricemia (most diuretics reduce urate clearance)
Hyperglycemia
Hypercalcemia
(thiazides reduce urinary calcium ion clearance 
precipitate clinically significant hypercalcemia in hypertensive patients with
hyperparathyroidism)
Hypercholesterolemia (a small  in plasma cholesterol concentration)
LOOP DIURETICS
(Furosemid,bumetanide,torasemide ,ethacrynic acid)
- useful in hypertensive patients with moderate or severe renal
impairment, or in patients with hypertensive heart failure.
- relatively short-acting (diuresis occurs over the 4 hours following a
dose)  used in hypertension if response to thiazides is inadequate
Mechanism of action:
- they inhibit the co-transport of Na+, K+ and Cl-  of Ca2+ and Mg2+ excretion
- they have useful pulmonary vasodilating effects (unknown mechanism)
Clinical uses:acute pulmonary oedema,hpertensive crisis,heart failure,
Oedema state,CRF when there is fluid retention,hypercalcaemia,forced
diuresis)
Lumen –
urine
Furosemide
Thick ascending
limb
Interstitium blood
Toxicity:
- hypokalemic metabolic alkalosis (increased excretion of K+)
- ototoxicity (dose dependent, reversible)
- decrease of Mg2+ plasma concentration (hypomagnesemia)
- hyperuricemia (competition with uric acid about tubular secretion)
- sulfonamide allergy
- risk of dehydration (> 4 L urine/ 24 h)
Imporatant drug interaction may occurs if loop diuretic is given
with Li+.Decrease of Na+ reabsorption can lead to increase of Li+
reabsorption  toxicity.
K sparing agent
Spironolactone , eplerenone , triamterene , amiloride
-these agents act on distal tubules &collecting duct, they lessen
the incidence of srious ventricular arrhythmias in heart failure &
in hypertention.
Spironolactone&eplerenone are both aldosterone
antagonist,spironolactone is effective in the Tx of
hyperaldosteronism.
Eplerenone (50-100mg) duration of action 24 hour, is a more
specific blocker of the aldosterone R (thereby preventing the
gynecomastia &sexual dysfunctions seen in up to 10%of those
given spironolctone),also provided additional benefit in post MI
patient by further reducing mortality,it effective as enalapril,40mg
daily,in regressing left ventricular hypertrophy& lowering BP.
eplerenone (inspra®,pfizer) is used in
1-hypertention
2- improve survival of stable patients with left ventricular (LV)
systolic dysfunction (ejection fraction ≤ 40%) & clinical evidence of
CHF after an acute MI.
SE :important( hyperkalemia )
Amiloride & triamterene:
-They are inhibit the sodium-proton exchanger
-always used in combination with thiazides to increase the diuretic
&to conteract the hypokalaemia which is caused by thiazide
-amiloride is preferable to triamterene (which excreted by kidneys)
New Antihypertensive Drug
• Aliskiren: (Tekturna®; Novartis):• The first new class of antihypertensive drug that inhibit
(RAAS) by direct targeting of renin enzyme .
• The concept behind direct renin inhibition is that by blocking
the system at the point of activation you will not get these
reactive or compensatory effect that you get with ACEI &
ARBs.
.
Efficacy of action
-once-daily aliskiren monotherapy provided sustained
24-hour BP control
-also reduce the early-morning BP surges that are
associated with increases in CV events.
- Aliskiren's unique mechanism of action, which would
also apply to combining aliskiren with another BPlowering drug, particularly another RAS blocker.
-Combining aliskiren with an ARB would provide
additional BP control, and prevent the ARB-associated
rise in angiotensin II. This is also true when combined
with an ACE inhibitor
The Aliskiren Advantages
• those who had been taking aliskiren remained below
BP baseline levels for up to 1 month after
discontinuing aliskiren therapy.
• Less incidence of cough & angioedema.
• Can be used across braod older versus younger men
versus women.
• Adding aliskiren to an ACE inhibitor reduced the
incidence of ACE inhibitor-induced cough in one
study.
Prescribing Aliskiren
• Aliskiren is indicated for the treatment of
hypertension, alone or in combination with other
antihypertensives.
• BP reductions with this drug usually occur within 2
weeks.
• The recommended starting dose of aliskiren is 150
mg/day, taken in 1 tablet; it can be titrated up to
300 mg/day.
• Higher doses increase the risk for diarrhea and
have not shown added efficacy.
Contraindications, Mild Side Effects
• GIT side effect appear to be dose related 2.3% diarrhea in
300mg daily dose.
• the incidence of cough was 1.1% with aliskiren and 0.6% with
placebo.
• Serious adverse events were rare but included 2 cases of
angioedema and 2 cases of periorbital edema.
• Discontinue use of aliskiren in any woman who becomes
pregnant.
• Those with bilateral renal artery stenosis should not use
aliskiren.
Dopamine receptor agonist
Fenoldopam is dopamine agonist (DA1) able to reduce BP in
sever hypertention with a sodium diuresis in contrast to
nitroprusside which causes sodium retention
However ,tachycardia is a prominent SE .it is licensed for use
in sever or malignant hypertention.
ideal characteristic effective,predictable onset ,easily titratable,
few SE ,metabolically inert.
Ibopamine was tested for chronic oral use in heart failure but
was withdrawn because of increased mortality.
Fenoldopam dosage and administration
• INJECTION 10 mg In 1 ml
• Infusion Rate 0.5-1.6 µg/kg/min
• Side effects
• More common:
• dizziness
• headache
• vomiting
• flushing
• nausea
• pain at the site of injection
• stomach pain
• sweating
• Rare or uncommon:
• chest pain
• palpitations
• tingling feeling, especially in the hands or feet
vasopeptidase inhibitor (VPI)
• Blood homeostasis and vascular tone are regulated through
at least 3 major closely interrelated pathways in which zinc
metallopeptidases modulate the concentration of vasoactive
mediators
• vasoconstrictors [angiotensin II (AII) and endothelin-1 (ET-1)
• vasodilators [bradykinin (BK) and atrial natriuretic peptide
(ANP).
• The first class of inhibitors to be developed were against
angiotensin-converting enzyme (ACE).
• recently followed by dual inhibitors of ACE/neprylisin (NEP),
NEP/endothelin-converting enzyme (ECE)
• finally triple ACE/NEP/ECE inhibitors. The dual and triple
inhibitors are defined as vasopeptidase inhibitors (VPI).
• Omapatrilat is a new antihypertensive agent
with a unique mechanism of action.
• It simultaneously inhibits two key enzymes
involved in BP homeostasis:
• neutral endopeptidase ,thus increases
vasodilatory peptides, including atrial natriuretic
peptide and brain natriuretic peptide , bradykinin and
also endothelin-1
• angiotensin-converting enzyme (ACE)
thus decrease vasoconstrictor peptide (AgII)
• Side effects as a result of treatment with dual
ACE/NEP Inhibitors carry a higher risk of angioedema
than pure ACE inhibitors.
• It has been hypothesized that the BK-induced NO
vasodilatation and subsequent increase in vascular
permeability was responsible for the occurrence of
angioedema
• NEP inhibitors are responsible for increased
circulating concentration of ET-1.The subsequent ET1-induced NO release and vasodilatation, through the
activation of the ETB-R present on endothelial cells
may be implicated in the worsening of the incidence of
angioedema too.
• The fact that the incidence of angioedema is higher
for black patients-for whom the ETS is predominant
than for the white patients is an argument in favor of
a possible role of ET-1 in the development of this
complication.
• It could be therapeutically advantageous to avoid the
NEP inhibition-induced ET-1 plasma concentration
while treating patients with dual ACE/NEP inhibitors
(eg, through combination with ECE inhibitors).
Action and efficacy of the triple
ACE/NEP/ECE inhibitor
-These compounds reduce the production of( AII )and (ET-1)
while increasing those of BK and NPs ; consequently, they
exert antifibrotic and antiinflammatory actions.
-Inhibiting the main 3 metallopeptidases that are the cornerstone
of vascular homeostasis with 1 molecule has the advantage not
only of improving blood pressure but also of simplifying the
dosage regimen of the treated hypertensive patients.
-Consequently, using triple VPIs as therapeutics should be able to
reduce the cost of the polypharmacy that is associated with the
management of hypertension and the treatment of CDs.
-One of the most precious advantages of triple VPIs over
omapatrilat is that the problem (ie, angioedema) that may be of
some concern for their development is documented
Endothelin antagonist
• Bosentan (Tracleer®)
antagonist of ETA and ETB
endothelin receptors, inhibit
vasoconstriction mitogenic
effect induced by endogenous
endothelins.
• decreases systolic and diastolic
arterial pressure.
• Bosentan is metabolized by
P450 cytochrome
• Bosentan is enzymatic inducer,
and drug interactions have
described.
• Administered by oral route
62.5mg-125mg tablet approved in
pulmonary hypertension
NADPH oxidase inhibitors
• NADPH oxidases have
recently been shown to
contribute to the
pathogenesis of
hypertension through
production of ROS
•
ROS have been shown
to promote hypertension
by causing endothelial
dysfunction, altered
contractility, and vascular
remodeling, which are
common characteristics
associated with the
disease.
-Studies indicate that altered superoxide production decreases
nitric oxide (NO) bioavailability by scavenging the compound
and creating highly reactive peroxynitrite.
-Peroxynitrite is then able to oxidize the NO synthase (NOS)
cofactor tetrahydrobiopterin BH4, which causes NOS
uncoupling and initiates endothelial dysfunction. Altered NO
bioavailability caused by endothelial dysfunction then leads to
impaired vasodilation.
-The development of specific inhibitors of these enzymes has
focused attention on their potential therapeutic use in
hypertensive disease.
-Targeting NADPH homologues may have distinct advantage
over current therapies because it would specifically prevent
the pathophysiological formation of reactive oxygen species
that contributes to hypertension.
- Anti-NADPH oxidase drugs as novel therapies for hypertension
is indeed promising.
References
-Journal of cardiovascular pharmacology (http//hinari-gw.who int
-www.cipladoc.com/.../vol3i01/cardionet.htm
-Wikipedia, the free encyclopedia.htm :
-Drug digest –drug library
-Drugs for the heart Lionel H. Opie,bernard J. Gersh
-http//www.medscape.com
-Clinical pharmacology D R Laurence
-The Internet Journal of Cardiology
(http--www_arabmedmag_com-issue-15-03-2005-)
Thank you...