اعداد الصيدلاني علي محسن هاشم. antihypertensive drugs

ال صيدالنياعدادهاشم محسن علي

Antihypertensive drugs

Hypertension

Systolic BP more than 140mmHg &/or diastolic BP more than 90mmHg.

Category• Normal• High normal

Hypertension• Stage 1• Stage 2• Stage 3• Stage 4

SystolicDiastolic

<130 <85

<139 <89

140-159 90-99

160-179 100-109

180-209 110-119

>210 >120

Classification of BP

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 (ß-blockers, 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:

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

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)

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 receptor3. Calcium-channel blockers 4. Direct vasodilators5. Diuretics

a) -adrenoreceptor antagonists

Mechanism of action:

- decrease myocardial contractility-the fall in cardiac output BP- they reduce renin secretion

Possible mechanisms include: -adrenoceptors located on sympathetic nerve terminals can promote noradrenaline release, and this is prevented by -receptor antagonists local generation of angiotensin II within vascular tissues is stimulated by -agonists.

1. Drugs influencing sympathetic nerves

cardio-selective: blockers atenolol, metoprololblockers with ISA acebutol blockers labetalol, carvedilol

cardio non-selective:blockers nadolol, propranolol,

blockers with ISA pindolol, oxprenolol

-adrenoreceptor antagonists

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 blockade to achieve more arterial dilation(carvedilol).

-well studied antiarrhythmic properties (sotalol).

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


b) -adrenoreceptor antagonists


- vasodilatation (reduce vascular resistence) and decreased blood pressure by antagonizing of tonic action of noradrenaline on 1

receptors (vascular smooth muscle)

competitive with: a. short-term action:non-selective - phentolamine

selective - prazosin b. long-acting

antagonists - doxazosin, terazosin

non-competitive with long-term action, non-selective - phenoxybenzamin

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 alpha1-blockers)

- oral administration of any of these drugs can cause nausea, vomiting, diarrhoea

- urinary incontinece

- priapism, nasal congestion


c) Centrally acting drugs2-agonist actions

Methyldopa

Central 2 agonist ,false transmitter

Clonidine, Moxonidine,Guanabenz,Guanfacine.

direct 2-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)

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.

- 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

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS (ACEI)Captopril, enalapril, quinapril, lisinopril, perindopril, ramipril,cilazapril

Indications

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


angiotensin-converting

enzyme

Angiotensin I(inactive)

Angiotensin II(active vasoconstrictor)

Bradykinin(active vasodilator)

Inactive metabolites

ACE inhibitors


angiotensinogen

angiotensin I

angiotensin II

renin

ACE

nonrenin proteasescathepsin

t-PAchymaseCAGE


Converting enzyme inhibitors lower blood pressure by reducing angiotensin II, and also by increasing vasodilator peptides

such as bradykinin.

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

Dilatation of arteriol reduction of peripheral vascular resistance, blood pressure and afterload

Increase of Na+ and decrease of K+ excretion in kidney


Pharmacokinetics:

- active when administered orally- most of ACEIs are highly polar, eliminated in the urine, without CNS penetration

fosinopril - metabolized by the liverenalapril, quinapril - prodrugs require metabolic conversion to

active metabolites

enalapril, quinapril and lisinopril - given once dailycaptopril - 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.


ACE inhibitors

Drug Duration of effect (hours)

Short-acting: captopril 6-8Medially-acting: enalapril 12

quinapril

Long-acting:

perindopril

24lisinopril

spirapril

ramipril


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


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 potasssium- sparing 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.


B) BLOCKERS OF AT1 RECEPTORtelmisartan,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 AT1-blockers

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 serin-

protease - stronger influence on the myocardial remodelling)


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 beta-blocker 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

- the stock solution should be

diluted and covered with foil to

prevent photodeactivation

- adverse effects: too rapid

reduction of BP, nausea,

palpitation, dizziness

cyanide metabolite accumulation –

tachycardia, hyperventilation

CN CN

CN CN

Fe

NO

CN

- -

--

++

-

+

3. Direct vasodilators

CALCIUM CHANNEL-BLOCKING AGENTS include- 1. 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 -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 blocker & the reverse is true.


Drug Effect onheart 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

Adverse effects of calcium channel-blocking agents

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.

Thiazides

Lumen –urine

Distal convoluted

tubule

Interstitium - blood


-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


- 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

Thick ascending limb

Furosemide

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.

-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 BP-lowering 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

Efficacy of action

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 ET-1-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

• 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

Endothelin antagonist

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...

اعداد الصيدلاني علي محسن هاشم. antihypertensive drugs

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