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Drugs 45 (2): 232-258, 1993
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Carvedilol
A Review of its Pharmacodynamic and Pharmacokinetic Properties,
and Therapeutic Efficacy
Donna McTavish, Deborah Campoli-Richards and Eugene M.
Sorkin Adis International Limited, Auckland, New Zealand
Various sections of the manuscript reviewed by: S.A. Doggrell, Department of Pharmacology and Clinical Pharmacology, University of Auckland, Auckland, New Zealand; A.G. Dupont, Department of Internal Medicine, Academisch Ziekenhuis - Vrije Universiteit Brussel, Brussels, Belgium; R. Eggertsen, Department of Medicine, Östra
Hospital, Göteborg, Sweden; W.H. Fríshman, Montefìore Medical Center, The Jack D. Weiler Hospital of the
Albert Einstein College of Medicine, Bronx, New York, USA; Y. Hattori, Department of Pharmacology, Hokkaido
University School of Medicine, Sapporo, Japan; J.C. Kaski, Department of Cardίological Sciences, St George's
Hospital Medical School, London, England; G. Leonetti, Centro Auxologico Italiano, Istituto di Ricovero e Cura
a Carattere Scientifíco, Milano, Italy; W.J. Louis, Clinical Pharmacology and Therapeutics Unit, Department of
Medicine, University of Melbourne, Heidelberg, Victoria, Australia; T.O. Morgan, Department of Physiology,
University of Melbourne, Heidelberg, Victoria, Australia; T. Ogîhara, Department of Geriatric Medicine, Osaka
University Medical School, Osaka, Japan; B.N.C. Prichard, Department of Clinical Pharmacology, University
College and Middlesex School of Medicine, University College London, London, England; E.B. Raftery, Cardiology Research Department, Northwick Park Hospital, Harrow, Middlesex, England.
Contents
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Summary
1. Pharmacodynamic Properties
1.1 Adrenoceptor Blocking Activity
1.1.1 In Vitro and In Vivo Studies
1.1.2 Human Studies
1.2 Cardiovascular Effects
1.2.1 Blood Pressure and Heart Rate
1.2.2 Peripheral Vascular Circulation
1.2.3 Myocardial Function
1.2.4 Cardioprotective and Neuroprotective Effects
1.3 Other Effects
1.4 Mechanisms of Action
2. Pharmacokinetic Properties
2.1 Absorption and Distribution
2.2 Metabolism and Elimination
2.3 Effects of Age and Disease States
3. Therapeutic Efficacy
3.1 Mild-to-Moderate Essential Hypertension
3.1.1 Noncomparative Studies, Dose Response Studies and Comparisons with Placebo
3.1.2 Comparisons with Other Antihypertensive Agents
3.1.3 Use in Combination with Other Antihypertensive Agents
3.1.4 Use in Special Patient Groups
3.2 Chronic Stable Angina Pectoris
Carvedilol: A Review
251
252
252
253
Summary
Synopsis
233
3.3 Congestive Heart Failure
4. Tolerability
5. Dosage and Administration
6. Place of Carvedilol in Therapy
¯i
Carvedilol is a ß-adrenoceptor antagonist which also causes peripheral vasodilation primarily
via a1-adrenergic blockade. Carvedilol produces its antìhypertemive effect partly by reducing total
peripheral resistance by blocking a1-adrenoceplors and by preventing ß-adrenoceptor-mediated
compensatory mechanisms. This combined action avoids many of the unwanted effects associated
with traditional ß-blocker or vasodilator therapy.
In clinical trials published to date, most of which enrolled small numbers of patients, the antihypertensive efficacy ofcarvedilol administered once daily was similar to that ofaíenolol, labetalol,
pindolol propranoloί metoprolol, nìtrendipine (in elderly patients), slow release nifedipine or captopril in patients with mild-to-moderate essential hypertension. Combined therapy with carvedilol
25mg and hydrochlorothiazide 25mg, nicardipine 60mg or slow release nifedipine 20mg has an
additive antihypertensίve effect. Carvedilol and atenolol at similar doses were equally effective at
reducing blood pressure in patients who had previously not responded adequately to hydrochlorothiazide monoîherapy.
As a result of its multiple mechanisms of action, carvedilol is suited for the management of
specific groups of hypertensive patients, such as those with renal impairment. In patients with noninsulin-dependent or insulin-dependent diabetes mellitus carvedilol does not appear to affect glucose
tolerance or carbohydrate metabolism.
Initial studies have demonstrated that carvedilol and slow release nifedipine have similar efficacy in patients with stable angina pectoris and there is evidence that carvedilol has a beneficial
haemodynamic effect in patients with congestive heart failure (NYHA class II or III) secondary
to ischaemic heart disease.
A postmarketing surveillance study has shown that carvedilol is generally well tolerated with
only 7% (164/2226) of patients (83% of the total number received 25mg daily for 12 weeks) withdrawing from treatment because of adverse events. Vertigo, headache, bronchospasm, fatigue and
skin reactions were the most common events causing withdrawal.
Thus, clinical experience to date suggests that carvedilol is likely to be a valuable addition to
the options currently available for treating patients with mild-to-moderate essential hypertension,
and may offer particular benefit in specific populations of hypertensive patients.
Pharmacodynamic Properties
Racemic carvedilol is an arylethanolamine -adrenoceptor antagonist with vasodilating properties. Antagonism of  -adrenoceptor-mediated responses with carvedilol (demonstrated in various animal models and in healthy volunteers) is similar in potency, but longer lasting (15 to 16
hours) than that of propranolol (12 hours), and much greater in both potency and duration of
effect than that of labetalol (1.5 hours). Some studies have shown that at a dose producing ß1blocking activity, carvedilol also antagonises ß2-adrenoceptors but to a lesser extent, thus indicating weak selectivity for ß1-adrenoceptors. However, other studies have failed to show any  adrenoceptor selectivity.
Antagonism of α1-adrenoceptors accounts for most of the vasodilatory activity of carvedilol,
although at high concentrations (>l μmol/L) antagonism of calcium channels has been observed
consistently in various animal models. Although this does not appear to contribute to the antihypertensive effects of carvedilol, it may be of significance in specific vascular beds. Carvedilol
exhibits no intrinsic sympathomimetic/partial agonist activity and only weak membrane-stabilising (local anaesthetic) activity.
234
Drugs 45 (2) 1993
Carvedilol has cardioprotective effects in animal models of acute myocardial infarction and
is more effective in this regard than propranolol at comparable ß-blocking doses. Carvedilol also
protects against neuronal damage in in vitro and in vivo models of brain ischaemia and has
antiproliferative effects in vascular smooth muscle in vitro.
Single oral doses of carvedilol as low as 12.5mg reduce resting and exercise blood pressure in
healthy volunteers. In hypertensive patients carvedilol dose-dependently reduced mean diastolic
blood pressure. Elderly hypertensive patients (aged > 65 years, baseline supine blood pressure
185/103mm Hg) respond equally well to carvedilol; a single 12.5mg dose adequately reduced
mean peak supine blood pressure in many patients. Single doses of carvedilol 25mg and nitrendipine 20mg were equally effective.
Carvedilol generally has little or no effect on heart rate or cardiac index in healthy volunteers;
however, cardiac output was reduced in exercising hypertensive patients treated with carvedίlol,
and the drug had less effect than propranolol or metoprolol on heart rate in resting or exercising
hypertensive patients.
In patients with coronary artery disease, initial results show that carvedilol improved exercise
capacity and left ventricular function and increased ejection fraction. There is also some evidence
that left ventricular hypertrophy regresses in patients with hypertension treated with carvedilol
and that the drug improves cardiac function in patients with idiopathic dilated cardiomyopathy.
Pharmacokinetic Properties
Carvedilol is rapidly absorbed when administered orally with maximum plasma concentrations (Cmax) reached 1 to 2 hours after single 25 or 50mg doses in healthy volunteers and hypertensive patients. Carvedilol undergoes extensive first-pass hepatic metabolism resulting in a
low and variable absolute bioavailability of about 25%. The rate of absorption (as indicated by
a slight increase in the time to reach maximum plasma concentrations), but not the extent of
absorption, is decreased by food. Carvedilol is highly lipophilic and is widely distributed into
extravascular tissues with a volume of distribution of 1.5 to 2 L/kg in healthy volunteers. Metabolism is primarily hepatic with less than 2% of a dose excreted unchanged in urine. Some
metabolites appear to be active but whether this is of any clinical relevance is uncertain. Elimination is primarily biliary with 60% of a dose excreted in faeces. Thus, dosage adjustment in
renally impaired patients is not required. However, peak plasma carvedilol concentrations and
bioavailability are significantly increased in patients with severe hepatic impairment (e.g. cirrhosis) and the use of carvediîol in these patients is not recommended,
Therapeutic Efficacy
Data from clinical studies, analysed individually and combined in a meta-analysis, have conclusively demonstrated that carvedilol administered as a once daily 25mg dose has a significant
antihypertensive effect in patients with mild-to-moderate essential hypertension. Indeed, a metaanalysis of 36 studies reported a decrease of 16/11mm Hg in mean systolic/diastolic blood pressures after 2 to 4 weeks of once daily (25mg) treatment in patients with a baseline blood pressure
of 166/103mm Hg. No significant difference in antihypertensive effect was seen when carvedilol
50mg was administered daily as a single dose or as two 25mg doses. A 24-hour antihypertensive
effect has been observed after once daily carvedilol administration in patients treated for 24
months.
Published studies to date comparing the antihypertensive effect of carvedilol with that of other
agents have generally enrolled small numbers of patients and may not have had sufficient statistical power to detect potential differences between treatments. Nonetheless, these studies have
shown that in hypertensive patients (generally treated for 4 to 12 weeks) once daily carvedilol
25 or 50mg had a similar effect to that of once daily pindolol 15mg, atenolol 50 to l00mg,
hydrochlorothiazide 25mg, or nitrendipine 2Omg (in elderly patients), or twice daily labetalol
2OOmg, propranolol 8Omg, metoprolol lOOmg, slow release nifedipine 20 to 4Omg or captopril 25
to 5Omg. In patients who had failed to respond sufficiently to hydrochlorothiazide therapy, the
addition of carvedilol or atenolol produced a similar reduction in blood pressure after 6 weeks,
with 67% of the carvedilol group and 71% of the atenolol group achieving a diastolic blood
Carvedilol: A Review
235
pressure  90mm Hg. Other studies have demonstrated an additive antihypertensive effect when
carvedilol 25mg and either hydrochlorothiazide 25mg, slow release nifedipine 2Omg, or nicardipine 60 mg/day were given in combination. In small groups of hypertensive patients with concomitant disorders, carvedilol reduced blood pressure in those with renal failure and in patients
with non-insulin-dependent diabetes, carvedilol 25mg once daily was as effective as nifedipine
lOmg 3 times daily.
Compared with placebo, carvedilol increases exercise capacity and reduces myocardial oxygen
consumption in patients with chronic stable angina pectoris and a 25mg dose administered twice
daily has similar effects on total exercise time and time to 1mm ST-segment depression as slow
release nifedipine 2Omg administered twice daily. In addition, initial studies show that carvedilol
12.5 to 5Omg twice daily has a beneficial effect (improved exercise time and resting left ventricular
ejection fraction) in patients with chronic congestive heart failure (NYHA class II or III) secondary to ischaemic heart disease, although lower doses may be needed for safe initiation of
therapy.
Tolerability
Results of a postmarketing surveillance study in 2226 patients treated with carvedilol for 12
weeks show that a daily 25mg dose administered as monotherapy is well tolerated by most patients.
Treatment was withdrawn because of adverse events in 7% of patients; the most common adverse
events responsible for withdrawal were vertigo (1.7%), headache (1.4%), bronchospasm (0.5%),
fatigue (0.5%) and skin reactions (0.5%). Orthostatic hypotension has been reported in less than
1% of patients receiving carvedilol and has necessitated withdrawal of therapy in a few patients
treated with a  5Omg daily dose.
Dosage and Administration
Most patients with mild-to-moderate hypertension respond to an oral carvedilol dose of 25mg
administered once daily but if necessary this can be increased to 50 mg/day. All patients should
initially receive 12.5mg daily for the first 2 days of therapy, and the maximum total daily dosage
should not exceed 5Omg. The recommended dosage for elderly hypertensive patients is 12.5mg
once daily; this can be titrated (at intervals of 2 weeks) up to a maximum of 50 mg/day. In
clinical studies, most patients with stable angina pectoris or congestive heart failure received 12.5
to 50 mg twice daily.
Carvedilol is not recommended for use in patients with hepatic dysfunction due to its increased bioavaiìability. Dosage adjustment is not necessary in patients with renal impairment.
1. Pharmacodynamic Properties
Carvedilol (fig. 1) is an arylethanolamine ßadrenoceptor antagonist which appears to be weakly
selective for ß1-adrenoceptors. The compound also
has vasodilating properties, due primarily to 1adrenoceptor blockade. This dual pharmacological
activity avoids many of the unwanted effects associated with agents that produce either vasodilation (e.g. reflex tachycardia) or -blockade (e.g.
peripheral vasoconstriction). Carvedilol has no intrinsic sympathomimetic activity and weak membrane-stabilising ability (Abshagen 1987; Bristow
et al. 1992; Sponer et al. 1987a).
1.1 Adrenoceptor-Blocking Activity
1.1.1 In Vitro and In Vivo Studies Carvedilol
competitively antagonises ß1-adrenoceptormediated responses in several experimental
models: isoprenaline (isoproterenol)-in-duced
positive inotropic and chronotropic responses in
isolated guinea-pig atria (Abshagen 1987; Hofferber
et al. 1988; Kawada et al. 1990; Nichols et al.
1989a; Ruffolo et al. 1990a); isoprenaline-in-duced
relaxation in dog coronary artery ring (Hat-tori et
al. 1989); isoprenaline-induced tachycardia in
pithed rats (Ruffolo et al. 1990a), and human
cardiovascular tissues (myocardial sarcolemma,
236
Fig. 1. Structural formula of carvedilol; * the point of asymmetry.
mammary artery, digital artery, metatarsai vein)
[de Mey et al. 1992; Monopoli et al 1989; Moulds
1984].
The relative affinity of carvedilol for receptors
can be evaluated based on its pA2 value (the negative decadic logarithm of the molar concentration of antagonist required to reduce the effect of
agonist by 50%). Carvedilol demonstrated greater
 -adrenoceptor
blocking
activity
than
propranolol in isolated canine artery (pA2 values
were 9.7 and 8.8, respectively) [Hattori et al. 1989]
and was more potent (9.0) than labetalol (8.2),
dilevalol (8.3) and brefanolol (7.8) in guinea-pig
atria (Hofferber et al. 1988). In addition, the
duration of ß1-adrenocep-tor-blocking activity in
various conscious animals was greater with
carvediíol (15 to 16 hours) than brefanolol (7.6
hours), labetalol (1.5 hours) or propranolol (12
hours) [Abshagen 1987; Hofferber et al. 1988;
Sponer et al. I987a].
The following 2-adrenoceptor-mediated responses were antagonised by carvedilol: isoprenaìine-induced bronchodilation in isolated guinea-pig
trachea (Abshagen 1987; Kawada et al. 1990; Nichols et al. 1989a; Ruffolo et al. 199Oa; Sponer et
al. I987a), and salbutamol (albuterol)-induced vasodilation in pithed rats (Nichols et al. 1991; Ruffolo et al. 199Oa).
In pithed rats, a dose of carvedilol giving a submaximal antihypertensive response in conscious
spontaneously hypertensive rats produced 7-fold
greater antagonism of ß1- than ß2- adrenoceptors,
indicating weak selectivity for ß1- adrenoceptors
(Nichols et al. 1991). In another study, carvedilol
demonstrated higher affinity (between 6- and 39fold depending on the method used to assess receptor affmity) for ß1- than for 2- adrenoceptors
Drugs 45 (2) 1993
in human ventricular myocardial tissue (taken from
patients with end-stage heart failure) [Bristow et al.
1992a]. However, this result cannot be taken as an
argument to use carvedilol in asthmatic patients.
Carvedilol also antagonises 1-adrenoceptors in
vitro and in vivo (Bristow et al. 1992b; Hofferber
et al. 1988; Kawada et al. 1990; Mayer et al. 1988;
Monopoli et al. 1989; Nichols et al. 1989a, 1991;
Ruffolo et al. 199Oa; Seki et al. 1988; Sponer et al.
1987b). pA2 values ranged from 7.3 to 8.0 against
the 1 -mediated contractile response to norepinephrine (noradrenaline) or phenylephrine in aortic strips compared with 6.5 for brefanolol or labetalol, 5.6 for dilevalol (Hofferber et al. 1988) and
8.3 for the specific 1- adrenoceptor antagonist,
prazosin (Kawada et al. 1990). At equivalent ßadrenoceptor-blocking doses, carvedilol was 50%
less active as an 1 -adrenoceptor antagonist than
labetalol (Ruffolo et al. 199Oa), and between 2 and
50 times less active than prazosin depending on
the tissue studied (Kawada et al. 1990). The ratio
of 1: 1 blockade was greater for carvedilol (7.6: 1
for a 50 mg dose, 12.5 : 1 for a lOOmg dose) than
for labetalol (4.9 : 1 for a 4OOmg dose) [Tomlinson
et al. 1988]. In human myocardial tissue from undamaged hearts, the ß1: α1-receptor binding ratio
was 1 : 2 for carvedilol compared with 1 : 77 for
bucindolol, a direct-acting vasodilator (Bristow et
al. 1992a).
Carvedilol has an asymmetric centre giving rise
to 2 enantiomers (fig. 1). In vitro investigations with
the purified stereoisomers of carvedilol show that
1 -adrenoceptor blockade can be attributed primarily to the S(-)-enantiomer (Bartsch et al. 1990;
Kuwahara & Misu 1989; Nichols et al. 1989b). In
contrast, both enantiomers exhibit similar 1-adrenergic blocking activity (Bartsch et al. 1990; Nichols et al. 1989b). Thus, the maximum pharmacological effects of carvedilol can be achieved in
the therapeutic dosage range only with the racemic
mixture.
At concentrations of  l μmol/L, carvedilol
noncompetitively inhibited the 2-adrenoceptormediated vasoconstrictor response to B-HT 920 in
canine saphenous vein (Nichols et al. 1989a, 1991).
As 2-adrenoceptor-mediated vasoconstriction in
Carvedilol: A Review
this model usually depends on the translocation of
extracellular calcium, and since there is no conclusive evidence that carvedilol acts directly on 2adrenoceptors, it has been suggested that at concentrations of  1 μmol/L (which markedly exceeds
that necessary for ß-adrenoceptor blockade) carvedilol may act as a calcium channel antagonist in
vitro. Indeed, carvedilol antagonised the vasopressor response to a calcium channel activator in the
pithed rat (Nichols et al. 1991) and relaxed potassium-depolarised rat uterus (Ruffolo et al. 199Oa).
Further, carvedilol suppressed the contractile effects of potassium and BAY K8644, a calcium
channel agonist, in canine coronary artery (Hattori
et al. 1989).
Calcium channel antagonists are highly effective vasodilators in cutaneous blood vessels (Rodeheffer et al. 1983; Smith & McKendry 1982) and,
although of minor importance to its overall antihypertensive activity, calcium channel antagonism
may be responsible for carvedilol-induced vasodilation observed in some local vascular beds. Indeed, in the rat acral cutaneous microvasculature
(where vascular tone is not maintained by peripheral 1-adrenoceptors), carvedilol increased cutaneous perfusion by 64% and reduced cutaneous
vascular resistance by 57% (Ruffolo et al. 199Ob).
In contrast, at a dose producing a similar antihypertensive response, labetalol decreased cutaneous perfusion by 25% without significantly increasing cutaneous vascular resistance (Ruffolo et
ai. 199Ob).
1.1.2 Human Studies
The in vitro affinity of carvedilol for ß1, ß2~ and
1-adrenoceptors has been confirmed in human
studies. Single intravenous doses of carvedilol
(15mg) and labetalol (40 and 8Omg) antagonised
ß1- and ß2-adrenôceptor-mediated effects of isoprenaline on blood pressure and heart rate in 24
healthy volunteers during 8 hours of testing (Cubeddu et al. 1987). The 1-mediated phenylephrine-induced pressor effect was also reduced.
-Adrenergic blockade has also been demonstrated by inhibition of exercise-induced tachycardia in healthy volunteers (Tomlinson et al. 1987;
237
von Möllendorff et al. 19&6). Suppression of exercise-induced tachycardia peaked 45 minutes after
oral administration of carvedilol 5Omg or metipranolol 5 or lOmg; the effect persisted for 10 hours
following carvedilol administration, but was no
longer evident 4.5 hours after administration of
metipranolol.
1.2 Cardiovascular Effects
1.2.1 Blood Pressure and Heart Rate
The effects of single oral doses of carvedilol on
blood pressure and heart rate have been investigated in small numbers of healthy volunteers and
in patients with essential hypertension (table I).
In healthy volunteers, carvedilol 12.5 to 2OOmg
reduced resting systolic and diastolic blood pressures with little or no associated reflex tachycardia
and, when administered as a single dose,
carvedilol 25mg, labetalol 2OOmg, propranolol
4Omg or pin-dolol lOmg were equally effective
(table I).
A single carvedilol dose of 25 or 5Omg significantly lowered resting systolic and diastolic blood
pressures and heart rate in patients with essential
hypertension (table I; fig. 2). Two hours after a
single 12.5 to 25 (mean 23.6)mg dose, mean supine
blood pressure was reduced from 160/97mm Hg to
138/86mm Hg (a decrease of 13/11%) in 18 resting
hypertensive patients (Omvik & Lund-Johansen
1991). In exercising patients, mean blood pressure
was reduced from 207/115mm Hg to 179/102mm
Hg and was accompanied by a decrease of 12% in
heart rate and an increase in stroke index resulting
in a slight (6%) reduction in cardiac index (Omvik
& Lund-Johansen 1991).
In another study, maximal decreases in mean
diastolic blood pressure of 15.5, 14.7, 22.5 and 9mm
Hg occurred between 3 and 7 hours after the first
dose of carvedilol 12.5, 25, 5Omg or placebo in 44
hypertensive patients (McPhillips et al. 1988). Using intra-arterial ambulatory blood pressure recording, Heber et al. (1987) recorded a significant
reduction in systolic and diastolic blood pressure
30 minutes after a single 25mg dose of carvedilol
in 12 hypertensive patients; a maximal reduction
of 30/18mm Hg was reported after 90 minutes and
238
Drugs 45 (2) 1993
Table 1. Summary of some single dose haemodynamic studies of oral carvedilol (Car), placebo (PI) and other antihypertensive a gents
in healthy volunteers and in patients with essential hypertension
Reference
No. of
Dose (mg)
subjects
Maximum percentage change from
baseline or placebo
DBP
SBP
HR
supine
standing
supine
standing
-34*
-46*
-38*
-7*
-2
-8*
-50*
-52*
-44*
-41
-52*
-38
-5
-3
-4
-50*
-56*
-48*
supine
TPR
standing
Healthy volunteers
Louis et al.
(1987)
8a
Sundberg et
al. (1987)
13b
Tomlinson et
at. (1987)
Car 25
Car 50
Lab 200
Car 50
Pin 10
Prop 80
PI
Car 12.5
Car 25
Car 50
Car 100
Car 200
Prop 40
Prop 80
Prop 160
Prop 320
Pin 2.5
Pin 5
Pin 10
Pin 20
Lab 50
Lab 100
Lab 200
Lab 400
-5
-8
-8*
-21*
-17*
-7
-7
-6
-8*
-7
-12*
-7
-12*
-3
-8
-10
-9*
-2
-5
-8
-19*
-22*
-2
NS
-5
-3
-11
-16*
-8
-9
-4
-7
-10
-12
-13*
NS
-21*
-15*
+9
+3
NS
-2
+5
-10*
-9
-12*
-11*
-1
-9*
-8*
-6
+6
+6
+7
+3
-18*
-15*
-14
NS
NS
-16
-16
+15
+13
Patients with essential hypertension
Dupont et al.
(1987)
10
10
Eggertsen et 10
al. (1984a)
10
Leonetti et al. 12
(1987)
Omvik &
18
Lund18c
Johansen
(1991)
Car 50
PI
Car 25
Car 50
Prop 80
Car 50
Car 25d
Car 25d
-8**
-11**
-3
-8**
-13**c
-13**
-14**
-7**
-16**
-6**
9**
-6**
-10**
-3
7**
-11*
-11**
NS
-6**
-13**
-4
-7**
-10**
-24**
9**
-10C
-8**
-12**
-11*
-12**
-25**
-10
-15**
-7
-6**
a Elderly volunteers ( 60 years).
b Results obtained 2h after drug administration.
c Results from patients after exercising
d Two patients (bodyweight < 70kg) received I2.5mg
Abbreviations: SBP = systolic blood pressure; DBP = diastolic Wood pressure; HR =heart rate; TPR = total peripheral
Lab = labetalol; Pin = pindoiol; Prop = propranolol; NS = not statistically significant; ** resistance; * p < 0.05 vs placebo or other
**p < 0.05 vs baseline.
active treatment;
Carvedilol: A Review
was maintained for the following 2 hours. A small
but significant decrease in heart rate was seen 70
minutes after administration.
During dynamic exercise (100W for men, 75W
for women), carvedilol 5Omg significantly reduced
the exercise-induced increase in systolic blood
pressure and slightly (but nonsignifícantly) reduced
the tachycardia response to exercise (Leonetti et al.
1987).
In a study comparing the effects of single dose
carvedilol 25mg and metoprolol lOOmg, both drugs
reduced blood pressure significantly (p < 0.05) although this effect tended to be more pronounced
with carvedilol 2 hours after administration (Morgan et al. 1987). Mean decreases in supine blood
pressure were 17/1Omm Hg in the carvedilol group
and 10/6mm Hg in the metoprolol group. Carvediiol had no significant effect on heart rate in this
study, but metoprolol significantly (p  0.01) reduced supine and standing heart rate by 14 and 18
beats/min, respectively. Similarly, in another study
carvedilol 25 or 5Omg reduced blood pressure significantly but had little effect on heart rate whereas
a single propranolol 8Omg dose reduced supine and
standing heart rate by about 25% and had little or
no effect on blood pressure (Eggertsen et al. 1984a).
Single oral doses of carvedilol 25mg and atenolol 5Omg, given in conjunction with diuretic
therapy, produced similar reductions in supine and
standing blood pressure in hypertensive patients
with a supine diastolic blood pressure > 95mm Hg
despite at least 4 weeks of prior therapy with bendroflumethiazide (bendrofluazide) 5mg daily (data
on file, SmithKline Beecham Pharmaceuticals). A
lower dose of carvedilol (12.5mg) had significantly
less effect on supine and standing blood pressure
and produced a significantly smaller reduction in
blood pressure on standing than the 25mg dose.
Carvedilol had a similar effect on blood pressure in elderly patients and their younger counterparts. In elderly hypertensive patients (aged 65 to
80 years, baseline supine blood pressure, 185/
103mm Hg) mean peak supine blood pressure was
reduced by 40/26mm Hg (vs 23/17mm Hg in
patients aged < 50 years with a baseline supine
blood pressure of 159/100mm Hg) after a single
239
Fig. 2. Mean systolic and diastolic blood pressure (SBP and
DBF) in 18 hypertensive patients at rest or during exercise
before and 2 hours after a single oral carvedilol 12.5 to 25mg
dose (after Omvik & Lund-Johansen 1991).
12.5mg carvedilol dose and by 33/22mm Hg (vs
24/12mm Hg) after a 25mg dose (Morgan et al.
199Oa). The maximum antihypertensive response
was seen after about 4 hours. Carvedilol 25mg and
nitrendipine 2Omg daily had similar effects on supine blood pressure in elderly (aged > 60 years)
hypertensive patients (Krönig et al. 1990). Systolic
and diastolic blood pressures measured 2 hours
after the first dose were reduced from 170/105 to
about 165/102mm Hg in both treatment groups.
1.2.2 Peripheral Vascular Circulation The
antihypertensive action of carvedilol is accompanied by a pronounced fall in total peripheral
resistance in healthy volunteers; a decrease of about
34% was reported after a single 5Omg dose which
remained evident 1 week later with continued dosing (Sundberg et al. 1987). Digital plethysmography revealed carvedilol-induced peripheral vasodilation following a threshold oral dose of 15mg
with a linear increase in response (r = 0.78) up to
75mg (von Möllendorff et al. 1986). Vasodilation
was observed 30 minutes after administration and
persisted for up to 3 hours. A significant increase
in arterial blood flow (maximum 156% of baseline)
and a decrease in peripheral (forearm) resistance
24O
(maximum 34%), which peaked after 4.5 hours and
persisted for the entire 6-hour testing period, were
observed in healthy volunteers after a single oral
75mg dose. Neither metipranolol 7mg nor carvedilol 5Omg affected venous capacity or tone (von
Möllendorffetal. 1986).
Other studies have confirmed a decrease in
forearm arterial resistance following administration of carvedilol 5Omg in patients with essential
hypertension (Cournot et al. 1992; Eggertsen et al.
1984b, 1987). Wrist occlusion negated the decrease
in forearm vascular resistance in the study by
Cournot et al. but the contribution of arteriolar dilation in the cutaneous circulation to the overall
reduction in blood pressure remains unclear. No
change in brachial artery diameter was noted despite a marked reduction in blood pressure, although brachial artery tangential tension decreased
significantly (Cournot et al. 1992).
Autoregulation of cerebral blood flow appears
to be unchanged in hypertensive patients treated
with carvedilol 25mg despite a marked reduction
in mean arterial blood pressure (James et al. 1992;
Kuriyama et al. 1990). Single intravenous infusions of carvedilol 5mg or propranolol 6mg had no
significant effect on coronary arterial resistance or
coronary blood flow related to rate-pressure product in patients with coronary artery disease, indicating that neither drug interfered with the adaptation of coronary flow to myocardial oxygen
demand (Sievert et al. 1990).
In spite of a marked reduction in renal perfusion pressure, renal blood flow was unchanged after
single or multiple doses of carvedilol 5Omg (Dupont et al. 1990). As a consequence, renal vascular
resistance was decreased and autoregulation of renal
blood flow was preserved. A small but statistically
significant decrease in glomerular filtration rate
(8%) and filtration fraction (10%) occurred in hypertensive patients after a single 5Omg-dose; glomerular filtration rate was, however, preserved
during 4 weeks of treatment with carvedilol (Dupont et al. 1987).
Drugs 45 (2) 1993
1.2.3 Myocardial Function No significant changes
in stroke index or cardiac index have been reported
after single oral carvedilol 20, 4O, or 6Omg doses in
healthy volunteers (Ajima et al. 1990). Mean
cardiac index was reduced by 16% (p < 0.001) in
sitting hypertensive patients 2 hours after a single
25 mg dose and by 6% (p < 0.05) in exercising
patients. However, these reductions are markedly
less that those associated with 'pure' 0adrenoceptor
antagonists,
particularly
in
exercising patients (Omvik & Lund-Johan-sen
1991).
During long term administration, carvedilol 25
mg once daily for 6 to 9 months reduced cardiac
index by 12% (supine), 17% (sitting) and 12% (after
exercise) in hypertensive patients; after 1 year cardiac index was reduced by 5% (not significant)
[Lund-Johansen & Omvik 1992]. In another study,
a 50 mg daily dose reduced cardiac output by 20%
after 4 weeks (p < 0.01 vs pretreatment value)
without affecting left ventricular ejection fraction
(Dupont et al. 1987).
Intravenous carvedilol 15mg infused over 15
minutes had no effect on the duration of the PR,
QRS or QT intervals, but a transient fall in T wave
amplitude was noted in 2 subjects (Cubeddu et al.
1987).
Several groups have investigated the effects of
carvedilol on cardiac haemodynamics in patients
with coronary artery disease (table II). Cardiac index was not significantly altered at rest or during
exercise in patients treated with a single carvedilol
5Omg dose; in contrast, a single 4Omg dose of propranolol decreased cardiac index, particularly during exercise (13% reduction, p 0.005) [Wendt et aí.
1987]. Unlike propranolol which increased pulmonary capillary wedge pressure during exercise,
carvedilol, by virtue of its vasodilating effects, decreased this parameter by 23% (p  0.005). In another study, diastolic function (as assessed by peak
filling rate index and first-third filling fraction) improved during carvedilol administration dose dependently (Lahiri et al. 1987).
After multiple doses of carvedilol in patients
with angina (Lahiri et al. 1987) or hypertension
(Heber et al. 1987), relative end-diastolic and end-
Carvedilol: A Review
241
Table II. Summary of the effects of carvedilol (Car) on cardiac haemodynamic s and exercise capacity in patients with exerciseinduced angina pectoris
Reference
No. of
patients
Dose
(mg)
Maximum percentage change from baseline or placebo
SBP
rest
DBF
exer-
rest
cise
HR
exer-
rest
cise
RPP
exer-
rest
LVEF
exer-
cise
cise
-4
-8
-4
-8*
-12
rest
exercise
Single-dose studies
Freedman et al.
(1987)
12
Kaski et al. (1985)
15
Wendt et al.
(1987)
16
Car 25
Car 50
-2
-8
-4
-11*
+2
-2
0
At 50
Car 25
-3
-16* a
-6
_7*a
<1
-1
-8
-16*
-10*
-5
Car 50
Prop 40
-11*
+9
-3
-9
-7
+5
+1
+4
-8
-7
-4
-14*
Car 25b
Car 50b
-5*
-9*
<1
-5
-2
-10*
-2
-9*
-17
-23*
-10*
-11*
-4
-14*
-11*
-14*
Multiple-dose study
Lahiri et al.
(1989)
6
+5
+20*
+5
0
a Mean arterial blood pressure.
b Carvedilol was administered daily for 2 weeks.
Abbreviations: SBP = systolic blood pressure; DBP = diastolic blood pressure; HR = heart rate; RPP = rate pressure product;
LVEF = left ventricular ejection fraction; At = atenolol; Prop = propranolol; statistically significant difference indicated by: * p  0.05
vs placebo. Absence of symbol indicates nonsignificant change or no p -value provided.
systolic volumes and heart rate were reduced, again
suggesting that carvedilol may decrease preload (i.e.
cause venodilation) in addition to decreasing afterload. The decreased diastolic volume results in
improved left ventricular function and ejection
fraction in patients with chronic stable angina (Lahiri et al. 1987, 1989).
The effects of carvedilol on cardiac haemodynamics in patients with idiopathic dilated cardiomyopathy have been investigated (Bristow et al.
1992b; Di Lenarda et al. 1991). Carvedilol 25 or
5Omg (duration of treatment not given) improved
cardiac function, as assessed by resting left ventricular ejection fraction, and decreased cardiac, but
not systemic adrenergic drive (Bristow et al. I992b).
Carvedilol and metoprolol at the same dose
(6.25mg) significantly reduced resting heart rate in
patients with idiopathic dilated cardiomyopathy but
only carvedilol significantly reduced mean pulmonary capillary wedge pressure and systemic vascular resistance while maintaining cardiac index (Di
Lenarda et al. 1991).
Regression of septal wall thickness (from 18.7
to 16.5mm) [Eichstäedt et al. 1992] and a 17% reduction in left ventricular mass index (Why &
Richardson 1992) in patients with hypertension indicate that carvedilol induces regression in left
ventricular hypertrophy in patients with hypertension. This would contribute to a decrease in myocardial ischaemia as a result of decreased myocardial work (and therefore oxygen demand). Thus,
like other drugs with -adrenoceptor blocking
properties, carvedilol appears to preserve myocardial function and may, therefore, have additional benefits in hypertensive patients with coronary artery disease.
The effects of carvedilol on arrhythmias have
been investigated in patients with hypertension
(n=12), ischaemic heart disease (n=4l), and congestive heart failure (NYHA class II or III) secondary to ischaemic heart disease (n=12) treated
for 4 to 8 weeks with carvedilol 25 to 100 mg daily
(Senior et al. 1992). Overall, the number of premature ventricular contractions reported in 24
hours was reduced from 25 to 6 in 77% of patients,
and an improvement in Lown's criteria was seen
Drugs 45 (2) 1993
242
in 50% of all patients with the greatest improvement observed in patients with congestive heart
failure (73% improved).
1.2.4 Cardioprotective and Neuroprotecüve
Effects
There is a substantial body of evidence supporting a cardiopfotective role for ß-adrenoceptor
antagonists, in humans, these agents protect against
ischaemia-induced myocardial injury, and in animal models of hypoxia and myocardial infarction,
various parameters of damage, such as glycogen
loss, increased pH of cardiac muscle and infarct
size have been reduced by ß-blockers administered
soon after coronary artery ligation. Depending on
the animal model used, a 47 to 89% reduction in
infarct size has been reported after treatment with
intravenous carvedilol prior to occlusion (Bril et
al. 1992; Feuerstein et al. 1992; Hamburger et al.
1991; Smith et al. I992a,b; Valocik et al. 1991).
Propranolol and celiprolol, administered at comparable ß-blocking dosages, had little or no effect
on infarct size in these animal models (Feuerstein
et al. 1992). In addition, carvedilol administered
before coronary artery occlusion reduced the extent of myocardial ischaemia/reperfusion injury and
significantly improved survival in a permanent
coronary artery occlusion model of myocardial infarction (Ruffolo et al. 1992; Smith et al. 1992). In
rats it has been shown that the loss of glycogen in
myocardial tissue as a consequence of hypoxic stress
was protected to a considerably greater extent by
carvedilol than by comparable ß-blocking doses of
propranolol (Bartsch et al. 1988).
The mechanism underlying the cardioprotective
action of carvedilol is not known; however, the enhanced cardioprotective effects of carvedilol over
propranolol at similar ß-blocking doses may suggest that carvedilol possesses additional cardioprotective effects which are unrelated to ß-adrenoceptor blockade. Recent studies have shown that
carvedilol inhibits oxygen free radical-initiated lipid
peroxidation in rat brain tissue and it was an order
of magnitude more potent than other ß-blockers in
this regard (Yue et al. I992a). Further, carvedilol
prevented macrophage- and Cu2+- induced human
low density lipoprotein oxidation (a contributing
factor in the progress of atherosclerosis) in vitro via
free radical scavenging (Yue et al. 1992b). Although the clinical relevance of these findings remains to be determined, it is possible that these
properties may provide the additional cardioprotection that has been observed with carvedilol in
animal models of acute myocardial infarction
(Ruffolo et al. 1992).
Free radical generation mediates part of the ischaemic neuronal damage caused by excitatory
amino acids such as glutamate. As carvedilol has
been shown to scavenge free radicals in in vitro
models, its neuroprotective activity in in vitro and
in vivo models of brain ischaemia has been investigated (Lysko et al. 1992). Carvedilol protected
cultured cerebellar granule cell neurons against glutamate-mediated toxicity [concentration producing
50% protection (ICso) 1.1 μmol/L] and inhibited
lipid peroxidation (ICso. 5 μmol/L). More importantly, in gerbils pretreated with carvedilol 3 mg/kg
for 6 days before being exposed to global brain ischaemia and reperfusion, carvedilol-treated animals had an increased number of viable neurons
compared with untreated control animals (Lysko
etal. 1992).
1.3 Other Effects
Proliferation of vascular smooth muscle cells in
response to mitogenic stimuli derived from macrophages, endothelial cells and platelets is a major
factor contributing to the development of atherosclerosis. Carvedilol produced a concentration dependent decrease in basal and endothelin-1 induced [3H]thymidine incorporation in rat aortic
vascular smooth muscle cells over the range 0.1 to
10 μmol/L (IC50 1 μmol/L) and reduced the mítogenic response to a variety of potent smooth
muscle rnitogens (such as angiotensin II, thrombin,
epidermal growth factor, and platelet-derived
growth factor) [Sung et al. 1992]. These effects were
reversible and were not demonstrated by other ßadrenoceptors at a similar concentration level.
Further studies are needed to explain the mechanisms underlying the antiproliferative effects of
Carvedilol: A Review
carvedilol, and to demonstrate the clinical importance of such effects.
Reflex stimulation of the renin-angiotensin-aldosterone system occurring in response to a decrease in total peripheral resistance induced by pure
vasodilators may lead to fluid retention and negation of the antihypertensive effect of these drugs.
This reflex effect is suppressed via antagonism of
ß-adrenoceptor blockers; plasma renin activity and
aldosterone levels are therefore unchanged or decreased by single or multiple doses of carvedilol
(Dupont 1990; Dupont et al. 1990; Leonetti et al.
1987; Morgan et al. 1987). Fluid retention (as assessed by changes in bodyweight or urinary sodium
retention) has not been observed in patients treated
with carvedilol (Dupont et al. 1987, 1990; Omvik
et al. 1992), and blood urea nitrogen and serum
creatinine have remained unchanged (Tomita et al.
1991). In addition, levels of atrial natriuretic peptide were reduced by 27% at rest (supine) in hypertensive patients after the first dose of carvedilol,
probably as a counter-regulatory response to the
reduction in cardiac index, but no further response
was seen during long term treatment or during exercise (Omvik et al. 1992).
As a result of its ability to antagonise 2-adrenoceptors (section 1.1.1), carvedilol may be expected
to induce clinical effects resulting from this action.
While the effects of carvedilol in asthmatic patients
have not been reported, single oral doses of 25 or
5Omg had no statistically significant effects on pulmonary function [forced vital capacity (FVC),
forced expiratory volume in 1 second (FEV1),
FEV1/FVC, peak expiratory flow rate (PEFR),
and maximum expiratory flow at 50% (MEFso) and
25% (MEF25) of vital capacity] in healthy volunteers (Sundberg et al. 1987; Tiedemann & Peters
1984).
No clinically significant adverse effects have
been reported on serum cholesterol, triglyceride,
high or low density lipoprotein-cholesterol, or apolipoprotein levels in normotensive or hypertensive
subjects in clinical trials (Ehmer et al. 1988; Goto
etal. l99l;Schnurretal. 1987; Seguchi et al. 1990).
These findings have been confirmed in a meta-analysis of 36 studies in which patients received car-
243
vedilol for a median of 8 to 12 weeks (Stienen &
Meyer-Sabellek 1992). However, in a subgroup of
patients with triglyceride levels >3.9 mmol/L, carvedilol reduced triglyceride levels by 1.4 mmol/L
(Seguchi et al. 1990). In a more recent study, carvedilol 25 to 50 mg/day (n = 116) and captopril 25
to 50 mg/day (n = 117) had similar favourable effects on serum lipids in hypertensive patients with
WHO stage I or II dyslipidaemia [high density
lipoprotein (HDL)- cholesterol <l.O mmol/L].
HDL-cholesterol levels increased by about 10%,
total cholesterol levels decreased by about 10% and
triglyceride levels decreased by about 14% with both
drugs (Hauf-Zachariou et al. 1992).
Although some -blockers may produce adverse
metabolic effects in patients with diabetes, carvedilol appears to have no effect on glucose homeostasis in hypertensive patients with non-insulindependent diabetes (Albergati et al. 1992; Ehmer
et al. 1988). Neither carvedilol nor nifedipine significantly affected glucose metabolism as assessed
by the intravenous glucose tolerance test after 4
weeks of drug treatment (Albergati et al. 1992). Another study showed that after 8 weeks of twice daily
administration of carvedilol 25 to 5Omg in 89
patients with non-insulin-dependent diabetes, fasting and postprandial blood glucose levels were
maintained within a narrow range, glycosylated
haemoglobin levels (an indication of long term
blood glucose control) were unchanged, and no
hypoglycaemic episodes were reported (Ehmer et
al. 1988). There have been no published reports of
the effects of carvedilol in patients with insulindependent diabetes, although unpublished data
(SmithKline Beecham) indicate that the drug provides similar efficacy and tolerability, without affecting blood glucose, in these individuals.
1.4 Mechanisms of Action
The data summarised in previous sections indicate that carvedilol reduces systolic and diastolic
blood pressure acutely primarily by decreasing total
peripheral resistance. Cardiac function is generally
preserved and heart rate is either unchanged or decreased slightly.
Drugs 45 (2) 1993
244
Carvedilol is a ß-adrenoceptor antagonist which
exerts its vasodilating activity primarily via antagonism of peripheral 1-adrenoceptors. At concentrations higher than those needed to antagonise
ß-adrenoceptors, carvedilol may act as a calcium
channel blocker. This activity may be important in
regional vascular beds, such as the cutaneous circulation, where carvedilol (unlike other vasodilators and ß-adrenoceptor antagonists) has a potent
vasodilator effect (see section 1.2.2).
Several lines of evidence suggest that mechanisms other than 1 -blockade are involved in the
vasodilatory effects of carvedilol (Sponer et al.
1987b). Indeed, Belz et al. (1988) have shown that
carvedilol 5Omg not only attenuated the vasoconstrictive effect of noradrenaline (norepinephrine)
on human hand veins, but also decreased the effect
of prostaglandin F2, a nonadrenergic vasoconstrictor. In addition, the relatively weak occupancy
of α-adrenoceptors by carvedilol cannot fully explain the effective inhibition of prostaglandin P2induced vasoconstriction in human hand veins in
vivo when compared with the α-blocker, prazosin,
again indicating another mechanism of vasodilation (Beermann et al. 1992).
The mechanisms underlying the cardioprotective effects of carvedilol have not been fully established but it seems clear that the antioxidant and
antiproliferative effects demonstrated in vitro may
be contributing factors. Although further studies are
needed to confirm the findings of in vitro and in
vivo studies in the clinical setting, there is no doubt
that the -blockade and vasodilation, along with
the reduction in oxygen consumption, play a considerable role in the cardioprotective effects demonstrated in different experimental models.
2. Pharmacokinetic Properties
The pharmacokinetic properties of carvedilol
have been investigated in healthy volunteers and
in patients with hypertension or angina pectoris.
The influence of age and renal or hematic disease
on the disposition of carvedilol has been reported.
Carvedilol concentrations in plasma or serum
and urine have been measured using high perform-
ance liquid chromatography (HPLC) with spectrofluorometric detection which has a lower limit of
detection of 0.38 to 5 μg/L in plasma or serum and
0.82 μg/L in urine (Louis et al. 1987; Neugebauer
et al. 1990; Powell et al. 1987; Reiff 1987; Varin et
al. 1986).
2.1 Absorption and Distribution
Carvedilol is rapidly absorbed after a single oral
dose with maximum plasma concentrations (Cmax)
achieved within 1 to 2 hours (tmax) in healthy
volunteers and hypertensive patients (table III).
Peak plasma concentrations of carvedilol increased
linearly with dose and absorption was not altered
after repeated doses (McPhillips et al. 1988; Morgan et al. 199Ob; table III). Furthermore, there was
no accumulation of carvedilol during multiple dose
administration, as indicated by similar mean area
under the plasma concentration-time curve (AUC)
values compared with single dose administration
(McPhillips et al. 1988).
Although the rate of absorption was decreased
slightly when carvedilol was taken with food (tmax
increased from 0.97 to l.3h), the extent of absorption was unaffected, as shown by unchanged AUC
and Cmax values (Louis et al. 1987; table III).
After oral administration carvedilol undergoes
extensive first-pass hepatic metabolism which results in a relatively low and variable absolute bioavailability of about 25% (von Möllendorff et al.
1987).
Carvedilol is available as a racemic mixture of
its R(+)- and S(-)-enantiomers and stereoselective
differences in pharmacokinetics have been reported (Neugebauer et al. 1990). In healthy volunteers, mean AUC values for the S(-)-enantiomer
were lower than those for the R(+)-enantiomer after
intravenous and oral administration of racemic
carvedilol. The difference was greatest after oral
administration with the enantiomeric ratio (R: S)
ranging from 1.6 to 4.4 (median 2.7). The mean
maximum plasma concentraion of R(+)-carvedilol
was 2.6-fold greater than that of S(-)-carvedilol and
absolute oral bioavailability was 31% for the R(+)-
Carvedilol: A Review
245
Table I. Mean or median pharmacokinetic values reported after single (sd) or multiple oral doses of carvedilol
Reference
Healthy volunteers
Louis et al. (1987)
von Möllendorff et al.
(1987)
Hypertensive patients
McPhillips et al. (1988)
Morgan et al. (1990b)
No. of
subjects
4a
4a
6a
18
19
44
8
21C
Rudorf & Ehmer (1988)
12
Carvedilol dose
(mg)
Duration
Pharmacokinetic parameters
Cmax
(μg/L)
tmax
(h)
AUC
(μg/L·h)
t1/2
(h)
25
50
50 + food
25
50
50b
sd
sd
sd
sd
sd
sd
67
122
128
0.97
0.97
1.3
337
717
741
21
66
1.47
1.2
157
348
128
0.66
327
4.3
12.5
25
50
I2.5od
25od
5Ood
I2.5od
25od
5Ood
I2.5od
25od
5Ood
25
25 + HCTZ 25
sd
sd
sd
4w
4w
4w
2w
2w
2w
2w
2w
2w
sd
sd
39
75
161
32
75
161
58
1.3
180
410
1097
184
343
1136
225
6.5
7.9
7.0
8.3
7.8
7.6
2.3
105
189
69
151
252
72
1.3
1.75
0.9
1.0
1.3
1.8
572
208
947
1600
272
4.3
5.0
1.9
4.7
5.3
5.8
1.5
276
6.6
60
1.8
1.8
2.2
7.06
6.35
a Volunteers aged 53 to 65 (mean 61) years.
b Administered as an oral suspension.
c Patients aged > 65 years.
Abbreviations: Cmax = maximum plasma carvedilol concentration; t max = time to achieve maximum plasma concentration;
AUC = area under the plasma concentration-time curve; t½ = terminal elimination half-life; HCTZ = hydrochlorothiazide; od = once
daily; w = weeks.
enantiomer and 15% for the S(-)-enantiomer in
healthy volunteers indicating marked stereoselectivity in first-pass hepatic metabolism (Neugebauer
et al. 1990).
Carvedilol is a highly lipophilic compound
which is extensively distributed into extravascular
tissues following absorption (Varin et al. 1986). The
volume of distribution is about 1.5 to 2 L/kg in
healthy volunteeers (Cubeddu et al. 1987; Varin et
al. 1986; von Möllendorff et al. 1987). Carvedilol
is highly bound to plasma proteins ( 95%) [von
Möllendorff et al. 1987]. Binding appears to be
lower for the S(-)- enantiomer than for the R(+)enantiomer (Fujimaki et al. 199Oa) and is un-
changed in patients with hepatic disease (Neugebauer et al. 1988).
2.2 Metabolism and Elimination
Carvedilol is rapidly and extensively metabolised with less than 2% of a dose recovered as unchanged drug in urine (Neugebauer et al. 1987;
Neugebauer & Neubert 1991). Clearance is almost
exclusively via hepatic metabolism with the major
metabolites being the glucuronide conjugate, aliphatic side-chain oxidative products and aromatic
ring hydroxylated conjugates; some of these appear
to be pharmacologically active although the clinical
Drugs 45 (2) 1993
246
relevance of this has not been established (Neugebauer & Neubert 1991). About 60% of the metabolites are excreted into bile and are eliminated
in faeces with urinary recovery accounting for 16%
of metabolites (Neugebauer et al. 1987).
In hypertensive patients, the terminal phase
elimination half-life of carvedilol after oral administration ranges from about 2 to 8 hours and was
about 2 to 5 hours in elderly (aged > 65 years)
hypertensive patients (table III). Three-compartmental analysis revealed a prolonged apparent terminal elimination half-life of up to 14.5 hours after
intravenous administration (Powell et al. 1987).
2.3 Effects of Age and Disease States
Since carvedilol undergoes extensive first-pass
hepatic metabolism, it is reasonable to expect that
its pharmacokinetic profile would be altered in
patients with hepatic impairment. Compared with
healthy volunteers, patients with cirrhosis showed
a 36% decrease (36.5 vs 23.3 L/h) in plasma clearance and a 280% increase in steady-state volume
of distribution (125 vs 321 L/h; Neugebauer et al.
1988). In these patients, a significant increase in
Cmax (104.3 vs 23.7 μg/L) and bioavailability (82.6
V5 18.6%) was observed compared with healthy
volunteers but elimination half-life was unaltered
(Neugebauer et al. 1988).
As carvedilol is eliminated primarily in faeces,
renal impairment would not be expected to necessitate dosage adjustment. Indeed, in hypertensive
patients with chronic renal failure, peak plasma
concentrations and elimination half-life of carvedilol were not significantly altered compared with
values obtained in healthy volunteers (Hakusui &
Fujimaki 1988; Kramer et al. 1992). In addition,
the pharmacokinetics of carvedilol were not altered in hypertensive patients with severe chronic
renal failure who were undergoing dialysis (Miki et
al. 1991).
The pharmacokinetics of single doses of carvedilol were not significantly changed in elderly
hypertensive patients (aged 64 to 79 years) compared with their younger counterparts (Morgan et
al. 199Ob), with a tendency towards increased peak
plasma concentrations and AUC values in elderly
patients.
3. Therapeutic Efficacy
The therapeutic efficacy of carvedilol has been
investigated in patients with essential hypertension, mainly of mild-to-moderate severity. Several
studies have compared the efficacy of carvedilol
with that of other antihypertensive agents and its
use in combination therapy with a diuretic or calcium antagonist has also been reported. Most of
these clinical trials involved small numbers of
patients and may not have had sufficient statistical
power to permit fair conclusions regarding the differences between treatments.
Carvedilol has demonstrated antianginal activity in
patients with chronic stable angina pectoris and
there are preliminary clinical data indicating its
potential in the treatment of patients with congestive heart failure (NYHA class II or III) secondary to coronary heart disease.
3.1 Mild-to-Moderate Essential Hypertension
3. 1.1 Noncomparative Studies, Dose Response
Studies and Comparisons with Placebo
Several studies have shown that a daily dose
of carvedilol 25 or 5Omg significantly reduces
systolic and diastolic blood pressure in patients
with mild-to-moderate hypertension at rest or
during exercise (Eggertsen et al. 1984b, 1987;
Heber et al. 1987; Leonetti et al. 1987; LundJohansen et al. 1992; Meyer-Sabellek et al. 1987;
Morgan et al. 1987; Schnurr et al. 1987). A
diastolic blood pressure of <9Omm Hg was
achieved in 85% (73 of 86) eva-luable patients
(pretreatment diastolic blood pressure 95 to
115mm Hg) treated for 12 months with carvedilol
25 mg twice daily in a noncomparative study with
9 patients requiring dosage adjustment (50 mg
twice daily or 25 mg once daily; Schnurr et al.
1987). In a meta-analysis of 36 clinical studies
which enrolled 3412 hypertensive patients, carvedilol 25mg administered once daily reduced mean
systolic and diastolic blood pressures (measured the
morning before drug administration) by 16/11mm
Carvedilol: A Review
Hg compared with baseline (166/103mm Hg); there
was no clinically significant advantage observed in
patients who received a single 50 mg dose (mean
change from baseline 18/13mm Hg) or 25mg twice
daily (mean change from baseline 15/1Omm Hg)
[Stienen & Meyer-Sabellek 1992]. A noncomparative study which used intra-arterial ambulatory recording to measure blood pressure has shown that
after 4 weeks of treatment with carvedilol 25 or 50
mg/day systolic and diastolic blood pressures were
reduced, and that this reduction was maintained
over 24 hours (Heber et al. 1987). Mean daytime
reductions in systolic and diastolic blood pressures
were 25 and 19mm Hg, respectively, in 12 hypertensive patients; at night-time mean blood pressures decreased by 13 and 8mm Hg, respectively.
Blood pressure was reduced by 26/16mm Hg at
peak isometric exercise.
When compared with placebo over a 4-week
treatment period, carvedilol 12.5, 25 and 50 mg
daily reduced blood pressure within 2 hours of
administration and maintained supine diastolic
blood pressure below baseline levels for 24 hours
(McPhillips et al. 1988; Meyer-Sabellek et al. 1987,
1988). Trough supine diastolic blood pressures after
4 weeks of treatment were 0.6, 7.3, 8.8 and 12.1mm
Hg below baseline in patients who received placebo, or carvedilol 12.5, 25 and 5Omg daily, respectively (McPhillips et al. 1988). Daily carvedilol
doses as low as 5mg have been effective in Japanese patients, who generally require lower therapeutic dosages than Caucasian patients (Ogihara et
al. 1987, 1988). A significant antihypertensive effect (p < 0.05 vs placebo) was demonstrated in 15
patients with mild-to-moderate hypertension who
were treated with carvedilol 25 or 5Omg twice daily
for 12 months followed by 12 months of once daily
treatment (50 or lOOmg) [Meyer-Sabellek et al.
1988]. Ambulatory blood pressure monitoring revealed a persistent 24-hour reduction in systolic and
diastolic blood pressure after 6 and 12 months on
a once daily regimen; mean daily doses after 24
months were 5Omg in 20% of patients and lOOmg
in 80% of patients.
247
3.1.2 Comparisons with Other
Antihypertensive Agents
Table IV summarises the results of several studies in which carvedilol has been compared with
other antihypertensive agents. In these studies, carvedilol 25mg once daily (in some studies 5Omg once
daily was administered) had a similar efficacy to
twice daily administration of labetalol 2OOmg, metoprolol lOOmg or captopril 25 to 5Omg, and to
once daily administration of pindolol 15mg,
hydrochlorothiazide 25mg or nitrendipine 2Omg in
elderly hypertensive patients.
Carvedilol 25mg once daily, atenolol 5Omg once
daily, and slow release nifedipine 2Omg twice daily
were compared in 293 hypertensive patients (Hall
et al. 1991). Patients were randomised to receive
therapy for 12 weeks; however, if an inadequate
response was observed after 4 weeks, the daily drug
dose could be doubled. Blood pressure (measured
1 hour postdose) was reduced in all treatment
groups [by at least 20mm Hg (systolic) and 10mm
Hg (diastolic)] with no significant differences observed between treatment groups. Doubling of the
dose was necessary in 30% of carvedilol recipients
(n = 29), in 24% of atenolol recipients (n = 23) and
in 27% of nifedipine recipients (n = 25).
The effects of carvedilol 25 to 50 mg/day and
captopril 25 to 50 mg/day have been compared in
283 evaluable hypertensive patients in a multicentre study (data on file, SmithKline Beecham).
After 8 weeks there was no marked difference in
response between the treatment groups with 79%
of carvedilol recipients and 70% of captopril recipients achieving a mean sitting diastolic blood pressure of 9Omm Hg and/or reduction in diastolic
blood pressure from baseline lOmm Hg according to intention-to-treat analysis. Further analysis
revealed a greater response in elderly
hypertensive patients (aged 65 years) and in
patients with a baseline diastolic blood pressure of
95 to 105mm Hg who were treated with carvedilol
compared with those who received captopril. About
45% of patients in each treatment group had failed
to respond (mean sitting diastolic blood pressure
90 mm H g o r a r ed uc ti o n fro m b as el i ne
 1 0 mmHg) after 2 weeks and required an in-
248
Drugs 45 (2) 1993
Table IV. Double-blind studies comparing carvedilol (Car) with other antihypertensive drugs when administered with or without
concomitant diuretic therapy in patients with mild-to-moderate essential hypertension
Reference
No. of
patients
Dosage
(mg)
Duration of
treatment
(weeks)
Percentage reduction compared with placebo or
pretreatment values
systolic/diastolic BP
supine
standing
HR
supine
Patient
response
rate (%)a
standing
ß-Blockers
Eggertsen et al.
(1984b)
Lambert et al.
(1991)
Morgan et al.
(1987)
Ollivier et al.
(1990)
Rittinghausen
(1988)
Young et al.
(1992)
10
10
10
16
17
14
30
31
39
40
38
35
Car 25 bid
Car 50 bid
Prop 80 bid
Car 25 od
Lab 200 bid
Car 50 od
Met 100 bid
Car 25 od
Lab 200 bid
Car 25 od
Car 50 od
Car 100 od
Pin 15 od
47
52
Car 25-50 od
At 50-1 00 od
4
4
4
8
13
8*/7*
9*/8*
9*/9*
6»
6b
13*/13*
16*/11*
14*/18*
16*/18*
c/14
9*/7*
876*
12*/10*
4b
6b
13*/16*
10*/13*
10*
19*
20*
14
9
16*
10*
14*
15*
15*
19*
19*
19*
17*
87
87
84
c
/15
84
100
84
84
91
c/18
8
8
c/16
Nitrendipine (Nit)
Kronig et al.
(1990)
33d
31d
Car 25 od Nit
20 od
12
Car 25-50 od
Cap 25-50 bid
8
Captopril (Cap)
Data on file,
SmithKline
Beecham
141
142
17*θ
Compared with, and use in combination with, hydrochloroth¡az¡de (HCTZ)
Dupont et. al.
(1990)
Langdon et al.
(1991)
van der Does et
al. (1990)
Widman et al.
(1990)
15
87 92 54
58 59
Car 25-50 od +
HCTZ 25 od Car
25-50 ode HCTZ
25-50 ode Car
25 od + HCTZ
25 od At 50 od l· HCTZ 25 od C
25 od + HCTZ
25 od At 50 od
+ HCTZ 25 od
1.5
3* NS
22*/19*
29*/2O*
11/10
79 78
79 70
16*β13*e
7*9 19
12/9
38 53 86 88
67
8{5f
10*9 8*9
9/1 1f 9/1 Of
71 39 50
1Γ/14*9
17169
11716*9
9*9
7*/9h
a Diastolic blood pressure  90 mm Hg except in the study by Kronig et al. (1990) where < 95mm Hg was used, b
Change in mean 24-hour ambulatory blood pressure values, c No values for systolic blood pressure provided, d
Patients aged  60 years.
e Dosage was doubted to Car 50 mg/day and HCTZ 50 mg/day in 32% of carvedi!ol recipients and in 30% of HCTZ recipients in
whom mean sitting diastolic blood pressure was > 90mm Hg or had not decreased by  10mm Hg since baseline assessment, f
Measurements taken in the sitting position. „.
g Percentage change from values recorded after 4 weeks of hydrochtorothiazide monotherapy. h
Percentage change from values recorded after 4 weeks of carvedilol or atenolσl monotherapy.
Abbreviations and symbols: At = atenolol; bid = twice daily; BP = blood pressure; HR = heart rate; Lab = labetalol; Met = metoprolol;
Pin - pindolol; Prop - propranolol; od = once daily; * p  0.05 versus placebo or pretreatment values.
Carvedilol: A Review
creased dosage. After a further 6 weeks of therapy
at the higher dosage level, 46% of the remaining
carvedilol recipients and 43% of the captopril recipients had achieved a normalised sitting diastolic
blood pressure ( 90mm Hg).
Carvedilol 25mg and nitrendipine 2Omg, both
administered once daily, had(similar antihypertensive effects in elderly hypertensive patients (aged
60 years, mean baseline blood pressure 170/
105mm Hg) [fig. 3]. After 12 weeks of treatment,
supine blood pressure was reduced by 22/19mm
Hg in the carvedilol group and by 29/20mm Hg in
the nitrendipine group. Almost 80% of patients in
each group achieved a diastolic blood pressure
95mm Hg after 12 weeks of therapy (Krönig et
al. 1990).
3.1.3 Use in Combination with Other
Antihypertensive Agents
In hypertensive patients who had failed to respond to 4 weeks of hydrochlorothiazide therapy,
the addition of carvedilol produced a marked reduction in blood pressure; in 1 study, 67% of
patients who received carvedilol 25mg once daily
and 71% of patients who received atenolol 5Omg
once daily in combination with hydrochlorothiazide 25 mg/day achieved a mean diastolic blood
pressure 9Omm Hg after 6 weeks (van der Does
et al. 1990; table IV). Mean sitting blood pressure
(measured 24 hours after drug administration) was
reduced from 158/101mm Hg after 4 weeks of
hydrochlorothiazide monotherapy (25 mg/day) to
140/90mm Hg after 2 days of concomitant carvedilol I2.5mg once daily (a decrease of 18/11mm Hg)
[Dupont et al. 1990]. No further reduction in blood
pressure was seen after increasing the carvedilol
dosage to 25mg once daily for an additional 7 days.
Two other studies have investigated the efficacy
of combined therapy with carvedilol (5 to 2Omg
daily) and a thiazide diuretic in Japanese hypertensive patients (Ogihara et al. 1991; Yasujima et
al. 1988). In patients with moderate-to-severe
hypertension (diastolic blood pressure >110mm Hg
after 1 to 2 weeks of diuretic therapy), about 80%
of patients had responded (diastolic blood pressure
< 100mm Hg or had decreased by lOmm Hg) after
249
12 weeks of combination therapy (Ogihara et al.
1991). A similar response rate (74%) was seen after
8 weeks of combined therapy in patients with mildto-moderate hypertension (Yasujima et al. 1988).
In both studies a dose dependent increase in response rate was observed over the administered
dosage range (5 to 2Omg once daily).
Data obtained from 14 hypertensive patients
(mean supine diastolic blood pressure 100 to
115mm Hg) show that combined treatment with
carvedilol 25mg once daily and slow release nifedipine 2Omg twice daily has an additive antihypertensive effect (Juttmann et al. 1992). Mean peak
Fig. 3, Mean supine systolic and diastolic blood pressures
and heart rate in elderly patients with mild-to-moderate essential hypertension before and at trough after 4 and 12 weeks'
treatment with carvedilol 25 mg/day (n = 33) or nitrendipine
20 mg/day (n = 32) [after Krönig et al. 1990]; * p < 0.05
compared with pretreatment values.
250
reductions in supine blood pressure after 1 week
were 21/ 11 mm Hg with carvedilol monotherapy,
20/16mm Hg with nifedipine monotherapy, and
ranged from 26 to 40mm Hg (systolic) and 14 to
23mm Hg (diastolic) after 1, 3 and 10 days of combined treatment. Mean trough blood pressure
(measured prior to the morning dose) did not decrease significantly with either drug given as monotherapy or during combined treatment possibly because the duration of treatment in this study did
not allow the full development of antihypertensive
effects.
An earlier study showed similar results in Japanese hypertensive patients who had not responded to 4 weeks of nicardipine 60 mg/day
therapy (mean sitting blood pressure 171/
101mm Hg) [Takabatake et al. 1988], Mean blood
pressure was 156/91 mm Hg (a decrease of 15/
1Omm Hg after 2 weeks of combined therapy with
nicardipine 60 mg/day and carvedilol (mean daily
dose 8.9 mg) and was 141/85mm Hg after 12 weeks
(a decrease of 30/16mm Hg).
3.1.4 Use in Special Patient Groups
The efficacy of carvedilol has been investigated
in 9 Japanese hypertensive patients with renal failure. Systolic/diastolíc blood pressure was lowered
from 172/101 to 150/87mm Hg after 2 to 4 weeks
of therapy with carvedilol 5 to 20 mg/day (Kohno
et al. 1988). In another study, 12 of 23 hypertensive Japanese patients with renal failure (serum
creatinine level 2 mg/100ml) achieved a blood
pressure of 150/90mm Hg or a decrease of mean
arterial blood pressure of  13mm Hg after 8 weeks
of carvedilol monotherapy; 74% of patients (14 of
19) receiving carvedilol plus a diuretic achieved a
similar response (Takeda et al. 1990).
Carvedilol 25mg twice daily was more effective
at reducing blood pressure than metoprolol 5Omg
twice daily in hypertensive patients with non-insulin-dependent diabetes (Ehmer et al. 1988). After
4 weeks, 23 of the 25 patients (92%) treated with
carvedilol showed a good response to therapy (defined as a reduction of diastolic blood pressure to
<9Omm Hg) compared with 79% of patients in the
metoprolol group. After a further 4 weeks of therapy
Drugs 45 (2) 1993
in which doses were doubled in nonresponding
patients, response rates were unchanged in the carvedilol group but increased to 83% in the metoprolol group. In another study, carvedilol 25mg
once daily was as effective as nifedipine lOmg administered 3 times daily in 20 patients with noninsulin-dependent diabetes; after 4 weeks mean sitting systolic/diastolic blood pressure was reduced
by 24/7mm Hg in the carvedilol group and by 2O/
8mm Hg in the metoprolol group with no significant difference between the groups (Albergati et al.
1992). No changes in glucose metabolism (as assessed by intravenous glucose tolerance testing),
levels of glycosylated haemoglobin, the number of
hypoglycaemic episodes or the use of oral hypoglycaemic medication were observed during these
studies (see section 1.3).
3.2 Chronic Stable Angina Pectoris
The use of conventional ß-adrenergic blocking
agents in the treatment of angina pectoris is well
established. However, in patients with left ventricular dysfunction ß-blockade may produce adverse
haemodynamic consequences such as increased
peripheral and coronary resistance, and decreased
cardiac output. Thus, drugs such as carvedilol,
which produce -blockade and vasodilation, would
be expected to offer the benefits of ß-blockade (i.e.
decreased myocardial workload) without the attendant unwanted effects of myocardial and peripheral vasoeonstriction (Kelly & Freedman 1989).
Carvedilol 25 or 5Omg twice daily has been
compared with placebo in patients with a history
of stable exercise-induced angina for at least 3
months (Rodrigues et al. 1986). Within 2 weeks,
carvedilol 25mg twice daily produced clinically and
statistically significant increases in exercise performance and tolerance as indicated by increased
time to 1mm ST-segment depression, reduced
myocardial oxygen consumption [rate-pressure
product (RPP)] during exercise, and increased total
exercise time (table V). 24-Hour ambulatory
electrocardiographic monitoring indicated reductions in the total number of episodes of ST-segment depression of 57% (carvedilol 25mg) and 47%
Carvedilol: A Review
251
Table V. Summary of some studies comparing carvedilol (Car) with placebo or nifedipine (Nif) in patients with chronic stable angina
pectoris
Reference
No. of
Study
Study
Dosage
patients
design
duration
(mg bid)
(weeks)
Percentage
change from placebo
total
time to 1mm
rate-pressure
ST-segment
depression
product at
peak exercise
exercise
time
**
Placebo
Lahiri et al. (1987)
Rodrigues et al.
18
17
sb
sb
2
Car 25
2
Car 50
Car 25
+22
+16*
-19
-16
Car 50
+24
+32*
-24
Car 25
Nif 20 SR
+34*
+22*
+41*
+29*
-13*
-8*
(1986)
-12
Nifedipine
van der Does
eí al. (1991)
74
69
db, pg
4
Abbreviations and symbols: bid = twice daily; db = double-blind; pg = parallel groups; sb = single-blind; SR = slow release. Statistically
significant difference compared with placebo: * p < 0.05 level.
(5Omg) while painful episodes of angina were reduced by 92% and 62%, respectively (Rodrigues et
al. 1986). Despite the increased workload achieved,
peak exercise ST-segment depression was not altered. Doubling the dose to 5Omg twice daily had
no clear dose-related effect on total exercise time
or exercise time to 1mm ST-segment depression,
but resulted in a dose-related decrease in RPP at
maximum workload (Rodrigues et al. 1986). A
more recent study has shown that carvedilol 2Omg
once daily reduced the frequency, magnitude and
duration of ST-segment depression in Japanese
patients with exertional angina; these effects persisted for 24 hours after drug administration (Kishidaetal. 1990).
Studies comparing the efficacy of twice daily
carvedilol 25mg and slow release nifedipine 2Omg
have shown that both drugs improved exercise tolerance, time to onset of angina and time to 1mm
ST-segment depression in patients with chronic
stable angina after 4 weeks (table V). Consumption
of nitroglycerin (glyceryl trinitrate) or number of
angina attacks were similar in both groups (van der
Does et al. 1991). In another study, carvedilol appeared to maintain its effect on total exercise time
and time to 1 mm ST-segment depression over a 6month treatment period; in contrast, the greater
initial effect seen in patients receiving propranolol
+ isosorbide dinitrate (80 + 2Omg twice daily) had
disappeared after 6 months (Nahrendorf et al.
1992).
3.3 Congestive Heart Failure
-Blocking drugs have been contraindicated in
patients with uncompensated congestive heart failure because of their negative inotropic properties.
However, beneficial effects (improvement in left
ventricular performance) have been reported in
patients with congestive heart failure treated with
-blockers (Engelmeier et al. 1985; Gilbert et al.
1990; Moser 1993). Because of its dual mechanism
of action, carvedilol has potential benefits for
patients with congestive heart failure; its ß-blocking activity providing protection from the adverse
effects of sympathetic stimulation and its vasodilating activity counterbalancing any acute adverse
haemodynamic effects (Bristow et al. I992b; Olsen
et al. 1991, 1992; Ruffolo et al. 1992).
Data from 12 patients with congestive heart
failure (NYHA class II or III) secondary to ischaemic heart disease show that carvedilol 12.5 to
5Omg twice daily for 8 weeks improved exercise
time (from 4.3 to 7.1 minutes, p<0.0001) and rest-
252
ing left ventricular ejection fraction (from 27 to
31%, p<0.02) while significantly (p<0.05) reducing
total systemic resistance, heart rate and pulmonary
arterial wedge pressure compared with baseline
measurements (DasGupta et al. 1990). Exercise
ejection fraction and cardiac index were not altered
significantly and left ventricular volume tended to
decrease at rest and during exercise. The negative
inotropic effects typically seen in patients with
congestive heart failure treated with ß-blockers may
therefore be reduced with carvedilol because of its
additional vasodilating properties.
4. Tolerability
Results of a postmarketing surveillance study
involving 2226 hypertensive patients (83% of
patients received carvedilol 25mg once daily as
maintenance monotherapy) treated for 12 weeks
have shown that carvedilol is well tolerated when
administered as a once daily 25mg dose (Cauchie
et al. 1992). Adverse events caused the withdrawal
of therapy in 7% (n = 164) of patients, 3% (65)
withdrew because of lack of efficacy and 1% (20)
withdrew for other reasons. The most common adverse events causing discontinuation of treatment
were vertigo (1.7%), headache .(1.4%), and bronchospasm, fatigue and skin reactions (each 0.5%).
The incidence of adverse events appears to be
dose-related. Rittinghausen (1988) reported that 8%
of patients receiving 25mg once daily as maintenance monotherapy experienced at least 1 adverse
event compared with 31 and 29% of patients who
received 50 or lOOmg daily doses, respectively. In
longer clinical trials in which treatment was given
for at least 12 months, adverse effects appeared to
decrease with time, particularly when treatment
exceeded 2 months, in part due to the patient dropout effect (data on file, Smith-Kline Beecham Pharmaceuticals).
In patients 64 years of age, orthostatic hypotension has been uncommon (< 2% of patients) with
carvedilol, although dizziness was more common
in older subjects than in those  64 years (Moser
1993). Dizziness in the elderly has been reported
much less frequently in studies which used the
Drugs 45 (2) 1993
12.5mg once-daily regimen for the first 2 days. This
was confirmed by the previously referred to postmarketing study (Cauchie et al. 1992), in which
6.9% of patients 65 years reported adverse events
suggesting hypotension, versus 7.5% of those <65
years.
Several other adverse events have occasionally
been reported in patients treated with carvedilol in
clinical studies. These included loose stools/diarrhoea (DasGupta et al. 1992; Lahiri et al. 1987;
Rodrigues et al. 1986), dry mouth and mucosal
swelling (Meyer-Sabellek et al. 1987), depression
(Eggertsen et al. 1984b, 1987), constipation (Ogihara et al. 1987), and itching and/or rash (Ogihara
et al. 1987; Schnurr et al. 1987).
The potential of carvedilol administered at the
recommended therapeutic dosage to induce orthostatic (postural) hypotension or syncope (not uncommon in patients treated with pure vasodilators) is relatively low (<l%; data on file, SmithKline
Beecham Pharmaceuticals). In some patients transient orthostatic hypotension has occurred after the
first dose (Dupont et al. 1987; Morgan et al. 1987),
but in a few patients, most of whom received carvedilol 50 mg/day, symptoms were severe enough
to warrant discontinuation of therapy (Louis et al.
1987; Morgan et al. 199Ob; Rittinghausen 1988).
Carvedilol does not appear to cause clinically
significant alterations in laboratory values (Dupont et al. 1987, 1990; Ehmer et al. 1988; Heber
et al. 1987; Meyer-Sabellek et al. 1987; Morgan et
al. 1987; Ogihara et al. 1987; Schnurr et al. 1987;
Seguchi et al. 1990; von Möllendorff et al. 1986;
Woodward et al. 1988) or in electrocardiographic
findings (von Möllendorff et al. 1986; Ogihara et
al. 1987).
5. Dosage and Administration
Most patients with mild-to-moderate essential
hypertension respond to an oral carvedilol 25mg
dose administered once daily; this may be increased up to 5Omg in single or divided daily doses
if necessary. However, it is recommended that all
patients receive 12.5mg daily for the first 2 days
of therapy, and the total maximum daily dose
Carvedilol: A Review
should not exceed 5Omg. Elderly hypertensive
patients should receive a 12.5mg once daily dose
which can be titrated at 2-weekly intervals to a
maximum of 50 mg/day. In clinical trials, most
patients with stable angina pectoris or congestive
heart failure received 12.5 to 5Omg doses administered twice daily.
Dosage adjustment is not required in patients
with renal impairment. Although carvedilol appears to have no effect on glucose homeostasis,
patients with both insulin-dependent and non-insulin-dependent diabetes should be monitored while
receiving carvedilol because of the risk of masking
acute hypoglycaemia. Carvedilol is not recommended for patients with hepatic dysfunction and
is contraindicated in patients with third-degree
heart block, uncompensated congestive heart failure, cardiogenic shock, severe bradycardia, or
asthma.
6. Place of Carvedilol in Therapy
Patients with hypertension are frequently treated
with a combination of drugs with different mechanisms of action both to improve blood pressure
control over that achievable with monotherapy, and
to avoid the unwanted effects of individual pharmacological agents by administering lower dosages
of each drug involved. Combined use of a ßadrenoceptor antagonist and a vasodilator has been
widely accepted, both for its haemodynamic logic
and its clinical efficacy and tolerability.
Carvedilol is a ß-adrenoceptor antagonist which
also exhibits peripheral vasodilating properties,
primarily via α1-adrenergic blockade. At doses
which antagonise ß-adrenoceptors, carvedilol reduces blood pressure without the disadvantages
seen with some ß-blockers, such as compromised
blood flow to individual organs, increased total
peripheral resistance, and unfavourable metabolic
effects. Similarly, the unwanted effects of vasodilatory agents such as stimulation of neurohormonal counter-regulatory mechanisms, and retention of water and electrolytes are not observed with
carvedilol. Thus, carvedilol exhibits 2 complementary pharmacological actions which combine to
253
produce an effective antihypertensive agent with
a favourable tolerability profile (see sections 3
and 4).
In short term clinical trials in patients with mildto-moderate essential hypertension, carvedilol administered as a single daily 25mg dose markedly
lowered blood pressure primarily via a reduction
in total peripheral resistance, with only moderate
effects on heart rate or cardiac output. Comparable
antihypertensive efficacy to other 
blockers (atenolol, labetalol, metoprolol, propranolol, pindolol), nitrendipine, nifedipine, captopril and
hydrochlorothiazide has been observed. Further,
when given in combination with hydrochlorothiazide, nicardipine or slow release nifedipine an
additive antihypertensive effect was seen compared with blood pressure levels established after
monotherapy with individual agents.
In addition to its well established antihypertensive efficacy in patients with essential hypertension, its distinctive pharmacological profile makes
carvedilol useful in specific populations of hypertensive patients. Thus, in patients with renal impairment, carvedilol preserves renal function without eliciting reflex stimulation of the reninangiotensin-aldosterone system or fluid retention.
Carvedilol also does not influence glucose tolerance or carbohydrate metabolism and therefore appears suitable for the treatment of hypertensive
patients with non-insulin-dependent diabetes.
Furthermore, in vitro and animal studies have
shown that carvedilol has cardioprotective and
neuroprotective properties that may contribute to
its overall efficacy in patients with hypertension,
angina pectoris or congestive heart failure. A few
clinical studies have demonstrated the benefits of
carvedilol in patients with chronic stable angina
pectoris. While additional studies in this patient
population are warranted, results thus far indicate
that exercise tolerance and time to onset of angina
are increased, and number of anginal episodes and
consumption of nitroglycerin are reduced in
patients treated with carvedilol. ß-Adrenergic antagonists are usually avoided in patients with heart
failure as their propensity to reduce cardiac output
may be detrimental. However, preliminary data
Drugs 45 (2) 1993
254
show that carvedilol improved several measures of
left ventricular function in patients with congestive
heart failure (NYHA class II or III) secondary to
ischaernic heart disease. Thus, the use of carvedilol
with its combined vasodilating and ß-adrenoceptor
blocking properties has potential benefits in patients
with congestive heart failure; further studies are required to clearly establish the role of carvedilol in
this patient group.
A postmarketing surveillance study has shown
that carvedilol 25mg administered once daily is well
tolerated, its -adrenoceptor antagonist properties
reducing tachycardia and oedema caused by vasodilation while its vasodilatory activity reduces
myocardial depression and decreased regional blood
flow. Unlike some 'pure' ß-blockers, such as atenolol or metoprolol, carvedilol appears to have
few adverse effects on plasma lipid and lipoprotein
levels.
Thus, the pharmacological profile of carvedilol,
combining ß-adrenergic antagonism and peripheral
vasodilation primarily via 1-adrenergic blockade,
distinguishes it from most agents currently used in
the treatment of hypertension, including 'pure' ßadrenergic blockers and vasodilators. Clinical experience has confirmed the pharmacological benefits of carvedilol in patients with mild-to-moderate
hypertension and it is likely that the drug will become an alternative treatment for this disorder,
particularly in patients with other complicating
factors such as coronary heart disease, non-insulin-dependent diabetes, hyperlipidaemia or renal
impairment.
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