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INTRODUCTION Hypertension is the term used to describe high blood pressure.

Blood pressure is a measurement of the force against the alls of the arteries as the heart pumps blood throughout the body. It may !ary according to age and se" of the patient. B# is measured in mm of mercury $Hg%. High B# increases the chance of stro&e' heart attac&' heart failure' &idney disease' and early death $Brunton' ()**%. Classification Systolic pressure mmHg &#a Normal +),**+ *(,*-.+ #rehypertension *(), *..), *1+ *0.2tage * hypertension *3), *0./, *-+ (*.( 2tage ( hypertension 4*.) 4(*.1 Diastolic pressure mmHg &#a .),/+ 0.),*).0),0+ *)./,**.+ +),++ 4*)) *(.),*1.( 4*1.1

Table 15 2ho ing classification of hypertension $6bate et al.' ())-%. 7any factors can affect blood pressure such as ho much ater and salt present in the body8 the condition of &idneys' ner!ous system' or blood !essels8 and the le!els of different body hormones $9a et al.' ())1%. 2ome causes of higher ris& of hypertension are5 : Obesity : stressed or an"ious : Too much salt inta&e : ;amily history : Diabetes : 2mo&e 7ost of the time' there are no symptoms of hypertension. Ho e!er' symptoms that may occur include confusion' ear noise or bu<<ing' fatigue' headache' irregular heartbeat' nosebleed and !ision changes $6bate et al.' ())-%. The antihypertensi!es are a class of drugs that are used to treat hypertension hich is high blood pressure. There are many classes of antihypertensi!es' hich lo er blood pressure by different means8 among the most important and most idely used are5 *% Diuretics (% 6drenergic receptor antagonists 1% Calcium channel bloc&ers 3% Renin Inhibitors -% 6C= inhibitors .% 6ngiotensin II receptor antagonists /% >asodilators

Figure 15 The potential site of action for antihypertensi!e drugs $#iasci&' ()).%. DIUR=TIC2 Diuretic drugs increase urine output by the &idney $i.e.' promote diuresis%. This is accomplished by altering ho the &idney handles sodium. If the &idney e"cretes more sodium' then ater e"cretion ill also increase. In general' the primary goal of diuretic therapy is to reduce e"tracellular fluid !olume in order to lo er blood pressure. 7ost diuretics produce diuresis by inhibiting the reabsorption of sodium at different segments of the renal tubular system $?labunde' ()**%. Types of diuretics are5 @ 9oop diuretics5 2ome drugs of this group are5 ;urosemide =thacrynic acid Bumetanide Torsemide @ Thia<ide diuretics5 2ome drugs of this group are5 Indapamide Hydrochlorothia<ide Chlorothia<ide Bendroflumethia<ide @ #otassium sparing diuretics5 2ome drugs of this group are5 6miloride Triamterene 2pironolactone @ Carbonic anhydrase inhibitors5 2ome drugs of this group are5 6ceta<olamide 7etha<olamide @ Osmotic diuretics. 2uch as mannitol

Figure 25 2pecific segments in the nephron targeted by diuretics $Thomas' ()))%. 7=CH6NI27 O; 6CTION5 *% 9oop diuretics5

Figure 35 Inhibition of sodium@potassium@chloride cotransporter by loop diuretics. 9oop diuretics inhibit the sodium@potassium@chloride cotransporter in the thic& ascending limb. This transporter normally reabsorbs about (-A of the sodium load8 therefore' inhibition of this pump can lead to a significant increase in the distal tubular concentration of sodium' reduced hypertonicity of the surrounding interstitium' and less ater reabsorption in the collecting duct. This altered handling of sodium and ater leads to both diuresis $increased ater loss% and natriuresis $increased sodium loss%. By acting on the thic& ascending limb' hich handles a significant fraction of sodium reabsorption' loop diuretics are !ery po erful diuretics. 9oop diuretics cause an increase in the renal blood flo by this mechanism. This diuresis lea!es less ater to be reabsorbed into the blood' resulting in a decrease in blood !olume $#iasci&' ()).%.

(% Thia<ide diuretics5

Figure 45 7echanism of action of thia<ide diuretics. They control hypertension in part by inhibiting reabsorption of sodium $NaB% and chloride $ClC% ions from the distal con!oluted tubules in the &idneys by bloc&ing the thia<ide@sensiti!e NaB@ClC symporter $#iasci&' ()).%. 1% Carbonic anhydrase inhibitors5

Figure 55 7echanism of action of 6ceta<olamide' a carbonic anhydrase inhibitor. These agents interfere ith the reabsorption of HCO 1@ . HCO1@ is reabsorbed in the pro"imal tubule and reDuires the acti!ity of carbonic anhydrase. HCO 1@ reabsorption ta&es place in a circuitous ay. Intracellularly carbonic anhydrase $C6 in the diagram% con!erts H(O and CO( to carbonic acid $H(CO1%. H(CO1 dissociates into HB and HCO1@.

The HCO1@ is transported across the basolateral membrane. H B is secreted into the tubular lumen in e"change for NaB. The HB combines ith a filtered HCO1@ $using C6% to form H(CO1 hich immediately dissociates into H(O and CO( that is reabsorbed. Therefore' filtered bicarbonate is reabsorbed for e!ery HB secreted $2upuran and 2co<<afa!a' ()))%. Carbonic anhydrase inhibitors' by bloc&ing the en<yme' pre!ent the reabsorption of NaHCO 1@. These inhibitors inhibit the transport of bicarbonate out of the pro"imal con!oluted tubule into the interstitium' hich leads to less sodium reabsorption at this site and therefore greater sodium' bicarbonate and ater loss in the urine $?labunde' ()**%. 3% #otassium sparing diuretics5

Figure 65 7echanism of action of potassium sparing diuretics' 6miloride and Triamterene. #otassium sparing diuretics increase diuresis by interfering ith the sodium@potassium e"change in the distal con!oluted tubule in the &idneys. They inhibit the NaBE?B pump by reducing NaB entry across the luminal membrane $?labunde' ()**%. -% Osmotic diuretics5 Osmotic diuretics are solutes that help dra ater bac& into the lumen by creating an opposing osmotic force. These osmotic solutes ha!e limited reabsorption in the nephron8 hence they are able to maintain the opposing osmotic force and &eep ater in the tubules. The decrease in ater reabsorption also creates a bac&@flo of sodium bac& into the tubule. The result is an increase in ater and sodium e"cretion and urine production. ="cretion of nearly all solutes' including NaB' ?B' Ca(B' 7g(B' Cl@' HCO1@' and phosphate' are also increased. Osmotic diuretics act on the loop of Henle and the pro"imal tubule. In the body' osmotic diuretics e"tract fluid from intracellular components and increase e"tracellular fluid !olume. 6s a result' blood !iscosity is decreased' and helps in lo ering blood pressure $9ee' ()).%. #ossible side@effects of diuretic include5 an increased need to go to the toilet feeling thirsty' di<<y' ea&' lethargic or sic&

lo blood pressure hen mo!ing from lying or sitting to standing


muscle cramps s&in rash raised uric acid le!els $that can lead to &idney problems and gout% raised blood sugar le!els $Blood #ressure 6ssociation' ())+% Dosage form Tablet Tablet Type Thia<ide diuretics 7anufactured by

Feneric name Brand name Hydrochlorothia<id 6curen e ;rusemide G =deloss 2pironolactone

Incepta 9oop diuretics G #harmaceuticals #otassium sparing diuretics Indapamide Idati" Tablet Thia<ide diuretics =plerenone =pleron Tablet #otassium sparing diuretics ;urosemide ;usid InHection and #otassium sparing 2Duare Tablet diuretics #harmaceuticals 2pironolactone and Tablet 9oop diuretics G Be"imco ;rusemide #otassium sparing #harmaceuticals Resitone diuretics Table 25 2ho ing some diuretics a!ailable in Bangladesh $Be"imco #harmaceuticals 9td' 2005; Incepta #harmaceuticals 9td.' *+++8 2Duare #harmaceuticals 9td.' *+0-). 2ometimes a combination of t o diuretics is gi!en because this can be significantly more effecti!e than either compound alone $synergistic effect%. The reason for this is that one nephron segment can compensate for altered sodium reabsorption at another nephron segment8 therefore' bloc&ing multiple nephron sites significantly enhances efficacy $?labunde' ()**%. 6DR=N=RFIC R=C=#TOR 6NT6FONI2T2 6DR=N=RFIC R=C=#TOR2 $or adrenoceptors%5 These are a class of metabotropic F protein@ coupled receptors that are targets of the catecholamines of the adrenal medulla' especially noradrenaline $norepinephrine% and adrenaline $epinephrine%. #hysiologically hen stimulated' epinephrine and norepinephrine bind to adrenergic receptors found in !arious tissue target sites ithin the body@ specifically in this case' the myocardial tissue of the heart causing !asoconstriction of the blood !essels due to increased cardiac output causing strain on the heart and !asculature. There are t o main groups of adrenergic receptors' I and J' ith se!eral subtypes. , I receptors ha!e the subtypes I* $a FD coupled receptor% and I( $a Fi coupled receptor%. , J receptors ha!e the subtypes J*' J( and J1 $Chen@I<u et al.' ()))%

Figure 75 The mechanism of adrenergic receptors.

Figure 85 6drenergic receptor subtype characteri<ation by distribution and physiologic function.

7=CH6NI27 O; 6CTION O; 6DR=N=RFIC R=C=#TOR25 6drenaline or noradrenaline are receptor ligands to either I*' I( or J@adrenergic receptors. I* couples to FD' hich results in increased intracellular Ca(B hich results in smooth muscle contraction. I(' on the other hand' couples to Fi' hich causes a decrease of c67# acti!ity' resulting in e.g. smooth muscle contraction. J receptors couple to Fs' and increases intracellular c67# acti!ity' resulting in e.g. heart muscle contraction' smooth muscle rela"ation and glycogenolysis $6bate et al.' ())-%. 6DR=N=RFIC 6NT6FONI2T25 It is a pharmaceutical substance that acts to inhibit the action of the adrenergic receptors. 7ore specifically' they can be di!ided into alpha bloc&ers or I@ adrenergic@antagonists and beta bloc&ers or beta@adrenoreceptor antagonists. 2ome I , adrenergic receptor antagonists5 @ #ra<ocin @ Do"a<ocin @ Tera<ocin @ Indoramin 2ome J , adrenergic receptor antagonists5 @ #ropranolol' 9abetalol $non@selecti!e J@bloc&ers% @ 7etoprolol' 6tenolol $J*@ selecti!e bloc&ers% 69#H6 B9OC?=R25 Types are5 I*@bloc&ers or antagonists and I(@bloc&ers or antagonists K6lpha bloc&erK usually refers to I*@bloc&ers' and agents that act at both types of receptors $6bate et al.' ())-%.

7=CH6NI27 O; 6CTION5 I@bloc&ers are pharmacological agents that act as receptor antagonists of I@adrenergic receptors $I@adrenoceptors%. It acts by binding ith the I@adrenergic receptors and bloc&s noradrenaline $norepinephrine% or adrenaline $epinephrine% from binding ith the receptors. Thus@ : It decreases arterial and !enous !asoconstriction and conseDuently decrease of peripheral resistance and lo ering of arterial pressure : It decreases platelet aggregation : It facilitates bladder e!acuation $;lynn' ()*)% B=T6@B9OC?=R25 J@bloc&ers are the drugs that competiti!ely bloc& beta@adrenergic substances $endogenous catecholamines , eg. adrenaline% to bind ith the beta receptors of the in!oluntary ner!ous system $autononomic ner!ous system% $Cruic&shan&' ()*)%. 7=CH6NI27 O; 6CTION5 This specific class of drugs or&s to bloc& the binding sites for epinephrine and norepinephrine on the adrenergic receptors $J* and J(% found on myocardial tissue. By bloc&ing the binding sites of these catecholamines' the o!erall effect is leads to reduced heart rate' along ith increased !asodilation of blood !essels resulting in a lo ering of blood pressure $;reemantle et al.' *+++%

Figure 95 The mechanism of action of beta@bloc&ers Generic name Bisoprolol ;umarate 6tenolol Car!edilol Brand name Bisocor Cardipro Durol Dosage form Tablet Tablet Tablet 7i"ed 6lpha B Beta bloc&ers Beta Bloc&ers Type Beta Bloc&ers 2Duare #harmacuetics Manufactured by

7etoprolol #resonil Tablet Incepta #harmacuetics tartrate Table 35 2ho ing some diuretics a!ailable in Bangladesh $Incepta #harmaceuticals 9td.' *+++8 2Duare #harmaceuticals 9td.' *+0-).

C69CIU7 CH6NN=9 B9OC?=R2 Calcium channel or !oltage@dependent calcium channel is an ion channel hich displays selecti!e permeability to calcium ions. 6t physiologic or resting membrane potential' channels are normally closed. They are acti!ated $i.e.' opened% at depolari<ed membrane potentials. 6cti!ation of particular !oltage@dependent calcium channels allo s Ca(B entry into the cell. 9@ type !oltage@dependent calcium channel' found in s&eletal muscle' smooth muscle' !entricular myocytes' causes smooth muscle and cardiac muscle contraction $Brunton' ()**%. Calcium channel bloc&ers' also called calcium antagonists' are drugs used to lo er blood pressure by slo ing or bloc&ing the mo!ement of calcium into the cells of the heart and blood !essel alls. This ma&es it easier for the heart to pump and idens blood !essels. 6s a result' the heart doesnLt ha!e to or& as hard' and blood pressure lo ers. Namely' these medicines or& by attaching to the target of a specific chemical signal and pre!enting the signal from reaching and acti!ating that target. Currently appro!ed CCBs bind to 9@type calcium channels $Brunton' ()**%. 7=CH6NI27 O; 6CTION5 The specific targets bloc&ed by calcium channel bloc&ers e"ist in high numbers both on blood !essels and in the heart' allo ing the drug to e"ert most of its influence in these areas. Reason for high blood pressure is because the muscles in the alls of the arteries tighten up. ;or the muscles lining the arteries to tighten' calcium must flo through tiny channels' called calcium channels' in the alls of the muscle cells $Ogbru' ())+%.

Figure 105 2ho ing ho calcium channel antagonists bloc& the in ard mo!ement of calcium by binding to the 9@type calcium channels in the heart and in smooth muscle of the peripheral !asculature $;auci et al.' 2008%. Calcium channel bloc&ers !essels. This causes@ or& by bloc&ing these calcium channels in cardiac muscle and blood

decrease in intracellular calcium leading to a reduction in muscle contraction. decrease in cardiac contractility

less contraction of the !ascular smooth muscle increase in arterial diameter $CCBs do not phenomenon called !asodilation blood pressure drops $Nelson' ()*)%. or& on !enous smooth muscle%' a

2ide effects of Calcium Channel Bloc&ers are5 Di<<iness or lightheadedness. 9o blood pressure.

Heart rhythm problems particularly. Dry mouth. =dema $s elling of an&les' feet' or lo er legs%. Headache. Nausea. ;atigue. 2&in rash. Constipation or diarrhea. $Na<ario' ()**%

Generic name Brand name Dosage form Manufactured by 9ercanidipine Hydrochloride 9arcadip tablet Incepta #harmacuetics >erapamil hydrochloride >eracal tablet 6mlodipine 6mlotab tablet 6mlodipine Camlodin tablet 2Duare #harmacuetics Nifedipine Nidipine tablet Diltia<em HCl Dilti<em 2R +) tablet Table 45 2ho ing some calcium channel bloc&ers a!ailable in Bangladesh $Incepta #harmaceuticals 9td.' *+++8 2Duare #harmaceuticals 9td.' *+0-). R=NIN INHIBITOR2 The renin@angiotensin system $R62% or the renin@angiotensin@aldosterone system $R662% is a regulatory system in the body' hich is responsible to maintain homeostasis of blood pressure. Mhen blood !olume is lo ' Hu"taglomerular cells in the &idneys secrete renin hich is an en<yme. Renin stimulates the production of angiotensin I from angiotensinogen $?umar et al.' ()*)%. 6ngiotensin I is then con!erted to angiotensin II by the en<yme angiotensin con!erting en<yme. 6ngiotensin II causes blood !essels to constrict' resulting in increased blood pressure. 6ngiotensin II also stimulates the secretion of the hormone aldosterone from the adrenal corte".

6ldosterone causes the tubules of the &idneys to increase the reabsorption of sodium and ater into the blood. This increases the !olume of fluid in the body' hich also increases blood pressure. If the renin@angiotensin@aldosterone system is too acti!e' blood pressure ill be too high $Ba&ris' ())/%.

Figure 115 The renin@angiotensin@aldosterone system $R662% 7=CH6NI27 O; 6CTION5 Renin inhibitors are antihypertensi!e drugs that inhibit the first step of the renin@angiotensin@aldosterone system $R662%. Renin inhibitors bind to the acti!e site of renin and inhibit the binding of renin to angiotensinogen. By inhibiting the R662 at the beginning renin inhibitors pre!ent the formation of 6ng I and 6ng II. This pre!ents ater and salt retention and arteriolar !asoconstriction. Thus renin inhibitors are effecti!e in lo ering blood pressure $Bro n' ())-%.


2cientists ha!e been trying to de!elop potent inhibitors ith acceptable oral bioa!ailability $Fross et al.' *+/(%. The process as difficult and too& about three decades. The first and second generations faced problems li&e poor bioa!ailability and lac& of potency. ;inally the third generation as disco!ered. These compounds ere non@peptidic renin inhibitors' had acceptable oral bioa!ailability and ere potent enough for clinical use. The first drug in this class as alis&iren hich recei!ed a mar&eting appro!al in ())/. 6s of Nanuary ()*(' it is the only renin inhibitor on the mar&et $Nensen et al.' ())0% 6C= INHIBITOR2 G 6NFIOT=N2IN R=C=#TOR B9OC?=R2 6s discussed pre!iously that in renin@angiotensin@aldosterone system $R662%' the &idneys produce renin for maintaining normal blood pressure. The renin stimulates the formation of the protein' angiotensin I' hich is then con!erted to angiotensin II by the angiotensin@ con!erting en<yme in the lungs $6bate et al.' ())-%. 6ngiotensin II is the most po erful constrictor of blood !essels &no n. It has three main effects5 Constriction of blood !essels. Re@absorption of ater by the &idneys. Release of the hormone aldosterone hich also causes ater re@absorption by the &idneys. Increaseing the !olume of the blood by adding more ater and constricting blood !essels increases blood pressure $' *++/%. T o classes of drugs ha!e the most substantial effects on the R66 system. These t o classes are the angiotensin receptor bloc&ers $6RB drugs% and the angiotensin con!erting en<yme inhibitors $6C= inhibitors%. Both of these classes of drugs lo er blood pressure by bloc&ing certain specific steps in the R66 chain $7a&off' ())-% 7=CH6NI27 O; 6CTION O; 6C= INHIBITOR25 The 6C= inhibitors bloc& the action of the angiotensin@con!erting en<yme in the lungs so that angiotensin I is not con!erted into angiotensin II. The production of this po erful blood !essel constrictor is thereby pre!ented. This reduces the amount of angiotensin II hich causes blood !essels to dilate. The amount of ater put bac& into the blood by the &idneys decreases. These actions reduce blood pressure $Han&ey' ())(%.


Figure 125 The mechanism of action of 6C=. Common ad!erse drug reactions of 6C= inhibitors include5 hypotension' cough' hyper&alemia' headache' di<<iness' fatigue' nausea' and renal impairment. 2ome e!idence also suggests 6C= inhibitors might increase inflammation@related pain $;ein' ())+% Generic name Bena<epril plus 6mlodipine Ramipril Brand name Benadip Ramoril Dosage form Tablet Tablet Type 6C= Inhibitor G Calcium 6ntagonist 6C= Inhibitor #lain Manufactured by Incepta #harmacuetics

=nalapril >asopril Tablet 6C= Inhibitor #lain 2Duare #harmacuetics 7aleate Table 55 2ho ing some 6C= drugs a!ailable in Bangladesh (Incepta #harmaceuticals 9td.' *+++8 2Duare #harmaceuticals 9td.' *+0-). 7=CH6NI27 O; 6CTION O; 6NFIOT=N2IN R=C=#TOR B9OC?=R25 6RB drugs' also &no n as 6ngiotensin II receptor antagonists' are medications that bloc& the action of angiotensin II by pre!enting angiotensin II from binding to angiotensin II 6T* receptors. The 6T* is a subtype of angiotensin receptor and is found in the heart' blood !essels' &idney' adrenal corte"' lung and brain and mediates the !asoconstrictor effects $6bate et al.' ())-%. Thus 6RBs@ , Dilate arteries and !eins and thereby reduce arterial pressure and preload and afterload on the heart , #romote renal e"cretion of sodium and ater $natriuretic and diuretic effects% by bloc&ing the effects of angiotensin II in the &idney and by bloc&ing angiotensin II stimulation of aldosterone secretion. , reduces blood pressure $?labunde' ()**%.


Figure 135 The mechanism of action of 6RB. Generic name 9osartan #otassium Olmesartan 7edo"omil 6mlodipine Besylat e and Olmesartan 7edo"omil Brand name 6ngiloc& Olmecar Dosage form Tablet Tablet Tablet Type 6RB 6RB and calcium channel bloc&er Manufactured by 2Duare #harmacuetics Be"imco #harmacuetics


Table 65 2ho ing some 6RB a!ailable in Bangladesh $Be"imco #harmaceuticals 9td' 2005; 2Duare #harmaceuticals 9td.' *+0-). >62ODI96TOR2 >asodilators are medications that open $dilate% blood !essels. They or& directly on the muscles in the alls of your arteries' pre!enting the muscles from tightening and the alls from narro ing. 6s a result' blood flo s more easily through the arteries' the heart doesnLt ha!e to pump as hard and your blood pressure is reduced $Fuyton and Hall' ()).%. 7=CH6NI27 O; 6CTION5 >asodilation is the result of rela"ation in smooth muscle surrounding the blood !essels. This rela"ation' in turn' relies on remo!ing the stimulus for contraction' hich depends on intracellular calcium ion concentrations and' conseDuently' phosphorylation of the light chain of the contractile protein myosin. Thus' !asodilation mainly or&s either by lo ering intracellular calcium concentration or the dephosphorylation of myosin $Mebb' ())1%.


Figure 145 The mechanism of action of 7ino"idil. >asodilators are strong medications and are generally used only as a last resort' hen other medications ha!enLt adeDuately controlled blood pressure.These medications ha!e a number of side effects' some of hich reDuire ta&ing other medications to counter those effects. 2ide effects include5 Chest pain Rapid heartbeat $tachycardia% Heart palpitations

;luid retention $edema% Nausea >omiting Di<<iness ;lushing Headache Nasal congestion ="cessi!e hair gro th $Brunton' ()**%.

6 !asodialator' a!ailable in Bangladesh' is Nitrosol containing Nitroglycerin 6erosol that releases a chemical called nitric o"ide. It has the effect of ma&ing the !eins and arteries rela" and iden $dilate% (Beximco !armaceutical" #t$% 2005). CONC9U2ION


Change in lifestyle can help to lo er blood pressure in some cases li&e losing eight if one is o!er eight' regular physical acti!ity' a healthy diet' cutting bac& if you drin& a lot of alcohol' stopping smo&ing' and a lo salt and caffeine inta&e $Milliams' ())1%. If one does some physical acti!ity on fi!e or more days of the ee&' for at least 1) minutes' for e"ample' bris& al&ing' s imming' cycling' dancing' etc.' it can reduce systolic blood pressure by (@*) mm Hg. =ating a !ariety of fruit and !egetables and starch@based foods $such as cereals' holegrain bread' potatoes' rice' pasta%8 not eating much fatty food such as fatty meats' cheeses' full@cream mil&' fried food' butter' etc.8 limiting salt in diet8 using !egetable oil to fry and lean meat can help can lo er systolic blood pressure by up to ** mm Hg. Cutting bac& on hea!y drin&ing to the recommended limits $i.e. one unit is in about half a pint of normal@strength beer' or t o thirds of a small glass of ine' or one small pub measure of spirits% can lo er a high systolic blood pressure by up to *) mm Hg. It is estimated that dietary and e"ercise inter!entions that are discussed can reduce blood pressure by at least *) mm Hg in about * in 3 people ith high blood pressure $' *++/%. If lifestyle changes are ineffecti!e to lo er blood pressure then it is ad!ised to lo er blood pressure ith the help of medication. Blood pressure !accinations are no being trialed and may become a treatment option for high blood pressure in the future $Bro n' ())+%.

6bate' 7.' 6bel' 2.' R.' 6c&ermann' B.' 9. et al $())-% &emi'gto'( T!e "cie'ce a'$ )ractice o* )!armac+. (*th edn. (nd !olume. #hiladelphia5 9ippincott Milliams G Mil&ins. Be"imco #harmaceuticals 9td $())-% O,ur ro$uct &a'ge( -ar$io.a"cularP /.ailable at( http5EE .be"imco@pharma.comEour@productsEour@product rangeEcardio!ascular.html $6ccessed5 (nd 6pril ()*(% Blood #ressure 6ssociation $())+% O0iuretic" 1 bloo$ )re""ure me$icatio'.P6!ailable at5 http5EE $6ccessed5 (nd 6pril ()*(%. Bro n' 7N $())+%. O2uccess and failure of !accines against renin@angiotensin system

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