3. Beta-blockers have long been used as first-line agents to treat hypertension and have also

been used as the reference drug in randomised controlled trials (RCTs), compared with other

agents, to treat hypertension. However, since the end of the last decade, systematic reviews,

meta-analyses, and RCTs have put in doubt the efficacy of these drugs in preventing

outcomes such as death and vascular events in hypertensive patients. In a recent meta-

analysis, Messerli and colleagues concluded that, in uncomplicated hypertension, neither

diuretics nor beta-blockers are acceptable as firstline treatment (Messerli 2008). Another

meta-analysis has shown that, in comparison with other antihypertensive drugs, the effect of

beta-blockers is less than optimal, with a raised risk of stroke. The authors concluded that

beta-blockers should not remain as the first choice of drug in the treatment of hypertension

and should not be used as reference drugs in RCTs of hypertension (Lindholm 2005). The

Blood Pressure Lowering Treatment Trialists Collaboration overview found that treatment

with any commonly used

regimen reduces the risk of cardiovascular events, but with somedifferences between

regimens. Regimens based on beta-blockers showed a trend toward greater risk reduction

compared with regimens based on angiotensin-converting enzyme (ACE) inhibitors, and

regimens based on calcium antagonists showed a trend toward greater risk reduction

compared with those based on beta-blockers (BPLTTC 2003). A Cochrane review evaluating

the efficacy of beta-blockers for treating hypertension concluded that available evidence does

not support the use of beta-blockers as firstline drugs (Wiysonge 2007). Moreover, RCTs

comparing betablockers with other drugs in hypertensive patients have shown negative

results. In the Losartan Intervention For Endpoint reduction in hypertension study (LIFE),

losartan prevented cardiovascular morbidity and death more frequently than atenolol for

similar reductions in blood pressure (Dahlöf 2002). Furthermore, in the Anglo-Scandinavian

Cardiac Outcomes Trial (ASCOT), an amlodipine-based regimen prevented major

cardiovascular events

more often and induced diabetes less frequently than an atenololbased regimen (Dahlöf

2005).Nevertheless, diagnostic criteria for hypertension and blood pressure targets have

evolved to lower values over the years; the efficacy of beta-blockers was established in

populations with higher levels of blood pressure. Hence, a metaanalysis including trials

fromdifferent decadesmay underestimate the efficacy of beta-blockers.

Clinical PharmacologyAlthough more than 100 beta-blockers have been developed, only about 30 are available for clinical use.3 Water-solublebeta-blockers (Atenolol, Nadolol) tend to have longer half-lives and are eliminated via the kidney. Lipid-soluble beta blockers (metoprolol, propranolol) are metabolized mainly in the liver and have shorter half-lives.4 Most of the drugs in the class are well absorbed after oral administration. The biologic half-life of Beta-blockers exceeds the plasma half life considerably. (e.g. propranolol, dosage twice a day despite a plasma half-life of 3 hours). Clearly, the higher the dose, the longer the biologic effect. Longer acting compounds and preparations are preferred for angina and hypertension(metoprolol XL, atenolol, nadolol, sotalol, inderal LA). Esmolol (I/V) has the shortest half life (10 min).Three types of Beta-receptors (β1, β2, β3) are variably distributed in tissues5. β1 receptors are mainly located in theheart while β2 receptors are found in vascular and bronchial smooth muscle. β3 receptors are located in the adipocytes and heart 3.

3. Adrenergic beta-antagonist drugs or beta-blockers: acebutolol, alprenolol, atenolol,

betaxolol, bisoprolol, bucindolol, bufuralol, bupranolol, butoxamine, carteolol, carvedilol,

celiprolol, epanolol, esmolol, labetalol,metoprolol, nadolol, oxprenolol, pindolol, propranolol,

sotalol, and timolol.

6. Beta-blocker therapy did not reduce the risk for post-stroke pneumonia, but significantly

reduced the risk for urinary tract infections. Different immune mechanisms underlying both

diseases might explain these findings that need to be confirmed in future studies.

6. Recent experimental studies showed an active interaction between the central nervous

system and the peripheral immune system, which can result in immunosuppression and

increased susceptibility for systemic infections after stroke [5–8]. This effect is thought to be

a compensatory response to protect the post-ischemic brain from overwhelming and

damaging inflammatory response, which is caused by infiltration of immune cells in the

ischemic brain area with oxidative stress, microglial and complement activation and damage

of the blood brain barrier [9, 10].

6. One of these immunosuppressive mechanisms after stroke is an activation of the

sympathetic nervous system, resulting in an induction of anti-inflammatory phenotype

immune cells [11]. In patients with ischemic and hemorrhagic stroke, increased

catecholamine levels and decreased peripheral immune response have been described

previously [12, 13]. Hyperactivity of the sympathetic nervous system hereby is mainly caused

by lesions of the anterior medial cortex and insular cortex [14, 15].

6.There is growing evidence that various mechanisms lead to high

susceptibility for infections after stroke. One of these mechanisms is the

activation of the sympathetic nervous system, which leads to peripheral

immunosuppressive effects [11]. These effects have been shown to be

reversed by propranolol administration indicating a noradrenergic

pathway and involvement of β1- or β2-receptors [16]. Based on this

evidence, we expected a decrease in infectious complications after stroke

among patients receiving beta-blockers. The observed difference in the

effect of beta-blocker therapy on pneumonia and UTI might be

attributable to different mechanisms by which infection and inflammation

are mediated in both conditions. Pneumonia after stroke is mostly related

to aspiration. Initial inflammation is triggered by chemicals like gastric

acid, resulting in a pneumonitis. A second step is a bacterial super-

infection resulting in pneumonia. In contrast, UTIs are primarily caused by

infectious agents and are often catheter-associated. iNKT cells have been

described to play a central role in the immune moieties that can function

as alarmins [16, 20]. Given the different mechanism in post-stroke

pneumonia and UTI, iNKT cells might be differently involved in immune

response in both

conditions. Activation of iNKT in the initial phase of UTI might therefore be

more striking through both the presentation of bacterial antigens and

recognition of circulating alarmins. Therefore, the influence of beta-

blocker therapy on rates of UTIs might be explained by the different

involvement and extent of activation of iNKT cells. However, it is also

possible that both conditions could involve other subsets of immune cells,

initially reacting on chemical or infectious agents, which are being

influenced differently by beta-blocker therapy. Moreover, UTIs are usually

caused by gram-negative bacteria, while pneumonia shows a more

complex picture with many classic gram-positive germs involved. Immune

reaction to both groups is quite distinct so that it might be possible that

the protective effect of beta-blockers is unique to gramnegative bacteria.

In other studies lower mortality, immunomodulatory effects and enhanced

inflammatory potential of immune cells have been found for patients with

sepsis and beta-blocker therapy [20–23]. Ackland et al. found protective

effects in rats allocated with β1-antagonists before a septic insult,

resulting in a significant reduction of mortality by preventing an

overwhelming pro-inflammatory state [24]. This study indicates that β1-

receptors are involved in peripheral immune modulation of systemic

inflammatory processes and might influence regulating processes

to guarantee an effective immune response.

Studies focusing on the role of beta-blocker therapy after stroke found

conflicting results on mortality and stroke outcome. In the beta-blocker

stroke (“BEST”) trial, patients continuing their prior therapy with

propranolol or atenolol had a better outcome after stroke [25].

However, the authors also found a higher mortality in patients taking

beta-blockers, which was associated with higher co-morbidities in the

beta-blocker group, while infection rates were not reported. In view of the

findings of beneficial effects of beta-blocker therapy in patients with

sepsis and the conflicting results in patients with stroke, the interpretation

of the higher mediumterm risk for death of patients with beta-blocker

therapy in our study is difficult. Patients in the beta-blocker group had

significantly more co-morbidities and were at higher risk for

cardiovascular disease. Therefore, overall risk of death could be higher in

these patients and full adjustment of confounding factors might not have

been possible. The influence of cardiovascular disease on mortality after

stroke can be underlined by findings from a study by Dziedzic et al., who

found a lower 30-day mortality of patients with beta-blocker therapy and

stroke, which was no longer statistically significant after removing

patients from the analysis, who died because of cardiac complications

[26]. However, as death of any cause was not a primary outcome of this

study, we did not take into account potential confounders of the

association of betablockers and death which were not affecting the link

between beta-blockers and infection. This is supported by the fact that

effects of post-stroke infections and death are heading in opposite

directions and that beta-blocker therapy did not affect mortality after

seven days. Moreover, rates of myocardial infarction did not differ

between patients with and without beta-blocker therapy in our study.

Besides the causes for higher mortality rates in the beta-blocker group,

we had to consider the differences in mortality rates between groups due

to a potential competing risk situation of the outcome death and other

endpoints. Patients who died earlier might have been more likely to

develop infectious complications if they had not died. In our sensitivity

analyses using the most extreme scenario (i.e. that all people who died

would have developed the respective infection) 1/3 of the observed effect

of beta-blocker therapy on UTIs was removed leading to a point Beta-

Blocker Therapy and Infections after Stroke estimate of 0.80. Thereby,

even this extremely conservative scenario confirmed a clinically relevant

risk reduction for UTIs in patients with beta-blocker therapy. In a study by

Laowattana et al, beta-blocker therapy was associated with lower stroke

severity at baseline [27]. We support this evidence by showing a trend

towards a lower baseline NIHSS in the beta-blocker group. However, it

seems unlikely that the lower NIHSS by one point (median difference) in

the beta-blocker group explains the lower rate of UTIs in the same group

through lower stroke severity. In addition, there was no difference in

change of NIHSS between the groups over time and therefore no

indication that this could increase the risk to develop an infection in one of

the groups.

In the same study, thrombin and erythrocyte sedimentation rate were

lower in patients taking beta-blockers indicating less systemic

inflammation. In contrast, in our study beta-blocker therapy was not

associated with less pronounced changes in leukocyte count or CRP, both

indicators for systemic infections. These findings suggest different effects

of beta-blocker therapy on specific markers of systemic infections,

indicating that these markers are not influenced equally by increased

catecholamine-levels.

Although β1-receptors seem to be involved in immunomodulating effects

after stroke, either indirectly by lowering the sympathetic tone or via

direct antagonism influencing the function of peripheral immune cells,

there is evidence for β2-receptor-mediated immunosuppressive

mechanisms associated with an increased sympathetic tone. In an in vitro

study by Platzer et al., allocation of catecholamines induced a β2-

receptor-mediated production of the immunosuppressive cytokine IL-10 in

monocytic cells [28]. Unselective beta-blockers could therefore combine

β1- and β2-receptor associated inhibition of immunosuppression after

stroke. It seems to be important to compare the incidence of infections

after stroke in patients receiving β1-selective beta-blockers with the

incidence in patients receiving non-selective beta-blockers and no beta-

blockers. However, studying this question is difficult because indications

for unselectivebeta-blockers are limited due to side effects like

bronchospasm and hypoglycemia.Recent studies found pleiotropic effects

of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase

inhibitors (statins), frequently prescribed after stroke to lower serum

cholesterol, on endothelial function, cell proliferation, inflammatory

response, immunological reactions and platelet function [19]. Statins have

been shown to be involved in immunological pathways, involving the

function of immune response on multiple levels (gene transcription

factors, cytokines, chemokines, immune cell function and proliferation)

[29]. Other studiesalso showed anti-inflammatory effects of statins in

autoimmune diseases. Therefore, we performed a stratified analysis in

order to elucidate a potential modifying effect of statin therapy on the

effect of beta-blocker therapy on post-stroke infections. The effect of beta-

blocker therapy on UTI rates was significantly larger in patients without

statin therapy. This might be explained by an anti-proliferative effect of

statins on T-cells [30]. Moreover, in a study by Fehr et al., statin

administration was associated with major histocompatibility class II (MHC

II) antigen down-regulation and the inhibition of superantigen-mediated T-

cell activation [31]. Inthe context of the findings of Wong et al [16], these

effects of statins on T-cell function might explain, why beta-blocker

associated reduction of infections after stroke were predominantly found

in patients without statin therapy. In patients with statin therapy, the

effect of betablockers is likely to be lower because of an anti-proliferative

effect of statins on iNKT cells, which have been demonstrated to play a

central role in stroke induced peripheral immunosuppression.

3. This review showed no evidence of reduction of recurrent stroke, total mortality, vascular

disease, and cardiovascular events in people with previous stroke treated with beta-blockers.

Some pathophysiological considerations may in part explain these findings.

Atherothrombotic vascular disease manifests, as a rule, as a cerebrovascular event (stroke or

TIA), myocardial infarction, or peripheral vascular disease. The predominant risk factors for

all these events are quite similar and include hypertension, diabetes mellitus, obesity,

dyslipidaemia, and cigarette smoking (Sacco 2006; Smith 2001). This similarity reflects the

systemic nature of atherothrombotic vascular disease. However, differences observed

between the risk factors specific for vascular disease suggest some degree of specificity in

pathophysiological processes. For example, dyslipidaemia is a well-established risk factor for

coronary artery disease, but its role in cerebrovascular disease is not well established (Sacco

1997). The theory of divergent pathophysiological mechanisms for stroke and coronary heart

disease has been reinforced by data from epidemiological studies and RCTs. Thus, the

specificity between different forms of vascular disease may explain the fact that the

beneficial effects of beta-blockers demonstrated in ischaemic heart disease may not be valid

with respect to cerebrovascular disease.

3. Beta-blockers have not demonstrated superiority over placebo for the secondary prevention

of stroke. We did not find any statistically significant differences in outcomes analysed

between the beta-blocker atenolol and placebo. Included studies did not analyse the potential

association between beta-blockers and increased risk of developing diabetes mellitus.

Therefore, no evidence supports the routine use of beta-blockers for secondary prevention

after stroke or TIA.

8. Carvedilol, a non-selective beta-blocker with alphablocker properties, currently used to

treat hypertension, heart failure and coronary artery diseases, has besides its cardioprotective

and vasculoprotective properties

also antioxidant effects. The antioxidant properties of carvedilol, and its relation to

mitochondrial oxidative phosphorylation, calcium homeostasis and energy production, make

this drug a unique beta-blocker, reinforcing its advantageous use in cardiac pathologies

associated with enhanced cellular oxidative stress. Carvedilol administered subcutaneously

directly after transient forebrain ischemia protected a population of neurons in the

hippocampal CA1 area in gerbils (Strosznajder et al., 2005). Thus carvedilol raises high

expectations also in the therapy of ischemia.

8. Carvedilol merupakan non-selective beta-bloker dengan alphabloker, saat ini digunakan untuk terapi hipertensi, gagal jantung, dan penyakit arteri coroner, selain itu juga memiliki efek kardioprotektif, vaskuloprotektif, juga antioksidan. Sifat antioksidan dari carvedilol dan hubungannya dengan fosforilasi oksidatif mitokondria, homeostasis kalsium dan produksi energi, membuat kerja beta-bloker yang unik, memperkuat penggunaan untuk mengobati kelainan jantung yang berhubungan dengan stres oksidatif seluler. Carvediol diberikan secara subkutan langsung pada iskemik otak depan yang dilindungi oleh banyak neuron hippocampal CA1 di gerbil. Jadi carvedilol juga memiliki efek yang tinggi pada terapi iskemik.

8. Carvedilol is a multiple-action antihypertensive agent with a potential for cardiovascular

protection beyond the

normalization of high blood pressure. It has alpha1- and beta-adrenergic receptor blocking

action, calcium channel blocking action, suppressive effect on cardiac necrosis and

neuroprotective activities in animal models of brain ischemia and infarction (Ruffolo et al.,

1990, Rabasseda 1998, Strosznajder et al., 2005). Carvedilol exerts an additional

neuroprotective activity as a Na+ channel modulator and glutamate release inhibitor (Lysko

et al.,1994). Recently, carvedilol was found to inhibit mitochondrial permeability transition,

mitochondrial swelling, oxidation of thiol groups, and to protect mitochondria against

oxidative damage induced by the xanthine oxidase/ hypoxanthine pro-oxidant system

(Oliviera et al., 2004, Oliviera et al. 2005, Carreira et al., 2006). Chronic administration of

carvedilol resulted in an improvement of memory retention (evaluated in the Morris water

maze task paradigms) and in attenuation of oxidative damage in the streptozotocin induced

model of dementia in rats (Prakash & Kumar, 2009). Carvedilol may have a potential in the

treatment of neurodegenerative diseases.

8. Carvedilol, (±)-1-(Carbazol-4-yloxy)-3-[[2-(omethoxyphenoxy) ethyl]amino]-2-propanol

was obtained from La Roche (Mannheim, Germany). Stock solution of carvedilol in the

concentration of 1 mmol/l was prepared by dissolution in wine acid and distilled water,

heated up to 37 °C and sonicated three times for 5 min.

4. Carvedilol is a third-generation, vasodilating noncardioselective β-blocker which lacks

intrinsic sympathomimetic activity (ISA). In addition to its β-blocking effects, it has

blocking effects at vascular α1-receptors, antioxidant, and calcium antagonist properties

(Opie and Yusuf 2005). Experimental models demonstrate that carvedilol blocks α1-, β1-,

and β2- adrenergic receptors (McTavish et al 1993) without exhibiting high levels of

inverse agonist activity. The lack of inverse agonist activity and ISA reduces the side-effects

and makes the compound better tolerated than the older β-blockers (Yoshikawa et al 1996).

6. Several authors (Savitz et al., 2000 and Goyagi et al., 2006) reported that carvedilol versus

propranalol protects the neurons after transient focal cerebral ischemia in rats, through the

preservation of mitochondrial function. It has an antiapoptotic role and can down regulate

the inflammatory cytokine gene expression of TNF-α and IL-1β.

3. In the COMET (Carvedilol Or Metoprolol European Trial) study, carvedilol improved

survival and cardiovascular hospitalizations more than the beta-1 selective beta-blocker

metoprolol tartrate (7). Carvedilol blocks both the beta-1 and -2 receptor, and has tighter,

more prolonged binding propertie to the beta-1 receptor than metoprolol, which results in a

greater sympatho-inhibitory activity than with metoprolol at the dosages used in the COMET

study (8). Carvedilol also blocks alpha 1-adrenergic receptors with enhanced peripheral

vasodilatation and renal sodium excretion (11), and has antioxidant and antiendothelin

effects. These additional effects may lead to improved vascular function and vascular

protection relative to the effect of beta-1 selective blockade alone.

As previous analyses have also indicated that carvedilol reduces the occurrence of sudden

death and death due to worsening HF (7), a decrease in ischemic events may well contribute

to this survival benefit, in addition to other mechanisms including hemodynamic

improvement and antiarrhythmic properties of carvedilol. The vascular endothelium

contains both beta-1 and -2 as well as alpha-1 receptors. Blockade of all 3 adrenergic

receptors by carvedilol provides for better endothelium- dependent vasodilatation than

more selective beta-blockade (18). Both in animal and human studies, carvedilol, but not

metoprolol, results in vasodilatation and better improves endothelial function (19,20). Also,

antioxidative and antiapoptotic properties of carvedilol may play a role in improving free

radical-induced endothelial dysfunction, reduce myocardial injury and infarct size after

ischemia reperfusion, and may affect atherosclerosis formation

7. Free radical generation mediates part of the ischemic neuronal damage caused by the

excitatory amino acid glutamate. Carvedilol, a novel multiple-action antihypertensive

agent, has been shown to scavenge free radicals and inhibit lipid peroxidation in swine

heart and rat brain homogenates. Therefore, we studied the neuroprotective effect of

carvedilol on cultured cerebellar neurons and on CA1 hippocampal neurons of gerbils

exposed to brain ischemia.

7. Carvedilol provided neuroprotection in both in vitro and in vivo models of

neuroinjury, where oxygen radicals are likely to play an important role. Therefore,

carvedilol may reduce the risk of cerebral ischemia and stroke by virtue of both its

antihypertensive action and its antioxidative properties. (Stroke 1992;23:1630-1636)

7. Carvedilol (Figure 1) is a novel multiple-action antihypertensive drug (reviewed in

Reference 11) that has recently been introduced to European markets. Clinical trial

comparisons with other major antihypertensive agents demonstrated that once-daily therapy

with carvedilol provided effective control of blood pressure with a favorable side-effect

profile.11 Carvedilol is both a competitive /3-adrenoceptor antagonist and a vasodilator, with

additional calcium channel antagonist properties at somewhat higher concentrations.12-14

We have recently reported that carvedilol is also a potent inhibitor of lipid peroxidation in

swine ventricular membranes.15 In that system, carvedilol was shown to have a potency

similar to the 21-aminosteroid antioxidant U74500A but was far better than all other /3-

blockers.15 Carvedilol also in a dose-dependent manner inhibited superoxide release from

human neutrophils,16 scavenged superoxide radicals, 16 and inhibited lipid peroxidation in

rat brain homogenates exposed to free radical-generating systems. 17 Furthermore, we have

also shown the efficacy of carvedilol in promoting myocardial salvage after ischemia induced

by transient or permanent ligation of the coronary artery in several species.I4-18-20 Cerebral

ischemia and injury are also known to be accompanied by lipid peroxidation following

oxygen free radical formation, 2'-23 and antioxidants such as the "lazaroids" are potent

inhibitors of lipid peroxidation,22-24 decreasing tissue damage and increasing neuronal

salvage.22-25 Similarly, the free radical scavenger superoxide dismutase is currently being

studied in clinical trials as a neuroprotectant in traumatic brain injury. Therefore, we

hypothesized that carvedilol would afford significant protection for neurons exposed to toxic

free radicals and have tested this hypothesis in our model of cultured rat

cerebellar granule cells and in the gerbil model of global brain ischemia.

7. Carvedilol is a unique antihypertensive compound because it is not only a vasodilator

and )3-adrenergic receptor blocker but also appears to be a useful antioxidant, rapidly

preventing lipid peroxidation in swine ventricular membranes15 and rat brain

homogenates17 with a potency two orders of magnitude greater than that of other /3-

blockers.15'17'26 Furthermore, it appears to be an oxygen free radical scavenger, scavenging

both chemically generated and human neutrophil-generated superoxide anions.16 Compared

with the lazaroid antioxidant U74500A, carvedilol is nearly equipotent against lipid

peroxidation15 and is far superior as a free radical scavenger.1617 The antioxidant activity of

carvedilol resides in the carbazole moiety.17 Carvedilol- mediated protection of cerebellar

granule cell neurons from glutamate excitotoxicity supports previous arguments of a role for

free radical generation in ischemiainduced neuronal damage, in which free radicals generated

by EAA receptor agonists would cause further EAA release.10 Because ischemic conditions

caused a 20-fold increase in glutamate release from hippocampal slices10 and are necessary

for glutamate excitotoxicity in cerebellar granule cells,1-7 continual free radical generation

and neurotransmitter release would likely contribute to sustained damage during ischemic

stroke. By scavenging free radicals, carvedilol would be likely to decrease EAA release; by

preventing glutamate-induced toxicity as shown here, fewer free radicals would be generated.

7. Because carvedilol prevented neuronal death and inhibited membrane lipid peroxidation in

cerebellar granule cells exposed to a free radical-generating system, the drug may be

sequestered in biological membranes. Maximal plasma concentrations of carvedilol in

humans averaged 173 /xg/1 (425 nM) after intravenous infusion of 12.5 mg and 66 jug/1 (162

nM) 1.2 hours after 50 mg p.o.,31 about an order of magnitude lower than the IC5Os reported

here for neuroprotection. However, carvedilol is a highly lipophilic compound29-31 that is

extensively bound to tissues, achieving a high distribution volume of 132 I.31 In addition,

hydroxylated derivatives of carvedilol increased the antioxidant activity 10- to 40-fold17 and

have been found as metabolites in humans. Further supportive evidence for protective

membrane sequestration comes from the ability of neurons grown with carvedilol for 24

hours to better withstand free radical-mediated cell death. Indeed, the multiple-dosing

regimen that we used for the gerbil neuroprotection studies favored an accumulative

mechanism achieved by daily dosing because bolus injections of 1 mg/kg s.c. as a 30-minute

pretreatment and 4-hour posttreatment had no protective effect. These results are similar to

those reported for the nonsteroidal lazaroid U78517F in the gerbil model of 15-minute

bilateral carotid artery occlusion, in that multiple dosing was required for efficacy.25

Although cerebral protection by the lazaroids has been noted in many cases,2225 not all

investigators have found these compounds to be neuroprotective, even with repeated

dosings.32-34

7. The neuroprotection results reported here support the efficacy of carvedilol as an effective

free radical scavenger and inhibitor of lipid peroxidation. We suggest that carvedilol may not

only relieve hypertension as a risk factor for stroke, but will also be better able to provide

additional benefits to patients by protecting against oxygen free radicals generated during

cerebral ischemia and stroke.

Farmakokinetik & farmakodinamik

4. Carvedilol is rapidly absorbed after an oral dose, reaching peak plasma drug concentrations

within 1 to 2 hours. Absorption is delayed an additional 1 to 2 hours when the drug is

administered with food (Morgan 1994). The plasma half-life of carvedilol ranges from 7 to

10 hours in most subjects; thus, the drug requires twice-daily dosing. In plasma, 98% of the

drug is bound to plasma proteins, predominantly to albumin (Morgan 1994). Carvedilol is

almost exclusively metabolized by the liver and its metabolism is affected by genetic

polymorphism of cytochrome P-450 2D6 activity. Drugs that inhibit cytochrome P-450 2D6

activity, such as quinidine, paroxetine, fl uoxetine, and propafenone, may also increase

plasma carvedilol concentrations. Thus, patients taking these drugs may be at particularly

high risk of hypotension due to excessive α-adrenoreceptor blockade. Clearance of carvedilol

is delayed in patients over 65 years of age. On average, their plasma carvedilol concentrations

are 50% higher than in younger patients (Frishman 1998). The pharmacokinetics of

carvedilol are significantly altered in patients with liver disease but not so in the presence of

renal failure (Neugebauer et al 1992; Kramer et al 1992; Frishman 1998). Less than 2% of the

parent drug recovers in the urine (Frishman 1998). Some of the metabolites of carvedilol

have β-adrenoreceptorantagonist activity, and one 4-hydroxyphenyl metabolite is

approximately 13 times as potent as carvedilol in this regard. Approximately 60% of these

metabolites are secreted with bile and excreted with the faeces (Frishman 1998).

Kelebihan :

7. The potential mechanisms responsible for the observed beneficial impact of carvedilol

compared to other BBs may in part be established through carvedilol’s pleiotropic effects

(antioxidant and vasodilating), which are not shared by the commonly prescribed b1-selective

BBs (i.e., atenolol, metoprolol, and bisoprolol).

Improved versus reduced cardiac output may allow carvedilol to improve insulin sensitivity,

whereas atenolol and metoprolol worsen insulin sensitivity.24 In the COMET study,

carvedilol, compared to metoprolol, reduced the risk for new diabetes development over the

5-year study by 22% (p¼0.048)3. In contrast to metoprolol and atenolol, carvedilol has a

neutral or favorable effect on levels of triglycerides and high-density lipoprotein

cholesterol.25 Additionally, in the Glycemic Effects in Diabetes Mellitus: Carvedilol-

Metoprolol Comparison in Hypertensives (GEMINI) randomized trial, 40% fewer patients

progressed to microalbuminuria in the carvedilol arm than in the metoprolol arm.25

7. Carvedilol lowers blood pressure mainly through vasodilation, whereas b1-selective BBs

do so by a reduction in cardiac output (an untoward effect in patients with HF).24