pharmacology of nebivolol

Pharmacological Research, Vol. 38, No. 6, 1998Article Number: fr980387

PHARMACOLOGY OF NEBIVOLOL

MARIO MANGRELLAa, FRANCESCA ROSSIa, FRANCESCO FICI b and FRANCESCOROSSIa,U

aInstitute of Pharmacology and Toxicology, Faculty of Medicine and Surgery, 2nd Uni¨ ersity ofNaples}Via Costantinopoli, 16-80128 Naples, Italy and bIstituto Luso Farmaco d’Italia S.p.A.,

Milan, Italy

Accepted 4 August 1998

Nebivolol is a new selective b -adrenergic blocking agent, that possesses a peculiar1pharmacodynamic profile and an original chemical structure, by which it differs fromtraditional b -blockers. Nebivolol is a racemic mixture of two enantiomers in equal ratios.1It is endowed with a highly selective b -blocking activity, and does not show an intrinsic1sympathomimetic activity. Nebivolol is endowed with peripheral vasodilating propertiesmediated by the modulation of the endogenous production of nitric oxide. It does notsignificantly decrease airway conductance compared with atenolol and propranolol.Nebivolol does not compromise the left ventricular function, but it may increase strokevolume, and does not reduce heart inotropism during exertion. Nebivolol is quite safe andis well tolerated, also when compared to traditional b-blockers. The most common adverseeffects are dizziness, headache and fatigue. Owing to its combined dual mechanism ofaction, nebivolol leads to a unique haemodynamic and therapeutic profile by which it maybe advantageous in essential hypertension, ischaemic heart disease and congestive heartfailure. Q 1998 The Italian Pharmacological Society

KEY WORDS: b-adrenergic antagonists, nebivolol, antihypertensive therapy, nitric oxide.

INTRODUCTION

Nebivolol is a b -adrenoceptor blocking drug that1possesses certain unusual pharmacological proper-ties by which it differs from conventional b -block-1ers in its chemical structure and in its haemody-

Ž . w xnamic profile Table I; Fig. 1 1 .wŽ . w Uw Uw U Ž U .xxx ŽNebivolol " - R S S - S -a ,a 9- iminobis-

. wmethylene -bis- 6-fluoro-3,4-dihydro-2 H-1-benzo-xxpyran-2-methanol contains four asymmetrical car-

Ž . w xbon atoms Fig. 1 2, 4 . Among the ten existingstereoisomers, nebivolol is a racemic mixture of

Ž .equal amounts of D-nebivolol SR -nebivolol and3Ž .L-nebivolol RS -nebivolol .3

The D-isomer is a potent, highly selective andlong-acting b -adrenoceptor blocking agent whose1haemodynamic profile resembles that of atenolol

Žand other usual b -blockers fall in cardiac output,1. w xincrease in systemic vascular resistance 2, 3 .

L-Nebivolol is responsible for the typical changesin the haemodynamic action of DL-nebivolol. L-

U Corresponding author.

Nebivolol, at doses that do not lower blood pressure,markedly enhances the antihypertensive propertiesof the D-isomer. The L-isomer of nebivolol appearsto moderate or reverse the negative inotropic car-

w xdiac actions of D-nebivolol 2, 3, 5 .The haemodynamic properties of nebivolol ap-

pears to be linked not only to the b -adrenoceptor1blocking action, but also to several mechanisms such

was the vasodilating endothelium-dependent effect 2,x3 .

PHARMACOLOGICAL ACTIVITY

Nebivolol interferes on b-adrenoceptor activity asŽ .well as several vasoactive factors nitric oxide , and

may be distinguished from other b-adrenergic antag-w xonists by its typical haemodynamic profile 2, 6, 7 .

Interactions with b -adrenoceptors1

AnimalsNebivolol binds at low concentrations to b-adren-

Ž . w xergic binding sites Table I 2, 8 . This activity is

1043]6618r98r120419]13r$30.00r0 Q1998 The Italian Pharmacological Society

Pharmacological Research, Vol. 38, No. 6, 1998420

Table IAffinities of various b-adrenergic blockers for b - and1

b -adrenergic receptors from lung tissue preparations2

y1( )b-Blocker K nmol l b rb Ratioi 1 2

( ) ( )b Rabbit lung b Rat lung1 2

Atenolol 396 7493 19Propranolol 2.8 0.62 0.22Pindolol 1.4 1.0 0.7Nebivolol 0.88 48 55

Notes: K , concentration of drug required to occupyiw x50% of the receptor binding site 1 .

attributed to D-nebivolol, whereas L-nebivolol is vir-w xtually inactive on the same receptors 2, 6, 9 .

In ¨itro, nebivolol antagonises the isoprenaline-in-duced heart rate increase, a change mediated by

Ž .b -adrenoceptor activation guinea pig . The b -1 11 w xselectivity is attributed to D-nebivolol 6, 8, 10 . The

simultaneous presence of L-nebivolol does not affectthe b-adrenergic antagonistic properties of D-

Ž . w xnebivolol Figs. 2 and 3; Table II 2, 6, 7, 9, 14 .Compared to other b-blockers, nebivolol exerts a

Ž .high selectivity for b -adrenergic receptors Table I1w x2, 6, 10 .

Nebivolol binds to b -adrenoceptors much less2

1D-Nebivolol antagonises the norepinephrine-induced increase of

Ž . Ž y1 .cAMP rat isolated myocites IC s15 nmol l much more50Ž y1 . w xefficaciously than L-nebivolol IC )1000 mnol l 6,7,10]13 .502 The stimulation of facilitatory pre-synaptic b -adrenoceptors2

results in potentiating norepinephrine release from vascular sim-pathetic nerve varicosities. The evoked norepinephrine releasemay play a functional role in hypertension. In rats and dogs,D-nebivolol, but not L-nebivolol, inhibits the fenoterol-inducedfacilitation of the evoked norepinephrine release from the simpa-

w xthetic nerves 15]20 .

Fig. 1. The two enantiomeric forms of nebivolol: L-Ž . Ž .nebivolol RS -nebivolol and D-nebivolol SR -nebivolol3 3

w x2,3 .

2 Ž .than to b -adrenoceptors Fig. 2 and has no effect1w xon the atypical b -adrenoceptors 1, 2, 6, 8, 9 .3

The results of in ¨itro studies were confirmed in¨ i o. In pithed normotensive rats, DL-nebivololŽ y7 y5 y1 .10 ]10 mol kg i.v. dose-dependently antago-nises the epinephrine-induced as well as the electri-cally-elicited increase in heart rate, whereas it does

Ž y8 y5not affect blood pressure. D-Nebivolol 10 ]10y 1 .mol kg i.v. dose-dependently lowers the

epinephrine-induced as well as the electrically-elicited changes in heart rate, but not the electri-cally-induced increase in blood pressure. L-Nebivololin doses -10y5 mol kgy1 i.v. does not affect theblood pressure responses to epinephrine; L-nebivolol10y5 mol kgy1 elicits no D-nebivolol-like haemody-namic effect. Long-term pretreatment with DL-

Ž y1 .nebivolol 10 mg kg orally for 7 days does notinterfere with electrically-elicited pressure response,but antagonises the corresponding heart rate in-crease. Therefore DL-nebivolol as well as D-nebivo-

Table IIInhibitory effects of nebivolol on isolated tissues

Agonist Tissue IC A50 hy 1 y 1( ) ( )mol l mol ly6Noradrenaline Rat caudal artery 1.4=10y5Ž .Clonidine qprazosin Dog saphenus vein )2.5=10y6Serotonine Rat caudal vein 2.5=10y6Guinea-pig ileum 5.4=10y5Rat gastric fundus )2.5=10

y6Histamine Guinea-pig ileum 5.2=10y5Guinea-pig right atrium )2.5=10

y6Methacholine Guinea-pig ileum f3.1=10y5Acetylcholine Rabbit duodenum )2.5=10y6Nicotine Guinea-pig ileum 1.8=10

y6PGF Dog saphenous vein )102a y5Pig coronary artery )10y6Rabbit caudal artery )3=10

2q y6Ca Rat caudal artery 1.8=10y6Rat aorta )10

y6Angiotensin II Guinea-pig ileum 3.1=10y6Bradykinin Guinea-pig ileum 3.1=10

Notes: IC , concentration of nebivolol causing 50% reduction of the effect of the agonist; A , concentration of50 hw xnebivolol causing 50% reduction of the maximal effect of the agonist 2, 6, 7, 10 .

Pharmacological Research, Vol. 38, No. 6, 1998 421

Ž .Fig. 2. Effects of nebivolol at various concentrations on isoprenaline-induced increases in heart rate HR in theŽ . Ž .guinea-pig right atrium a and on isoprenaline-induced relaxations in the trachea b . Nebivolol is more potent as an

w x Ž .antagonist on the b -adrenergic responses in atria than on b -adrenergic responses in the trachea 6 . Keys: a Nebivolol1 2I, 1.6=10y9 mol ly1; ^, 6.2=10y9 mol ly1; `, 2.5=10y8 mol ly1; ', 9.9=10y8 mol ly1; v, 4=10y7 mol ly1; B,

Ž . y6 y1 y6 y1 y5 y1solvent. b Nebivolol ^, 1.6=10 mol l ; `, 6.2=10 mol l ; I, 2.5=10 mol l ; B, solvent.

lol, but not L-nebivolol, behave like selective b -1w xadrenoceptor blockers 6, 7, 11]13, 21, 22 .

Non-selective b-adrenoceptor antagonists cancause or worsen pulmonary constrictive reactions.This effect is related to b -adrenoceptor antago-2nism. In anaesthetised guinea-pigs, propranolol, anon-selective b-adrenoceptor antagonist, signifi-cantly enhances bronchoconstriction induced by his-

Ž y1 .tamine 3 mg kg i.v. , whereas nebivolol, at doses

Žwhich significantly lower heart rate 0.125]2.5 mgy1 .kg i.v. , does not modify pulmonary reactivity to

Ž . w xhistamine Fig. 2 6, 11The metabolic effects of nebivolol are inconsis-

tent. In anaesthetised dogs, nebivolol shows lesseffects than atenolol or propranolol in modifyingmetabolic processes mediated by the stimulation of

Žb -adrenergic receptors glycemia, tissutal response2. Ž . w xto insulin Table III 23 .

Ž . Ž . ŽFig. 3. Effects of D-nebivolol ` and L-nebivolol I in isoprenaline-induced increase in heart rate guinea-pig isolated.right atria . The logarithm of ED of isoprenaline in the presence of nebivolol divided by the ED of isoprenaline in the50 50

Ž . Ž y1. w xabsence of nebivolol ordinate is plotted ¨s nebivolol concentration abcissa, mol l 2 .


Table III( )Inhibition of isoprenaline-induced cardiovascular and metabolic responses by b-adrenoceptor antagonists dogs

y1( )Response b-Antagonist ID , m g kg50

Nebi olol Atenolol Propranolol

Heart rate 58 47 34Diastolic blood pressure 713 506 36Glucose 183 )640 20Insulin 416 752 78Lactate 243 )640 7Free fatty acids 100 28 103

Ž .Notes: ID , intravenous dose causing 50% inhibition of the response to isoprenaline ¨s control vehicle-treated group50w x23 .

HumansThe effects of nebivolol on b -adrengic receptors,1

were documented during bicycle ergometer exerciseand in comparison to other b-blockers. During exer-

Ž .cise, single doses of nebivolol induced 1]30 mgdose-related well-sustained b -blocking properties,1with a peak effect on heart rate slowing down thatoccurs between 2 and 4 h after drug intake, inhealthy volunteers. This effect is confirmed after 7days of nebivolol administration in healthy volun-

w xteers as well as in hypertensive patients 3, 24, 28 .Ž .Furthermore, nebivolol 5 mg shows more b -1

Ž .selective activity than atenolol 50 mg or propra-Ž .nolol 40 mg when the dose needed to increase

finger tremor by 500% with isoprenaline, a b-agonistthat induces tremor via the stimulation of b -adren-2

w xergic receptors, is evaluated 27, 28 .In volunteers undergoing the salbutamol inhala-

Ž .tion test, nebivolol 5 mg appears less effective thanŽ . Ž .atenolol 100 mg and propranolol 40 mg in antag-

onising the bronchodilating effect of salbutamol,caused by the stimulation of b -adrenergic receptor2in the bronchi. These findings confirm the strict

w xb -selective activity of nebivolol 6, 26, 29 .1

Interactions with other receptorsNebivolol may interact in an inhibitory way on

Ž5-hydroxy-tryptamine -receptors 5-HT -recep-1A 1A. Ž . w xtors Table II 10 . The stimulation of 5-HT -re-1A

ceptors in the guinea-pig isolated intestinal tissuesresults in the inhibition of the twitch contractionfrom electrically-stimulated enteric cholinergic

w x Žnerves 30, 31 . Nebivolol in high doses IC s80050y1 .nmol l inhibits the muscle response to nerve

stimulation. Methiotepin, a serotoninergic receptorantagonist, does not antagonise this effect. To date,no functional response to 5-HT -receptors binding1A

w xof nebivolol has been documented 1]3, 13, 14, 32 .Nebivolol is less active or inactive on other neuro-

transmitter receptors than b-adrenergic or 5-HT1AŽ . w xones Table II 2, 3, 6, 7, 10, 12 .

Furthermore, nebivolol has no effect or is effec-tive only at micromolar concentrations on Ca2q-induced or prostaglandin F -induced vasoconstric-2 a

Ž . w xtions Table II 6, 7, 12 .

Acti¨ ity on release of nitric oxideŽNebivolol lowers blood pressure acutely sponta-

.neously hypertensive rats . This acute effect is notŽshared by other b-adrenergic antagonists atenolol,

. Ž . w xpropranolol nor by D-nebivolol alone Fig. 4 1, 2 .Nebivolol can cause endothelium-dependent re-

Ž . w xlaxation Fig. 5 2, 33]38 . The vasodilating activityis a typical feature of nebivolol, so it has not beendocumented with any other b -adrenoceptor antago-1

Žnist alprenolol, nadolol, propranolol, carvedilol,.celiprolol, dilevalol . This vasorelaxing effect:

v does not depend on the stimulation of adren-Žergic vasodilating receptors nebivolol is de-

. wvoid of intrinsic sympathomimetic activity 6,x15, 33, 39 ;

v does not depend on interference with atypicalŽb -adrenoceptors nebivolol does not signifi-3

. w xcantly act on these receptors 33, 40, 41 ;w xv does not depend on a -blocking property 28 ;1

v is not affected by pretreatment with phen-tolamine or propranolol, which antagonises a-

w xand b-adrenoceptors, respectively 33 ;v is not prevented by methysergide, a 5-HT -,1

w xand 5-HT -receptors antagonist 2, 33 ;2v does not depend on an increase in

prostaglandin-related endothelium-derivedŽcompounds vasodilation is not inhibited by

. w xpretreatment with indomethacine 33, 37 ; andŽ .v is prevented by nitro-L-arginine L-NAME , an

w xinhibitor of NO-synthase 37 , as well as bymethylene-blue, an inhibitor of soluble

w xguanil-cyclase 42 .ŽNebivolol and its active metabolites aromatic hy-

.droxylated and alicyclic oxidised metabolites mayarise in vascular tissue levels able to enhance NO-release in ¨ i o as well in ¨itro. The vasodilatingactivity may significantly contribute to the beneficial

w xhaemodynamic effects of nebivolol 37, 38, 43, 44 .In man, nebivolol lowers vascular resistance both

in normal subjects and hypertensive patients. TheŽ y1 .infusion of nebivolol 1.83]354 mg min , for 6 min

in the brachial artery causes a dose-dependent in-crease in forearm blood flow, whereas blood flow inthe contralateral arm remains unchanged. This va-sodilating effect is shown to be mediated by the


Ž . Ž y1. Ž y1. ŽFig. 4. Effects of single intraperitoneal IP doses of propranolol 10 mg kg , atenolol 2.5 mg kg , pindolol 10 mgy1. Ž y1.kg and nebivolol 1.25 mg kg on arterial blood pressure in conscious spontaneously hypertensive rats. Mean

U w xvalues"SEM. P-0.05 9 .

L-arginine:NO pathway. Carbachol, an endothelium-dependent vasodilator, sodium nitroprusside, an en-dothelium-independent vasodilator, and nebivolol,co-infused subsequently, induce a significant in-crease in forearm blood flow. The vasodilating effect

of nebivolol and carbachol is significantly impairedŽ y1 .by the co-infusion of L-NMMA 2 mg min , an

inhibitor of nitric oxide synthase. In contrast, theincrease in blood flow by nitroprusside, which occursindependently from the NO pathway, is not influ-

Ž . Ž . Ž .Fig. 5. Nebivolol-induced vasorelaxation canine coronary artery pretreated with PFG , with Eq or without Ey2aw xendothelium, and effects on nitro-L-arginine 36 .


enced by the co-infusion with L-NMMA. These find-ings suggest that the vasodilating action of nebivololcomes about via the endothelium-dependent NO-pathway. Atenolol given intravenously at doses that

Žinhibit isoprenaline-induced vasodilation 10]200 mgy1 .min , for 6 min , has no effect on forearm bloodw xflow 37, 45 .

Nebivolol reduces also human venous vascularresistance in a dose-dependent and gradual manner.Nebivolol administered into the dorsal veins precon-stricted by phenylephrine, causes an increase invenous blood flow. This effect is significantly re-duced by co-infusion of L-NMMA, but is not af-fected by the preconstriction with PGF , a non-2 a

adrenergic venoconstrictor. Infusion of atenolol doesnot induce changes in venous blood flow in the same

w xexperimental model 38 .Despite the fall in blood pressure, glomerular

filtration rate and renal plasma flow do not signifi-

cantly change in hypertensive patients after 3 weeksŽ . w xof nebivolol treatment 5 mg daily 46 .

Haemodynamic profileNebivolol lowers blood pressure acutely and re-

duces vascular peripheral resistance, without com-promising left ventricular function, but increasing

Ž . w xstroke volume Fig. 6 3]7, 9, 47]50 . These effectswcontrast those caused by traditional b-blockers 5, 7,

x12, 19 .The antihypertensive activity of nebivolol may be

attributed to its b-antagonistic properties. The va-sodilating properties may depend on mechanismsin which the increase in NO-release from endo-

Ž . wthelial cells may be involved Fig. 5 3, 6, 15, 33, 34,x36]38, 42, 45]47 .

In man, nebivolol improves the heart filling mech-anisms and overall left ventricular performance. In

Žpatients with essential hypertension, nebivolol 5 mg

Ž . Ž . Ž .Fig. 6. Percentage changes in the heart rate HR , cardiac output CO , stroke volume SV , and systemic vascularŽ . Ž . Ž .resistance SVR after administration of various doses of DL-nebivolol blank columns , D-nebivolol slashed columns ,Ž . Ž . U

L-nebivolol grey columns , and atenolol blank columns . Significantly different from its own control; `, significantlydifferent from DL-nebivolol-induced effect; q, significantly different from L-nebivolol-induced effect; D, significantly

w xdifferent from D-nebivolol-induced effect; v, significantly different from atenolol-induced effect 6, 9 .


.daily, for 1 month significantly decreases both sys-tolic and diastolic blood pressure, lowers the meanblood pressure, significantly decreases peripheralvascular resistance, maintains or increases cardiacoutput, but does not modify pulmonary artery pres-sures. In hypertensive patients with high

ŽPEPcrLVETc ratio PEP s pre-ejection period;LVETs left ventricular ejection time; cscorrected

.for heart rate at baseline, due to a prolongedPEPc-value when compared to normotensive sub-jects, nebivolol significantly improves PEPcrLVETc

Žratio from 0.40"0.015 with placebo to 0.63"0.013;.PF0.001 , mainly due to a significant shortening of

the PEPc. There is no significant correlation betweenthese changes and the lowering effect on bloodpressure, suggesting that the improvement in ven-tricular performance is not linked to an afterload

w xreduction only 44, 46, 51, 52 .In patients with essential hypertension, nebivolol

significantly improves the early transmittal peak flowvelocity and the left ventricular peak filling ratenormalised to stroke volume, compared to atenolol,which decreases or does not affect peak filling rate,and increases the left ventricular end-diastolic di-ameter. Nebivolol, but not metoprolol, significantlydecreases the PEPrLVET ratio as measured by

w xsystolic time intervals 25, 53, 54 . This finding isadvantageous in patients with the compromisedfunction of the left ventricle or decrease in leftventricle compliance, probably linked to an impair-

w xment of diastolic filling 55 .

Other effectsNebivolol reduces renin and aldosterone plasma

levels and increases atrial natriuretic factor levels asw xwell as atenolol and acebutolol 46, 56]58 .

The direct actions of nebivolol on kidneys arepoor. Nebivolol does not significantly modifyglomerular filtration rate nor plasmatic flow in the

w xkidney 46 .However, both D-nebivolol and L-nebivolol pro-

vide cytoprotective effects against ischaemic da-mage, by a mechanism not related with b-blockadew x59, 60

PHARMACOKINETICS

Pharmacokinetics of nebivolol were extensively stud-ied in healthy young male and female subjects aswell as in hypertensive patients. Major pharmacoki-netic features depend on genetic oxidative polymor-

Ž .phism debrisoquine-type , related to cytochrome P-450IID6.

Nebivolol is rapidly absorbed orally in extensiveŽ .metabolisers EMs , in which it rises the peak plasma

Žlevel 0.5]2 h after a single intake of 15 mg 3]6 h.post-dosing in poor metabolisers, PMs . Food does

not alter the rate or extent of absorption. After oraladministration of nebivolol 5 mg once daily for 7days to volunteers the peak plasma concentration is

w xsubstantially higher in the EMs than in the PMs 61 .First-pass metabolism in EMs reduces the abso-

lute oral bioavailability to 12% while in PMs theabsolute oral bioavailability averaged 96%, indicat-ing low presystemic elimination.

The metabolism of nebivolol is the major route ofŽ .elimination Fig. 7 . Its major pathway is aromatic

hydroxylation. In PMs glucuronidation of unchangednebivolol, alicyclic mono-oxidation with subsequentglucuronidation and N-dealkylation are the majorpathways. In EMs, N-dealkylation mainly in combi-nation with hydroxylation, alicyclic mono-oxidationand aromatic hydroxylation followed by glucuronida-tion, and glucuronidation of unchanged nebivolol

Ž .are the major metabolic pathways Fig. 7; Table IV .The aromatic hydroxylated and alicyclic oxidisedmetabolites have the same pharmacological andbinding features as nebivolol, while the N-dealkylated metabolites and the glucuronides show

w xlittle or no activity 61, 62 .The apparent volume of distribution ranges from

Ž y1 .695 to 2755 l 10.1]39.4 l kg . Binding to plasmaŽ .protein mainly albumins is hardly stereospecific

Ž98.1"0.2% for D-nebivolol; 98.0"0.3% for L-.nebivolol ; 46% of D-nebivolol and 51% of L-

w xnebivolol distribute in red blood cells 61]63 .Plasma concentration of unchanged nebivolol cor-

relates well to subject metabolic phenotype. Theterminal half-life of unchanged nebivolol averages10.3 h in EMs and 31.9 h in PMs, because ofdifferential clearance, fourfold lower in PMs than inEMs. In PMs, plasma concentrations of unchangednebivolol are markedly higher and drug eliminationis slower than in EMs, because PMs are unable toadequately hydroxylate nebivolol at the aromaticmoiety. However, the formation of active hydroxy-metabolites by first-pass hydroxylation in EMs re-sults in compensating for the difference in un-changed drug levels between both phenotypes. Con-sequently, a comparable antihypertensive effect maybe found in EM as well as in PM hypertensive

w xpatients 44, 61, 62, 64, 65 .

Table IVEffect of metaboliser phenotype on nebivolol metabolism

Metabolic Metaboliser phenotypepathway Extensi e Poor

metaboliser metaboliser

Aromatic hydroxylation qqq qAlicyclic oxidation qq qqGlucuronidation qqq qqqN-dealkylation q q

Notes: q, slight; qq, moderate; and qqq, substan-w xtial 43 .


Fig. 7. Nebivolol structure and major metabolic pathways. UAsymmetric centres; ª , major sites of metabolism; 1,w xaromatic hydroxylation; 2, alicyclic oxidation; 3, glucuronidation; 4, N-dealkylation 61 .

The pharmacokinetics of nebivolol in healthy el-derly subjects as well as in hypertensive patients withmoderate and severe renal disease, is comparable tothose in young healthy subjects. However, plasmalevels of the separate enantiomers plus hydroxy-metabolites are significantly increased in renal dis-ease patients, although no clinically relevant differ-ences are found for blood pressure, heart rate andECG parameters and the incidence of adverse eventsis similar. Therefore no dose-adjustment is required

w xin patients with renal disease 44, 61, 62, 65]67 .

THERAPEUTIC PROPERTIES

Nebivolol is a potent b -adrenoceptor antagonist1with unusual haemodynamic properties:

v it causes a decrease in vascular peripheralresistance both in healthy volunteers and inhypertensive patients, in contrast to typical

w xb-adrenoceptor antagonists 68]75 ; andv in contrast to classical b-adrenoceptor antago-

nists, nebivolol may improve left ventricularw xperformance 60, 69, 71, 72, 75]78 .

Essential hypertensionŽ .Nebivolol 5 mg daily is as efficacious as any

other b-adrenoceptor antagonist against hyperten-sion, with no appreciable difference between peakand through drug levels. It achieves a higher blood

Žpressure normalisation rate than metoprolol 200 mg. Ž .daily . Nebivolol 5 mg daily lowers diastolic blood

pressure and heart rate at rest and during exerciseŽ . Žas well as atenolol 100 mg daily or propranolol 80

.mg daily . Systolic blood pressure is significantly

reduced by nebivolol as well as atenolol, without anyw xorthostatic effect 3, 24, 25, 49, 50, 64, 68]72, 78]80 .

Furthermore, the favourable effects of nebivololon haemodynamics could be advantageous in hyper-tensive patients with a high PEPrLVET ratio, inwhich nebivolol may improve ventricular perfor-

w xmance 25, 46, 51]55 .

Ischaemic heart diseaseb-adrenergic antagonists are drugs chosen for the

secondary prevention in patients who have experi-enced an acute myocardial infarction. In these

Ž .patients nebivolol 5 mg daily causes a significantdecrease in PEP and PEPrLVET ratio, while me-

Ž .toprolol 100 mg daily does not modify these find-ings. In patients with ischaemic heart disease and

Ždocumented diastolic dysfunction PEPrLVET ).0.45 , or in post-myocardial infarction patients with

Žimpairment in left ventricular performance ejection. Žfraction -50% and diastolic filling, nebivolol 5 mg

.daily improves left ventricular and diastolic func-tion. Both myocardial ischaemia and hypertensionare characterised by a progressive stiffening of theventricle leading to a diastolic dysfunction. Higherdiastolic peak filling rates during nebivolol treat-ment indicate an improvement in ventricular disten-

w xsibility and relaxation 61, 73, 81 .In patients with ischaemic left ventricular systolic

dysfunction, but without clinical evidence of is-chaemia or congestive heart failure, both atenololŽ . Ž50 mg daily, 8]10 weeks and nebivolol 2.5 or 5 mg

.daily, 8]10 weeks reduce heart rate both at rest andduring maximal exercise. Nebivolol, but not atenolol,produces a parallel downward shift of thepressure]volume relationship during early diastolicfilling and improves the early peak filling rateŽ .q10%, P-0.05 . Moreover, nebivolol increases the


Žmaximal exercise duration by 44 s P-0.05 ¨s base-.line . Thus, the improving effect of nebivolol on

diastolic distensibility during the rapid filling phase

of the left ventricle may have a higher impact onfunctional capacity rather than changes in systolic

w xfunction 82 .

Ž . Ž . w xFig. 8. Incidence % of adverse events reported for nebivolol and placebo in placebo-controlled trails ns419 94 .Keys: I, Nebivolol; B, placebo.


Congestië heart failureIn congestive heart failure associated with coro-

naropathy, nebivolol causes a decrease in arterialblood pressure and heart rate at rest and duringexercise, without significantly modifying cardiac out-put, because the decrease in heart rate due to b-blockade is compensated by the increase in stroke

w xvolume 73, 83, 84 . In patients in stable NYHAŽfunctional Class II or Ill, nebivolol 5 mg daily, 12

.weeks; ¨s placebo significantly decreases heart rate,increases stroke volume, maintains cardiac output,and reduces left ventricular end-diastolic pressureand end-diastolic stress. This leads to an increase in

Ž .the ejection fraction from 23 to 33% P-0.01 andan improvement of the diastolic left ventricular per-

w xformance 69 .In patients of NYHA Classes I or II treated with

diuretics andror digitalis, and in patients with stablecongestive heart failure, in which nebivolol is admin-

Ž . Žistered chronically 2]3 months , nebivolol 5 mg.daily significantly improves exercise tolerance, while

Ž .atenolol 50 mg daily and placebo have no effectw x85, 86 .

OthersFurthermore, vascular wall distensibility and com-

pliance increase significantly during nebivolol treat-Ž .ment 5 mg daily . This favourable influence could

protect vessels from atherosclerosis. Propranolol, anon-selective b-blocker, does not alter compliance,while pindolol, a b-blocker with intrinsic sym-pathomimetic activity, and bisoprolol, a selective

w xb -blocker, improve compliance 87]89 .1Nebivolol may prevent anxiety and increases in

heart rate induced by situational stress. These ef-fects may be of additional benefit in the treatment

w xof hypertensive patients 68, 90, 91 .

SIDE EFFECTS

Nebivolol is well tolerated. The following side ef-fects have been reported: bradycardia, dizziness,headache, asthenia, tachycardia, palpitations, rash,dry mouth, insomnia, nausea, fatigue, chest pain,

w xparaesthesia, oedema of extremities, anxiety 92, 93 .Figure 8 shows the adverse event profile of nebivololŽ .5 mg daily, 3 months in placebo-controlled trials on

w xpatients with essential hypertension 94 .Nebivolol has not been shown to interfere with

insulin sensitivity nor adversely affect the lipid pro-w xfile in hypertensive patients 95 .

CONCLUSIONS

Nebivolol is efficacious against essential non-com-plicated hypertension and useful for treatment of

patients suffering from complicated hypertension.Its particular haemodynamic properties characteriseit among other b-adrenergic antagonists.

D-Nebivolol is a highly selective b -blocker and1long-acting b-adrenoceptor antagonist. DL-Nebivolollowers both systolic and diastolic blood pressureacutely in ¨ i o and causes a decrease in peripheralvascular resistance, without depressing left ventricu-lar function. These haemodynamic effects are

w xprobably due to L-nebivolol 6, 9, 19, 43 .Furthermore, both DL-nebivolol and its enan-

tiomers are devoid of intrinsic sympathomimetic ac-w xtivity 6, 19, 34 .

L-Nebivolol at doses which do not interfere withb-adrenoceptors, reduces the arterial blood pressure

w xin ¨ i o 39 . Furthermore, L-nebivolol promotes NOrelease from endothelial cells, while D-nebivolol isvirtually devoid of this activity. These findings mayexplain the decrease in peripheral vascular resis-

wtance documented with DL-nebivolol 19, 28, 29, 31,x35 .The effects of DL-nebivolol on left ventricular

function are mostly due to the b-blocking action ofD-nebivolol, while L-nebivolol, which is virtually de-void of b-blockade, enhances the haemodynamiceffects of D-enantiomer and improves the actions oftraditional b-blockers on cardiac function.

Main pharmacokinetic features depend on geneticŽ .oxidative polymorphism debrisoquine-type , related

to cytochrome P-450IID6.In conclusion, nebivolol is an effective, safe and

selective b -adrenoceptor antagonist with peculiar1pharmacodynamic and pharmacokinetic features. Itshaemodynamic effects are unusual and indicate thatnebivolol may be efficacious in many cardiovascular

Žpathologies, also in those ventricular dysfunctions,.congestive heart failure , in which traditional b-

blockers are inefficacious, controversial or con-traindicated.

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