193

Labetalol: A Review of Its Pharmacology,

Pharmacokinetics, Clinical Uses and
Adverse Effects
E. Paul MacCarthy, M.R.C.P.I., and Saul S. Bloomfield, M.D

Labetalol is a combined alpha- and beta-adenoceptor blocking agent for oral and intravenous use in
the treatment of hypertension. It is a nonselective competitive antagonist at beta-adrenoceptors and a
competitive antagonist of postsynaptic alpha, -adrenoceptors. Labetalol is more potent at beta than at
alpha, adrenoceptors in man; the ratio of beta-alpha antagonism is 3 3 after oral and 6.911 after
intravenous administration.
Labetalol is readily absorbed in man after oral administration, but the drug, which is lipid soluble,
undergoes considerable hepatic first-pass metabolism and has an absolute bioavailability of approxi-
mately 25%. There are no active metabolites, and the elimination half-life of the drug is approximately 6
hours.
Unlike conventional beta-adrenoceptor blocking drugs without intrinsic sympathomimetic activity,
labetalol, when given acutely, produces a decrease in peripheral vascular resistance and blood pressure
with little alteration in heart rate or cardiac output. However, like conventional beta-blockers, labetalol
may influence the renin-angiotensin-aldosterone system and respiratory function.
Clinical studies have shown that the antihypertensive efficacy of labetalol is superior to placebo and to
diuretic therapy and is at least comparable to that of conventional beta-blockers, methyldopa, clonidine
and various adrenergic neuronal blockers. Labetalol administered alone or with a diuretic is often
effective when other antihypertensive regimens have failed. Studies have shown that labetalol is effec-
tive in the treatment of essential hypertension, renal hypertension, pheochromocytoma, pregnancy
hypertension and hypertensive emergencies. In addition, preliminary studies indicate that labetalol may
be of value in the management of ischemic heart disease.
The most troublesome side effect of labetalol therapy is posture-related dizziness. Other reported side
effects of the drug include gastrointestinal disturbances, tiredness, headache, scalp tingling, skin
rashes, urinary retention and impotence. Side effects related to the beta-adrenoceptor blocking effect of
labetalol, including asthma, heart failure and Raynaud’s phenomenon, have been reported in rare
instances. (Pharmacotherapy 1983;3:193-219)

OUTLINE Pharmacokinetic Properties

Animal Pharmacology Assay
Absorption
Actions at Beta-Adrenoceptors
Distribution
Actions at Alpha-Adrenoceptors
Metabolism
Blockade of Norepinephrine Uptake
Excretion
Effects of Norepinephrine Release and
Metabolism Pharmacodynamic Properties
Direct Vasodilator Action
Clinical Pharmacology
Antiarrhythmic Action
Hemodynamic Effects Actions at Beta-Adrenoceptors
Antihypertensive Effect in Hypertensive Animals Actions at Alpha-Adrenoceptors
Relative Alpha- and Beta-Adrenoceptor Blocking
Animal Toxicology
Activity
Hemodynamic Effects
Effects on Renin-Angiotensin-Aldosterone
System
Effects on Plasma and Urinary Catecholamines
From the Hypertension Program and Division of Clinical Phar- Other Endocrine and Metabolic Effects
macology and Toxicology, Department of Internal Medicine, Uni- Effects on Respiratory Function
versity of Cincinnati Medical Center.
Address reprint requests to E. Paul MacCarthy, M.B.,B.Ch.,
Effects on Body Fluid Volumes and Renal
Director, Hypertension Program, University of Cincinnati Medical Function
Center, Mail Location 565, Cincinnati, OH 45267. Electrophysiological and Antiarrhythmic Effects
194 PHARMACOTHERAPY VOLUME3, NUMBER
Clinical Uses
Essential Hypertension
Emergency Hypertension
Pheochromocytoma and Clonidine Withdrawal
Pregnancy Hypertension
Ischemic Heart Disease
Anesthetic Practice
Adverse Effects and Precautions
Dosage
Conclusions
Labetalol hydrochloride (Normodyne,’’ Schering;
Trandate,@Glaxo) is 2-hydroxy-5-[1-hydroxy-2-(1-
methyl-3-phenylpropyl) aminoethyl] benzamide hy-
drochloride; its chemical structure is shown in Figure
1. The drug is a modification of conventional beta-
adrenoceptor blocking drugs in which the isopropyl
group has been replaced by an arylalkyl substitution
and there is a salicylamide moiety on the aromatic
terminus. It has two optical centers and four possible
diastereoisomers. The labetalol used for animal and
human investigations is a mixture of equal propor-
tions of the four stereoisomers.’
Labetalol is a specific competitive antagonist at
both alpha- and beta-adrenoceptors that has been
developed for oral and intravenous use in the treat-
ment of hypertension. The drug has a number of
additional clinical applications. It has been the sub-
ject of several recent
Animal Pharmacology
Pharmacological studies of labetalol in animals
have been extensively reviewed in a number of re-
ports.7-9
Actions at Beta-Adrenoceptors
Labetalol possesses both alpha and beta-adreno-
ceptor blocking properties, but it appears to be a
more potent inhibitor at beta-adrenoceptors than al-
pha-adrenoceptor~.~.~ Its degree of potency at beta
and alpha adrenergic receptors is influenced by the
experimental conditions, with differences in animal
species or tissue preparations affecting the affinity of
labetalol for adrenoceptors. Over a range of in vitro
and in vivo animal studies, labetalol was 6-1 0 times
less potent than phentolamine at alpha-adrenocep-
tors, 1.5-4times less potent than propranolol at beta-
adrenoceptors, and 4-8 times less potent itself at
alpha than at beta-adrenoceptors.8
4, JULY/AUGUST
1983
Propranolol
OCH2- CH-CH-NH
@ dH /i dH(CH3),
Labetalol
H,NOC
Ho Q-!I- cH,- NH-c \
,CH3
CH,-CH,
Figure 1. Structural formulas of propranolol and labetalol.
Labetalol competitively inhibits the response of
beta-adrenoceptors both to exogenous catechola-
mines and to sympathetic nerve stimulation. In iso-
lated tissue preparations and intact laboratory ani-
mals, the positive inotropic and chronotropic
responses to isoproterenol are inhibited by labeta-
I o I . ~In~addition,
~ labetalol inhibits the positive chron-
otropic responsesto cardiac sympathetic nerve stim-
ulation and stimulation of spinal preganglionic
sympathetic o u t f l ~ w . ~
The beta-adrenoceptorblocking action of labetalol
is non-selective. Both beta, - and beta,-adrenocep-
tors are blocked to a similar extent and the PA, val-
ues vary from 7.05 to 8.31.’~~
Labetalol was initially reported to possess little in-
trinsic agonist activity at beta-adrenoceptors as
judged from experiments with spinal dogs and anes-
thetized dogs depleted of endogenous catechola-
mines by pretreatment with syrosingopine and from
experiments with guinea-pig atria.7s8More recent ex-
periments suggest a very small degree of intrinsic
agonist activity at beta,-adrenoceptors.lOSlight posi-
tive inotropic and chronotropic effects with labetalol
were demonstrated in guinea-pig isolated atria and
in the dog heart-lung preparation. These effects
were still present after 6-hydroxydopamine pretreat-
ment but were abolished by propranolol. However, in
anesthetized, ganglionically blocked dogs, labetalol
caused negligible changes in heart rate,loawhich in-
dicates that the drug is relatively devoid of intrinsic
beta,-sympathomimetic activity. Recent studies sug-
gest that labetalol may possess intrinsic agonist ac-
tivity at beta,-adrenoceptors, as evidenced by its
ability to inhibit spontaneous and acetylcholine-in-
duced contractions of isolated rat uteri,”, l2 and by
causing vasodilation in the hindlimb of anesthetized
dogs.lZa
A number of studies have shown that labetalol
produces effects that are consistent with a mem-
 EVALUATION OF LABETALOL
brane stabilizing action or quinidine-like effect. In
high doses (>104M) labetalol produced a direct
negative inotropic effect in isolated left atria in spinal
dogs and in anesthetized dogs pretreated with syro-
ing go pine.^,^ Labetalol also possesses two other
propertiesthat arise from membrane stabilization -
it abolishes ouabain-induced arrhythmias and is a
potent local anesthetic agent.7
Actions at Alpha-Adrenoceptors
The stimulation of alpha-adrenoceptors by exoge-
nous catecholamines or sympathetic nerve activa-
tion is competitively inhibited by labetalol, as dem-
onstrated in various isolated tissue preparations and
intact 13, l4 Alpha-adrenoceptors have
been classified into two subtypes: alpha,, which are
usually but not necessarily located postsynaptically
on smooth muscle, and alpha,, which are usually but
not invariably located presynaptically on adrenergic
nerve Alpha,-adrenoceptors mediate the
effector organ response to noradrenergic stimula-
tion, whereas alpha,-adrenoceptors mediate nega-
tive feedback inhibition of neurotransmitter release.
These subtypes of alpha-adrenoceptors are differ-
entiated by their differing sensitivity to alpha-adreno-
ceptor agonists and antagonists.I6 Labetalol ap-
pears to be a selective inhibitor of postsynaptic or
alpha,-adrenoceptors with little or no effect on the
presynaptic or alpha,-adreno~eptors.~~
Studies in the rat vas deferens have produced
evidence for a selective blocking action of labetalol
at postsynaptic alpha,-adrenocept~rs.~~ 18, l9 The
twitch response of the rat vas deferens to motor
nerve Stimulation can be inhibited by activation of
presynaptic alpha-adrenoceptors with agents such
as oxymetazoline or clonidine. This inhibitory effect
is antagonized by presynaptic alpha-adrenoceptor
blocking agents such as yohimbine, but labetalol has
no effect, indicating no presynaptic alpha-adreno-
ceptor blocking a ~ t i v i t y . ~
In guinea-pig ileum, release of acetylcholine from
postganglionic cholinergic nerves is inhibited by nor-
epinephrine released from sympathetic nerves.2o
Norepinephrine acts on alpha-receptors, thought to
be located on the cholinergic nerve terminals, and
these alpha receptors have been characterized as
alpha, in type. Labetalol in concentrations of up to 3
x loaM did not block these presynaptic alpha,-re-
ceptors, which is further evidence of its selective
blocking action on alpha,-receptors.20Labetalol has
also been shown to be ineffective in reversing the
sedation produced by clonidine in rats, an effect me-
diated through alpha,-adrenoceptors in the central
nervous system.21
Labetalol does not appear to possess intrinsic
agonist activity at alpha-adrenoceptors as judged by
its failure to cause contractions of guinea-pig mesen-
teric vein, rabbit and aortic strips and cat splenic
s t r i p ~ . l~3 However,
*~* after cardiac autonomic block-
MacCarthy and Bloomfield 195
ade with propranolol and scopolamine methylbro-
mide in conscious rabbits, labetalol produced a posi-
tive inotropic response which was interpreted as a
possible partial alpha-adrenoceptoragonist action of
the drug.,,
The alpha- and beta-adrenoceptor blockade pro-
duced by labetalol is For example, in rab-
bit aortic strips labetalol displaced the norepineph-
rine concentration-effect curve to the right by about
200 fold, but had no effect on the contractile re-
sponses to histamine, 5-hydroxytryptamine, acetyl-
choline or barium chloride. Similarly, in guinea-pig
left atrium labetalol displaced the isoproterenol con-
centration-effectcurve to the right by about 1300 fold
but had no effect on positive inotropic responses to
calcium chloride.
Although most of the alpha,-adrenoceptor block-
ing activity of labetalol is attributable to the SR ste-
reoisomer and nearly all of its beta-adrenoceptor
blocking activity resides in the RR stereoisomer,
each of the stereoisomers contributes to the overall
pharmacological profile of the drug.'
Blockade of Norepinephrine Uptake
Labetalol, in concentrations between 1OaM and
104M, produced a dose dependent increase in nor-
epinephrine overflow from isolated cat spleen after
splenic nerve tim mu la ti on.'^ This effect did not occur
in the presence of desmethylimipramine or cocaine
in concentrations that block norepinephrine uptake,
but was still observed in the presence of piperoxan in
concentrationsthat block presynaptic alpha-adreno-
ceptors. The conclusion from this study was that la-
betalol elevated neurotransmitter overflow by block-
ing uptake, and that, in the concentrations used, it
had no detectable antagonist action at presynaptic
alpha-adrenoceptors.A number of other in vitro stud-
ies have confirmed that labetalol does indeed block
uptake, although its potency in this regard varies
from one tissue to another.17
Effects on Norepinephrine Release and Metabolism
Labetalol has been shown to release [3H]from rat
anococcygeus muscle, rat ventricular tissue and dog
saphenous veins that were preloaded with -[3H]nor-
It was concluded from these studies
that labetalol releases norepinephrine from an in-
traneuronal storage site and that the norepinephrine
is subsequently metabolized by cytoplasmic mono-
amine oxidase. However, in contrast to the foregoing
studies, labetalol had no effect on the spontaneous
efflux of (-)rH] norepinephrine or its metabolites in
the cat isolated spleen.,' Thus, the ability of labetalol
to release norepinephrineor its metabolites from iso-
lated tissues appears to be dependent on the type of
experimental tissue. Furthermore, in intact animals
or man, labetalol does not appear to possess a prop-
erty for releasing n~repinephrine.'~
The effects of labetalol on the metabolism of -[3H]
norepinephrine released from adrenergic nerve ter-
196 PHARMACOTHERAPY VOLUME
3, NUMBER
minals have been studied in the isolated blood per-
fused cat spleen.27 Following stimulation of the
splenic nerves, labetalol produced a dose-depend-
ent increase in the proportion of [3H] recovered as
[3H]norepinephrineand a decrease in the proportion
recovered as the deaminated metabolite [3H] dihy-
droxyphenylethyleneglycol (DOPEG). This type of
behavior is characteristic of drugs that inhibit neu-
ronal uptake.28The drug had no detectable effect on
either the degradative enzymes MA0 and COMT, or
on extraneuronal uptake. Its effects on norepineph-
rine metabolismwould therefore appear to be due to
inhibition of neuronal uptake.
Direct Vasodilator Action
The antihypertensive action of labetalol has been
attributedto concomitant peripheral alpha- and beta-
adrenoceptor a n t a g ~ n i s mHowever,
. ~ ~ ~ ~ since its hy-
potensive effectiveness is greater than would be pre-
dicted from its alpha- and beta-adrenoceptor
blocking potency, the drug may have an additional
action.
Johnson and associates found that labetalol
caused a fall in blood pressure in anesthetized dogs
despite previous treatment with large intravenous
doses of propranolol and phent~lamine.~~ Similarly in
barium contracted rabbit portal vein strips, labetalol
caused relaxation in the presence of high concentra-
tions of propranolol and phentolamine. It was con-
cluded from these studies that the antihypertensive
effect of labetalol was via synergistic alpha- and
beta-adrenoceptorblockade plus a direct vasodilator
action.30A vasodilator effect of labetalol has also
been demonstrated in the hindlimb of anesthetized
dogs.12" Intra-arterial labetalol caused dose-related
vasodilator responses by a mechanism independent
of alpha-adrenergic blockade. The vasodilation was
probably mediated by beta,-receptor stimulation
since the responsewas inhibited by propranolol. Fur-
thermore, labetalol reduced blood pressure in anes-
thetized ganglionically blocked dogs, a preparation
devoid of neurogenic sympathetic tone and one in
which beta-blockers do not decrease blood pres-
sure. 2a
Further evidence for a direct vasodilator action of
labetalol is derived from studies in the isolated per-
fused gracilis muscle of the dog where, after alpha-
and beta-adrenoceptor blockade with propranolol
and phentolamine, intra-arterial injections of la-
betalol produced dose-related decreases in perfu-
sion pressure.31In addition, in adenalectomized, va-
gotomized spinal dogs, both labetalol and
hydralazine elicited a fall in blood pressure without
changing heart rate or cardiac output.31
Antiarrhythmic Action
Farmer and associates showed that intravenously
administered labetalol abolished both catechola-
mine and ouabain-induced arrhythmias in barbital-
4, JULY/AUGUST
1983
anesthetized dogs.7 Recently, the electrophysiologi-
cal effects of labetalol on rabbit atrial, ventricular and
Purkinje cells, in normoxia and hypoxia, were report-
ed.32Labetalol was found to possess twice the po-
tency of procaine as a local anesthetic on frog nerve
and had substantial Class 1 activity on rabbit atrial
and ventricular tissues, implying restriction of fast
inward current. The drug was also shown to abbrevi-
ate the action potential (AP) plateau in normoxic
atrial muscle but attenuated AP-shortening due to
hypoxia. A significant slowing of all phases of
repolarization (Class 3) in normoxic ventricular mus-
cle was also produced by labetalol. In addition, the
drug was shown to have no negative inotropic action
in normoxia or hypoxia, and there was no evidence
for slowing of A-V nodal conduction. The conclusion
from these studies was that labetalol could have use-
ful direct antiarrhythmic actions, in addition to any
protective effect against coronary occlusion- or re-
perfusion-induced arrhythmias that might be attrib-
uted to blockade of adrenoceptors.
In another study labetalol 2 and 5 mg/kg signifi-
cantly reduced the number of premature ventricular
contractions and the frequency of ventricular fibrilla-
tion during left anterior descending artery occlusion
in the chloralose anesthetized cat.33During reperfu-
sion in this study, labetalol 5 mg/kg failed to reduce
the number of premature ventricular contractions,
but abolished mortality due to ventricular fibrillation.
Thus, this study confirmed the antiarrhythmic effec-
tiveness of labetalol during experimental myocardial
ischemia and reperfusion and suggested that the
drug may prove to be effective in the prevention and
treatment of malignant ventricular dysrhythmias as-
sociated with acute myocardial infarction in man.
Hemodynamic Effects
The hemodynamic effects of labetalol are attribut-
able to its adrenoceptor-blocking actions,8 though
beta,-agonist and direct vasodilator activities have
also recently been shown to contribute to the overall
30 The observed responses, especially the
heart rate response, vary from one experimental sit-
uation to another, depending on the balance of auto-
nomic influences. In barbital-anesthetized dogs,
whose sympathetic tone is high and parasympathet-
ic tone is low, labetalol, like propranolol, reduced
heart rate, cardiac contractility, cardiac output and
cardiac work. These effects are attributable to beta-
adrenoceptor blockade. Labetalol, in contrast to pro-
pranolol, decreased rather than increased total pe-
ripheral resistance and produced larger falls in blood
pressure at equipotent beta,-adrenoceptor blocking
doses. These differences were attributed to periph-
eral vasodilation resulting from the vascular alpha-
adrenoceptor blocking action of labetalol. In con-
scious dogs, in which sympathetic tone is low and
parasympathetic tone high, labetalol lowered blood
pressure but, in contrast to the response in barbital-
anesthetized dogs, increased heart rate. This in-
 EVALUATION OF LABETALOL
crease in heart rate was attributed to withdrawal of
vagal tone in response to peripheral vasodilation. In
the conscious rat, labetalol had little or no effect on
heart rate despite lowering blood pressure.
In conscious rabbits, bolus intravenous injection of
labetalol produced an initial rise in left ventricular
pressure associated with a decrease in myocardial
contractility as assessed by left ventricular dP/dt.,,
Antihypertensive Effect in Hypertensive Animals
In conscious renal hypertensive dogs and DOCA
and spontaneously hypertensive rats, labetalol
caused dose-dependent falls in systolic blood pres-
sure, the heart rate being unchanged or slightly
~ a i s e d . ’The
~ ~ increase
,~~ in heart rate was attributed
to a reflex response to peripheral vasodilation.
These results were in marked contrast to those ob-
tained with propranolol, which did not lower blood
pressure in conscious hypertensive animals despite
a large fall in their heart rates. Thus, the antihyper-
tensive effect of labetalol in these models did not
appear to result from its beta-adrenoceptor blocking
action. Further studies in DOCA hypertensive rats
revealed that the antihypertensive effect of labetalol
was evident only at dose levels producing significant
alpha-adrenoceptor blockade, and the time course
of the two effects was similar.26Thus, the acute anti-
hypertensive effect of labetalol in hypertensive ani-
mals probably results from its alpha-adrenoceptor
blocking action, although an alternative or additional
action cannot be excluded. In contrast to the findings
in DOCA hypertensive rats, lower doses of labetalol
reduced blood pressure in spontaneously hyperten-
sive rats.12aThese doses (2.5and 10 mg/kg) pro-
duced only slight alpha-blockade, suggesting that a
beta,-agonist vasodilator effect may have contrib-
uted to the antihypertensive response.
Animal Toxicology
Levy and Richards have summarized the toxic ef-
fects of labetalol in various animal species.17 In the
rabbit, cat and dog, oral doses of labetalol 50 mg/kg
produced vasodilation, ptosis, reduced motor activity
and, on occasion, vomiting. These effects were at-
tributed to the known pharmacological actions of the
drug. In the mouse, oral doses of labetalol 12.5to
100 mg/kg caused slightly reduced motor activity
and ataxia, whereas in the rat 50 mg/kg orally
caused no observable effects. The oral LD, values
of labetalol in the mouse and rat exceed 2 g/kg, while
the intravenous LD, of the drug in these species is
aproximately 50-60 mg/kg.
Extensive subacute and chronic toxicity studies in
the mouse, rat and dog have failed to reveal any
evidence of toxicity from labetalol. Studies of labeta-
101 during reproduction in the rat and rabbit showed
no significant adverse effect of the drug on pregnan-
cy or on fetal development. However, autoradi-
MacCarthy and Bloomfield 197
ography of the fetuses of Dutch rabbits given radiola-
beled labetalol revealed noticeable radioactivity in
the eye.34Subsequent investigationrevealed that la-
betalol, but not is metabolites, was reversibly bound
to melanin. Since melanin occurs in the uveal tract,
specific studies, including detailed ophthalmological
and histological examinations were performed in
rats, rabbits, cats and dogs. These studies failed to
show any evidence of ocular
Mutagenicity studies of labetalol using microor-
ganisms showed no evidence of a mutagenic effect
at concentrations of the drug that were overwhelm-
ingly greater than clinically effective concentra-
t i o n ~ .Chronic
’~ studies in rats and mice have shown
no evidence of increased carcinogenicity with la-
betalol treatment.34a
Pharmacokinetic Properties
Assay
A fluorescence assay for labetalol with a limit of
detection of 20 ng/ml and a coefficient of variation of
5% was reported by Richards and
However, this procedure requires extensive glass-
ware preparation, uses a very long extraction, and is
prone to quenching, high background fluorescence
and possible interferen~e.~~ Recently, investigators
have reported methods using high pressure liquid
chromatography (HPLC) for measuring labetalol
concentrations as low as 4 ng/rr~I.~~t36a* 37, 37a These
methods appear to be more sensitive and specific
than the fluorescence assay.
Absorption
Labetalol is rapidly absorbed after oral administra-
tion in the rat, rabbit, dog, monkey and man.38
McNeill and associates39reported a very large vari-
ation in bioavailability (1 l-86%), elimination half-life
(1.7-6.1hr) and peak plasma levels of labetalol after
administrationof 100 and 200 mg doses in hyperten-
sive patients. However, this large variation is most
likely due to the relatively insensitive fluorescence
assay used rather than to intersubject variability. A
more recent study that utilized the sensitive HPLC
assay reported on the bioavailability and pharmaco-
kinetics of labetalol in normotensive This
study indicates that the pharmacokinetics of labeta-
lo1 are best described by a two-compartment open
model. After single oral dosing with a 200 mg tablet
or a 200 mg solution of labetalol, the drug was rapidly
absorbed with absorption half-lives (t,,2ka)of 0.23and
0.14 hr for the tablet and solution, respectively. Maxi-
mum plasma drug concentrations (Cmw)of 107 and
145 ng/ml were attained at 0.82 hr and 0.50 hr (T,,,=),
respectively. This report concluded that the drug IS
completely absorbed after oral administration but is
subject to extensive first pass metabolism. The ab-
solute bioavailability of labetalol was 25% in this
study.
198 PHARMACOTHERAPY VOLUME3, NUMBER
Other investigators have also reported a low sys-
temic bioavailability for labetalol that is attributable to
extensive hepatic first-pass 40 Food
ingestion appears to increase the bioavailability of
orally administered labetalol by as much as 380h.41,42
The bioavailability of labetalol is also increased by
concomitant administration of ~ i m e t i d i n e .The ~~
mechanism of this interaction has not been fully
elucidated.
There is a significant increase in both the bioavail-
ability and elimination half-life of labetalol in elderly
Indeed, a recent study confirmed that a
low dose of labetalol was effective in the treatment of
hypertension in the These findings should
be remembered when using the drug in this age
group.
Multiple-dose pharmacokinetics of labetalol have
recently been reported in hypertensive patients giv-
en the drug orally, either in a dose of 200 mg every 8
hr or 300 mg every 12 hr for 5 The individual
plasma drug concentration-time data were best de-
scribed by a two-compartment open model with first
order absorption. In both dosage regimens, labetalol
was rapidly absorbed with an absorption half-life of
0.32hr, and the maximum plasma drug concentra-
tions were attained at about one hour.
Distribution
Pharmacokinetic studies after intravenous admin-
istration of labetalol in man indicate a rapid and ex-
tensive extravascular distribution of the 39a, 40
In the study of Leitz and after intrave-
nous infusion labetalol was rapidly and extensively
distributed into the extravascular systems with a dis-
tribution half-life (tlh,) of 0.07hr, a volume of distribu-
tion of 15.7Iiters/kg, and an elimination half-life (tl,2P)
of 5.52hours. In the study of Kanto and c011eagues~~
the volume of distribution at steady state was also
relatively high, being 9.4 liters/kg. Thus, during
chronic treatment most of the labetalol is located in
the peripheral tissue compartment. This is further
supported by a low plasma protein binding of about
50?'0.~'
Chung and associates recently studied the rising
multiple dose steady-state pharmacokinetics of la-
betalol in hypertensive patients who received doses
ranging from 200 to 600 mg every 12 These
investigators found that steady-state plasma levels
of labetalol were predictable from the pharmacoki-
netic data and were reached by the third dose in
every dose level. In addition, the steady-state area
under the plasma drug concentration-timecurve dur-
ing the dosing interval increased proportionally as
the dose increased. This study showed linear phar-
macokinetics for labetalol.
Radiochemical analysis of tissues of rats, rabbits,
and dogs after injection of labeled labetalol revealed
highest concentrations of radioactivity in lung, liver
and kidney.38Negligible amounts of the drug were
found in brain and this finding was attributed to a
4,JULY/AUGUST
1983
Lipid Soluble Water Soluble
Timolol
Propranolol I Metoprolol Nadolol .
fl> Labetalol Pindolol Atenolol
) V
Figure 2. Solubility characteristics of various beta-adeno-
ceptor blocking drugs including labetalol (adapted from
reference 46).
lower degree of liposolubility for labetalol in compari-
son to propranolol which enters brain tissue more
readily. However, as shown in Figure 2,it is notewor-
thy that labetalol is more lipid soluble than most of
the other currently available beta-adrenoceptor
blockers, and this may account for its property of
large hepatic first-pass metab01isrn.~~
Metabolism
Labetalol undergoes extensive metabolism in the
gut wall and liver of animals and man after oral ad-
ministration.%Most of the drug is converted to glu-
curonides, but there are species differences in the
major routes of metabolism. In the mouse and rat,
the major urinary metabolite is o-phenyl glucuronide,
but in the dog another glucuronide predominates. In
man, labetalol is mainly metabolized to an alcoholic
glucuronide under the influence of UDP glucuronyl
transferase, but approximately 15% of a given dose
is converted to the o-phenyl glucuronide. Neither of
these metabolites shows pharmacological activity
after oral administration.
The presence of chronic liver disease has been
shown to reduce the hepatic first-pass metabolism of
labetalol, and in such instances a lower dosage may
be n e ~ e s s a r y . ~ ~
Excretion
Labetalol and its metabolites are rapidly and com-
pletely excreted in the urine and feces (via the bile) of
animals and man." In man less than 5% of a dose is
excreted unchanged in the urine.38The proportions
of radioactivity found in the urine of various species
given oral [3H] labetalol were rat 48%, rabbit 6l%,
dog 66%, Cynamolgus monkey 50%, and man
60%.17The remainderof the radioactivity was excret-
ed in the bile and appeared in the feces.
McNeil and reported a high variability
in elimination half-life (1.7to 6.1 hours) of labetalol in
hypertensive subjects, but this high variability is most
 EVALUATION OF LABETALOL MacCarthy and Bloomfield 199

likely the result of the less sensitive assay method stolic blood pressure.
employed and the duration of sampling times (0-8 There is some evidence of a relationship between
hours) from which the half-life was estimated. More steady-state plasma labetalol levels and blood pres-
recent information shows that the terminal elimina- sure control in that most, but not all, patients with
tion half-lifein normal subjects, using more sensitive lower steady-state levels on a given dose required
and specific assay methodology and a 0-24 hour higher maintenance doses to achieve blood pres-
duration of sampling times, is approximately 6.8 sure However, in the study of Sanders and
The total body clearance of labetalol in this colleagues, no correlation was found between the
study was reported to be 32.8 ml/min/kg. In hyper- steady-state concentration of labetalol and the anti-
tensive patients, the elimination half-life of labetalol hypertensive response.61In this study the degree of
was found to be about 8 ~ o u ~ s . ~ ~ ~ ~beta-adrenoceptor ~ ~ blockade, measured as isopro-
In patients with severely impaired renal function, terenol CD, paralleled the changes in plasma la-
the distribution and elimination kinetics of the drug betalol concentration.
are similar to those reported in subjects with normal After intravenous administration of labetalol 1-2
renal fun~tion.~*~ 49a These findings together with the mg/kg to hypertensive patients, a significant fall in
experience of a number of clinical studies indicate systolic and diastolic blood pressure occurs within 5
that it is unnecessary to modify the dose of labetalol minutes.62s63Joekes and Thompson reported a
in the presence of moderate or severe renal fail- maximal hypotensive response 20-40 minutes after
~re.~O. 51 intravenous infusion of labetalol 0.5-1 mg/kg over
10-20 minute
Pharmacodynamic Properties
After oral administration of labetalol to normal sub- Clinical Pharmacology
jects or hypertensive patients, a hypotensive re-
The pharmacologic properties of labetalol and the
sponse occurs within 2 hours and is maximal within 3
pure beta-adrenoceptor blocking drugs that have
52, 53 The fall in blood pressure is dose relat-
been approved for clinical use by the Food and Drug
ed and is sustained over an 8-hour period after drug
Administration are compared in Table 1.
administration. Continuous monitoring of blood pres-
sure in patients receiving labetalol has shown that
Actions at Beta-Adrenoceptors
smooth control of blood pressure is achieved
throughout a 24-hour Continuous intra- Labetalol, administered orally or intravenously to
arterial blood pressure monitoring studies have man, displaces to the right the log-dose response
shown that the drug is equally effective whether ad- curves for isoproterenol-induced increases in heart
ministered two or three times 57 Indeed rate and reductions in diastolic blood pressure.65In
Breckenridge and associates found that a single dai- addition, labetalol competitively inhibits isoproter-
ly dose was effective, but they advised that a twice enol-inducedvasodilation of superficial hand veins in
daily schedule is generally more suitable because a man.66These effects are evidence that labetalol is a
large (>1 g) single dose might sometimes cause nonselective beta-adrenoceptor antagonist.
nausea and postural h y p o t e n s i ~ nWilcox,
. ~ ~ howev- Comparison of the effects of labetalol and of pro-
er, found that a single dose of labetalol is not effec- pranolol on isoproterenol-induced responses show
tive in maintaining a lowered blood pressure over a no qualitative d i f f e r e n c e ~Both
. ~ ~ inhibitedthe effects
24-hour of isoproterenol in a similar manner, but propranolol
In the study of Richards and colleagues, a close was more potent on a weight basis. Estimates of the
relationshipwas found between the logarithm of the relative potency to antagonize both beta,- and beta,-
plasma concentration of labetalol and reductions in adrenoceptor sites fell in the range 4 - 6 1 for pro-
exercise tachycardia and in exercise systolic blood pran~lol:labetalol.~~ The dose-responsecurve of the
pressure.35In another study59a in which twelve mod- increase in cardiac output produced by graded
erately hypertensive patients received doses of la- doses of isoproterenolwas also shifted to the right by
betalol ranging from 100 to 600 mg every 12 hours, labetalol. These responses were not influenced by
log-linear relationships were shown between dose the administration of phentolamine in sufficient
and mean arterial blood pressure and also between doses to produce further alpha-adrenoceptor an-
area under the plasma concentration time curve and tagonism, indicating that the effects were due to the
mean arterial blood pressure. However, other inves- beta-adrenergic blocking action of labetalol and that
tigators have failed to show a correlation between they were not influenced by its alpha-adrenergic
the areas under the plasma labetalol concentration- blocking activity.
time curve and the corresponding area under the The rise in both heart rate and systolic blood pres-
blood pressure fall-time curve after acute oral admin- sure from vigorous physical exercise is reduced by
i s t r a t i ~ n .In~ ~
the same study, however, the fall in drugs with beta-adrenoceptor blocking properties.
plasma labetalol levels during the first hour after in- Studies performed with orally or intravenously ad-
travenous labetalol administration was inversely re- ministered labetalol have shown that there is a dose
lated to the subsequent maximal fall in supine dia- related reduction in exercise heart rate and systolic
200 PHARMACOTHERAPY VOLUME
3, NUMBER
4, JULY/AUGUST
1983

Table 1. Pharmacologic Properties of Beta-Adrenoceptor Blocking Drugs

Membrane Intrinsic
Stabilizing Sympathomi- p, -Selective Lipid
Drug Activity metic Activity Blockade Solubility
Atenolol (Tenormins) 0 0 ++ 0
Metoprolol (Lopressors) 0 0 ++ +
Nadolol (Corgards) 0 0 0 0
Pindolol (Viskens) ? ++ 0 +
Propranolol (InderaP) ++ 0 0 ++
Timolol (Blocadreng) 0 0 0 +
Labetalola (Normodyne" ,
Trandatea) + 0 0 ++
aLabetalol also has a, -adrenergic blocking activity, direct vasodilator activity, and intrinsic beta,-sympathomimetic
activity.

blood p r e ~ s u r e68. ~In~the

~ same subjects, comparing
labetalol with propranolol, similar qualitative effects
were shown, but propranolol was more potent. The
extent of the difference in potency was four to sixfold
and similar to that shown with the response to isopro-
teren01.~~ The tachycardia induced by tilting was in-
hibited by labetalol, but again propranolol was more
potent. This potency difference between labetalol
and propranolol was less marked, however, when
assessing the inhibition of the tachycardia induced
by Valsalva's maneuver.69
A recent study reported that labetalol administered
intravenouslyto man produced a significant transient
increase in blood glucose, and this response was
attributed to glycogenolysis via a beta,-agonist ac-
tion of the
Actions at Alpha-Adrenoceptors
In man, labetalol competitively antagonizes the
vasoconstrictor response of forearm veins to norepi-
nephrine.'j6In addition, the oral and intravenous ad-
ministration of labetalol inhibits the increases in
blood pressure induced by alpha-adrenoceptor stim-
ulation with phenylephrine, and linear log dose-re-
sponse curves of these increases are shifted to the
right in a parallel m ~ a n n e r . ~A~ more
, ~ ' recent study
has shown that there is a progessive decline in the
dose of phenylephrine required to induce a 20% in-
crease in systolic blood pressure during prolonged
oral labetalol treatment.71aThe investigators inter-
preted this finding to mean that there is a progressive
decline in the alpha-adrenoceptor blocking effect of
oral labetalol during chronic administration.
Although exogenously infused norepinephrine ex-
erts both alpha and beta agonist effects in man, the
predominating circulatory responses are those me-
diated through alpha-adrenoceptors. Hence, dose-
related increases in blood pressure occur that are
accompanied by reflexly-induced reductions in heart
rate and cardiac output. Labetalol competitively an-
tagonized the systolic and diastolic pressor effects
induced by norepinephrine but left the reflex reduc-
tions in heart rate and cardiac output unaffe~ted.~,
The modification by labetalol of norepinephrine-in-
duced increases in blood pressure was similar to that
observed after the administration of phent~lamine.~~
In contrast, the cardioselective beta-adrenergic
blocking drug atenolol had no effect on the increases
in blood pressure induced by norepinephrine.
The systemic administration of epinephrine to man
exerts both alpha and beta agonist effects but its
predominant effect within the circulation depends on
the dose admini~tered.~, After propranolol, epineph-
rine administration led to marked increases in systol-
ic and diastolic blood pressure accompanied by re-
ductions in heart rate and probably cardiac output.74
Administration of high doses of epinephrine after la-
betalol caused increases in diastolic pressure but the
increases in systolic blood pressure were attenuated
compared with those observed before labetalol ad-
ministration.At high dose levels of epinephrine after
labetalol, reductions in heart rate and cardiac output
occurred, and this pattern of change was similar to
that occurring after norepinephrine.
Immersing a hand in ice cold water for 60 seconds
elevates blood pressure in normal man but does not
cause other major circulatory changes. This experi-
mental procedure has been used to test alpha-
adrenoceptor blocking drugs. Propranolol adminis-
tered orally did not inhibit the cold-induced increase
in blood pressure, but labetalol administered orally in
comparable beta-blocking doses did produce a sig-
nificant inhibitory effect.75
Although a majority of studies in animals have
shown that labetalol does not appear to possess
intrinsic alpha-adrenoceptoragonist a c t i ~ i t y , l~3 .the
~,
drug has been reported to cause scalp tingling in
some patients, an effect which has been suggested
to be a sensitive index of alpha-adrenoceptor stimu-
lation.'j6I76
 EVALUATION OF LABETALOL MacCarthy and Bloomfield 201

Relative Alpha- and Beta-Adrenoceptor Blocking
Activity
The potency differences exerted by labetalol at
alpha and beta sites have also been estimated. Rich-
ards and colleagues have found that a single oral
dose of labetalo1400 mg produced a shift to the right
of the dose-response curve to isoproterenol (in-
creases in heart rate and fall in diastolic blood pres-
sure).71 Likewise, log dose-response curves to
phenylephrine (increases in systolic blood pressure)
also showed a rightward parallel displacement.
Comparing the shift of the curves, it was found that
the ratio of alpha:beta-antagonism was approxi-
mately 1 :3. When labetalol was given intravenously
the ratio was 1 :6.9.35There is no clear-cut evidence
that the ratio between alpha- and beta-adrenergic
blocking properties of labetalol changes with the
dosage of the drug.
Hemodynamic Effects
The major hemodynamic effects of labetalol in
man are a reduction in systemic arterial pressure
and total peripheral vascular resistance, without sig-
nificant alteration in either resting heart rate or cardi-
ac o ~ t p u t . This
~ ~ -pattern
~~ of effects is in contrast to
those seen after administration of drugs with beta-
adrenoceptor blocking properties alone and has
been attributed to the combined alpha- and beta-
adrenoceptor blocking properties of labetalol.
A number of studies have examined the hemody-
namic effects of acute intravenous administration of
labetalol and these studies are summarized in Table
2.w4. 78-83a Acute intravenous administration of labeta-
101 reduces blood pressure and peripheral vascular
resistance in the supine position without significantly
reducing cardiac output or stroke volume. Heart rate
is not significantly altered in the supine position but
usually falls in the standing position and during exer-
cise. There is also a tendency for labetalol to pro-
duce a decrease in cardiac output in the upright posi-
tion and during exercise. The pattern of response to
labetalol at rest is similar to that obtained with the
combination of intravenous propranololand hydrala-
zine80 or the combination of prazosin plus a beta-
adrenoceptor blocking agent.84
In the study of K o ~ hintravenous
,~~ labetalol de-
creased pulmonary artery pressures at rest in both
the supine and standing positions but had no effect
on pulmonary arterial pressures during exercise. La-
betalol, administered orally, reduced mean pulmo-
nary artery and capillary wedge pressures at rest in
the sitting position in the study by Fagard and associ-
a t e ~They
. ~ ~failed to demonstrate an effect of labeta-
lo1 on pulmonary vascular resistance and felt that
pulmonary arterioles react differently to labetalol
than systemic arterioles. On the venous side of the
circulation, labetalol seems to produce a small but
inconsistent decrease in central and peripheral ve-
nous blood pressures in patients with hyperten-
sion.81
The influence of intravenous labetalol and pro-
pranolol on the blood pressure response to isometric
and dynamic exercise was examined in a study of
young normotensive subjects.86 Labetalol, but not
propranolol, significantly decreased the hyperten-
sive responseto exercise. In another study labetalol,
but not propranolol, reduced the hypertensive re-
sponse to orgasm in female subjects.a7The increase
in blood pressure due to psychic stress is also re-

Table 2. Hemodynamic Effects of Intravenous Labetalol in Hypertensive Patients

Systemic
Reference No. Labetalol Blood Heart Cardiac Stroke Vascular
and Author Patients Dose Position Pressure Rate Output Volume Resistance
Prichard et aI8O 12 0.5 rng/kg Supine .1 -
I

--
= = 1
Joekes et aIw 14 0.5-1 rnglkg Supine 1 -
2.

--
2.
1
K o ~ h ~ ~ 13 50 rng Supine 1 - 2.

-
==

Upright 1 1 1 -
1
Exercise 1 1
- -1 -t 1
Bahlmann et a181 9 0.6-1.6 rng/kg Supine 1 -
-
-
--
-
-- .1
Svendsen et a179 10 50 rng Supine .1 -
-- 1
Upright J. 1
=
==
1
=
Exercise 1 - 1 2.

Trap-Jensen et ale* 8 0.75 rng/kg Supine 1 - 2. NR 1

Psychic Stress 1 1 .i NR =
- - 1
.1 --1
-
Agabiti-Rosei et aV3 18 100 rng Supine I

Dunn et a183a 12 0.5-1 rng/kg Supine .1 1 = -

I

45"tilt 1 -- 1 1 t
.1 = Statistically significant reduction; t = Statistically significant increase; = = No significant change; NR = Not reported.
202 PHARMACOTHERAPY VOLUME
3, NUMBER
4, JULY/AUGUST
1983

duced by labetalol, and this effect is attributed to its
alpha-adrenoceptor blocking property.88During dy-
namic forearm exercise, labetalol produced a de-
crease in forearm blood flow and an increase in cal-
culated vascular ~ e s i s t a n c eIn
. ~this
~ study, however,
labetalol produced a decrease in forearm oxygen
uptake that suggested an increase in mechanical
efficiency.
vascular resistance, without any change in cardiac
index or in left ventricular end-diastolic pressure ra-
ti0.92
There have been a number of reports on the
hemodynamiceffects of labetalol administered orally
to hypertensive subjects for periods ranging from
one week to 20 months in doses of 300 to 2400 mg
84, 94 These investigations are summa-
93v

The acute hemodynamic effects of labetalol and
propranolol were compared recently in a randomized
study in patients with angiographically proven coro-
nary artery disease.go Propranolol induced signifi-
cantly greater depression of left ventricular function
both at rest and during exercise than labetalol. This
difference was attributed to the vasodilator activity of
labetalol and the associated decrease in afterload.
The acute hemodynamic effects of labetalol in pa-
tients with coronary artery disease and stable angina
have also been examined by another group of inves-
tigator~.~’ In this study labetalol decreased resting
mean arterial pressure, heart rate and the pressure-
rate product. Cardiac output and pulmonary wedge
pressure did not change significantly, but there were
significant decreases in systemic and pulmonary re-
sistances. Coronary vascular resistance decreased,
and this was accompanied by an increase in coro-
nary sinus blood flow after labetalol administration.
Recently, Condorelli and associates also reported
that labetalol administered intravenously to patients
with coronary artery disease induced a significant
reduction in rate-pressure product and in peripheral
rized in Table 3 and show a number of consistent
findings. Blood pressure is reduced, as is heart rate
at rest supine, upright and during exercise. However,
the effects of labetalol on systemic vascular resis-
tance and on stroke volume and cardiac output are
usually, but not always, consistent. It is evident that
labetalol is capable of reducing systemic vascular
resistance under various conditions of rest and exer-
cise. A comparative study of the effects of labetalol
and propranolol on the peripheral circulation in hy-
pertensive patients has recently been
There was no significant difference between the
drugs in their effect on the blood-pressure response
to handgrip. However, compared with no treatment
labetalol attenuated the blood pressure rise at near-
maximal handgrip. Resting vascular resistance and
basal vascular tone were significantly lower during
treatment with labetalol than when the patients were
taking propranolol.
The effect of chronic oral labetalol therapy on ce-
rebral blood flow has also been in~estigated.~~ La-
betalol and a number of pure beta-adrenoceptor
blocking drugs did not reduce cerebral blood flow,

Table 3. Hernodynamic Effects of Oral Labetalol in Hypertensive Patients

Systemic Pulmonary
Duration No. Max. Dose Blood Heart Cardiac Stroke Vascular Vascular
Author (Weeks) Patients (gidaily) Position Pressure Rate Output Volume Resistance Resistance
-
~ _ _ _ _ _

Edwards 4 11 0.8 Supine 1 1 -

t -
- NR
et aIg3 Exercise 1 1 1 -
- -- NR
Mehta 1 6 1.6 Supine 1 1 = NR 1 NR
et Upright 1 1 -
I

NR 1 NR
Exercise 1 1 NR NR
--
NR
-
NR
--
Fagard 2.5 18 0.3-2.4 Supine 1 1 1 -
-
et aIg4 Upright 1 1 1 = 1 -
--
Exercise 1 1 1 t 1
Lund-Johansen 52 15 0.2-0.8 Supine 1 1 -
I

t -1 NR
et ale4 Upright 1 1 1 -
I
- NR
Exercise 1
1
1
1 -1 t
t
1
1
NR
-1
K o ~ h ~ ~ 85 9 0.6-2.4 Supine -

Upright 1 1 -
-
t 1 -

Exercise 1 1 ==
t 1 t
-
Svendsen 13 8 0.6-0.9 Supine 1 1 ==
-- --t 1 -
et a179 Upright
Exercise
1
1
1
1 1 =z -1
-
NR
t
t = Statistically significant increase; = = No significant change; 1 = Statistically Significant reduction; NR = Not reported.
 EVALUATION OF LABETALOL
despite significant reductions in blood pressure.
Effects on Renin-Angiotensin-AldosteroneSystem
Chronic oral administration of labetalol in doses
ranging from 150-2400 mg daily produced decre-
ments in both supine and upright plasma renin activ-
ity in a number of In the majority
of these studies, the net renin-suppressive ef-
fect was proportional to basal renin values and
was evident even at low doses of labetalol. The
increase in plasma renin activity that occurs
with exercise is also suppressed by oral labetalol
therapy.97 However, a number of investigators
have failed to demonstrate a significant effect of
oral labetalol therapy on resting plasma renin activ-
ity.77.lo1-lo3
Although there was no significant overall
change in plasma renin activity with labetalol, in
these latter studies there was considerable variation
in individual values. Louis and associates also failed
to show a significant effect of intravenous labetalol
on supine plasma renin activity.lol However, signifi-
cant reductions in plasma angiotensin II concentra-
tion, especially in patients with high basal values,
has been reported after acute intravenous adminis-
tration of labetalol.62v lo4
63v
Chronic oral labetalol therapy failed to produce a
significant change in plasma aldosterone concentra-
tion in a number of ~ t u d i e slo3
. ~However,
~~ Lijnen and
associatesg7found a significant decrement in plasma
aldosterone concentration with oral labetalol, as did
Trust and colleagues after intravenous administra-
tion of the d r ~ g .Urinary
~ ~ , ~ aldosterone
~ excretion
has also been reported to be suppressed by oral
labetalol therapy.w
Effects on Plasma and Urinary Catecholamines
Considerable attention has been paid to the effect
of labetalol on plasma and urinary catecholamines
since it became apparent that estimations of urinary
catecholaminesfrom labetalol treated patients could
lead to a false-positive diagnosis of pheochromocy-
toma.lo5A metabolite of labetalol, possibly 5-(1-hy-
droxy-2 aminoethy1)-salicylamide, has been impli-
cated in causing spurious elevations in urinary
catecholamines and metanephrineswhen these are
measured with fluorimetric or photometric as-
says.1oG1o8 Since fluorimetric methods may lead to
false-positive findings, it has been recommended
that either urinary vanillylmandelicacid (VMA) or uri-
nary 4-hydroxy-3-methoxymandelic acid (HMMA),
and not catecholamine or metanephrine excretion,
should be measured when screening for pheo-
chromocytoma in patients who are being treated with
labetalo1.106-log
When specific methods for catecholamineestima-
tion, such as high-pressure liquid chromatographic
or radioenzymatic techniques, are employed, chron-
ic oral treatment with labetalol does not increase
plasma or urinary norepinephrineor epinephrine lev-
e l ~ The . study~ of Kornerup
~ ~ and ~col-
MacCarthy and Bloomfield 203
leagues, in contrast to the foregoing investigations,
found that chronic oral treatment with labetalol in
doses ranging from 300-2400 mg daily produced a
decrease in plasma norepinephrine but no signifi-
cant change in plasma epinephrine concentration.l12
However, in this study patients received concurrent
treatment with furosemide.
Alter acute intravenous administration of labetalol
in hypertensive patients, mean supine plasma epi-
nephrine and norepinephrine levels rose to maxi-
mum values at 2 and 10 minutes after injection re-
spectively, but the increases were not statistically
significant.lol Dunn and c011eagues~~~ found that
plasma norepinephrine rose significantly after intra-
venous administration of labetalol to patients with
essential hypertension. A recent study compared the
effects of acute intravenousadministrationof labeta-
lo1 and nitroprusside and found that labetalol pro-
duced a greater rise in plasma norepinephrine rela-
tive to the fall in mean arterial pressure compared
with nitropr~sside.~~~ It was felt that this dispropor-
tionate effect of labetalol may limit its antihyperten-
sive efficacy. In two other reports, acute intravenous
administration of labetalol increased plasma norepi-
nephrine in the supine position, when standing, dur-
ing exercise and during psychic 11’ Plasma
epinephrine was increasedonly in the standing posi-
tion and during psychic stress. Agabiti-Rosei and
colleagues have reported that the reduction in blood
pressure after intravenous and oral labetalol treat-
ment is more pronounced when basal pretreatment
plasma norepinephrine levels are high.83
Other Endocrine and Metabolic Effects
The effect of intravenous labetalol on a number of
other endocrine and metabolic functions in hyperten-
sive subjects has been studied.l16 Plasma glucose
rose significantly after labetalol administration, while
no changes were observed in serum free fatty acids,
insulin, C-peptide and growth hormone levels. Al-
though the reason for the increase in plasma glucose
was not apparent, the authors felt that it may be
related to the rise in norepinephrine levels observed
after intravenous labetalol. Another investigator also
reported a significant increase in plasma glucose
concentration after intravenous labetalol that was
not attributable to the hypotensive effect of the drug,
but was possibly due to increased glycogenolysis
from a beta2-adrenoceptoragonist action of labeta-
loL7O Other investigators, however, have failed to
demonstrate a significant increase in blood glucose
level after intravenous labetalol administration.83a
Oral administration of labetalol300-1200 mg daily to
hypertensive males for 4 weeks was reported to pro-
duce a small increase in mean fasting blood glucose
level but no alteration in insulin activity or response
to an oral glucose tolerance test.’l7
~ In the
~ study~ of Barbieri
~ ~ ~ ~
and colleagues,116 ~
Serum
204 PHARMACOTHERAPY VOLUME
3, NUMBER
prolactin concentration was significantly increased
after intravenous labetalol administration, with the
increase being more marked in female subjects.
Subsequent studies by this group of investigators
failed to demonstrate an effect of oral labetalol on
serum prolactin, but suggested that the hyperprolac-
tinemia after intravenous labetalol is mediated inside
the blood-brain barrier.l18The effect of labetalol on
serum gastrin has also been studied, and infusion of
the drug produced no change in fasting serum gas-
trin levels, but did lower basal and pentagastrin-stim-
ulated gastric acid output.llg
The effects of labetalol on blood lipids in a large
group of normal volunteers has been reported in a
comparative study versus the beta-adrenoceptor
blocking agent oxpreno101.120Both labetalol and ox-
prenolol reduced serum cholesterol levels. The
drugs had no significant effect on HDL cholesterol
levels, so that the total cholesteroVHDL cholesterol
ratio was significantly decreased. Changes in serum
triglyceride levels after both labetalol and oxprenolol
administrationwere slight and did not reach statisti-
cal significance. In another study in 10 hypertensive
subjects, treatment with labetalol300-1200 mg dai-
ly for 4 months produced no change in total serum
cholesterol and triglycerides, whereas there was an
increase in the VLDL-TCTTG ratio.121Another group
of hypertensive patients treated for 12 months with
labetalol showed falls in mean plasma triglyceride
and total cholesterol concentrations, but the
changes were not significant.Iz2Frishman and asso-
ciates performed a double-blind randomized place-
bo-controlledcomparison of labetalol and metoprolol
in 70 hypertensive patients and reported the effects
of each drug on plasma lipid 1 e ~ e l s .Four
l ~ ~ months
therapy with labetalol(300-1200 mg daily) produced
no significant alteration in fasting plasma cholester-
ol, triglyceride, HDL-cholesterol, LDL-cholesterolor
the HDUtotal cholesterol ratio. Thus, long-term ad-
ministrationof labetalol appears to have no unfavor-
able effects on plasma lipid levels.
A recent study123a reported an influence of labeta-
lo1on the prostaglandin system. Prolonged oral ther-
apy with labetalol caused a reduction in previously
elevated plasma levels of the prostacyclin metabolite
6-keto-PGF1, but no effect on plasma thromboxane
beta, concentration in patients with essential hyper-
tension.
Effects on Respiratory Function
Because of its non-cardioselective beta-adreno-
ceptor blocking property, labetalol might be antici-
pated to produce adverse respiratory effects in pa-
tients with chronic obstructive pulmonary disease.
However, since alpha-adrenoceptors in the human
lung may be important in the pathogenesis of bron-
choconstriction under certain circumstances, it is
possible that the alpha-adrenoceptor blocking prop-
erty of labetalol could mitigate some of the potential
adverse respiratory effects due to its beta-adreno-
4, JULY/AUGUST
1983
ceptor blocking action. A number of studies in
healthy subjects failed to show reductions in forced
expiratory volume in 1 second (FEV,) or resting and
post-exercise peak expiratory flow rates after labeta-
101 therapy, despite considerable reductions in these
parameters after propranolol a d m i n i s t r a t i ~ nlZ5. ~ In
~~~
addition, labetalol failed to enhance the fall in FEV,
induced by inhaled histamine, whereas such an en-
hanced response was seen after propranolol admin-
i ~ t r a t i 0 n .Comparisons
l~~ have also been made in
healthy subjects of the bronchial and cardiac beta-
adrenoceptor blocking effects of labetalol, atenolol
and acebutolo1.126 Bronchial beta-adrenoceptor
blockade was assessed after each drug as the dose
of albuterol (salbutamol) needed to cause a 50%
increase in specific airway conductance. Acebutolol
100 mg and 200 mg and labetalol 150 and 300 mg
produced more bronchial beta-adrenoceptor block-
ade than atenolo150 mg and 100 mg. In open studies
in hypertensive patients given intravenous labetalol
1 or 2 mg/kg or oral labetalol300,600 and 1200 mg
on consecutive days, there was no significant
change in peak expiratory flow
In a study in asthmatic patients, there was no sig-
nificant change in resting FEV, after labetalo120 mg
intravenously or placebo, but there was a significant
reduction after 5 mg of propran0101.~~~ In this study
there was no significant difference between the treat-
ments with respect to the response to albuterol 200
pg given one hour after the drug. Another study com-
pared the effects of single doses of labetalo1300 mg
and atenolol 100 mg on airways obstruction in pa-
tients with hypertension and asthma.lZga There were
no significant differences between the effects of
these drugs on F.E.V.,. However, when compared
with placebo, labetalol significantly reduced the ef-
fect of inhaled albuterol (salbutamol) on F.E.V.,.
The effect of labetalol on lung function in hyperten-
sive patients with chronic obstructive pulmonary dis-
ease has been compared to that of propranolol,
atenolol and metopr0101.~~~ In this study, which em-
ployed drug dosages that produced similar blood
pressure decrements, propranolol was the only drug
that significantly increased airways obstruction as
meaured by FEV,, forced vital capacity and specific
airways resistance. Two other studies also failed to
demonstrate adverse respiratory effects during oral
labetalol treatment in patients with chronic obstruc-
tive pulmonary disease coexistent with hypertension
or angina.131, I3la
In a recent randomized, double-blind comparison
of labetalol and verapamil in hypertensive patients
with coexisting chronic obstructive airways disease,
labetalol but not verapamil produced a significant
reduction in FEV, and forced vital capacity.132In a
comparative study of labetalol and propranolol in hy-
pertensive patients without obstructive airways dis-
ease, both drugs produced impairment of pulmonary
function, but propranolol caused a greater reduction
than labetalol after 8 weeks of
In an open study of labetalol that included 54 pa-
 EVALUATION OF LABETALOL
tients with a known history of bronchospasm, bron-
choconstrictionnecessitating withdrawal from the tri-
al occurred in 9 of them ( 1 6.6Y0).'~~ This compared
with an overall withdrawal rate of 7.2%. Thus, it
would seem prudent to avoid using labetalol in pa-
tients with clinically overt reversible airways obstruc-
tion.
Effects on Body Fluid Volumes and Renal Function
Labetalol monotherapy (300-1 200 mg daily) in 12
patients with essential hypertension for a period of
4-1 5 weeks produced insignificant increases in
plama volume and extracellular fluid
contrast, Weidmann and colleagues found that la-
betalol, given alone in increasing doses during a 6-
week period, produced increases in body weight,
plasma volume and blood volume of 1.7,21 and 17%
respecti~ely.~~ Another study also found an increase
in plasma volume (of 294 ml) after 8 weeks of labeta-
lo1 monotherapy (average daily dose 585 mg) in 13
patients with essential hypertension.136Propranolol
monotherapy, in contrast, failed to increase plasma
volume in this study. Thus, it seems likely that fluid
retention can occur during monotherapy with labeta-
101 and that addition of diuretics is a rational approach
in the event of an inadequate blood pressure re-
sponse.
A number of investigators have shown that short-
or long-term administration of labetalol to patients
with essential hypertension is not associated with a
reduction in glomerular filtration rate or renal plasma
137-142 This is in contrast to reports of a reduc-
tion in renal plasma flow and glomerular filtration rate
with chronic propranolol admini~trati0n.l~~ The lack
of reduction in renal blood flow during labetalol ther-
apy may be related to alpha-adrenoceptor blockade
in the renal vasculature or a lesser reduction in cardi-
ac output compared with propranolol therapy. The
only study which conflicts with the foregoing findings
is that of Keusch and colleagues who found that
labetalol monotherapy (mean daily dose 1459 mg)
for 6 weeks produced decreases in renal plasma
flow and glomerular filtration rate of 21 and 16.6%
respectiveIy.ll0Labetalol has been used successful-
ly in patients with chronic renal failure and hyperten-
sion. In the study by Bailey,5146 of 51 patients with
renal impairment, including 5 patients with renovas-
cular disease, responded to labetalol with a fall in
average standing blood pressure from 176/112 to
138/89 mm Hg. The drug has not been implicated in
producing a deterioration in renal function in such
patients.51,138,141.144
Electrophysiologicaland Antiarrhythmic Effects
The electrophysiological effects of intravenous la-
betalol were studied by His bundle electrocardiog-
raphy in 12 patients who had normal left ventricular
function and no clinical or electrocardiographic evi-
dence of significant conducting system disease.145
Labetalol had inconsistent effects on AV nodal re-
MacCarthy and Bloomfield 205
fractoriness but slightly prolonged the AV nodal con-
duction time and atrial effective refractory period,
with only small changes in heart rate. No effect on
the His Purkinje system was noted. The effects on
sinus cycle length and sinoatrial conduction time
were small and variable. Thus, labetalol appears to
have less effect on the AV node than propranolol,
atenolol and acebutolol, while having more effect on
the atrium than propranolol and acebutolol, but less
than that of a t e n o I 0 1 . ' ~It~ remains
~~~ to be seen
whether the electrophysiological properties of la-
betalol are modified by ischemia or are different in
patients with conducting system disease.
In
A recent study confirmed the antiarrhythmic effec-
tiveness of labetalol in man.149Labetalo1800 mg dai-
ly was administered to 10 patients with essential hy-
pertension and frequent premature ventricular
contractions (PVCs). The drug significantly lowered
blood pressure and produced a significant reduction
in PVCs after 2 weeks therapy, with a nearly com-
plete extinction of PVCs at the end of the fourth week
of treatment. There has also been a recent report
that intravenouslabetalol was successful in restoring
sinus rhythm in approximately 80% of patients with
severe hypertension and a variety of dysrhyth-
rnias.l5OThus, labetalol appears to have potential as
an antiarrhythmic agent in man.
Clinical Uses
Essential Hypertension
There is now considerable experience with the use
of labetalol in the treatment of essential hyperten-
~ i o n .151-153
~ ~ . A variety of studies using both fixed and
titrated doses of labetalol found the drug to be at
least as effective in lowering blood pressure as a
wide range of other antihypertensive agents, admin-
istered alone or in combination. Many studies have
shown that labetalol administered alone, or with a
diuretic, is often effective when other regimens, in-
cluding beta-blockers, have failed.15"159Between
60-80% of severe (diastolic blood pressure >120
mm Hg) and previously uncontrolled hypertensives
responded satisfactorily to labetalol, as did up to
88% of mild to moderate hypertensives in a recent
large series.153
Labetalol in both fixed dose and individually titrat-
ed doses has been compared with placebo in sever-
al investigation^.^^, lo7*1 6 w 2 The majority of these
studies showed a significant antihypertensive effect
for labetalol compared with placebo, and a dose re-
lated fall in blood pressure during labetaloltreatment
has been well documented.lo2-160 A number of com-
Darative studies of labetalol and diuretics have been
conducted and the majority have shown labetalol
to be equivalent or superior to thiazide diuretics in
relation to antihypertensive efficacy.lmslm The ad-
dition of labetalol to a diuretic regimen produces a
further dose related fall in blood pressure (see Fig-
ure 3).16"166
206 PHARMACOTHERAPY VOLUME3, NUMBER
4, JULY/AUGUST
1983

160

150

T
140 T m
130

1m
A

I"
E
g 110

i
tE 100

P=
ul
s
100
2
5aa
80 9 0 1
t tt t

Figure 3. Standing blood pressure and heart rate responses to 50 mg/day hydrochloro-
thiazide (HCTZ) alone and hydrochlorothiazide plus incremental doses of labetalol in 8
patients with essential hypertension (reference 165).

There are now several published studies compar-
ing labetalol directly with other beta-adrenoceptor
blocker^.^^^^ 167-175a Pugsley and associates per-
formed a between patient comparison of labetalol
and propranolol in 18 previously untreated patients
with severe hyperten~ion.'~~ They reported that la-
betalol and propranolol produced similar decreases
in supine blood pressure, but that labetalol produced
a greater decrease in standing pressure and less
bradycardia. Nicholls and c011eagues~~~ compared
labetalol (maximum dose 2400 mg daily) and pro-
pranolol (maximum dose 960 mg daily) in a random-
ized crossover study in 24 hypertensive patientswho
were receiving thiazide diuretic therapy. In this study
the antihypertensiveeffect of labetaloland proprano-
lo1 were comparable, but labetalol was associated
with a higher frequency of side effects. Three pa-
tients (13%) were not controlled with the maximum
 EVALUATION OF LABETALOL
dose of labetalol, and four (17%) with the maximum
dose of propranolol. Hunyor and dem-
onstratedthat the antihypertensive effect of labetalol
(averagedaily dose 585 mg) was greater than that of
propranolol (average daily dose 234 mg). H a r ~ a l d ’ ~ ~fective as the combination in lowering blood pres-
reported that labetalol 100 mg could be substituted
for propranolol40 mg in 18 patients who were receiv-
ing multiple drug regimens, without significant loss of
blood pressure control.
Comparative studies of labetalol and pindolol have
shown similar blood pressure control and a similar
frequency of side effects.170* 174 A variable dose com-
parative trial of atenolol, pindolol, labetalol and meto-
prolol found similar blood pressure control for all four
The pattern of reported side effects was
similar, but numerically less, with labetalol than aten-
0101, metoprolol or pindolol. In a recent double-blind
crossover in patients with essential hyper-
tension, labetalol200-600 mg twice daily was some-
what more effective in lowering upright blood pres-
sure than atenolol 50-150 mg twice daily. A fixed
dose double-blind crossover study of labetalol and
alprenolol reported a greater antihypertensive re-
sponse to labetalol, but this was counterbalanced by
a higher frequency of side effects.’72The foregoing
comparative studies indicate that labetalol is as
effective an antihypertensive agent as pure beta-
adrenoceptor blocking drugs and in some instances
is superior, especially when standing blood pressure
measurements are being compared.
Labetalol has also been compared with the combi-
nation of beta-adrenoceptorblockers plus direct-act-
ing vasodilators. Barnett and per-
formed a double-blind comparative study in mild to
moderately severe hypertensives and found that la-
betalo1600 mg twice daily was approximately equiv-
alent to pindolol 15 mg twice daily plus hydralazine
150 mg daily. In a fixed-dose randomized study,
West and c011eagues~~~ found that labetalol 600 mg
daily was as effective as propranolol 160 mg daily
plus hydralazine 100 mg daily in lowering standing
blood pressure, but that the combination reduced
supine blood pressure more effectively. In a recent
randomized crossover trial, labetalol plus hydro-
chlorothiazide was compared with the combination
of propranolol, hydralazine and hydrochlorothia-
~ i d e . The
’ ~ ~ study concluded that labetalol plus
hydrochlorothiazide was as effective as the other
combination in the treatment of uncomplicated hy-
pertension. Two other studies compared labetalol
with the combination of beta-adrenoceptor blockers
plus dihydra1a~ine.l~~-Labetalol produced equiv-
alent reductions in standing but not in supine blood
pressure, as did the combination therapy.
Comparative studies of labetalol and the combina-
tion of alpha- and beta-adrenoceptor blocking drugs
have also been performed. In one study labetalol
produced significantly greater reductions in supine
and standing blood pressure than the combination of
oxprenolol and phentolamine.lsl In another open
MacCarthy and Bloomfield 207
study of 31 hypertensive patients, labetalol was sub-
stituted for the combination of various beta-adreno-
ceptor blocking drugs and the alpha-adrenoceptor
blocker prazosin.le2Labetalol appeared to be as ef-
sure, but it produced more side effects.
Labetalol has also been shown to be at least as
effective an antihypertensive drug as methyldopa,
clonidine, various adrenergic neuronal blockers and
the calcium-channelblocker verapamil. Prichard and
B ~ a k e sreported
’~~ that blood pressure control with
labetalol was similar to treatment with methyldopaor
the sympathetic inhibitory drugs bethanidine, debri-
soquine and guanethidine. Dargie and
substituted labetalol for methyldopa, clonidine and
adrenergic neuronal blockers in patients with severe
resistant hypertension, and the therapeutic result
was satisfactory. A randomized within patient dose
titration study reported that labetalol 1200-1 800 mg
daily was more effective in lowering blood pressure
in supine, sitting and standing positions and after
exercise than the adrenergic neuronal blocker beth-
anidine 30-45 daily.lB3Sanders and c011eagues~~~
performed a variable-dose crossover trial using pla-
cebo, labetalol and methyldopa in 20 patients; a
maximum dose of 1000 mg three times daily of each
drug was used. The antihypertensive properties and
the relative frequency of adverse effects of the two
drugs were similar. The antihypertensive effect of
labetalol has also been compared with that of cloni-
dine in a randomized crossover study in 17 patients
being treated with a thiazide Doses of
each agent were titrated until normotension or intol-
erable side effects occurred. The mean daily doses
required were labetalol 476 mg and clonidine 0.355
mg. Twelve patients complained of tiredness and dry
mouth during clonidine therapy, and two patients had
unsteadiness, one a rash and one limb weakness
during labetalol administration. In a recent double-
blind comparative study, labetalo1200 mg twice daily
produced a similar reduction in blood pressure as
verapamil 160 mg twice daily.132
The foregoing studies indicate that labetalol is as
effective an antihypertensive agent as most other
currently available hypotensive drugs administered
singly or in combination. However, an apparent lack
of hypotensive response to labetalol has been re-
ported in black patients in the United Kingdom de-
spite doses up to 3200 mg daily.ls6By comparison, in
11 previously untreated and 26 previously treated
Caucasian patients there was a significant reduction
in blood pressure. In contrast to this study, more
recent studies from South 186b have failed to
show a major racial disparity in the antihypertensive
efficacy of labetalol. Tolerance to the antihyperten-
sive effect of labetalol does not seem to develop
during prolonged administrati~n.’~~, The drug has
also been shown to combine effectively with a num-
ber of other antihypertensive agents, including
diuretics and v a s ~ d i l a t o r s . ~ ~ ~ ~
166v
208 PHARMACOTHERAPY VOLUME
3, NUMBER
Emergency Hypertension
In contrast to beta-adrenoceptor blocking drugs
that do not possess alpha-adrenoceptorblocking ac-
tivity, labetalol promptly lowers raised blood pres-
sure when given orally or intravenously and has
been used effectively in the management of various
hypertensive emergencies. A prompt hypotensive
response has been observed within two hours of oral
treatment with labetalol 300 or 400 mg in severe
hypertension, and an oral regimen has been shown
effective in treating such hypertensive emergencies
as accelerated hypertension or hypertensive en-
cephal~pathy.’~~~~~
Labetalol may be administered intravenously in
circumstances where a very prompt reduction in
blood pressure is indicated or when the patient can-
not take the drug by mouth. The drug offers several
advantages over alternative parenteral antihyperten-
sive agents, since it permits controlled steady lower-
ing of blood pressure without significant changes in
heart rate or cardiac output. These properties enable
the drug to be administered safely in patients with
concomitant coronary artery disease. In addition,
since intravenous labetalol does not produce a sig-
nificant reduction in cerebral blood flow it may be
preferable for use in patients who also have cerebro-
vascular disease.lg3
There are now many favorable reports of the use
of labetalol in the treatment of severe hypertension
194-200 The
83*Io4,
and hypertensive 63v
drug has also been used successfully to control
marked tachycardia and hypertension in association
with severe tetanus.20i,202, 202a In contrast, a small
number of other investigators have failed to obtain
satisfactory blood pressure responses in a signifi-
cant number of patients after intravenous labeta-
1 0 1 . In ~ these
~ ~ ~ latter
~ ~ studies, the drug was usually
administered as a single bolus and the majority of
the nonresponderswere already receiving other an-
tihypertensive drugs, including beta-adrenoceptor
blockers, prazosin or other sympatholytic agents.
Thus, the hypotensive response to intravenously ad-
ministered labetalol may be reduced in patients who
are already receiving treatment with other beta- and
alpha-adrenoceptor blocking drugs. Pearson and
Havard, however, reported that labetalol remained
effective in patients who were receiving concomitant
beta-adrenoceptor blocking therapy.127
After intravenous bolus administration of labetalol
the majority of patients show a hypotensive re-
sponse after 5 minutes and a maximum response 10
minutes after administration.62The antihypertensive
response may persist for 6 hours or more after a
single intravenous Labetalol reduces blood
pressure when given by fast (over 1 minute) or slow
(over 15 minutes) intravenous injection.lg6The ex-
tent of the reduction in arterial pressure is inde-
pendent of the rate of injection, but the rate of fall of
blood pressure can be controlled by varying the rate
4,JULY~AUGUST
1983
of injection. Although labetalol has usually been ad-
ministered intravenously as a single bolus or repeat-
ed small boluses, a number of investigators advo-
cate graded incremental infusion of the drug,
because this mode of administration gives a smooth-
er reduction of blood pressure and is less prone to
untoward effect^.^^^^ looCumming and associatesig7
have administered labetalol intravenously to a total
of 70 hypertensive patients without adverse neuro-
logical or cardiological sequelae. However, there is
one report of a hemiparesis developing in a patient
36 hr after bolus administration of labetal01.~~~ A
pressor response has also been reported after intra-
venous bolus administration of labetalol to a patient
who was already receiving other antihypertensive
agents.208The degree of blood pressure reduction
after intravenous labetalol appears to be related to
pretreatment basal norepinephrine concentration
Ig9
and also to the age of the
A number of comparative studies of intravenously
administered labetalol have been conducted. Trust
and associates62compared labetalol 100-1 25 mg
intravenously with propranolol 10 mg intravenously
in 5 patients and found that labetalol was more effec-
tive in lowering blood pressure, but less effective in
reducing pulse rate. The effects of labetalol 1-2 mgl
kg intravenously were compared with those of dia-
zoxide 3-5 mg/kg intravenously in a randomized
crossover study in severely hypertensive patients.lg8
It was concluded that the short-term effects of in-
travenous labetalol were comparable to those of
diazoxide. Pearson and associatesig3 found that in-
travenous labetalol 150 mg produced a similar re-
duction in blood pressure as diazoxide 300 mg intra-
venously. In contrast to these studies, Yeung and
found that labetalol 100 mg intrave-
nously was less effective than diazoxide 300 mg in-
travenously or clonidine 300 p g intravenously. Al-
though this study and another203 suggest that
labetalol may not be as effective as diazoxide, it
would appear to be less likely to induce profound
hypotension and adverse neurological or cardiologi-
cal sequelae.
Pheochromocytoma and Clonidine Withdrawal
The mode of action of labetalol would seem to
make it especially suitable for the treatment of se-
vere hypertension due to excessive catecholamine
secretion, as in pheochromocytoma or after cloni-
dine withdrawal. Indeed, there have been several
reports of successful use of labetalol under these
circumstances.161~ 2os212
Ig7, Takeda and associ-
ates161 reported that labetalol treatment achieved
good blood pressure control in 21 of 30 patients with
pheochromocytoma. They also noted that labetalol
was more effective in patients with predominantly
epinephrine-secreting tumors and in patients with
sustained, rather than paroxysmal, hypertension. Al-
though the combined alpha- and beta-adrenoceptor
blockade with labetalol appears useful in patients
 EVALUATION OF LABETALOL
with pheochromocytoma, there have been at least
two reports that oral labetalol may provoke a hyper-
tensive crisis in such '14 Subsequent
treatment with phentolamine and phenoxybenza-
mine achieved satisfactory control of blood pressure
in these latter two reports. The pressor response to
labetalol in these reports may be the result of the
preponderance of beta-adrenoceptor blockade after
oral dosing that leaves alpha-adrenoceptor stimula-
tion relatively unopposed.An alternative explanation
may be the failure of labetalol, a selective postsynap-
tic alpha,-adrenoceptor antagonist, to prevent cate-
cholamine-induced vasoconstriction via stimulation
of postsynaptic alpha,-adrenoceptors. Such alpha,-
adrenoceptors have recently been demonstrated in
vascular smooth muscle.215
Labetalol has been used successfully in the man-
agement of hypertensive crises after clonidine with-
drawal and has also been used prophylactically to
prevent such crises during withdrawal from cloni-
dine.197~309,216 However, there has also been a report
of severe rebound hypertension during gradual clon-
idine withdrawal and concurrent oral labetalol ad-
m i n i ~ t r a t i o nThus,
. ~ ~ ~oral labetalol may have similar
disadvantages as described for the treatment of
pheochromocytoma, and like other beta-adrenocep-
tor blockers, should be avoided unless alpha-adren-
ergic blockers have already been given in the form of
intravenous phentolamine or intravenous labetalol
itself.
Pregnancy Hypertension
Recent studies of the use of labetalol in pregnant
women with severe hypertension have been encour-
aging.21a226Not only does labetalol satisfactorily
control blood pressure in the pregnant woman, but it
may also exert a beneficial effect on fetal pulmonary
mat~rity."~This effect on lung maturation may be
mediatedthrough a partial beta,-adrenoceptor agon-
ist action since Nicholas and found a
similar effect with salbutamol (albuterol) in rabbits.
Although labetalol has been shown to cross the pla
cental barrier, it does not appear to produce adverse
effects on the fetus antenatally, during labor or post-
partum.220* '' Clinically significant fetal hypoglyce-
mia, fetal bradycardia or fetal respiratory depression
are not usually associated with maternal labetalol
therapy. Pharmacokinetic studies have shown that
the clearance and volume of distribution of labetalol
are not altered during
The effect of labetalol on human utero-placental
blood flow has been investigated using a radioactive
indium technique, and results from this study indi-
cate that labetalol effectively reduces maternal blood
pressure without diminishing utero-placental blood
flow.228During chronic treatment with labetalol, drug
levels in breast milk ranged from 22 to 45% of the
maternal blood labetalol concentration.220In another
studyzzEa in which nine healthy non-pregnant lactat-
ing mothers were given a single 200 mg dose of
MacCarthy and Bloomfield 209
labetalol, the milk to plasma concentration ratios
ranged from 0.68 to 0.88 through 12 hours post
dose. The 0-12 hour labetalol milk AUC/plasma
AUC ratio was 0.64. There was no evidence to sug-
gest that drug conjugates were secreted in breast
milk. Only very small amounts of labetalol are secret-
ed in breast milk (approximately 0.004°/0of the dose)
after oral administration of the drug. No adverse ef-
fects have been noted in neonates of patients who
breast fed during labetalol therapy.
Myometrial irritability is not problematical during
labetalol treatment, and the drug has not been re-
ported to impair labor or complicate caesarean sec-
tion. Improvements in maternal renal function with
reductions in proteinuria have been reported during
labetalol 222 Labetalol has also been
shown to increase platelet counts in patients with
severe preeclampsia and thrombo~ytopenia.~~~
Oral administration of labetalol in doses ranging
from 330-1800 mg daily has been shown to effec-
tively control hypertension during pregnan-
cy.2199220* 222 Two randomized comparative studies of
labetalol and methyldopa in the treatment of hyper-
tension in pregnancy have been reported. Lamming
and reported that labetalol 400-800
mg daily gave better blood pressure control than
methyldopa 750-1 500 mg daily. However, Redman
and recently reported that blood pres-
sure control was similar in two groups of patients
treated with either labetalol 300-1200 mg daily or
methyldopa 1-4 g daily.
In the situation in which rapid reduction of blood
pressure is required, such as in severe preeclampsia
or eclampsia, labetalol may be administered intrave-
nously with satisfactory results.222, 2 3 ~ 2 3 2In a recent
comparative study with intravenous dihydralazine,
labetalol infusion appeared to offer significant ad-
vantages.224
Although there have been a number of favorable
reports on the use of labetalol in the treatment of
hypertension in pregnancy, its use under these cir-
cumstances must still be regarded as investigation-
al. More extensive studies are indicatedto confirm its
safety when administered during pregnancy and to
clearly demonstrate its superiority over the more es-
tablished antihypertensivedrugs used in pregnancy.
Ischemic Heart Disease
The combined alpha- and beta-adrenoceptor
blocking properties of labetalol may confer some ad-
vantages over conventional beta-adrenoceptor
blocking drugs in the management of patients with
ischemic heart disease. The alpha-adrenoceptor
blocking component of the drug may minimize the
propensityfor coronary artery spasm to develop with
beta-adrenoceptor blockade alone, while offsetting
any tendency for dysrhythmias secondary to alpha-
adrenoceptor stimulation. In addition, labetalol has
been shown to have favorable hemodynamic effects
210 PHARMACOTHERAPY VOLUME3, NUMBER
in normotensive patients with documented coronary
artery disease and would appear to be less likely to
provoke cardiac failure than conventional beta-
adrenoceptor bl~ckers.~O~ gl, 233
The initial investigations of labetalol in patients
with ischemic heart disease have been encouraging.
Boakes and Prichard studied the effects of acute
injection of propranolol, pindolol and labetalol on ex-
ercise tolerance in normotensive patients with angi-
na p e ~ t o r i sAll
. ~ three
~ ~ agents gave approximately
similar increases in exercise tolerance. Condorelli
and associates compared the effect of labetalol 100
mg twice daily and placebo on exercise tolerance in
19 normotensive subjects with angiographic evi-
dence of coronary artery disease.92Labetalol pro-
duced significant reductions in systolic and diastolic
blood pressure as well as heart rate and the rate-
pressure product. In addition, ST segment depres-
sion was reduced by labetalol, and there was an
increase in exercise tolerance. Oral labetalol has
also been used effectively in hypertensive patients
with coexisting angina p e ~ t o r i s Lubbe ~ ~ ~ and agents for this purpose include ganglionic
. ~ ~ ~and
Whitez35substituted labetalol for existing beta-adren-
oceptor blockers in the treatment regimens of 17
hypertensive patients with angina pectoris. They
found that labetalol produced a significant improve-
ment in control of angina pectoris without further im-
provement in control of blood pressure at rest, during
isotonic exercise or on performance of the cold pres-
sor test. They speculated that labetalol increases
myocardial blood supply by an increase in coronary
perfusion due to its vasodilatory action. When la-
betalol therapy is withdrawn abruptly, there does not
appear to be a sharp increase in blood pressure
or anginal symptoms.z38This is in contrast to the
situation after abrupt cessation of conventional
beta-adrenoceptor blocking Further com-
parative studies with conventional beta-adrenocep-
tor blockers, nitrates and calcium ion antagonists are
indicated to clearly define the role of labetalol in the
management of angina pectoris.
There have also been reports of the successful
use of labetalol in the management of hypertension
associated with acute myocardial infarction. Incre-
mental infusion of labetalol lowered blood pressure
safely and effectively in 15 hypertensive patients
with acute myocardial infarction.z40Timmis and col-
l e a g u e ~also
~ ~found
~ that labetalol was effective in
lowering blood pressure in patients with acute myo-
cardial infarction and did not produce adverse hemo-
dynamic effects. These investigators concluded that
labetalol infusion in patients with acute myocardial
infarction is unlikely to precipitate heart failure and is
likely to be of value in reducing myocardial oxygen
requirement. No information is available at present
regarding a potential benefit of labetalol to reduce
mortality and morbidity among survivors of a myo-
cardial infarction. However, based on the experience
with other beta-adrenoceptor blocking agents, a
beneficial effect of labetalol could be anticipated.
Overall, the initial reports of the use of labetalol in
4, JULY/AUGUST
1983
patients with ischemic heart disease are encourag-
ing, but more extensive and more definitive studies
are needed before the drug can be recommendedfor
routine therapy in such patients.
Anesthetic Practice
The established and potential roles for the use of
labetalol in anesthetic practice have been reviewed
recently.z42The drug is valuable for correcting un-
controlled hypertension before anesthesia and dur-
ing surgery, where it can be administered either oral-
ly or intravenously. It may also be used effectively to
counter acute hypertensive responses during laryn-
goscopy and various surgical procedures, including
pheochromocytoma A recent report sug-
gests that the drug may be effective in the treatment
of cancer pain when it is administered via a peridural
catheter.z1la
Induced hypotension is a useful technique to mini-
mize blood loss during certain surgical procedures,
blockers and nitroprusside. However, these drugs
are frequently accompanied by tachyphylaxis and
undesirable tachycardia. Labetalol is not associated
with these unwanted effects, and it has been used
effectively with halothane and other anesthetic
agents for controlled hypotensive anesthesia dur-
ing a variety of surgical procedures, including otolog-
ical operations and coarctation Stable
blood pressure and heart rate is maintained through-
out anesthesia with the combination of labetalol and
halothane, and the degree of hypotension can be
adjusted by altering the concentration of halothane.
However, a high concentration of halothane (33%)
should not be used with labetalol because of the risk
of large reductions in cardiac output.243On comple-
tion of surgery, blood pressure and heart rate can be
easily restored to normality by the administration of
atropine sulfate. Although Cope reportsz45that pa-
tients with ischemic heart disease may receive la-
betalol during anesthesia without any untoward ef-
fect, there has been a report of severe myocardial
depression and death in such a patient during la-
betalol therapy and 0.5% halothane anesthesia.z48
Adverse Effects and Precautions
Several reports on labetalol treatment in large
groups of patients have discussed the nature and
frequency of side 161, z49 Side effects are
generally mild and of three types (in order of frequen-
cy): (a) non-specific; (b) related to alpha-adrenocep-
tor blockade; and (c) related to beta-adrenoceptor
blockade. Nonspecific gastrointestinal side effects
have been reported in up to 15% of patients and
include nausea, vomiting, abdominal pain, diarrhea
and constipation. Other less frequently reported non-
specific side effects are tiredness, headache, and
skin rashes. A variety of skin rashes, including a
maculopapularerythematous rash, urticaria, atypical
 EVALUATION OF LABETALOL
lichen planus and bullous lichen planus may rarely
occur~160. 188.25&252
The most troublesome side effect reported during
labetalol therapy is posture related dizziness which
occurs in about 5% of patients and is related to al-
pha-adrenoceptor blockade. It tends to occur more
frequently in the early stages of treatment, in patients contrast, a comparative study of labetalol and meth-
receiving concomitant diuretic therapy, and during
treatment with higher dosages of the drug.I5’ Other
less frequently reported side effects that are also
probably related to alpha-adrenoceptor blockade in-
clude nasal stuffiness, sexual dysfunction, and uri-
nary retention.188 The phenomenon of formication or
scalp tingling has been reported in a minority of pa-
tients after both oral and intravenous administration
of the drug and tends to disappear on continued
treatment.66’ 253, 254 Circumoral paresthesia has
767
also been reported in association with labetaI01.~~~ tients withdrew from labetalol therapy due to side
Sexual side effects such as decreased libido, impo-
tence, failure of ejaculation and retrograde ejacula-
tion are uncommon. However, there have been sin-
gle case reports relating labetalol treatment to the
development of Peyronie’s disease256and pria-
~ i s mbut , ~a~definitive
~ causative relationship was
not established.
Side effects related to the beta-adrenoceptor
blocking action of labetalol are infrequent (frequency
of 3% or less) and include the following: vivid
dream^,'^*^^^ asthrna,l6’*l E 7 Raynaud’s phenom-
enon,lmcIaudication,ls8muscle cramps,117* myosi-
ti^,^^^ and heart failure.260Side effects from beta-
adrenoceptor blockade are generally less
troublesome during labetalol treatment than during
therapy with pure beta-adrenoceptor blocking
drug^.'^^^ Antinuclear antibody tests may become
positive at low titer during chronic labetalol ther-
apy,leebut these are not usually accompanied by any
symptoms or signs of immunological diseases. How-
ever, a lupus-type illness has been reported in a
patient during labetalol therapy.261Antimitochondrial
antibodies may also develop during chronic labetalol
therapy, but these do not appear to be clinically im-
portant.18ev 262 There have been no clinical reports of should also be avoided in patients with asthma until
ophthalmological side effects related to labetalol
treatment.15’ No adverse drug interactions have
been reported. However, on the basis of its known
pharmacological properties, labetalol would be ex-
pected to counteract the effects of alpha- and beta-
adrenoceptor agonist drugs.
The nature and frequency of side effects during
labetalol therapy have been compared with those
occurring during treatment with other antihyperten-
sive agents in a number of well conducted studies.
Horvath and c011eagues~~~ found no difference in the betalol orally.
frequency or type of side effects of labetalol com-
pared with bendrofluazide. In a comparative study of
labetalol and propranolol in 24 patients with hyper-
tension,’% 2 patients were unable to tolerate pro-
pranolol and 5 labetalol because of symptomatic
side effects. This difference was not significant and
there was no difference in the number of spontane-
MacCarthy and Bloomfield 21 1
ously reported side effects between the two drugs. In
a comparative study of labetalol and clonidine in 17
hyperten~ives,’~~ labetalol caused headache in 2 pa-
tients, unsteadiness in 2, rash in l and limb weak-
ness in 1 , whereas clonidine produced tiredness in
10 patients, dry mouth in 12 and headache in 2. In
y l d ~ p afound
’ ~ ~ no significant differences in adverse
effects.
Kane recently reviewed the results of labetalol
treatment in 8573 hypertensive patients for periods
up to five years.153Eleven different studies of the use
of labetalol in general practice formed the basis for
this report. The withdrawal rate attributable to side
effects was between 6 and 13%, but only one of the
11 studies was placebo-controlled. Takeda and as-
sociates16i reported that approximately 5% of pa-
effects, whereas Waal-Manning and Simpson’88re-
ported an unusually high side effect withdrawal rate
of 25%. Overall, however, labetalol appears to be
well tolerated and has a low frequency of side ef-
fects; in some instances side effects have been less
than on previous treatment regimens. In the report of
Cumming and intravenousadministra-
tion of labetalol 1 mg/kg to 15 severely hypertensive
patients, followed by a further series of 50 mg bo-
luses, produced significant side effects. These ad-
verse effects included nausea (5 patients),vomiting
(2), scalp tingling (3),burning sensation in the groin
( l ) ,pain at the injection site (2), faintness (2), pallor
(4) and shivering (1). Such a high frequency of side
effects has not been observed in other studies of
intravenous labetaI01’~~~ lg6. 1 9 ~ 2 0 and
0 the drug is usu-
ally very well tolerated when administered by this
route.
Labetalol should be used with caution or avoided
in instances where the beta-adrenoceptor blocking
action of the drug could prove harmful. Such an in-
stance is heart failure; the drug is probably best
avoided in patients crucially dependent on their sym-
pathetic drive to maintain cardiac output. The drug
further information is available on its effects on respi-
ratory function in asthmatics. Since intermittent clau-
dication and Raynaud’s syndrome may be exacer-
bated by labetalol therapy, the drug should be used
with caution or avoided in patients with these condi-
tions. In order to diminish the potential for a pressor
response to the drug in patients with pheochromocy-
toma, it seems preferable to establish alpha-adreno-
ceptor blockade with intravenous labetalol or some
other alpha-blocking agent, before commencing la-
Dosage
The recommended starting dose for oral labetalol,
used alone or in combination with a diuretic, is 100
mg twice daily. The dose may be increased to 200
mg twice daily after two days, and further dose incre-
ments may be made every one to three days until an
212 PHARMACOTHERAPY VOLUME3, NUMBER
optimum response is obtained. The usual mainte-
nance dose of labetalol is 200-400 mg twice daily.
However, some patients with severe hypertension
may require 1200-2400 mg of labetalol daily in two
or three divided doses, with a thiazide diuretic in
addition, in order to achieve a satisfactory response.
Precise information regarding the necessity for
modification of dosage in patients with hepatic or
renal disease is not available, but the study of Ho-
meida and associates4' suggests that the dosage
should be reduced in patients with substantial liver
disease. Data are currently lacking regardingthe dia-
lyzability of labetalol; thus, it is not possible to make
firm recommendations regarding dosage adjust-
ments in patients undergoing peritoneal or hemodi-
alysis.
Labetalol may be administered intravenously by
either of two methods. The first method is by slow
continuous intravenous infusion, and the second is
by repeated bolus injection. If given by infusion, a
solution should be made by diluting 200 mg labetalol
(40 ml) to 200 ml with a standard intravenous soh-
tion such as 5% dextrose. The recommended rate of
infusion is 2 mg labetalol (2 ml of infusion solution)
per minute, until a satisfactory response is obtained;
the infusionshould then be stopped. The usual effec-
tive cumulative dose is 50 to 200 mg, and the infu-
sion may be repeated every 6-8 hours to maintain
satisfactory blood pressure control. If given by bolus
injection, a dose of 20 mg labetalol should be given
intravenously over a period of 2 minutes. Additional
bolus injections of 40-80 mg may be given at 10
minute intervals until an optimum response is ob-
tained. The maximum recommended total dose of
labetalolby either of the methods of administration is
300 mg. Patients should remain supine when given
labetalol intravenously and should not assume the
upright position for 3 hours after drug administration,
in order to avoid excessive postural hyp0ten~ion.l~'
Conclusions
Labetalol has combined alpha- and beta-adreno-
ceptor blocking properties and is a safe and effective
agent for oral and intravenous use in the treatment of
various forms of hypertension. The drug is suitable
for all grades of hypertension and for patients who
have failed to respond to other therapy. It may be
used successfully as monotherapy, or it may also be
used effectively in combination with other antihyper-
tensive agents such as diuretics or vasodilators. The
antihypertensive efficacy of labetalol is at least com-
parable, if not superior, to that of pure beta-blockers,
methyldopa, clonidine and various adrenergic neu-
ronal blockers. However, it remains to be clearly
shown that labetalol has a definite advantage over
combined treatment with propranolol and prazosin.
Indeed, the fixed ratio of alpha- to beta-adrenergic
blockade implicit in a single drug molecule may be a
disadvantage if fine adjustment of individual drug
4, JULY/AUGUST
1983
effects are required. A major advantage of labetalol
over conventional beta-blockers, which do not pos-
sess intrinsic sympathomimetic activity or additional
alpha-blocking properties, is that cardiac output is
well maintained during therapy. The side effects that
occur with labetalol are often transient, and in many
cases are less common than with other antihyperten-
sive agents, including other beta-blockers.
A major advantage of intravenously administered
labetalol over other parenteral antihypertensive
agents is its ability to produce a controlled steady
lowering of blood pressure without significant
changes in heart rate or cardiac output. In addition,
the drug offers the advantage of parenteral adminis-
tration in emergency situations, followed by oral ther-
apy when long-term blood pressure control is neces-
sary. Thus, labetalol should prove to be a very useful
addition to the list of currently available oral and par-
enteral antihypertensive agents.
Preliminary studies also indicate that labetalol
may be of value in pregnancy hypertension, in hypo-
tensive anesthesia and in the management of ische-
mic heart disease.
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 EVALUATION OF LABETALOL
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MacCarthy and Bloomfield 21 7
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Commentaries
Commentary 1
Labetalol is the first drug that has been demonstratedto
simultaneously antagonize both alpha and beta adreno-
receptors. In theory an agent possessing such combined
activity should be ideally suited for the therapy of hyperten-
sion. The important question, however, is whether this
drug in reality offers any significant advantages over cur-
rently available antihypertensive medications and more
specifically over currently marketed beta blockers. That
the alpha and beta blocking properties of labetalol do in
fact both play a role in the drug’s antihypertensiveeffects
have been clearly demonstrated in studies in animals and
man. That this combined effect offers any obvious benefits
in most clinical situations has not been so clearly demon-
strated. Certainly in clinical trials, labetalol is as efficacious
as other therapy, and in some cases, it has been success-
ful where other drugs have failed. Unfortunately,the rela-
tive contraindications to beta blocker therapy, such as
bronchospasm and congestive heart failure, also apply to
labetalol. It remains to be seen whether labetalol is a better
choice than the traditional beta blockers or one of the se-
lective beta blockers in clinical situations where use of
such an agent is felt necessary despite relative contraindi-
cations.
What then are some of the potential advantages of la-
betalol? Compared to the traditional beta blockers, labeta-
lo1 appears to have a more rapid onset of antihypertensive
effect, to better preserve coronary and renal blood flow,
and to be less prone to decrease cardiac output. Its avail-
ability in both parenteral and oral preparations as well as
its preliminarily proven efficacy in urgent hypertensive situ-
ations is another advantage. There is something definitely
appealing about being able to use the same agent for
acute and chronic regulation of a patient’s blood pressure.
The role of labetalol in the therapy of black patients with
hypertensionis discussed in the review by Drs. MacCarthy
and Bloomfield and deserves further study. The traditional
beta blockers have been shown to be less effective against
hypertension in blacks compared to whites. The results to
date with labetalol have been variable so that further inves-
tigation is needed to determine whether the additional al-
pha antagonism of this agent makes it more suitable for
this specific population. Clinical studies also exist to sup-
port the use of labetalol in the prevention of angina pec-
toris. Conceptually at least, it would appear advantageous
to use a drug that does not augment coronary artery vaso-
constriction, a property that labetalol has over the tradition-
al beta blockers.
Future research with labetalol and similar agents should
prove to be both fruitful and exciting. Studies are needed to
further define the role of this agent in combinationtherapy.
The use of labetalol in the elderly hypertensive patient and
in the patient with isolated systolic hypertension are also
both potential applications, although the propensity to
cause orthostatic symptoms may be limiting. We would