Sorkin 1987

Drug Evaluation
Drugs 33: 296-345 (1987)

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Nicardipine
A Review of its Pharmacodynamic and Pharmacokinetic
Properties, and Therapeutic Efficacy, in the Treatment of
Angina Pectoris, Hypertension and Related Cardiovascular
Disorders
Eugene M. Sorkin and Stephen P. Clissold

ADIS Drug Information Services, Auckland
Various sections of the manuscript reviewed by: Y. Balli SubraltUlnian, Lifewatch Re-
search/Brunei Institute for Bioengineering, Harrow, Middlesex, England; G. DiPasquale,
Servizio di Cardiologia, Ospedale Bellaria, Bologna, Italy; T. Fujita, Department of In-
ternal Medicine, University of Tsukuba, Niihari-gun, Ibaraki-ken, Japan; C. Hanet, Uni-
versite Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium;
R.G. MeAllilter Jr, Veterans Administration Medical Center, Lexington, Kentucky, USA;
W.G. Nayler, University of Melbourne Department of Medicine, Austin Hospital, Hei-
delberg, Victoria, Australia; c.J. Pepine, University of Florida Division of Cardiovascular
Medicine, Gainesville, Florida, USA; E.B. Raftery, Northwick Park Hospital and Clinical
Research Centre, Harrow, Middlesex, England; M.F. RoussetUl, Universite Catholique de
Louvain, Ciiniques Universitaires Saint-Luc, Brussels, Belgium; S. Scheidt, New York
Hospital-Cornell Medical Center, New York, New York, USA; P.W. Serruys, Erasmus
Universiteit Rotterdam, Rotterdam, The Netherlands; T. Talulbatalu, School of Medi-
cine, Kanazawa University, Kanazawa, Japan; S.H. Taylor, Department of Medical Car-
diology, The General Infirmary, Leeds, England; P.D. Yerdouw, Erasmus Universiteit
Rotterdam, Rotterdam, The Netherlands.
Contents Summary .................................................................................................................................... 297

I. Pharmacodynamic Properties .............................................................................................. 301
1.1 Electrophysiological Effects of Nicardipine ................................................................. 30 I
1.2 Haemodynamic Effects .................................................................................................. 303
1.2.1 Effect on Blood Pressure ...................................................................................... 303
1.2.2 Effect on Heart Rate ............................................................................................. 303
1.2.3 Effect on Cardiac Haemodynamics ..................................................................... 306
1.2.4 Haemodynamic Effects of Nicardipine Compared with, and in Combination
with, Other Cardiovascular Drugs ................................................................................. 307
1.3 Effect on Coronary Circulation and Myocardial Oxygen Consumption .................. 309
1.4 Cardioprotective Effect .................................................................................................. 310
1.5 Effect on Peripheral Vascular Circulation ................................................................... 312
1.6 Cerebrovascular Effects ................................................................................................. 312
1.7 Renal Effects ...................................................................................... ............................. 313
1.7.1 Effect on Renal Blood How, Renovascular Resistance and Glomerular
Filtration Rate ................................................................................................................. 313
I. 7.2 Effects on Plasma Renin Activity, Angiotensin and Aldosterone .................... 314
1.7.3 Other Renal Effects ............................................................................................... 315
1.8 Other Effects ................................................................................................................... 315
Nicardipine: A Review 297
1.8.1 Effects on Airway Conductance ........................................................................... 315

1.8.2 Endocrine Effects .................................................................................................. 316
1.8.3 Antiatherosclerotic Effects .................................................................................... 317
1.8.4 Effect on Platelets ................................................................................................. 317
1.9 Mechanism of Action .................................................................................................... 317
2. Pharmacokinetics .................................................................................................................. 318
2.1 Absorption ...................................................................................................................... 320
2.2 Distribution .................................................................................................................... 321
2.3 Metabolism ..................................................................................................................... 321
2.4 Elimination ..................................................................................................................... 322
2.4.1 Half-Life ................................................................................................................. 322
2.5 Effect of Disease on Pharmacokinetics ........................................................................ 323
3. Therapeutic Trials ................................................................................................................ 323
3.1 Angina Pectoris .............................................................................................................. 323
3.1.1 Use in Stable Angina Pectoris ............................................................................. 326
3.1.2 Use in Angina at Rest and Coronary Artery Spasm ......................................... 328
3.2 Hypertension .................................................................................................................. 328
3.2.1 Non-Comparative Studies .................................................................................... 328
3.2.2 Placebo-Controlled Trials ..................................................................................... 329
3.2.3 Comparative Trials ............................................................................................... 331
3.3 Other Uses ...................................................................................................................... 332
3.3.1 Cardiac Failure ...................................................................................................... 332
3.3.2 Cerebrovascular Disorders ................................................................................... 333
4. Side Effects ............................................................................................................................ 335
5. Drug Interactions .................................................................................................................. 337
6. Dosage and Administration ................................................................................................. 337
7. Place of Nicardipine in Therapy ......................................................................................... 337
Summary
Synopsis Nicardipine 1 is an antagonist of calcium influx through the slow channel of the cell
membrane and has been shown to be an effective and relatively well-tolerated treatment
for stable effort angina and rest angina due to coronary artery spasm, and mild to mod-
erate hypertenSion. Although its exact mechanism of action in these disease states has not
been precisely defined, the potent coronary and peripheral arterial dilator properties of
nicardipine, with concomitant improvements in oxygen supply/demand and reductions in
systemic vascular resistance, are of major importance.
Clinical studies have shown that nicardipine appears to be effective in the treatment
of chronic stable exercise-induced angina pectoris and possibly in angina at rest due to
coronary artery spasm. In the treatment of stable angina, nicardipine has proved to be
equally as effective as nifedipine. However, haemodynamic and clinical studies indicate
that nicardipine may have a further advantage of not depressing cardiac conduction or
left ventricular function, even in patients with compromised cardiac pumping ability. Ni-
cardipine also appears to be useful as initial monotherapy or in combination with other
antihypertensive drugs when used in the treatment of mild to moderate hypertension, and
may have some advantages over other vasodilators in this regard in that it may not be
as frequently associated with fluid retention or weight gain as other similar drugs. In the
1 'Bionicard' (Bioindustria); 'Cardene' (DuPont Critical Care); 'Nerdipina' (Ferrer); 'Ranvir' (Gen-
tili); 'Nicardal' (Italfarrnaco); 'Nicodel' (Mitsui); 'Dacarel' (Roemmers); 'Loxen', 'Perdipina', 'Roxen'
(Sandoz); 'Cardene', 'Ridene', 'Rycarden', 'Rydene', 'Vasonase' (Syntex); 'Perdipine' (Yamanouchi).
treatment of hypertension nicardipine has been shown to be as effective as drugs such as

hydrochlorothiazide. cyclopenthiazide. propranolol and verapamil in short term studies
although confirmation of its long term · usefulness in well-designed clinical trials is still
required. Similarly. although the use of nicardipine in other disorders such as congestive
heart failure and cerebrovascular disease has provided encouraging preliminary results.
more studies are needed to clarify its place in their treatment.
Side effects appear to be dose related and more frequent within the first few weeks of
therapy. Most of these effects are minor and transient in nature and include headache.
flushing and peripheral oedema.
Thus. there is no doubt that nicardipine provides a suitable alternative to other drugs
available for the treatment of angina and hypertension. However. further well-designed
comparative clinical trials are needed to clarify its relative place in the long term man-
agement of these disorders.
Pharmacodynamic Nicardipine, in common with other calcium antagonists, inhibits the slow inward
Properties current of calcium in normal cardiac tissues. In humans, nicardipine has either signifi-
cantly shortened or had no effect on sinus nodal recovery time. In clinically practical
doses nicardipine has had few untoward effects on sinoatrial and atrioventricular nodal
function, and because it has not shown any major antiarrhythmic effects it may be safe
for patients with some cardiac conduction disturbances.
Intravenous and oral doses of nicardipine may produce dose-related decreases iit mean
arterial blood pressure and increases in heart rate of up to 30% and 8 to 26%, respectively,
and the duration of these effects - which may be as long as 3 hours - have generally
been greater in patients at rest than in those at exercise. Although reductions in blood
pressure have been effectively maintained for several months without evidence of tachy-
phylaxis, increases in heart rate occasionally seen after acute administration are not ob-
served after long term (greater than 2 months) oral treatment.
The primary haemodynamic effect of nicardipine is peripheral vasodilatation leading
to a reflex increase in cardiac pumping activity. Thus, cardiac index is increased while
systemic vascular resistance is decreased, and these effects are maintained during long
term therapy. The magnitude ofthe blood pressure reduction induced by nicardipine has
been shown to be directly related to the concurrent decreases in systemic vascular re-
sistance. Cardiac pumping ability is probably improved due to a reduction in afterload.
Although nicardipine has been shown to cause similar haemodynamic responses to
nifedipine when given orally to healthy subjects, intracoronary injections of nifedipine
in patients with coronary artery disease resulted in decreases in left ventricular contrac-
tility and relaxation, while intracoronary nicardipine produced no such effects. In patients
at rest, nicardipine appears to increase cardiac index to a greater extent than verapamil,
while pulmonary artery occluded pressure is increased after verapamil but not after ni-
cardipine administration. Additionally, although ·verapamil and nicardipine produced
similar haemodynamic effects during exercise, verapamil achieved these results at the
expense of a significantly increased left ventricular filling pressure, while nicardipine did
not.
The addition of nicardipine to patients receiving ,8-blockers has further reduced blood
pressure and decreased left ventricular systolic pressure and systemic vascular resistance
from values obtained with ,8-blockers alone. Moreover, heart rate, cardiac output and
ventricular relaxation, which are decreased after ,8-blocker therapy, are normalised after
the introduction of nicardipine to the treatment regimen. Thus, cardiac pump function
and inotropic activity appear to be improved after nicardipine is added to ,8-blocker
therapy. In contrast, nifedipine may produce a small but definitely negative inotropic
effect when added to ,8-blocker therapy. Since beneficial haemodynamic and cardiac
pumping effects result from the addition of nicardipine to patients previously treated
with ,8-blockers, even in patients with impaired left ventricular function, nicardipine may
present no additional hazard to patients already receiving ,8-blockers.
The administration of nicardipine to patients with coronary artery disease results in

an increase in coronary blood flow due to coronary vasodilatation and decreases in cor-
onary vascular resistance. Nicardipine may have a relatively greater affinity for coronary
vessels than those in other vascular beds since it apparently reduces coronary vascular
resistance to a greater extent than systemic vascular resistance. In patients receiving fl-
blockers, the addition of nicardipine has further increased coronary blood flow and de-
creased coronary vascular resistance by as much as 21 and 32%, respectively.
By virtue of its ability to decrease systemic vascular resistance (afterload), nicardipine
may improve blood distribution in ischaemic myocardial tissue thus imparting to the
drug cardioprotective properties. Since it has also been shown to reduce left ventricular
lactate production in patients with angina pectoris, it may be that nicardipine improves
perfusion and aerobic metabolism in chronically ischaemic areas, leading to improve-
ments in ventricular function.
Other pharmacological effects of nicardipine include increased peripheral blood flow
and decreased peripheral vascular resistance, as well as a potent dose-related cerebral
vasodilating effect. Nicardipine may also increase renal blood flow and glomerular fil-
tration rate and decrease renovascular resistance, whereas plasma renin activity may be
slightly or markedly increased. Interestingly, although plasma aldosterone concentrations
do not appear to be significantly affected, nicardipine administration has resulted in
modest and short-acting natriuretic effects due to an effect on the renal tubule.
Pharmacokinetic Although more well-designed investigations involving larger numbers of volunteers

Properties and patients are required for a better understanding of the pharmacokinetic properties
of nicardipine, studies have shown that after oral administration nicardipine is rapidly
and completely absorbed, with peak plasma concentrations occurring between 20 minutes
and 2 hours. Despite the fact that nicardipine is well absorbed, it has a low systemic
bioavailability due to extensive presystemic metabolism. Non-linear increases in peak
plasma concentrations, areas under the plasma concentration-time curves (AVCs) and
systemic bioavailability occur after both intravenous and oral doses of nicardipine, sug-
gesting that liver drug metabolising enzymes become saturated with nicardipine or its
metabolites at higher doses of the drug. The administration of nicardipine to elderly
patients may result in higher minimum and maximum plasma concentrations, possibly
due to a decreased first-pass effect in this patient population. Conversely, food has been
found to decrease both the maximum plasma concentrations and AVCs obtained after
oral administration of the drug. Plasma concentrations ofnicardipine exhibit no tendency
to increase during prolonged periods of administration.
In vitro studies using human plasma have shown that over 90% of nicardipine is
plasma protein bound at concentrations of 100 J.tgfL, and volumes of distribution in
healthy volunteers have ranged from 0.6 L/kg to 63L.
Nicardipine is rapidly and extensively removed by hepatic first-pass extraction during
its entrance into the systemic circulation and is metabolised to inactive metabolites. Less
than 0.03% of parent drug is recovered from the urine of humans. The plasma elimination
half-life of nicardipine has ranged from 44 to 107 minutes in most studies with clearance
of the drug due mainly to hepatic mechanisms. In healthy volunteers, intravenous ni-
cardipine clearance values were 0.4 to 0.9 L/h/kg to 72 L/h, while progressive decreases
in clearance values with increasing oral doses of the drug indicate a saturation of the
hepatic removal mechanisms. Nicardipine is excreted mainly through the bile and faeces
and the drug may be used in patients with severe renal failure; slightly higher values for
Cmax and AVC in this class of patient indicate that a dosage at the lower end of the
recommended range is appropriate. Pharmacokinetic data from patients with liver dis-
ease is not available and nicardipine should be used with caution in such patients.
Therapeutic Trials In many placebo-controlled trials for periods of up to I year, nicardipine has been
shown to be effective in stable exercise-induced angina as assessed by decreases in anginal
frequency and glyceryl trinitrate (nitroglycerin) consumption, and improvements in ob-

jective parameters such as work performance and time to onset and magnitude of ST-
segment changes during exercise. Short term comparative trials have demonstrated that
the antianginal efficacy of nicardipine is comparable to that of nifedipine, verapamil,
diltiazem, propranolol and atenololol. Compared with nifedipine, nicardipine produced
similar decreases in the number of anginal episodes per week and sublingual glyceryl
trinitrate consumption, and increases in total exercise time, time to angina and Imm
ST-segment depression. Similarly, in vasospastic angina, nicardipine decreased both the
frequency of symptomatic and asymptomatic episodes of angina and sublingual glyceryl
trinitrate consumption by up to 81%.
In several open and placebo-controlled trials in patients with mild-to-moderate es-
sential hypertension, the antihypertensive efficacy of nicardipine has been maintained
for periods of up to 1 year. Nicardipine monotherapy decreased mean arterial blood
pressure by more than 13mm Hg in 46 and 82% of newly diagnosed hypertensives in
daily dosages of 30 and 60mg, respectively, indicating its potential usefulness in the initial
treatment of the disease. In placebo-controlled trials, dose-related percentage decreases
in supine and sitting systolic/diastolic blood pressures of 17/20 and 20/ 16mm Hg, re-
spectively, have been recorded. Short term compafative studies demonstrated that ni-
cardipine was at least as effective as drugs like hydrochlorothiazide, cyclopenthiazide,
propranolol and verapamil in patients with mild to moderate hypertension. Limited stud-
ies have shown that nicardipine enhances the antihypertensive effects of other drug com-
binations. When added to antihypertensive regimens containing atenolol, nicardipine
produced further significant reductions in blood pressure without causing increases in
heart rate.
Despite encouraging results, the clinical evaluation ofnicardipine in other therapeutic
areas such as congestive heart failure and cerebrovascular disease has been of a prelim-
inary nature. Firm conclusions regarding its relative efficacy in these areas await further
research.
Side Effects Side effects resulting from nicardipine administration, most of which are minor and
transient in nature, appear to be dose related and more frequent during the first few
weeks of therapy with the drug. Vasodilatation-related effects such as flushing, headache
and peripheral oedema, which are extensions of the main pharmacodynamic properties
of the drug, have occurred in as many as 37% of patients treated with nicardipine. How-
ever, placebo administration to these same patients yielded vasodilatation-related side
effects in 23% of the group. Overall, vasodilatation-related side effects from nicardipine
in clinical studies to date have necessitated withdrawal of approximately 11 to 14% of
patients. Other cardiovascular side effects, including increased anginal symptoms, exer-
cise-induced hypotension, palpitations, dyspnoea and myocardial infarction have been
reported in as many as 27 and 14% of patients receiving nicardipine and placebo, re-
spectively. Other side effects involving the central nervous, gastrointestinal, musculo-
skeletal or dermatological systems occur infrequently and with minor intensity. The ab-
rupt withdrawal of nicardipine after 5 months of continuous therapy in patients with
chronic stable angina pectoris has not resulted in increases in anginal symptoms com-
pared to those reported prior to entry into the study.
Dosage and Administration In adults with essential hypertension or angina pectoris, oral nicardipine should be
initiated at a dosage of 20mg 3 times daily. If the desired therapeutic response has not
been achieved after 2 weeks of treatment the dosage may be increased to 30 to 40mg 3
times a day.
Nicardipine is a dihydropyridine calcium ant- 1984). In slow channel dependent tissues, which
agonist structurally related to nifedipine (fig. 1). It include the sinoatrial (SA) and atrioventricular (AV)
produces blockade of the transmembrane inward nodes, the major cationic species traversing the cell
movement of calcium, resulting in coronary and membrane is calcium. Thus, the effects of slow
peripheral vasodilatation which have been found channel blocking agents such as the calcium block-
to give benefit to patients with angina pectoris, ers are most evident in these tissues (Singh et al.
hypertension and related cardiovascular disorders. 1984; Wit & Cranefield 1974; Zipes & Fischer
1974). A summary of the clinical electrophysiolog-
1. Pharmacodynamic Properties ical properties of nicardipine and other frequently
1.1 Electrophysiological Effects of Nicardipine
used calcium channel blocking agents is presented
in table I.
Although there have been few detailed studies
In isolated rabbit hearts nicardipine has dose-
investigating the electrophysiological effects of ni-
cardipine, the electrophysiological basis of action dependently decreased the spontaneous rate of the
of other calcium blockers has been extensively re- SA node and prolonged the sinus recovery time
viewed (Antman et al. 1980; Mitchell et al. 1982; (Tamamura et al. 1981, 1983), effects which have
Singh et al. 1984). Briefly, normal cardiac tissues likewise been reported for nifedipine, diltiazem and
may be separated into 2 groups (slow and fast verapamil (Kawai et al. 1981). In human studies,
channel tissues) based upon their action potential however, intravenous nicardipine has either sig-
characteristics (Mitchell et al. 1982; Singh et al. nificantly shortened (p < 0.05) or had no effect on
Nicardipine Nifedipine Nitrendipine
Diltiazem Verapamil
Fig. 1. Chemical structures of nicardipine. nifedipine and nitrendipine (dihydropyridine derivatives). diltiazem (a benzothiazepine
derivative) and verapamil (a papaverine derivative).
Table I. Clinical electrophysiological properties of some calcium antagonists (adapted from Singh et a!. 1983; nicardlpine data taken
from Campbell et a!. 1985; Horio et a!. 1983; Matsui et a!. 1982)
Parameter Nicardipine Nifedipine Dlltiazem Verapamil
R-R interval tl t~
QRS 0 0 0 0
P-R 0
A-H oa 0
H-V 0 0 0 0
Atrial ERP tl 0 0 0
AV node ERP tl tl tt
AV node FRP t~· tl tt
Ventricular ERP 0 0 0 0
His-Purkinje ERP 0 0 0
Bypass tract ERP 0 0 ? tl
SNRT tlo/) 0 ()C ()C
Ventricular automaticity 0 0 0
a Prolonged in patients given autonomic blocking agents.

b No effect in sick sinus syndrome.
c Prolonged in sick sinus syndrome.
Key and abbreviations: 0 = no effect; ~ - decrease; t = increase; tl ,. variable effect; ERP ,. effective refractory period;
FRP = functional refractory period; SNRT '" sinus node recovery time; an ellipsis (...) indicates data not provided.
sinus nodal recovery time (Horio et al. 1983; Mat- (Horio et al. 1983; Matsui et al. 1982). Thus, it has
sui et al. 1982). been suggested that nicardipine may be safe for
In isolated AV nodes of rabbits, nicardipine patients with some conduction system disturb-
prolonged AV effective and functional refractory ances because in clinically practical doses nicard-
periods and AV conduction time (A-H interval) in ipine has few untoward effects on SA and AV no-
a dose-dependent manner (Tamamura et al. 1981, dal function, and may not have any antiarrhythmic
1983). These effects were similar to those produced effects (Horio et al. 1983; Tamamura et al. 1983).
by nifedipine, diltiazem and verapamil in studies It was further intimated by these authors that any
performed by Kawai et al. (1981) using isolated effects of nicardipine on human cardiac conduc-
rabbit hearts. In patients with cardiac disease (sick tion are masked by the potent vasodilating prop-
sinus syndrome, AV block, premature ventricular erties of the drug which cause a reflex increase in
contractions, etc.), nicardipine has had no effect on sympathetic tone (see section 1.3).
the A-H or H-V intervals (Horio et a!. 1983; Mat- Importantly, in anaesthetised open-chest dogs,
sui et al. 1982). Although varying effects have been nicardipine in doses sufficient to enhance the cor-
reported on the atrial effective refractory period, onary circulation (section 1.3) failed to reduce con-
AV effective and functional refractory period and duction delays produced by coronary occlusion
sinus nodal recovery time have been reported, in under a constant atrial pacing (Nakaya & Kanno
2 patients with Wolff-Parkinson-White syndrome 1982). Thus, nicardipine may not have major ef-
the accessory conduction pathway was not affected fects on re-entrant ventricular arrhythmias.
Electrocardiographic observations in 10 healthy in patients at rest than at exercise (Baba et al. 1986;
volunteers given intravenous nicardipine in doses Campbell et al. 1984; Iliopoulou et al. 1983; Jack-
of 10 to 160 ~gfkg over 1 minute have demon- son et al. 1984; Kishi et al. 1984; Silke et al. 1984b,
strated that T-wave amplitude reductions were dose 1985a; Taylor et al. 1982; Visser et al. 1984; table
related (Campbell et al. 1985; Iliopoulou et al. II; fig. 2).
1983). However, when corrected for heart rate, the Some investigations have revealed a tendency
measured changes in the Q-T interval were not sig- for nicardipine to reduce diastolic blood pressure
nificantlyaffected. No significant changes have been to a greater degree than systolic blood pressure
observed in the P-R, QRS or Q-T intervals or in (Coruzzi et al. 1985; Iliopoulou et al. 1983; Jackson
the QRS pattern during short (3-week) and longer et al. 1984; Kishi et al. 1984; Silke et al. 1984a,b,
term (3- to 5-month) administration of the drug 1986b); however, this has not always been the case
(Gheorghiade et al. 1985). (Taylor et al. 1985b). Campbell et al. (1985) have
stated that this results from baroreceptor-mediated
1.2 Haemodynamic Effects compensatory changes which are manifested in part
by the increased pulse rate produced by the drug
The haemodynamic effects of nicardipine have (section 1.2.2). However, Levenson et al. (1985)
been investigated utilising both non-invasive found that the antihypertensive activity of oral ni-
(random zero sphygmomanometer, pulse rate) and cardipine 40mg resulted in similar reductions of
invasive (Swan Ganz catheter) techniques. The in- systolic and diastolic pressures, decreasing both by
vasive techniques have allowed continuous moni- 14% in 15 patients with essential hypertension.
toring of right atrial and pulmonary artery pres- In any case, a significant decrease in supine
sures, while other haemodynamic parameters have mean blood pressure due to nicardipine has been
been determined by additional direct and indirect shown to be maintained for several months with-
methods. Clinical and acute haemodynamic stud- out evidence of tachyphylaxis (Fujita & Noda 1983;
ies have been performed in normal volunteers and section 3.2). The decreases in blood pressure due
in patients with various cardiovascular disorders to nicardipine administration are related to con-
(for a recent review see Silke et al. 1986a). Acute current changes in the total peripheral resistance
haemodynamic effects after oral and intravenous (section 1.2.3).
administration of nicardipine are summarised in
table II. 1.2.2 Effect on Heart Rate
Acute administration of nicardipine results in a
1.2.1 Effect on Blood Pressure statistically significant increase in heart rate, which,
Nicardipine has been shown to produce dose- as with its antihypertensive effects, is dose de-
related decreases in resting blood pressure in pendent (Aoki et al. 1982; Campbell et al. 1984,
healthy volunteers and in patients with hyperten- 1985; Iliopoulou et al. 1983; Jackson et al. 1984;
sion or coronary artery disease (Baba et al. 1986; Jamieson et al. 1985; Silke et al. 1984a,b, 1985a,b)
Iliopoulou et al. 1983; Jackson et al. 1984; Kishi [table II]. Following intravenous administration
et al. 1984; Silke et al. 1984a,b, 1985a, 1986b; Tay- (IOmg) heart rate increased by 13 to 26% in patients
lor et al. 1982). Intravenous doses of nicardipine with coronary artery disease (Jackson et al. 1984;
lOmg have resulted in mean arterial pressure de- Rousseau et al. 1984a; Silke et al. 1984a,b, 1985a;
creasing by as much as 30% (Visser et al. 1984; fig. Visser et al. 1984), while single oral doses of 40mg
2). The onset of reduction in blood pressure oc- increased heart rate by 8 to 16% in healthy volun-
curred within I and 20 minutes after intravenous teers and in patients with essential hypertension
and oral administration, respectively, and blood (Iliopoulou et al. 1983; Levenson et al. 1985). Sig-
pressure lowering effects lasted as long as 3 hours. nificant increases in heart rate occurred within 1
Reductions in blood pressure were generally greater minute of intravenous and 30 minutes of oral
Table II, Summary of some single-dose haemodynamic studies of nicardipine in volunteers and patients with cardiovascular disease Z
;:;'
I>l
References Patient population Dose Patient status Maximal statistically significant percentage changes from baseline
[no. of subjects] [(mg) route]
&.
'0
MAP MBP SBP DBP HR CI CO SVI SVR PVR MPAP LVFP 5'
~
(PCWP)
;J;.
~
<>
<
Burlewet Chronic 2 IV Rest -15 ± +41 +41 -40 -21 iii'
~
al. (1986) CHF [10] followed Exercise -8 ± ± ± ± ±
by IV
infusion"
Greenbaum et al. Chronic LV 10 IV (n = 3) Rest ± ± ± ± +32 -23 ± ± ±

(1986) failure [9] 20 IV (n = 6) Rest -19 -22 +20 +64 +35 -50 -45 ± ±
Jackson et al. Stable AP 2.5 IV Rest - 5 -3 -6 ± +18 +17 -19 ±

(1984) [10] Exercise ± ± ± ± ± ± ± ±
10 IV Rest -17 -4 -22 +18 +59 +33 -47 +67
Exercise -10 ± -9 +12 +8 ± -18 ±
Kishi et al. Vascular 0.5 IV (n =5) Rest -18 -16 -18 ± ± ± -26 ± ± ±
(1984) disease b [14] 1 IV (n = 9) Rest -35 -34 -36 ± +24 +24 -49 -32 ± ±
2 IV (n = 7) Rest -33 -31 -32 ± +26 +24 -50 -26 ± ±
Lahiri et al. Depressed LV 10lV Rest -23 -20 +28 +71

(1986) function [10]
Lambert et al. CAD & 2 IV Rest -13 +17 +36 -38

(1985b) depressed followed
LVF [15] by IV
infusion c
Levenson et al. EH [15] 40po Rest -14 -14 -14 +8

(1985)
McCredie et al. Vols [6] 20pOd Rest ± +21 +17 ± -15 ± ± ±

(1985) Vols [9] 30pOd Rest ± +13 +27 ± -24 ± ± ±
Rousseau et al. IHD [10] 5-10 IV Rest -23 -24 -23 +26 +63 -51 ± +33
(1984a)
...,
0
~
Z
Silke et al. AMI 1.25 IV· Rest -3 ± -4 +4 +12 -13 ± n'
....
I>l
(1984a) [15] 1.25 IV· Rest -3 ± -5 +8 +18 ±18 ± Po
2.5 IV· Rest -4 -2 -7 +11 +21 -20 ± '§:
::I
5 IV· Rest -8 -7 -11 +18 +33 -29 ± ~
;l>
~
Silke et al. CAD 10lVi Rest -12 -9 -14 +13 +30 - 31 ± "<
<ii'
(1985a) [12] Exercise -5 -5 ± +5 +16 -19 -20
~
Silke et al. CAD & 10lV Rest -6 -5 -8 ± +18 +14 +20
(1985c) stable AP Exercise -3 ± -2 ± ± ± ±
[10]
Silke et al. (1986) Stable AP [6] 10lV Rest -15 -8 -23 +13 +46 +22 -45 +33
Visser et al. CAD 10 IV Rest -30 +26 +40 -47

(1984) [12] Exercise -22 +13 +20 -36
a Nicardipine 2mg was given by intravenous injection and followed by an intravenous infusion (100 ltg/min) titrated to diminish mean arterial pressure at rest by 15%
of control.
b Patients were anaesthetised and were studied during vascular surgery.
c Nicardipine 2mg was given by intravenous injection and followed by an intravenous infusion (mean dose 97 ltg/min) to maintain a decrease in systolic blood pressure
of 10 to 20mm Hg.
d Dose given every 8 hours for 4 doses.
e Nicardipine doses given at 15-minute intervals until a cummulative total of 10mg administered.
Data recorded after a cummulative total of nicardipine 10mg administered, as per Silke et al. (1984a).
Abbreviations : MAP = mean arterial pressure; MBP = mean blood pressure; SBP = systolic blood pressure; DBP = diastolic blood pressure; HR = heart rate; CI
cardiac index; CO = cardiac output; SVI = stroke volume index; SVR = systemic vascular resistance; PVR = pulmonary vascular resistance ; MPAP = mean pulmonary
artery pressure; LVFP = left ventricular filling pressure; PCWP = pulmonary capillary wedge pressure; LV = left ventricular; CHF = congestive heart failure; AP = angina
pectoris; CAD = coronary artery disease; LVF = left ventricular function; EH = mild-to-moderate essential hypertension; vols = healthy volunteers; IHD = ischaemic heart
disease; AMI = acute myocardial infarction (patients examined within 4 to 18 hours of symptom onset; IV = intravenous; po = oral; ± = no statistically significant change
from baseline value.
patients (Corea et a1. 1981; Lederballe-Pedersen et

a1. 1980). Although reflex tachycardia may be del-
+40 eterious in patients with ischaemic heart disease,
longer term (greater than 2 months of treatment
+30 with oral nicardipine 60 to 120mg per day) nicar-
dipine administration causes no change in resting
heart rate (Fujita & Noda 1983; Gelman et al. 1985;
+20 Littler & Young 1985). Thus, heart rate apparently
returns to control (pretreatment) levels as a result
...'"
.2 + 10 of baroreceptor resetting while the systemic vaso-
'"
:-
dilator effects persist (Young et a1. 1984).
eE
0
u 0
E 0
1.2.3 Effect on Cardiac Haemodynamics
g (table II)
.,
Cl
c: The overall cardiac haemodynamic effect of ni-
1'u! -10 cardipine is to increase cardiac pumping activity;
.,
Cl this may result as a reflex response to its primary
'"
E
action, dilation of peripheral arteriolar resistance
.,
~ -20
a.. vessels, or it may occur as a result of cyclic AMP
phosphodiesterase inhibitory properties of nicard-
-30 ipine (Norman et a1. 1983; Sakamoto et a1. 1978).
In any event, nicardipine has been noted to sig-
-40 * nificantly increase cardiac index and cardiac out-
put in dose-related fashion, while simultaneously
reducing systemic vascular resistance in healthy
*
SVR
- 50
volunteers and patients with coronary artery dis-
ease, hypertension and left ventricular failure
(Kakutani & Bando 1983) [table II; fig. 2]. Nicar-
Fig. 2. Supine haemodynamic effects at rest ~ and during ex-
ercise (0) in 12 patients with coronary artery disease given a
dipine lOmg administered intravenously acutely
single intravenous dose of nicardipine 10mg; HR = heart rate; increased resting cardiac index and decreased rest-
CI = cardiac Index; MAP = mean arterial pressure; SVR = sys- ing systemic vascular resistance by 30 to 59% and
* 29 to 51 %, respectively (Jackson et a1. 1984; Rous-

temic vascular resistance; significantly different from control val-
ues: = p < 0.001 (after Visser et al. 1984). seau et a1. 1984a; Silke et a1. 1984a,b, 1985a; Visser
et a1. 1984)..
administration, and lasted as long as 3 hours These haemodynamic effects were shown to be
(Campbell et a1. 1984; Iliopoulou et a1. 1983). In maintained during long term drug treatment (60
addition, increases in heart rate are greater in mg/day for 4 months in 10 patients with essential
patients at rest than in those undergoing exercise hypertension), and the magnitude of the blood
(Jackson et a1. 1984; Silke et a1. 1984b, 1985a; Tay- pressure reduction induced by nicardipine was re-
lor et a1. 1982; Visser et a1. 1984) [fig. 2]. lated to the concurrent changes in systemic vas-
Nicardipine-induced increases in heart rate are cular resistance (Fujita & Noda 1983).
due to reflex adrenergic stimulation following a re- The additional correlation between increased
duction in total peripheral resistance (section 1.2.3), cardiac index and decreased systemic vascular re-
and are compatible with increased catecholamine sistance suggests that the improved cardiac pump-
concentrations seen after nifedipine administration ing ability results from afterload reduction (Camp-
in normotensive, hypertensive and heart failure bell et a1. 1984, 1985; Fujita & Noda 1983;
Iliopoulou et al. 1983; Jackson et al. 1984; Jamie- of intracoronary injections of nicardipine 0.17mg
son et al. 1985; Kakutani & Bando 1983; Kishi et (n = 10) and nifedipine O.lmg (n = 11) in patients
al. 1984; Lambert et al. 1985b; McCredie et al. 1985; with coronary artery disease. It was reported that
Silke et al. 1984a,b, 1985a; Visser et al. 1984), and while nicardipine affected neither the mean rate of
in fact the net effect of nicardipine is to improve rise of left and right ventricular pressures (dP/dt)
left ventricular function in patients with left ven- nor the time-constants of the fall in left ventricular
tricular failure (Greenbaum et al. 1986; Lahiri et pressure, nifedipine depressed dP/dt, increased left
al. 1986). Further support for afterload reduction ventricular end-diastolic pressure and prolonged the
has been reported in several studies where nicar- time-constants (p < 0.01 for each vs control values)
dipine was shown to significantly increase left ven- despite an increased heart rate and a lower left ven-
tricular ejection time while decreasing pre-ejection tricular systolic pressure. These effects were main-
period (Campbell et a1. 1984; Iliopoulou et al. 1983; tained during atrial pacing. Thus, in this study, in-
Jamieson et al. 1985; Lahiri et al. 1986; Silke et al. tracoronary administration of nicardipine had no
1986b). In fact, the lower the initial ejection frac- effect on left ventricular contractility and relaxa-
tion the greater the improvement achieved by ni- tion, whereas intracoronary nifedipine decreased
cardipine (Silke et al. 1986). This may have clinical both.
application in the treatment of heart failure (sec- The haemodynamic effects of nicardipine were
tion 3.3.1). Moreover, the decreases in blood pres- compared with those of verapamil following intra-
sure and systemic vascular resistance associated venous administration in a randomised single-blind
with nicardipine administration have not been as- study in 30 patients with coronary artery disease
sociated with significant changes in left or right (Silke et al. 1985b). At rest, nicardipine 7.5mg and
ventricular filling pressures (Kishi et al. 1984; verapamil 16mg both significantly (p < 0.01) de-
McCredie et al. 1985), indicating that nicardipine creased mean arterial pressure, systemic vascular
causes a dilation of arterioles with a minimal effect resistance and afterload, and increased (p < 0.01)
on venules (Kishi et al. 1984; Lipkin & Poole-Wil- stroke volume index. However, cardiac index was
son 1985). increased more with nicardipine than with vera-
pamil (25% vs 12%; p < 0.01 for nicardipine and
1.2.4 Haemodynamic Effects of Nicardipine p < 0.05 for verapamil versus controls), while pul-
Compared with, and in Combination with, monary artery occluded pressure increased after
Other Cardiovascular Drugs verapamil (p < 0.01) and did not significantly
change after nicardipine administration. During
Other Calcium Antagonists exercise, neither drug improved stroke volume in-
Nicardipine appears to produce similar haemo- dex, while pulmonary artery occluded pressure was
dynamic effects as nifedipine when given orally to significantly increased with verapamil (p < 0.01).
healthy subjects. In a double-blind crossover study It is important to note that although systolic blood
in which 6 healthy volunteers were given single oral pressure decreased during both the rest and exer-
doses of either nicardipine 40mg or nifedipine cise periods for each drug, left heart filling pressure
20mg, maximum reductions in systolic and dia- was relatively unchanged after nicardipine but in-
stolic blood pressures of 15/10 and 10/8mm Hg, creased after verapamil administration. In addi-
respectively, were achieved (Iliopoulou et a1. 1983). tion, heart rate was increased by nicardipine but
Mean heart rate increased 16% with nifedipine and decreased by verapamil both at rest and during ex-
12% with nicardipine, while mean pre-ejection pe- ercise. Even though the 2 drugs similarly affected
riod/left ventricular ejection time ratios were de- other haemodynamic parameters during exercise,
creased 16 to 17% with each drug, reflecting in- verapamil achieved these results at the expense of
creased myocardial contractility. a significantly increased left ventricular filling pres-
Rousseau and Pouleur (1984) studied the effects sure.
Therefore, intravenous verapamil, due to its ne- ease and stable angina pectoris; after 20 minutes,
gative dromotropic and inotropic effects, may pro- the second drug was administered and haemodyn-
duce greater left ventricular depression than nicar- amic measurements were repeated. Nicardipine re-
dipine. This would have obvious implications in duced blood pressure and systemic vascular resist-
the treatment of patients with compromised card- ance while augmenting cardiac and stroke volume
iac function when intravenous calcium antagonists indices (table II). Metoprolol decreased blood pres-
are administered. sure but also reduced heart rate and cardiac index
(p < 0.01) while increasing systemic vascular re-
I1-Blockers With and Without Other Calcium sistance (p < 0.01). However, combination therapy
Antagonists reduced systemic blood pressure and heart rate (p
Pouleur et al. (1984) assessed the effect of intra- < 0.01) with relatively modest effects on cardiac
venous nicardipine 2.5mg (n = 9) and sublingual index, stroke index, systemic vascular resistance
nifedipine 20 to 30mg (n = 8) on left ventricular and pulmonary artery occluded pressure, in part
inotropy and relaxation rate in patients with cor- dependent on the order of drug administration.
onary artery disease pretreated with intravenous Overall, the net haemodynamic effect of this com-
propranolol 0.1 mg/kg. Propranolol pretreatment bination therapy was an improved cardiac per-
decreased heart rate, peak dP/dt, increased left formance compared with either nicardipine or me-
ventricular end-diastolic pressure and slowed left toprolol monotherapy.
ventricular relaxation rate. In addition, cardiac Further investigations of nicardipine and 11-
output decreased from 4.7 to 3.7 L/min (p < 0.05). blockers were carried out by Rousseau et aI. (1984a),
Concomitant nicardipine or nifedipine decreased in which the acute combined effects of intravenous
left ventricular systolic pressure by 25 to 26mm Hg nicardipine 5 to 10mg and intravenous proprano-
(p < 0.01), increased heart rate by 12 to 23% (p < lol 0.1 mg/kg on myocardial contractility, left ven-
0.05) and increased cardiac output by about 30% tricular pump function and on systemic and pul-
(p < 0.05) compared with values during propran- monary pressures in 9 patients with ischaemic heart
olol pretreatment. When the changes in systolic disease were examined. As can be seen in table III,
function induced by nicardipine and nifedipine after propranolol, nicardipine still decreased mean
were compared, despite identical changes in heart arterial pressure and systemic vascular resistance,
rate and left ventricular systolic pressure, pump and improved ejection phase indices. Cardiac out-
function and inotropic activity were more im- put and ventricular relaxation, both decreased after
proved by nicardipine. Nicardipine produced no propranolol, returned to baseline values with ni-
myocardial depression, as indicated by a lack of cardipine. Furthermore, nicardipine improved end-
change in peak dP/dt and maximal left ventricular systolic volume and ejection fraction while maxi-
pressure/volume ratio. In contrast, the changes in mal left ventricular pressure/volume ratio was un-
systolic pressure and heart rate induced by nifed- changed.
ipine were not accompanied by significant de- Thus, nicardipine administration after propran-
creases in systolic wall stress, and nifedipine pro- olol improved haemodynamic and left ventricular
duced a small but definite negative inotropic effect. pump functions with negligible inotropic effects,
Furthermore, the beneficial effects of nicardipine even in patients with impaired left ventricular
were still evident after l1-blockade, indicating that function. Although nicardipine may therefore pre-
the haemodynamic improvements were not related sent no additional hazards to patients already re-
to reflex sympathetic increases. ceiving l1-blockers, and may in fact improve de-
Silke et al. (1985c) evaluated the acute resting creased pump function and elevated vascular
and post-exercise haemodynamic effects of intra- resistances without adversely affecting the inotro-
venous nicardipine 10mg (n = 10) and metoprolol pic state, additional studies involving long term
IOmg (n = 10) in patients with coronary artery dis- administration of oral {1-blockers would be desir-
Table III. Combined haemodynamic effects of propranolol pine has also been shown to be equipotent to ni-
(PROP) 0.1 mg/kg and nicardipine (NC) 2.5mg administered fedipine in decreasing coronary vascular resistance
intravenously to 9 patients with coronary artery disease (after
and increasing coronary blood flow although these
Rousseau et al. 1984a)
effects have been of longer duration with nicardi-
Parameter Baseline PROP PROP + pine (Bongrani et al. 1985b; Razzetti et al. 1984;
NC Takenaka et al. 1985). However, nicardipine was
10 times less potent than nifedipine in producing
HR (beats/min) 71 60** 74tt
negative inotropic effects at concentrations causing
LVEDP (mm Hg) 18 21* 21* coronary vasodilatation (Bongrani et al. 1985b;
Peak + dP/dt (mm Hg/sec) 1833 1514** 1541*t Schiantarelli et al. 1983). Furthermore, nicardipine
was found to be as much as 10 and 100 times more
MAP (mm Hg) 99 105* 89°tt
potent than verapamil and papaverine, respec-
CO (L/min; n = 5) 4.7 3.7* 4.9t tively, in decreasing coronary vascular resistance
SVR (dyne· sec' cmos; 1696 2352* 1504t (Bongrani etal. 1985b; Schientarelli et al. 1983).
n = 5) Increases in coronary blood flow due to nicardi-
T, (msec) 47 55** 48tt pine occur without corresponding changes in
myocardial oxygen consumption (Takenaka et
Abbreviations: HR = heart rate; LVEDP = left ventricular end- al. 1985).
diastolic pressure; dP/dt = rate of rise of left and right ventric-
ular pressures; MAP = mean aortic pressure; CO = cardiac out- Studies performed in patients with coronary ar-
put; SVR = systemic vascular resistance; T, = relaxation index tery disease have consistently shown that nicardi-
(time constant of isovolumic pressure fall). Significantly different pine produces coronary vasodilatation, as coronary
from baseline: * = p < 0.05; ** = P < 0.01. Significantly different blood flow is increased and coronary vascular re-
from propranolol alone: t = p < 0.05; tt = p < 0.Q1.
sistance is decreased. These effects have occurred
despite reductions in aortic pressure and no changes
in myocardial oxygen consumption (Berland et al.
able to confirm this potentially beneficial effect of 1986; Gheorghiade et al. 1985; Josephson et al.
nicardipine. 1986; Rousseau & Pouleur 1984; Rousseau et al.
1984b) [table IV]. Interestingly, in 13 of 14 patients
1.3 Effect on Coronary Circulation and with coronary artery disease intravenous nicardi-
Myocardial Oxygen Consumption pine decreased coronary vascular resistance to a
greater extent than systemic vascular resistance
Animal studies have indicated that nicardipine without producing depressant effects on ventricu-
is a potent coronary vasodilator which does not lar function (Lambert et al. 1985b; table IV). Over-
possess significant cardiodepressant properties. Ni- all, nicardipine produced a coronary resistance
cardipine increased coronary blood flow and myo- change 1.24 times the resistance change for the sys-
cardial oxygen tension in a dose-dependent man- temic vascular bed. A similar difference in sensi-
ner, and decreased coronary vascular resistance tivity of the 2 vascular beds for nicardipine has
while antagonising the coronary vasoconstrictor ef- been recorded in in vitro studies (Ohtsuka et al.
fects of autologous blood, acetylcholine, leuko- 1983).
trienes, potassium and noradrenaline (norepineph- Administration of intravenous propranolol to
rine) [Armstrong & Dumez 1985; Berdeaux & patients receiving nicardipine has not resulted in
Giudicelli 1985; Bongrani et al. 1985b; Doursout myocardial depressant effects, and mean aortic
et al. 1985; Eglen et al. 1983; Hashimoto et al. 1982; pressure and rate-pressure product values were sig-
Hof 1983; Lefer et al. 1984; Nakaya & Kanno 1982; nificantly decreased compared with predrug values
Razzetti et al. 1984; Satoh et al. 1985; Schiantarelli (Rousseau et al. 1984c, 1985). Moreover, nicardi-
et al. 1983; Takenaka et al. 1976, 1985]. Nicardi- pine has increased myocardial blood flow by 13
Table IV. Summary of some studies of the effect of nicardipine (NC) on coronary circulation and myocardial oxygen consumption
(MV0 2) in patients with coronary artery disease
References No. of Dose (mg) Patient MBF CVR aA-V02 RPP MV0 2
patients [route] status
Lambert et al. 15 2 [1V]a Resting +44 -40 ±

(1985b) Atrial pacing (n = 6) +19 -29
Rousseau et al. 10 2.5 [IV] Atrial pacing b +15 -20 ± -6 ±

(1984c) Cold pressor testb +7 -16 -11 ±
12 2.5-5 [IV] Atrial pacing +13 -23 -11
Atrial pacingC +21 -32
Rousseau et al. 10 2.5 [IV] Resting +39 -35 -25 ±

(1985) Atrial pacing +13 -13 -10 ±
Cold pressor test ± ± -6 ±
a 2mg IV followed by intravenous infusion (97 ltg/min) adjusted to maintain a 10 to 20mm Hg decrease in systolic blood pressure.
b Data combined with 11 patients given nisoldipine 0.06 to 0.12 ltg/kg IV.
c NC given after propranolol 0.1 mg IV given; data presented on table represent percentage changes from values measured after
propranolol administration.
Abbreviations: MBF = myocardial blood flow; CVR = coronary vascular resistance; /J.A-V02 = arterial-coronary sinus oxygen differ-
ence; RPP = rate-pressure product; IV = intravenous injection. All values reported are in percentages and are reported as statistically
significant changes from pre-NC values; ± = no statistically significant changes from pre-NC values.
and 21% and decreased coronary vascular resist- ular calcium appears to be partly responsible for
ance by 23 and 32% compared with values meas- ischaemic myocardial cell death (Katz & Reuter
ured before and after the prior intravenous admin- 1979), with the net result of this process being an
istration of propranolol, respectively (Rousseau et irreversible loss of mechanical and electrical activ-
a1. 1984c; table IV). ity within the cells of the ischaemic myocardium.
Whether coronary flow remains augmented with Inhibition of the inward transport of calcium by
long term nicardipine therapy has yet to be deter- nicardipine may therefore prevent mitochondrial
mined; however, available data from acute studies calcium overload and consequently preserve the
have shown that nicardipine is a powerful coron- structure and function of myocardial cells while
ary vasodilator. protecting against the deleterious effects of hypoxia
and ischaemia (Braunwald 1982; Fleckenstein et a1.
l.4Cardioprotective Effect 1983; Henry 1980; Nayler 1980, 1983; Nayler &
Grinwald 1981; Nayler et a1. 1980; Stone et a1. 1980;
Myocardial ischaemia and subsequent reperfu- Winniford et a1. 1982). In addition, it is likely that
sion may lead to· an accumulation of excess cyto- the effect of nicardipine on coronary haemodyn-
solic calcium and result in inhibition of adenosine amics and myocardial oxygen consumption (sec-
triphosphate (A TP) production by the mitochon- tion 1.3) contributes to a cardioprotective effect.
dria. In turn, this depression of ATPsynthesis can An in vitro study using ventricular strips of
eventually affect the sodium and calcium pumps guinea-pig left myocardium showed that nicardi-
and ultimately cause additional calcium accumu- pine decreased creatine kinase leakage during is-
lation in the cytoplasm and mitochondria, thus chaemia and that myocardial excitability was re-
further decreasing the ATP-generating capacity of covered during reperfusion (Duriez et a1. 1985). It
the mitochondria (Cheung et a1. 1986; Frey et a1. was thought that this cardioprotective effect may
1980; Shen & Jennings 1972). Increased intracell- have resulted from a delay in ischaemia-induced
calcium overload. Also, nicardipine was shown to (Alps et al. 1983a). In dog models of myocardial
preserve myocardial ATP and creatine kinase in ischaemia nicardipine treatment significantly mod-
other animal models of ischaemic myocardium, ified the general haemodynamic response to left
suggesting that the drug may be effective in pre- anterior descending coronary artery ligation, and
serving high energy stores and the viability of myo- produced a greater degree of infarct healing than
cardial cell membranes (Armstrong & Ferrandon was found in non-treated animals (Alps et al.
1985; Shikama et al. 1985; Sunamori et al. 1983). 1983b). Similarly, superimposed ST-segment ele-
However, Bongrani et al. (1985a) reported that al- vations in epicardial electrocardiograms were in-
though nicardipine administered before ischaemia hibited by nicardipine and the total area of necro-
in rabbit hearts was able to protect the myocard- tic tissue in the areas of the occluded myocardial
ium against ischaemic and reperfusion damage, this vascular beds was significantly (p < 0.05) smaller
protection was dependent upon the existence of in dogs treated with nicardipine (35%) than in those
sufficient amounts of pre-existing high energy stores not treated with the drug (68%). In addition, ni-
to maintain homeostasis with respect to calcium. cardipine was without any potentially undesirable
Hashimoto et al. (1985) suggested that the bene- effect on intra-atrial, intraventricular or atrioven-
ficial effects of nicardipine on myocardial ischae- tricular cardiac conduction (Alps et al. 1985). Sim-
mia in anaesthetised dogs are due not only to in- ilar results to the above studies were reported by
creases in myocardial oxygen tension caused by Endo et al. (1986). Nicardipine also produced de-
increases in regional myocardial blood flow, but creases in left ventricular systolic pressure and left
also to direct protective effects of nicardipine on ventricular end-diastolic pressure in these animals.
ischaemic myocardial cells. Thus, Berdeaux and Therefore, as well as being able to decrease peri-
Giudicelli (1985) reported that nicardipine-in- pheral resistance and hence afterload (section 1.2.3),
duced myocardial vasodilation was homogeneous nicardipine also decreased venous return (preload).
between the endocardium and the epicardium of Thus, it may be inferred that these favourable ef-
the ischaemic and non-ischaemic zones during in- fects on preload and afterload may contribute to
termittent coronary occlusion in dogs, while during beneficial (i.e. cardioprotective) blood distribution
permanent coronary occlusion the nicardipine-in- in ischaemic states.
duced myocardial vasodilation mainly developed There have been few studies investigating the
within the endocardium of the ischaemic zone, cardioprotective effect of nicardipine in humans.
leading to a beneficial transmural blood flow re- In 10 patients with angina pectoris in whom 14C_
distribution in that zone. Furthermore, Endo et al. lactate was infused, the left ventricular lactate ex-
(1986) reported that nicardipine (I 0 ~g/kg loading traction fraction increased more than the 14C-Iac-
dose followed by 8 ~gjkg for 6 hours) initiated prior tate extraction ratio after intravenous nicardipine
to and early after (15 min) coronary artery occlu- administration, indicating a reduction in left ven-
sion in dogs significantly (p < 0.05) limited infarct tricular lactate production (Rousseau et al. I 984c,
size by 37% to 49%. However, when administra- 1985). Similarly, in a randomised double-blind
tion was delayed for 3 hours, infarct size was not parallel group study of up to 5 weeks duration in
reduced. 35 patients with angina pectoris, myocardial lac-
Similarly, in a series of studies performed in ba- tate uptake decreased to a significantly greater ex-
boons and dogs, Alps et al. (I 983a,b, 1985) re- tent on propranolol 40mg twice daily (from 47 to
ported that nicardipine exerted a marked protec- 30 ~mol/min) than on nicardipine 30mg twice daily
tive effect in limiting the size and enhancing the (from 24 to 22 ~mol/min) [Rousseau et al. 1986].
healing of myocardial infarctions. In baboons, This reduction in left ventricular lactate produc-
intravenous pretreatment and intravenous or oral tion further supports the idea that nicardipine im-
post-ligation treatment with nicardipine reduced proves perfusion and aerobic metabolism in chron-
total infarctions from 41 % (controls) to about 20% ically ischaemic areas (Hanet et al. 1986). This, in
concert with increases in coronary blood flow in- injury during periods of reperfusion following cere-
duced by the drug (section 1.3), would allow en- bral ischaemia (Borzeix & Cahn 1983; Grotta et al.
hanced oxygen utilisation and reduced lactate pro- 1984). Consequently, calcium antagonists such as
duction in underperfused areas, potentially leading nicardipine may decrease ischaemia and abolish all
to improvements in ventricular function (Pouleur calcium-dependent contractile activations of the
et al. 1983; Rousseau et al. 1984c, 1985, 1986). cerebral vasculature (Grotta et al. 1986; section 1.9).
Nicardipine has been reported to cause marked
1.5 Effect on Peripheral Vascular Circulation cerebral vasodilation accompanied by reductions
in cerebral vascular resistance in cats, dogs and
Few studies have evaluated the effects of nicar- monkeys, to suppress cerebral vasoconstriction in
dipine on the peripheral vasculature in man. dogs caused by noradrenaline, aminophylline, car,
Nevertheless, nicardipine, by virtue of its strong bocyclic thromboxane A2, 5-hydroxytryptamine,
arterial dilating ability, has been shown to increase potassium or angiotensin II, and to lessen or pre-
peripheral blood flow with concomitant improve- vent basilar artery vasoconstriction in the cat in-
ments in arterial compliance. duced by autologous blood, prostaglandins E2 and
Nicardipine significantly decreased forearm F2a, and serotonin (Handa 1975; Handa et al. 1975;
vascular resistance in healthy volunteers and Matsui et al. 1979; Nakayama et al. 1985; Oishi et
patients with essential hypertension, by as much al. 1978; Roca & Balasch 1984; Takenaka 1974;
as 45% after single-dose and long term (3-month) Takenaka & Handa 1979; Takenaka et al. 1976;
administration (Hulthen et al. 1985; Levenson et Yamamoto et al. 1983). Middle cerebral artery or
al. 1985; Thuillez et al. 1984). The reduction in internal carotid artery spasm induced by mechan-
forearm vascular resistance has been simultan- ical stimulation has also been completely reversed
eously accompanied by significant (p < 0.01) in- by topical application of nicardipine 0.001 to 0.01
creases in brachial artery compliance (by 51 to 68%) gIL to constricted artery segments (Handa 1975;
and diameter (21 %), brachial blood flow (61 %) and Handa et al. 1975). In addition, the vertebral va-
significant decreases in brachial artery impedance sodilating effects ofnicardipine have not been found
(20 to 22%) [Levenson et al. 1985; Thuillez et al. to be influenced by propranolol, atropine or di-
1984]. In addition, close correlations between base- phenhydramine, indicating that adrenergic, cholin-
line serum calcium concentrations and percentage ergic or histaminergic mechanisms are not in-
changes in forearm vascular resistance and blood volved in this action (Takenaka et al. 1976). Thus,
flow were noted by Levenson et al. (1985), indi- cerebral vasodilatation due to nicardipine can be
cating that decreases in peripheral vascular resist- attributed mainly to a direct vasodilatory action.
ance might be related to serum calcium concentra- The dose-related actions of nicardipine de-
tions. Thus, the ability of nicardipine to increase scribed above have resulted in marked and long-
brachial artery diameter may be taken as an indi- lasting increases in vertebral artery inflow and sag-
cation of its ability to dilate large peripheral arter- ittal sinus outflow, and cerebral blood flow as
ies with concomitant increases in arterial compli- measured by a microsphere technique, in the dog,
ance. Furthermore, because nicardipine also internal carotid artery blood flow in the rhesus
decreases forearm vascular resistance, it can be seen monkey, and cortical and cerebral blood flow in
that the drug also dilates small arteries (Levenson the cat and dog, as measured by a Xenon-133
et al. 1985; Thuillez et al. 1984). clearance method (Hof 1983, 1984; Matsui et al.
1979; Takenaka 1974; Takenaka & Handa 1979;
1.6 Cerebrovascular Effects Takenaka et al. 1976; Yamamoto et al. 1983; Young
et al. 1981, 1983). These increases in cerebral blood
It has been proposed that a cytotoxic factor such flow have been accompanied by increases in oxy-
as calcium influx might produce ongoing cellular gen delivery to the brain and elevations of cere-
brospinal fluid pressure in dogs (Montero et al. Nishikawa et al. (1986) investigated the effects
1986; Takenaka & Handa 1979). of intravenous boluses ofnicardipine (0.01 to 0.03
The cerebral vasodilatation induced by nicard- mgjkg) in 47 surgical patients without intracranial
ipine has been shown to be 50 to 300 times more pathology. Although the drug consistently in-
potent than that of papaverine and several other creased (p < 0.001) cerebrospinal fluid pressure,
cerebrovascular reference drugs, including isoxsu- these increases were not clinically significant and
prine and cinnarizine (Roca & Balasch 1984; Tak- were always accompanied by simultaneous de-
enaka 1974; Takenaka et al. 1976). This effect is creases in arterial blood pressure, which resulted
more prolonged after nicardipine that that achieved in reductions of cerebral perfusion pressure. Thus,
after the administration of papaverine (Takenaka in the absence of intracranial pathology, nicardi-
& Handa 1979). pine may not cause harmful intracranial sequelae;
When administered into the vertebral artery of however, these data suggest that it might be pru-
dogs, nicardipine (0.3 to lO ~g/kg) produced cere- dent to avoid the use of nicardipine in patients with
bral vasodilatation without affecting systemic blood intracranial hypertension (Nishikawa et al. 1986).
pressure (Takenaka et al. 1976). Thus, nicardipine
is a more potent cerebral than peripheral vasodi- l. 7 Renal Effects
lator (Nakayama et al. 1985; Oishi et al. 1978; Tak-
enaka et al. 1976; Yamamoto et al. 1983). 1.7.1 Effect on Renal Blood Flow,
There have been few studies investigating the Renovascular Resistance and Glomerular
cerebrovascular effects of nicardipine in humans. Filtration Rate
Thuillez et a1. (1984) reported that nicardipine 20mg Experimental studies in dogs have shown that
3 times daily for 4 days in 6 volunteers, while not intrarenal infusions of nicardipine produce signifi-
affecting systemic blood pressure, significantly in- cant increases in renal blood flow and glomerular
creased carotid artery diameter and blood flow by filtration rate while decreasing renovascular resist-
lO and 35%, respectively, with peak effects occur- ance; thus, the overall effect of nicardipine is that
ring 4 hours after administration. Xenon-I 33 clear- of peripheral vasodilatation (Abe et al. 1983). In
ance studies have shown that intravenous nicard- rats, oral doses of 5 mg/kg have decreased reno-
ipine 1 ~g/kg increased cerebral blood flow by 5 to vascular resistance and increased renal blood flow,
29%, while up to I 0 ~g/kg increased flow by 11 to leading to diuresis and natriuresis within I hour of
17% (p < 0.01), with minimal decreases in sys- treatment (Rosenkranz et al. 1984). Similarly, in
temic arterial pressure (Handa 1975; Savage & saline-loaded rats, oral doses of nicardipine 10 mgj
James 1986; Takenaka & Handa 1979). Gaab et al. kg significantly increased 6 hour-urine volume and
(1985) reported that the topical application of ni- sodium excretion (Takenaka et al. 1985). However,
cardipine to the operation site in 6 patients under- larger doses (12 mg/kg) delayed these effects until
going surgery for extracranial anastomosis pro- 7 hours after nicardipine administration, possibly
duced marked dilatation in the small arterial due to reflex increases in plasma renin activity
cortical vessels and relaxation of cerebral vaso- consequent to decreases in arterial pressure pro-
spasm. The width of the cortical arteries also induced by the drug (section 1.7.2).
creased. However, delays in the onset of these ac- It has been reported that acute (20 to 30mg) and
tions prompted the authors to suggest that multiple-dose (20 to 30mg 3 times daily for 6 to 9
cerebrovascular contraction is temporarily main- days) administration of oral nicardipine did not
tained by calcium already present in the cells. If significantly alter renal blood flow or glomerular
this assumption is correct, smooth muscle relaxa- filtration rate in hypertensive patients with or
tion induced by nicardipine will occur only after without impaired renal function (Chaignon et al.
intracellular calcium stores have been used up 1985; Lee et al. 1986). However, in patients with-
(Gaab et al. 1985). out renal disease, renovascular resistance was sig-
nificantly (p < 0.05) reduced after both the acute plasma renin activity (Abe et a1. 1983). Rats given
and multiple nicardipine doses (Chaignon et a1. oral nicardipine 5 mg/kg showed no significant
1985). These results differ somewhat from those changes in plasma aldosterone concentrations, but
obtained by Yokoyama and Kaburagi (1981, 1983) when given 12 to 20 mg/kg, plasma aldosterone
in which single doses of oral (20mg) and intraven- concentrations became significantly elevated 1 hour
ous (33 ~g/min) nicardipine increased glomerular after administration, gradually returning to base-
filtration rate and renal blood flow. Momose (1986) line values 3 to 5 hours later (Rosenkranz et a1.
and Baba et a1. (1986) reported similar results in 1984, 1985). It was postulated that the larger re-
26 surgical and 7 hypertensive patients given intra- ductions of arterial pressure induced by the in-
venous nicardipine 10mg over 20 minutes, and creased doses of nicardipine might result in a reflex
0.5mg over 30 seconds, respectively. Furthermore, increase in renin secretion, and angiotensin II and
renovascular resistance decreased by 30% (p < 0.05) aldosterone concentrations. This would then pre-
in the study reported by Baba et a1. (1986). vent immediate diuresis and natriuresis (section
Yokoyama and Kaburagi (1981) studied 17 1. 7.3) by increasing renal vasoconstriction and
patients with essential hypertension in which intra- sodium and water retention, with the end result
venous nicardipine (33 ~g/min) increased glomer- being an increase in blood pressure to overcome
ular filtration rate and renal blood flow by 62 and the negative feedback of the renin-angiotensin sys-
77%, respectively, and decreased renovascular re- tem. At this point, diuresis and natriuresis, due to
sistance by 37%. Patients with chronic glomerulo- the subsequent return of plasma aldosterone con-
nephritis with hypertension showed decreases in centrations to normal, would occur.
renovascular resistance of 16%, while those with Administration of acute intravenous (5 mg/h for
glomerulonephritis without hypertension did not 2.5 hours) or longer term oral (20 to 30mg 3 times
show any significant changes in these parameters. daily for up to 6 weeks) doses of nicardipine to
The authors suggested differences in renal patho- healthy volunteers or patients with essential hyper-
physiology between patients with essential hypertension has produced slight to significant (p < 0.01)
tension and chronic glomerulonephritis, with es- increases in plasma renin activity, while not af-
sential hypertensives having calcium-dependent fecting the plasma concentrations of noradrenaline
increased renal vascular tone (Yokoyama & Ka- or adrenaline (epinephrine) [Asplund 1985; Chaig-
buragi 1981). non et a1. 1985; Coruzzi et a1. 1985; Elliott et a1.
In addition, oral nicardipine 20mg produced in- 1985; Pasanisi et a1. 1985; Takabatake et a1. 1982;
creases in glomerular filtration rates of 6 and 5% Thuillez et a1. 1984; Van Schaik et a1. 1984, 1985].
in 10 essential hypertensives and 10 healthy sub- In a randomised double-blind parallel group study
jects, respectively (Van Schaik et a1. 1984). How- with either nicardipine 30mg 3 times daily (n =
ever, after 7 days of 3-times-daily treatment, it was 26) or placebo (n = 24) for 6 weeks, a mean in-
reported that glomerular filtration rates had increase in plasma renin activity of 52% was meas-
creased by 25% in the hypertensive patients but ured in those receiving the active drug (p < 0.01).
only by I % in the healthy subjects. Thus, increases Initial basal or stimulated plasma renin activity did
in glomerular filtration rates in patients with es- not correlate with blood pressure reduction in the
sential hypertension may be responsible for in- nicardipine group (Asplund 1985). These studies
creases in natriuresis seen in these patients (section also showed that, compared with placebo, plasma
1.7.3). aldosterone concentrations did not differ or slightly
decreased after nicardipine administration. Fur-
1.7.2 Effects on Plasma Renin Activity, thermore, nicardipine did not inhibit the signifi-
Angiotensin and Aldosterone cant increases in aldosterone secretion or decreases
Intrarenal infusion of nicardipine to anaesthe- in plasma renin activity produced by subsequent
tised dogs produced increases in renin release and intravenous infusion of angiotensin II. In addition,
nicardipine substantially attenuated the pressor re- with essential hypertension but without target or-
sponse that occurred after the intravenous admin- gan damage, acute (30mg) and long term (20 to
istration of angiotensin II, limiting increases in 40mg 3 times daily for 2 months) oral nicardipine
mean arterial pressure to 14 and 17mm Hg after administration produced significant (p = 0.05) di-
intravenous (5 mg/h for 2.5 hours) and oral (30mg uretic effects during the day; however, overall ur-
3 times daily for 7 days) administration, respec- inary volume throughout a 24-hour period was not
tively. This compared with a 24mm Hg increase significantly increased after the long term therapy
measured after placebo administration (Elliott et (1772 versus 2014ml). Furthermore, a significant (p
al. 1985). Thus, there is no evidence that inhibition < 0.05) natriuretic effect was observed only after
of aldosterone release contributes to the antihyper- the acute dosing (Young et al. 1985).
tensive mechanism of action of nicardipine. In fact, Van Schaik et al. (l984, 1985) studied the renal
the above data may suggest that nicardipine effects of oral nicardipine after acute (single dose
administration can abolish whatever pressor role 20mg) and short term (20mg 3 times daily for 7
may be played by angiotensin II in hypertensive days) administration to 10 healthy volunteers and
patients, without interrupting the normally func- 10 patients with essential hypertension. Both groups
tioning mechanisms responsible for electrolyte reg- of subjects exhibited maximal diuresis (p < 0.01)
ulation (i.e. aldosterone). after 7 days of treatment. During water loading ni-
cardipine significantly increased urine volume and
1.7.3 Other Renal Effects urinary excretion of sodium. In another study,
In dogs, intrarenal infusion of nicardipine 5 ILg/ similar increases in urinary sodium excretion of
min significantly increased urinary sodium and po- 95% were reported in 17 patients with essential
tassium excretion and urine flow (p < 0.05) [Abe hypertension given intravenous nicardipine 33 ILg/
et al. 1983]. It appeared that this diuretic action min, and an increase in urinary potassium excre-
occurred as a direct consequence of increases in the tion of 46% was also reported (Yokoyama & Ka-
glomerular filtration rate, decreases in fractional buragi 1981). However, these changes in electrolyte
reabsorption of sodium in the proximal tubules, excretion and urinary volume were not observed
and alterations in intrarenal haemodynamics (in- in patients with chronic glomerulonephritis.
creases in renal blood flow and decreases in re-
novascular resistance). Rosenkranz et al. (l984, 1.8 Other Effects
1985) studied rats and demonstrated that low oral
doses (5 mg/kg) produced a significant diuresis, na- 1.B.1 Effects on Airway Conductance
triuresis and kaliuresis 3 hours after dosing. Doses The role of calcium in airway function has been
of 12 mg/kg produced a significant retention of reviewed by Russi and Ahmed (1984). Thus, con-
urine, sodium and potassium beginning 1 hour after traction of bronchial smooth muscle and release of
administration, followed by increases in the excre- chemical mediators such as histamine and slow-
tion of these substances over the next several hours. reacting substance of anaphylaxis (SRS-A) result
These delays in urinary excretion were thought to from the influx of calcium ions across cell mem-
have resulted from reflex increases in renin secre- branes from the extracellular to the intracellular
tion due to decreases in arterial pressure produced compartment of mast cells and basophils (Fore-
by the higher (l2 mg/kg) doses of the drug (section man et al. 1977; Kirkpatrick 1975; Middleton 1980).
1.7.2). Therefore, agents which have the capacity to re-
In man, nicardipine produces some suppression duce the stimulus-associated cellular influx of cal-
of tubular function as indicated by modest and cium ions may theoretically be of benefit to asth-
short-acting natriuretic effects (Baba et al. 1986; matic patients.
Chaignon et al. 1985; Fagan et al. 1986; Momose In vitro studies using guinea-pig tracheal prep-
1986; Young et al. 1985). In 7 untreated patients arations have shown that nicardipine may inhibit
tracheobronchial smooth muscle contractions in- essary to determine whether nicardipine might
duced by physiological agents such as acetylchol- potentially impair glucose tolerance. While in vitro
ine, histamine, 5-hydroxytryptamine and leuko- studies measuring insulin release from rat pan-
triene 0 4, and non-physiological agents such as creatic islets show that nicardipine may indeed in-
barium chloride, potassium chloride, calcium hibit glucose-induced insulin release (AI-Mahmood
chloride and tetraethylammonium (Abdallah et al. et al. 1986), others (Marre et al. 1985a, 1986) have
1981; Advenier et al. 1984; Baronti et al. 1983; Cer- suggested that the concentrations of nicardipine re-
rina et al. 1983). Nicardipine also reduced hist- quired to effect such inhibition are much greater
amine release from basophils in in vitro human than the concentrations known to reduce vascular
whole blood and dispersed lung and tonsilar cells tone.
stimulated with antigen and anti-1gB, or anti-IgE Dow et al. (1985) studied 6 volunteers in a ran-
and the calcium ionophore A23187 (Kim et al. domised double-blind crossover trial in which the
1985; Tanizaki et al. 1985). On the other hand, in subjects were given either intravenous glucose 0.33
single-dose in vivo studies in 10 patients with non- g/kg or intravenous tolbutamide 200mg after re-
specific bronchial hyper-reactivity, nicardipine ceiving intravenous nicardipine 5 mg/h for 3 hours
20mg orally failed to inhibit acetylcholine-induced daily or placebo for 7 days. The results of this study
bronchospasm (Advenier et al. 1983; Baronti et al. demonstrated that nicardipine did not impair, and
1983). even increased, glucose-stimulated insulin secre-
The relevance of the above findings to any pro- tion, findings that parallel those reported by Marre
tective action that nicardipine may afford asth- et al. (1985b) in 7 hypertensive patients with es-
matic patients is questionable. Both in vitro and in tablished glucose intolerance given nicardipine 90
vivo studies have reported that concentrations of mg/day for 2 weeks. Similarly, long term admin-
nicardipine required to inhibit physiological me- istration of nicardipine did not reduce the hypog-
diators are much greater than the peak plasma con- lycaemic action of tolbutamide, as the insulin re-
centrations of nicardipine that are achieved with sponse to tolbutamide was not reduced after
conventional doses of the drug (Cerrina et al. 1983; nicardipine treatment. In addition, Sakata and
Kim et al. 1985). It has thus been suggested that Miura (1984) reported a hypertensive patient with
any protective effect ofnicardipine in patients with insulin-dependent diabetes whose daily require-
asthma may more likely result from its actions on ment of insulin remained unchanged after the oral
the bronchial musculature than inhibition of mast administration of nicardipine 60mg for 6 weeks.
cell (IgE-dependent) mediator release (Kim et al. However, Sando et al. (1983) suggested that nicar-
1985). In addition, Koshino et al. (1985) suggested dipine may aggravate plasma glucose control in
that nicardipine does not block the direct effect of non-insulin-dependent diabetics, possibly by sup-
SRS-A on smooth muscle, but that it blocks cal- pressing insulin secretion. Further studies are
cium influx required for the synthesis of SRS-A needed to determine not only if nicardipine inter-
and its release. In any case, longer term investi- feres with either the secretion or peripheral action
gations in patients with bronchial asthma are of insulin, but also its long term effects in diabetics,
still required before a proper assessment of the with particular attention to vascular effects.
beneficial effects, if any, of nicardipine in the The effect of intravenous nicardipine 5 mg/h for
treatment of such patients can be properly eval- 3 hours on basal and stimulated pituitary hormone
uated. release has been reported by Isles et al. (1985). In
6 healthy volunteers, nicardipine had no signifi-
1.8.2 Endocrine Effects cant effect on the concentrations of follicle-stim-
Since in vitro studies have shown that extracel- ulating hormone, luteinising hormone, prolactin,
lular calcium is essential for insulin release (Grod- or thyroid-stimulating hormone. Additionally, 28
sky & Bennett 1966; Hellman 1975), it was nec- days treatment with oral nicardipine 30mg 3 times
daily in 12 volunteers had no effect on thyroid vance of these findings is uncertain. In the only
homeostasis (Dow et al. 1986). related study done in man, Gheorghiade et al.
(1985) reported that nicardipine (up to 120 mg/day
1.8.3 Antiatherosclerotic Effects for up to 5 months of treatment) did not affect the
Several reports have indicated that agents in- serum triglyceride or cholesterol eoncentrations in
terfering with calcium influx into cells, including 18 patients with chronic stable angina pectoris.
nifedipine and verapamil, can inhibit atheroscler-
otic plaque formations in rabbits or primates 1.8.4 Effect on Platelets
maintained on hypercholesterolaemic diets (Henry The effects of nicardipine on in vitro whole blood
& Bentley 1981; Hollander et al. 1979; Kramsch & platelet aggregation were studied by Greer et al.
Chan 1978; Kramsch et al. 1980, 1981, 1982; Rou- (1986), and it was reported that nicardipine inhib-
leau et al. 1983; Wartman et al. 1967). These re- ited aggregation to collagen and arachidonic acid
sults have suggested that calcium antagonists may in a dose-dependent manner, but had minimal ef-
have potential therapeutic utility in the treatment fects on aggregation to ADP. Although nicardipine
of atherosclerosis. acted synergistically with prostacyclin (PGI 2) to in-
The effect of nicardipine in possibly inhibiting hibit aggregation, it did not affect thromboxane A2
the development of atherosclerosis has been in- production. However, PGIz production from whole
vestigated in rabbits and rats. Naito et al. (1984) blood was significantly increased at high concen-
did not report any significant differences in serum trations of the drug.
concentrations of total cholesterol, triglycerides, The same investigators (Greer et al. 1985) fur-
phospholipids or high-density lipoprotein (HDL) ther studied a possible synergism of nicardipine and
cholesterol in rabbits given a 1% cholesterol diet aspirin in the inhibition of in vitro platelet aggre-
and nicardipine 60 mg/day for 14 weeks. In con- gation. At concentrations ofnicardipine (10 mg/L)
trast, Ohata et al. (1984) and Willis et al. (1985) and aspirin (5 mg/L) which on their own had little
showed that nicardipine reduced the risk factors
effect on platelet aggregation, a combination of both
contributing to the development of atherosclerosis
drugs resulted in a significantly (p < 0.05) greater
and suppressed the formation of atherosclerotic le-
inhibition of platelet aggregation. Further studies
sions and accumulation of cholesterol in normal
are needed to determine whether nicardipine alone
animals and animals fed a high (1.5 to 2%) chol- or in combination with aspirin may thus be of value
esterol diet. Nicardipine, in doses of 10 to 100 mg/
in the prophylaxis of vascular problems where
kg, decreased low-density lipoprotein (LDL) chol-
platelet aggregation is involved in the pathogen-
esterol levels in rats, with corresponding increases
esis.
in HDL cholesterol levels (Ohata et al. 1984; Ohba
et al. 1985). Since HDL cholesterol may be a 'pro-
tective factor' against the development of coronary 1.9 Mechanism of Action
heart disease, and LDL cholesterol is one of the
risk factors for atherosclerosis (Hulley et al. 1980), Studies using human and animal vascular
nicardipine may thus have antiatherosclerotic ef- smooth muscle and cardiac muscle have provided
fects. However, the exact mechanism of action of evidence that nicardipine acts primarily by inhib-
nicardipine in producing these potentially benefic- iting calcium influx through the plasma mem-
ial effects is not known. Furthermore, the doses branes of these tissues (Baisch et al. 1982; Endoh
used in these animal studies were at least 10 times et al. 1980; Fujiwara & Kuriyama 1983; Satoh et
greater than those used in clinical practice, and it al. 1980; Takenaka et al. 1985; Terai et al. 1981;
has been pointed out that the sensitivity of animals Watanabe et al. 1981). Thus, in common with other
to atherogenic diets shows great individual differ- calcium antagonists, nicardipine competitively
ences (Naito et al. 1984). Thus, the clinical rele- blocks the cell membrane slow channels, resulting
in a decreased influx of calcium into the cell during as estimated by the rate-pressure product, is usu-
the active state (Fleckenstein et al. 1972). ally unaffected (section 1.3). This is due to the high
Although much has been written on the cellular degree of systemic vasodilatation (and hence a re-
and subcellular mechanism of action of calcium duction of left ventricular afterload) and resultant
antagonists (Antman et al. 1980; Braunwald 1982; decreases in blood pressure produced by nicardi-
Cheung et al. 1986; Flaim et al. 1982; Fleckenstein pine (sections 1.2.1 and 1.2.3) [fig. 3].
1977; Fleckenstein et al. 1972; Mannhold 1984; Sil- The underlying haemodynamic alteration in es-
ver et al. 1984; Stone et al. 1980), their precise tablished essential hypertension is an increase in
mechanism of action in the treatment of angina total peripheral resistance (Folkow 1982). Hence,
pectoris, hypertension and other vascular disorders since vascular tone and the maintenance of an el-
is still unclear (Flaim et al. 1982). However, these evated blood pressure is controlled by intracellular
authors have shown that in myocardial and smooth calcium concentrations in smooth muscle (Erne et
muscle cells, elevated intracellular calcium concen- al. 1984), inhibition of calcium influx by nicardi-
trations increase the binding of calcium to the reg- pine may produce arteriolar dilatation and de-
ulatory proteins troponin and calmodulin, respec- creases in total peripheral resistance leading to de-
tively, leading to muscular contraction. Reduction creases in blood pressure (sections 1.2.1 and 3.2)
of calcium influx by nicardipine thus produces [fig. 3].
electromechanical decoupling, resulting in inhibi-
tion of contraction and consequent relaxation of 2. Pharmacokinetics
the cardiac or smooth muscle fibres. Therefore,
calcium inhibition leads to a relaxation of coronary There have been few published studiesinves-
and peripheral arterial vascular tone with their at- tigating the pharmacokinetics of nicardipine in
tendant haemodynamic effects (fig. 3). man. Those studies which have been reported in-
In their review on the role of calcium antag- volved small numbers of volunteers and even
onists in the treatment of angina pectoris, Theroux smaller numbers of patients to whom nicardipine
et al. (1983) stated that the efficacy of these drugs would be expected to be administered (i.e. those
in this disease entity was probably dependent on with hypertension, angina pectoris or cerebrovas-
their general abilities to increase myocardial oxy- cular disease). In addition, the methodology and
gen supply and decrease myocardial oxygen de- results of these studies were not always clearly
mand. Nicardipine has been shown to increase the stated or reported. Thus, further well designed and
oxygen supply to the myocardium by relieving cor- reported studies are needed to more adequately de-
onary artery spasm (section 3.1.2) and decreasing fine the pharmacokinetic properties of nicardipine,
coronary artery tone and coronary vascular resist- especially in patients. Importantly, since nicardi-
ance (section 1.3; fig. 3). The decreases in coronary pine is eliminated largely via hepatic metabolism,
vascular resistance have led to greater increases in pharmacokinetic data in patients with liver disease
coronary blood flow than peripheral blood flow, are clearly needed before the drug is routinely used
indicating a selective vasodilating effect of nicar- in this type of patient.
dipine on the coronary vasculature (Takenaka et Plasma concentrations of nicardipine in phar-
al. 1976, 1985). macokinetic studies have been measured using
Factors which may cause a decrease in myo- several quantitative techniques. Gas-liquid chro-
cardial oxygen demand include vasodilatation, re- matography following oxidation of nicardipine to
duced blood pressure and afterload, slowing of the its pyridine analogue, which also measures a pyr-
heart rate and negative inotropy (Theroux et al. idine analogue metabolite (section 2.3), has a sen-
1983). Although nicardipine neither decreases heart sitivity of 0.5 to 3 mg/L (Clair et al. 1985; Higuchi
rate nor produces negative inotropic effects (sec- et al. 1975a). It is thought that the ratio of the
tions 1.2.2 and 1.2.3), myocardial oxygen demand, plasma concentrations of this metabolite to those
Negative inotropic effect j Peripheral arterial

(negligible) vascular tone
j Coronary artery spasm j Systemic vascular resistance

j Coronary artery tone
j Coronary vascular
resistance
j Blood pressure
t Heart rate
t Contractility
Positive inotropic effect
Fig. 3. Effect of nicardlpine on the myocardium and the coronary and peripheral arterial systems; t= increase; j = decrease (after
Lichtfen et al. 1984).
of nicardipine remain approximately constant so moval of the pyridine analogue by thin-layer chro-
that the qualitative aspects of data obtained by this matography (Higuchi & Kawamura 1981). Finally,
method are not affected. Gas chromatography-mass Massey et al. (1984) utilised high pressure liquid
spectrometry, with a sensitivity limit of 5 mg/L, chromatography to produce a specific method for
has also been used and is a highly specific method the simultaneou,s determination of nicardipine and
for determining unchanged nicardipine after the re- the pyridine metabolite in plasma.
2.1 Absorption trations have also been reported by others (Seki &
Takenaka 1977; Silke et al. 1984a; fig. 4). Higuchi
Pharmacokinetic studies in animals and man and Shiobara (1980a) showed that after single oral
have shown that after oral administration nicard- doses of 10, 20, 30 and 40mg, areas under the
ipine is rapidly and completely absorbed (Higuchi plasma concentration-time curve (AVC) were 1.4,
et al. 1977). In humans, peak plasma concentra- 4.6, 10.3 and 24.2 mg/L· min, respectively, and
tions are reached between 20 minutes and 2 hours systemiC bioavailabilities were 6.5, 10.2, 16.5 and
after oral administration, thereafter declining via 30.3%, respectively. Therefore, despite the fact that
first-order rate kinetics (Clair et al. 1985; Forette nicardipine is well absorbed, its systemic bioavail-
et al. 1985; Graham et al. 1984, 1985; Higuchi & ability is low, apparently due to extensive presys-
Shiobara 1980a; McCredie et al. 1985; Okura 1983; temic metabolism (Higuchi & Shiobara 1980b; sec"
Rush et al. 1986; Seki & Takenaka 1977; Thuillez tion 2.3).
et al. 1984) [fig. 4]. The rapid absorption of nicar- The dispropOI1ional increases in AVC with lin-
dipine has been attributed to its high aqueous sol- ear dose increments indicate that systemic bio-
ubility. availability increases with increasing doses of ni-
Intravenous nicardipine in doses of 5 and IOmg, cardipine. The non-linear increases in plasma
given over 10 minutes, resulted in plasma concen- concentration and systemic bioavailability further
trations of 68 and 123 ~g/L, respectively, in patients suggest that presystemic metabolic pathways be-
with coronary artery disease (Rousseau et al. come saturated with nicardipine or its metabolites
I 984a). Maximum plasma concentrations in 6 (Graham et al. 1984, 1985; Higuchi & Shiobara
volunteers given single oral doses of nicardipine 1980a; section 2.3). This idea is supported by the
10,20, 30 and 40mg were 13, 32, 91 and 253 ~g/ results obtained by Thuillez et al. (1984) which
L, respectively (Higuchi & Shiobara 1980a). Sim- demonstrated that the relative bioavailability of a
ilar non-linear increases in peak plasma concen- sustained release formulation of nicardipine was
markedly decreased (60%) compared with that of
a conventional tablet formulation. This reduction
in bioavailability is thought to be due to the high
:J' 180
plasma concentrations achieved after oral admin-
~ istration of a conventional preparation of nicard-
.§ 150
ipine, in some cases resulting in saturation of bio-
~c:
transformation processes. Such high plasma
2l 120
8 concentrations would not be achieved after the
tIS administration of a sustained release formulation
E 90
! (Thuillez et al. 1984).
In comparison with middle-aged (mean age 54
~
'0. 60
years) hypertensive patients, elderly patients (mean
~
age 86 years) showed comparatively higher mini-
~ 30
mum and maximum plasma concentrations of ni-
cardipine after oral administration of 90 mg/day
~~~====~==~;;~~~
o 2 3 4 8 for more than 1 week (18 and 107 ~g/L, and 38
Time (hours) and 291 ~gjL, respectively) [Forette et a1. 1985]. It
is thought that this difference may be due to a de-
crease in the first-pass effect in elderly patients.
Fig. 4. Mean plasma concentrations of nicardipine in fasted
healthy volunteers after the single-dose oral administration of
However, Brown and colleagues (1986) reported
10mg (e; n = 2), 20mg (t:.; n = 2) and 40mg (II; n == 6) latter that nicardipine plasma concentrations showed no
Seki & Takenaka 1977]. tendency to accumulate with time in a group of 57
elderly (median aged 70 years) hypertensive patients the fourteenth or twenty-first day of treatment,
who were treated with nicardipine 10 to 30mg 3 suggesting that a steady-state had been established
times daily for 8 weeks. within the first 14 days of administration (Higuchi
Although food has been found to decrease both et al. 1980). 48 hours after the final dose, radio-
the maximum plasma concentrations and AVCs activity was detected only in the liver, kidney,
obtained after oral administration, bioavailability plasma and blood (Higuchi et al. 1980).
appears to peak on the third day of oral adminis- In vitro ultracentrifugation studies using human
tration, thereafter declining to some extent (Gra- plasma have shown that over 90% of nicardipine
ham et al. 1984). However, the extensive presys- is bound to plasma protein at concentrations of 100
temic elimination of nicardipine (section 2.3) has ~g/L; the amount of bound nicardipine decreased
resulted in large degrees of inter- and intrasubject with increasing drug concentrations (Higuchi &
variation in plasma concentrations (Graham et al. Shiobara 1980b). However, using isotope tech-
1984; Higuchi et al. 1980). This degree of variation niques, equilibrium dialysis and incubation exper-
has been shown to be reduced following multiple iments, Vrien et al. (1985) demonstrated that the
dose administration (Graham et al. 1984). Thus, overall binding of nicardipine in serum varied from
although individual patients may show large fluc- 98 to 99.5% and correlated with serum lipid con-
tuations in plasma concentrations, mean values centrations. In addition, this binding of nicardi-
taken on different days in 6 patients with cerebro- pine, which was predominantly to ai-acid glyco-
vascular disease given nicardipine 20mg 3 times proteins, human serum albumin and lipoproteins,
daily for 28 days were very similar (Higuchi et al. was noted to be dependent on pH, and increased
1980). In another 6 patients continued on nicard- if the pH or non-ionised nicardipine fraction in-
ipine 20mg 3 times daily for 1 year, mean plasma creased. Nicardipine has also been shown to re-
concentrations after 12 months of treatment were versibly bind to erythrocyte membrane proteins
again very similar to those obtained in the first 4 (Lagercrantz et al. 1984).
weeks of treatment (Higuchi et al. 1980). These re- In 2 volunteers given intravenous nicardipine
sults also indicate that the plasma concentrations 0.01 and 0.02 mg/kg, volumes of distribution were
of nicardipine exhibit no tendency to increase dur- calculated to be 0.644 and 0.641 L/kg, respectively
ing prolonged periods of administration. (Higuchi & Shiobara 1980a). An apparent volume
of distribution of 63L was reported in 6 healthy
2.2 Distribution volunteers given intravenous nicardipine 160 ~g/
kg (Campbell et al. 1985).
Maximum concentrations of radioactivity were
found in the tissues of rats 0.5 to 1 hour after oral 2.3 Metabolism
administration of radiolabelled nicardipine 3 mg!
kg (Higuchi et al. 1977). Highest concentrations of When nicardipine was administered orally to
the drug were recovered from the liver, kidney and rats, dogs, monkeys and humans, the plasma con-
lung, with the heart, spleen, muscle and brain concentrations of unchanged drug were less than those
taining much less radioactivity than the plasma achieved after intravenous administration, despite
(Higuchi et al. 1977, 1980). Intravenous adminis- the good absorption of the drug (Higuchi & Shiob-
tration of nicardipine produced similar distribu- ara 1980a). The dosages of nicardipine capable of
tion patterns as oral administration, with the pan- causing vasodilatation in healthy volunteers after
creas, intestinal wall and salivary gland also intravenous administration were also less than the
containing radioactivity in greater amounts than dosages required after oral dosing (Seki & Tak-
the blood (Higuchi et al. 1977). No difference in enaka 1977). In addition, when 14C-Iabelled nicar-
the tissue distribution in rats given radiolabelled dipine 30mg was given in an oral solution to 4
nicardipine 3 mg/kg for 21 days was found after healthy volunteers, parent compound comprised
only a minor fraction of the circulating radioactiv- et al. (1984) have confirmed a very low renal clear-
ity after 1 hour (Rush et al. 1986). This finding, in ance of nicardipine, since the urinary elimination
concert with the above results, suggests that nicar- of unchanged drug ranged from 0.6 to 3.5~g per 24
dipine undergoes rapid first-pass metabolism dur- hours after oral administration of 20mg 3 times
ing its entrance into the systemic circulation. Hig- daily, or 30mg in a sustained release formulation
uchi and Shiobara (1980b) have further shown that twice daily, for 4 days in 6 healthy volunteers.
nicardipine is metabolised only in the liver, so that No evidence for any non-linearity in eliminat-
the presystemic metabolism of nicardipine is due ion processes involving intravenous nicardipine has
to hepatic metabolism. Long term administration been found in studies involving doses of up to 20mg
of nicardipine shows no evidence of hepatic mi- (Graham et al. 1984). Intravenous administration
crosomal enzyme induction in man (Dow & Gra- of nicardipine in human volunteers produced
ham 1984). clearance values which ranged from 0.31 to 0.91
The metabolism of nicardipine in humans is L/h/kg (Graham et al. 1984; Higuchi & Shiobara
rapid and extensive (Dow & Graham 1986; Hig- 1980a; Jamieson et al. 1985; Silke et al. 1986) to
uchi et al. 1977, 1980; Higuchi & Shiobara 1980a; 72 L/h (Campbell et al. 1985). Oral administration
Rush et al. 1986; Seki & Takenaka 1977). There of nicardipine to 6 volunteers in doses of 10, 20,
are 2 main classes of metabolites: those where the 30 and 40mg produced plasma clearance values of
dihydropyridine ring is intact and those where ox- 7.86, 5.4, 3.84 and 1.62 L/h/kg, respectively (Hig-
idation has occurred resulting in a pyridine uchi & Shiobara 1980a), similar to data obtained
analogue metabolite. Although several metabolites in different species (rats, dogs, monkeys) where ni-
resulting from sequential metabolism of the N- cardipine also disappeared from the plasma more
benzyl side chain have been identified, the extent rapidly after an oral dose (due to presystemic elim-
ination) than after an intravenous dose (Higuchi &
of oxidation that occurs in vivo has not yet been
Shiobara 1980a). The decrease in clearance noted
clearly determined. Major metabolites appearing
with increasing oral doses of the drug demonstrates
in the urine are the glucuronide conjugates of the
that the hepatic removal mechanisms for nicardi-
alcohol metabolites (Graham et al. 1985; Rush et
pine are saturable (Baky 1985). Higuchi and Shiob-
al. 1986). Studies involving either a single dose, or
ara (l980a) speculated that the disappearance of
administration 3 times daily for 3 days, have shown
orally administered nicardipine was rate-limited by
that less than 0.03% of unchanged nicardipine is
its absorption from the gastrointestinal tract. Thus,
recovered in the urine in humans after oral or
it may be that the elimination half-life of nicard-
intravenous administration (Seki & Takenaka
ipine (section 2.3.1) corresponds to its absorption
1977).
half-life.
The vasodilating potency of all metabolites of
Animal studies have shown that radiolabelled
nicardipine thus far identified is less than I% of
nicardipine is excreted mainly through the bile and
that of the parent drug (Higuchi etal. 1975b; Shi- faeces (66 to 72% over a 48-hour period) regardless
banuma et al. 1980). Thus, the pharmacological ef- of whether the drug is given intravenously or orally
fects attributed to nicardipine are due mainly to (Higuchi et al. 1977). However, Rush et al. (1986)
the parent compound itself. reported that in 4 healthy volunteers given a 30mg
oral dose of radiolabelled nicardipine, urinary and
2.4 Elimination faecal elimination of the dosed radioactivity was
about 60% and 35%, respectively, over a 96-hour
As nicardipine is extensively metabolised and period.
unchanged drug is essentially absent from the urine
(section 2.3), it is considered that the clearance of 2.4.1 Half-Life
the drug is due mainly to its metabolic clearance Intravenous administration of nicardipine 0.01
by the liver (Higuchi & Shiobara 1980a). Thuillez and 0.02 mg/kg in 2 healthy volunteers resulted in
elimination half-lives of 63 and 50 minutes, re- administration of 20mg 3 times daily for 8 days to
spectively (Higuchi & Shiobara 1980a). These val- 14 patients with renal insufficiency and to 10
ues are very similar to the mean elimination half- healthy subjects and demonstrated no increase in
lives (range 44 to 73 minutes) reported after intra- antihypertensive effect and no abnormal accumu-
venous administration of nicardipine 10 to 20mg lation or prolongation of elimination half-life in
in healthy volunteers in other studies (Campbell et patients with renal insufficiency. Furthermore,
al. 1984; Jamieson et al. 1985; Seki & Takenaka haemodialysis did not appear to influence the ki-
1977). While Clarke et al. (1983) reported a mean netics ofnicardipine. In addition, there was no evi-
elimination half-life of 107 minutes after intraven- dence of a need for a compensatory nicardipine
ous nicardipine 160 ~gJkg was administered to 6 dose at the end of dialysis. Since the metabolites
~ormotensive males, wide interindividual varia- ofnicardipine have little or no activity and no tox-
bility occurred in a similar study by Graham et al. icity in comparison with the parent compound
(1984). In this study the mean elimination half-life (section 2.3; unpublished data on file, Yamanouchi
in 5 volunteers who received intravenous nicard- Pharmaceutical Co.), the authors concluded that
ipine 5 mgJh for 3 hours was 285 minutes. nicardipine may be used in patients with severe
In 6 volunteers given single oral doses of ni- renal failure without any change in the dose and
cardipine of between 10 and 40mg elimination half- frequency of its administration (Clair et al. 1985).
lives ranged between 45 and 97 minutes (Higuchi However, since nicardipine is eliminated largely by
& Shiobara 1980a), while in another study in 12 metabolic degradation to inactive metabolites, there
volunteers given single doses of oral nicardipine is a need for pharmacokinetic data in patients with
10, 20 or 40mg the mean elimination half-life was liver disease before dosage recommendations can
81 minutes (Seki & Takenaka 1977). be made in this class of patient.
2.5 Effect of Disease on Pharmacokinetics 3. Therapeutic Trials

3.1 Angina Pectoris
Following administration of nicardipine 20 and
30mg to patients with impaired renal function with
associated hypertension and to healthy volunteers, An imbalance between myocardial oxygen sup-
peak plasma concentrations were attained after 1 ply and demand may result in myocardial ischae-
hour (Lee et al. 1986). At both dose levels the mia. This imbalance can be directly related either
patients with renal insufficiency achieved higher to some degree of coronary artery atherosclerosis,
maximum plasma concentrations (20mg: 38 vs 24 and/or to an alteration in coronary artery tone,
~g/L; 30mg: 78 vs 37 ~g/L) and AUCs (20mg: 66 which in its most extreme form results in arterial
vs 38 ~g/L' h; 30mg: 154 vs 62 ~g/L • h). These in- spasm. Although nicardipine has been used pri-
creases in Cmax and AUC in the nicardipine group marily in the treatment of patients with chronic
were associated with a decrease in overall clearance stable angina pectoris, most studies have been of
(20mg: 6.4 vs 11.6 L/h; 30mg: 3.5 vs 8.0 L/h), how- short duration (less than 4 months) and have not
ever, there was no correlation between nicardipine involved large patient populations. In addition, data
clearance and plasma drug concentrations. After from trials in which nicardipine has been com-
repeat administration of nicardipine, 20 and 30mg pared with other antianginal agents have not been
3 times daily for 9 days, Cmax and AUC values extensive. Thus, additional long term controlled
were slightly increased and clearance values slightly studies involving greater numbers of patients are
decreased in all groups, although there was no evi- needed before the role of nicardipine in angina pec-
dence of drug accumulation. toris can be specifically defined. Nevertheless, en-
Clair and associates (1985) determined mini- couraging results with nicardipine have thus far
mum nicardipine plasma concentrations following been obtained in patients with angina pectoris.
Z
(=i'
Bjerle et al. 17 r, db, co NC: 90 4w +4 +5 -50 -4
....
Il>
(1986) PR: 120 4w +2 +5 -57 -27 ~
'"0
Bowles et al. 38 r, db, co NC: 90 4w +42*** +30*** -35 -31
S·
+1 ~
(1986)d NF: 30 +42**- +35*** -31 -28 +3 ;l>
Bowles et aI., ~
134 p NC: 120 4w +30*** <1>
(1983)d NF: 60 +39***
<
(D'
D: 180 +55*** ~
D: 360 +54***
V: 360 +70***
PR: 240 +54***
Di Pasquale et al. 12 r, db, co NC: 80 6w +18* +19* +20*' -67* -77* +1

(1984)d NF: 40 +21** +30** +36**' -56* -38* +4
Logan et al. 40 r, db co NC: 90 4w +13** +21* +39** -26** +1
(1986) AT: 100 4w +22** +34** +66** -51** -25**
McGill et al. 22 r, db, co NC: 90 4w +21*** +28** +50** -51* -67 0

(1986) PR: 120 +16*** +30** +50** -55* -42 -27**
Rodrigues et al. 20 r, db, co NC: 90 4w +11*

(1986) V: 360 +33***
a Number of patients who completed the trial and were included in the statistical evaluations.
b Patients entered into an open-label phase of 5 months of either NC 90 or 120 mg/day, followed by a 6-week randomised double-blind crossover trial in which they
received either placebo or NC 90 or 120 mg/day. Data in this table were measured during this crossover period after 6 months of continuous NC therapy.
c 49 patients.
d Placebo-controlled study.
e Results listed indicate maximum responses at dose range listed.
f Time to 1.5mm ST-segment depression.
Abbreviations: 0 = open; sb '= single-blind; co = crossover; r = randomised; db = double-blind; p = parallel; NF = nifedipine; D = diltiazem; V = verapamil; P = propranolol;
AT = atenolol; w = weeks; m = months; ± = quantitative values not given but reported to be statistically insignificant from placebo values. An ellipsis (...) indicates
value not given. Significantly different from control or placebo values: * = p < 0.05; ** = p < 0.01; *** = P < 0.001.
3.1.1 Use in Stable Angina Pectoris received 90 mg/day, 21% rerceived 60 mg/day and
Classic stable effort angina is characterised by 10% received 120 mg/day. Six patients (11%) were
the occurrence of sudden retrostemal chest pain withdrawn due to a lack of efficacy while 12 patients
which is precipitated by exercise of relatively short (21%) received concomitant antianginal therapy
duration and is closely associated with severe ath- which had been started prior to the study.
erosclerotic coronary artery obstruction. In the ma-
jority of patients with chronic disease, chest pain Placebo-Controlled Trials
and ST-segment depression are reproducible at a Several studies have shown nicardipine, at a
given workload and this appears to be directly re- daily dosage of 30 to 120mg, to provide significant
lated to the imbalance noted above between myo- beneficial effects in angina pectoris compared with
cardial oxygen supply and demand (Braunwald effects produced by placebo administration (fig. 5;
1982; Scheidt 1982; Theroux et al. 1983). Until re- Thomas et al. 1986; table V). Total treadmill ex-
cently, nitrates and is-blockers have been the drugs ercise duration, time required to produce anginal
principally chosen for the clinical management of symptoms, and time required to provoke an ST-
stable angina, although the calcium antagonists segment depression of at least Imm have signifi-
seem to represent a major advance in this thera- cantly increased by up to 73%, 20% and 81 %, re-
peutic area (Theroux et al. 1983). spectively, while the number of anginal attacks and
The antianginal activity of nicardipine has been sublingual consumption of glyceryl trinitrate tab-
investigated in a number of placebo-controlled lets per week decreased by up to 68% (table V).
studies as well as in comparative trials involving Sustained subjective and objective benefits from
standard first-line treatments such as propranolol, nicardipine administration have been recorded for
atenolol and nifedipine. Efficacy in these studies periods of 6 months to 1 year (Gheorghiade et al.
has been assessed by evaluating the frequency of 1985; Khurmi et al. 1984; Scheidt et al. 1986).
anginal attacks and glyceryl trinitrate (nitroglyc- It is interesting to note that in most instances
erin) consumption. In addition, some studies also no significant change in the rate-pressure product
measured objective parameters such as exercise (which correlates closely with myocardial oxygen
duration, work performance and changes in ST- consumption during exercise in patients with is-
segment depression in the electrocardiogram. chaemic heart disease) occurred during nicardipine
treatment despite significant improvements in ex-
Non-Comparative Studies ercise tolerance (table V). Thus, nicardipine may
In an open study involving 18 patients with also enhance myocardial oxygen supply (section 1.9)
chronic stable angina pectoris, nicardipine titrated as well as reduce myocardial oxygen demand
up to a dosage of 120 mg/day (mean 98 mg/day) (Bowles et al. 1986; Gheorghiade et al. 1985;
significantly improved subjective and objective Khurmi et al. 1984; Scheidt et al. 1985) [section
symptoms of ischaemia (table V). In fact, 4 months 1.3].
into treatment, 47% of patients were noted to be
angina-free during exercise testing (Deedwania et Comparisons with Other Antianginal Agents
al. 1985). Similarly, Armstrong and associates The antianginal efficacy of nicardipine, and
(1986b) found that nicardipine was an effective other calcium antagonists, atenolol and propran-
treatment for stable angina pectoris in an open olol, have been compared in patients with chronic
study of 12 months duration. Sustained benefit in stable angina pectoris. While Bala Subramanian
terms of a reduced rate of angina attacks, decreased (1984), and Rodrigues et a1. (1986) reported that
consumption of glyceryl trinitrate tablets, and sig- verapamil and diltiazem yielded more favourable
nificantly increased exercise tolerance was docu- results than nicardipine (table V), the antianginal
mented in a group of 47 patients. Nicardipine dos- efficacy ofnicardipine has been shown to be com-
age was adjusted between 30 and 120 mg/day; 67% parable with that of nifedipine (Armstrong et al.
+30
*
*
Number of
+20 sublingual
Anginal glyceryl
'"
Q)
:l
+10 attacks
per
trinitrate
tablets used
co> week per week
.8 0
Q)
0
Treadmill Time to Time to 1mm
'"
c.. time (min) angina (min) ST-segment
depression
E
g (min)
Q) -20
0>
c
'"
J:=
0
Q)
Ol
'"
C -40
~
Q)
Q.
-60
-70 *
*
Fig. 5. The effects of 2 weeks' treatment with nicardipine 90 mg/day.; n = 20) or nicardipine 120 mg/day []; n = 18) on treadmill
test results, frequency of anginal attacks, and sublingual glyceryl trinitrate consumption in a randomised double-blind crossover study
*=
in patients with chronic stable angina pectoris. Results are expressed as the percentage change (increase or decrease) from cor-
responding placebo values. Significantly different from placebo values: p < 0.05 (after Gheorghiade et al. 1985).
1986a; Bowles et al. 1983). Indeed, investigations reported by Armstrong and associates (1985a) in a
by Bala Subramanian (1984, 1986) appear to in- single-blind comparison of nicardipine 90 mg/day
dicate that nicardipine 120 mg/day is equivalent and nifedipine 60 mg/day in 31 patients with sta-
to nifedipine 60 mg/day, and these seem to be sim- ble angina. In this study nicardipine was associated
ilar in potency to propranolol 160 to 240 mg/day. with fewer adverse effects and in fewer patients than
Similarly, DiPasquale et al. (1984) compared the nifedipine.
efficacy of oral nicardipine 80 mg/day and nifed- Nicardipine 30mg 3 times daily and atenolol
ipine 40mg/day in 12 patients with chronic stable 100mg once daily were also shown to possess sim-
angina pectoris in a randomised double-blind ilar efficacy in 50 patients with stable angina pec-
crossover trial. Both drugs, compared with pla- toris (Logan et al. 1985, 1986). During this ran-
cebo, were very effective in preventing anginal epi- domised 4-week crossover study, both drugs
sodes - decreasing sublingual glyceryl trinitrate produced statistically significant improvements
consumption, and significantly increasing both ex- over placebo with regard to exercise duration,
ercise duration and the time required to produce workload, time to angina, time to 1mm ST-seg-
anginal symptoms during exercise - and there were ment depression, maximum ST-segment change
no significant differences between these 2 drugs in and number of anginal attacks per week. Similar
any of these indices of efficacy. Similar results were results were obtained in the studies by McGill et
al. (1986) and Bjerle et al. (1986) in which nicar- double-blind placebo and nicardipine treatment
dipine was compared with propranolol (table V). periods. During this 2-week study period, nicard-
Although both drugs produced many similar bene- ipine 40 to 160 (mean dose 89) mg/day decreased
ficial antianginal effects, propranolol effected re- the mean frequencies of both symptomatic and
ductions in heart rate and peak rate-pressure prod- asymptomatic episodes of myocardial ischaemia (9
uct while nicardipine did not. In addition, maximal patients responded with a ~ 50% reduction in an-
workload attained and the threshold level of work- gina frequency) and sublingual glyceryl trinitrate
load causing angina were significantly greater with consumption by 81 %. Although these results would
nicardipine compared with propranolol, and ni- seem to indicate that nicardipine is effective in pre-
cardipine was associated with fewer side effects venting angina at rest due to coronary artery spasm,
(McGill et al. 1986). further investigations are needed to confirm these
findings.
3.1.2 Use in Angina at Rest and Coronary
Artery Spasm 3.2 Hypertension
Angina at rest is a syndrome characterised by
episodes of spontaneous and unprovoked isch- Nicardipine has been studied primarily in open
aemic cardiac pain at rest (usually at night or early and placebo-controlled trials in patients with mild
morning), associated with ST-segment elevation to moderate hypertension. Many of the placebo-
and relieved by sublingual glyceryl trinitrate (Gins- controlled trials incorporated features of good
burg et al. 1982; Prinzmetal et al. 1959; Schroeder clinical trial design known to minimise variation
1982). Although the precise mechanisms are un- and bias (such as 'run-in' placebo periods, random-
known, there is substantial evidence that coronary isation and single- or double-blinding). Dose-ad-
artery spasm (a transient narrowing of an epicard- justment periods, carried out in many of the stud-
ial artery of sufficient severity to induce ischaemia) ies revealed that the best antihypertensive results
plays a major pathophysiological role in the isch- occurred with daily dosages of nicardipine ranging
aemia of angina at rest (Braunwald 1982; Theroux from 30 to 120mg (Forette et al. 1985; Takabatake
et al. 1983). Evaluation of patients with this type et al. 1982; Taylor et al. 1982, 1985a,b). Open and
of angina is made difficult by the variable course placebo-controlled trials have shown that nicardi-
of the disease, by the wide range of clinical severity pine significantly lowers elevated blood pressures
among patients, and because many episodes are for periods of up to 2 years. Short term compar-
asymptomatic (Theroux et al. 1983; Waters et al. ative studies demonstrated that it was as effective
1981). as drugs such as propranolol, verapamil and
Gelman et al. (1985) investigated the use of ni- hydrochlorothiazide but this requires confirmation
cardipine in 17 patients with vasospastic angina at in a few well designed longer term clinical trials.
rest, many of whom had had an inadequate re-
sponse or unacceptable adverse effects with pre- 3.2.1 Non-Comparative Studies
vious anti anginal medication. After a single-blind A summary of non-comparative studies inves-
nicardipine dose titration period of 2 to 7 weeks tigating the antihypertensive efficacy of nicardi-
in which the optimal dose of nicardipine was con- pine in patients with mild to moderate essential
sidered to be the maximal tolerated dose that pro- hypertension is presented in table VI. The majority
vided at least a 50% reduction in anginal frequency of studies have clearly shown that nicardipine ad-
at rest compared with placebo, a 2-week double- ministered alone, and occasionally in combination
blind placebo-controlled crossover study was per- with other antihpertensive agents such as diuretics
formed to evaluate the efficacy of the drug. Am- or {j-blockers, significantly reduces supine, sitting
bulatory electrocardiographic monitoring was car- and standing blood pressures. Indeed, in a multi-
ried out in 14 of 17 patients at the end of the centre genera:l practice trial involving 140 patients,
nicardipine 30 to 120 mg/day for up to 2 years cantly greater reductions in blood pressure than
reduced mean supine blood pressure from a base- placebo in patients with mild to moderate essential
line value of 170/ I 05mm Hg to I 46/86mm Hg after hypertension (table VI). In one of the largest stud-
12 months (in approximately 120 patients) and to ies, Taylor and associates (I 985b) found that 32 of
145/87mm Hg in about 30 patients who completed 33 patients achieved a target diastolic blood pres-
2 years of treatment (Murray et al. 1986c). Overall, sure ~ 95mm Hg while being treated with nicar
an average clinical success rate (blood pressure < dipine ~ 30mg 3 times daily. In this study each
160/95mm Hg) of 60% was obtained throughout patient was treated with nicardipine 10, 20, 30 and
the study in those patients receiving nicardipine as 40mg 3 times daily in a crossover trial and, al-
monotherapy. though no clearcut relationship between dosage and
Takabatake and associates (1982) demonstrated blood pressure reduction was documented, there
in their studies that an antihypertensive effect was was a dose-related trend in the decrease of systolic
evident within 2 weeks of initiating therapy with blood pressure. Average resting heart rate signifi-
nicardipine. It was further noted that nicardipine cantly (p < 0.01) increased from 81 to 87 beats/
monotherapy decreased mean blood pressure by min in the nicardipine group.
more than 13mm Hg in 46% and 82% of the newly Sitting blood pressure was reduced by 20/16%,
diagnosed hypertensives in dosages of 30 and 60 compared with placebo values, in a group of 16
mg/day, respectively, thus indicating that nicardi- elderly hypertensive patients treated with nicardi-
pine monotherapy may be effective as the initial pine 30 to 90 mg/day for 4 weeks (Forette et al.
treatment of hypertension in some cases. In the 16 1985). A 'good' blood pressure response « 160/
patients who had responded poorly to previous 95mm Hg) was achieved in 10 of 16 nicardipine-
antihypertensive therapy, addition of nicardipine treated patients and in 3 of 15 patients who re-
to their treatment regimen effectively decreased ceived placebo. Similarly, in a double-blind 8-week
mean blood pressure by more than 13mm Hg, and parallel group study involving 88 elderly patients,
'normalised' blood pressure (mean blood pressure Brown and associates (1986) found that nicardi-
less than 107mm Hg) in 81.3% and 50% of the pine 10 to 30mg 3 times daily (usually 20mg 3 times
patients, respectively. Thus, nicardipine was also daily) produced a significantly greater reduction of
shown to enhance antihypertensive efficacy when mean blood pressures than placebo (17/ II mm Hg
used in combination with other antihypertensive vs 5/5mm Hg; p < 0.001). 76% of the nicardipine
drugs. group, but only 13% of the placebo group, obtained
Nicardipine has likewise been shown to possess a 'good or excellent' antihypertensive response.
antihypertensive properties in patients with severe Kolloch et al. (1985) assessed the efficacy of
chronic renal failure (Clair et al. 1985; Lee et al. adding placebo or increasing doses of nicardipine
1986). Doses of 60 mg/day in 14 such patients sig- to the dosage regimen of patients with essential
nificantly decreased both supine and standing blood hypertension concomitantly being treated with at-
pressures (table VI). There was no evidence of pro- enolol 100 mg/day (table VI). Compared with pla-
gressive increases of antihypertensive effect as a re- cebo, the addition ofnicardipine (15 to 60 mg/day)
sult of the impaired renal status of the patients produced further significant (p < 0.05) reductions
(Clair et al. 1985). in supine and standing blood pressures. Similar re-
Finally, similar to results reported by Young et sults were reported by Bellet et al. (1985) in which
al. (1984), Takabatake et al. (1982) reported no ni- the addition of pindolol 15 mg/day to patients re-
cardipine-induced significant changes in heart rate. ceiving either nicardipine 60 to 90 mg/day (n =
18) or placebo (n = 31) produced further signifi-
3.2.2 Placebo-Controlled Trials cant reductions in blood pressure in the nicardi-
In comparative studies of up to 17 weeks dur- pine-pindolol group compared with the placebo-
ation, nicardipine was shown to produce signifi- pindolol group. Donnelly and associates (1986) in-
Table VI. Some clinical trials of the use of nicardipine (NC) in the treatment of mUtt-to-moderate essential hypertension
References No. of Duration Dosage Reduction of blood pressure (%)b

patients of study (mg/day)
(NC group)" (weeks) supine sitting standing
Non-comparative trials
Clair et al. (1985) 14C 60 15'"/17''' 11"'/17*"
Fujita & Noda (1983) 10 16 60 11"/12"
Levenson et al. (1985) 11 12 60-90 12"'/10'"
Littler & Young (1985) 8 8 60-120 15"/8'
Murray et al. (1986c) 140<' up to 104 30-120 15"/17"
Takabatake et al. 31 d 8 30-60 20"'/16'"

(1982) 14" 8 30 22"'/14'"
17f 8 60 17"'/17'"
169 8 30-60 19"'/18'"
6h 8 30 18"/20"
10i 8 60 19"'/19
Taylor et al. (1985a) 73 52 30-120 15/22 16/23
Young et al. (1984) 8 8 60-120 13"/8' 14'/k 13'1'
Placebo-controlled trials
Asplund (1985)r 26 6 90 21"'/15'" 18"'/14'"
Bellet et al. (1985)m 52 4 60-90 12"'/12'" 11"'/11'"

14" 60-90 16"/17'" 15'/17"
Forette et al. (1985)m 16 4 30-90 20"'/16'"
Kolloch et al. (1985) 10 150 5'P/3

10 1 30<' 8"P/9"P
10 2 600 12"P/13"P
vestigated the efficacy of adding nicardipine to the a rational and beneficial combination in the treat-
treatment regimen of patients inadequately con- ment of hypertension in patients with good cardiac
trolled by enalapril 20mg daily in a placebo-con- function: the increase in peripheral resistance seen
trolled study. After 2 weeks' therapy, steady-state during long term (j-adrenoceptor blockade may be
blood pressures were significantly (p < 0.05) lower prevented by vasodilation induced by nicardipine,
in the nicardipine/enalapril group (mean supine BP and atenolol may prevent reflex tachycardia in-
158/96) than in the placebo/enalapril group (mean duced by nicardipine and decrease the number and
supine BP 172/106). frequency of side effects caused by vasodilation.
Although there was a reduction in heart rate after However, Bellet et al. (1985) and Littler and Young
treatment with atenolol, no consistent change oc- (1985) noted that in patients with essential hyper-
curred after the addition of either nicardipine or tension treated with oral nicardipine 60 to 120 mg/
placebo (Kolloch et al. 1985). Thus, the combined day for up to 14 weeks the heart rate was not dif-
use of nicardipine and atenolol or pindol01 may be ferent from the control values despite a persisting
Table VI. Contd
References No. of Duration Dosage Reduction of blood pressure (%)b

patients of study (mg/day)
(NC groupt (weeks) supine sitting standing
Taylor et al. 6 15 1/1 15 1/1

(1982)q 1 30 6/6 30 6/6
2 60 12/161 60 12/16
2
Taylor et al. 31 12-17 30-120 17***/20"*

(1985b)q
a Number of patients included in statistical analysis.

b Reduction in systolic/diastolic blood pressure at the end of each treatment, compared with pretreatment values.
c Patients with hypertension secondary to severe chronic renal failure.
d Number of patients who entered the study.
e Entire group of 31 newly diagnosed hypertensives who had not used antihypertensive treatment previously.
f 14 of the 31 newly diagnosed hypertensives who received the same dose of NC (30 mg/day) for 8 weeks.
g 17 of the 31 newly diagnosed hypertensives who received NC 60 mg/day for the last 4 weeks of treatment.
h Entire group of 16 hypertensive patients previously unsuccessfully treated with diuretics, ~-blockers or both. These treatments
were continued concomitantly with NC treatment.
6 of the 16 previously treated hypertensives who received the same dose of NC (30 mg/day) for 8 weeks.
j 10 of the 16 previously treated hypertensives who received NC 60 mg/day for the last 4 weeks of treatment.
k Mean supine intra-arterial blood pressure.
Mean supine systolic intra-arterial blood pressure.
m Random double-blind trial.
n 18 of 52 patients in the NC-treated group and 31 of 44 patients in the placebo-treated group (p < 0.001) did not achieve goal
blood pressures of .;; 160/95mm Hg after 4 weeks of treatment. Pindolol 15 mg/day was then added to the treatment regimen
of these patients. Significance of percentage reductions in blood pressure of NC-pindolol group are compared here to the placebo-
pindolol blood pressure reductions after 100 days of treatment.
o Patients also received atenolol 100 mg/day for study duration. Baseline values here include 1 week's treatment with atenolol.
p p < 0.05 compared to other group of 10 patients receiving atenolol plus placebo.
q Crossover trial.
Significantly different from pretreatment or placebo values: * = p < 0.05; ** = P < 0.01; *** = p < 0.001.
fall in blood pressure. An apparent resetting of the studies involving small numbers of patients (table
baroreceptor reflex is thought to occur (Young et VII). In general practice trials, the same dosage of
a1. 1984), and if this is the case, simultaneous treat- nicardipine tended to be slightly more effective than
ment with ,8-adrenoceptor antagonists may not be cyclopenthiazide O.5mg plus potassium 1200mg, in
required to reduce heart rate readings after long terms of a greater reduction of diastolic blood pres-
term nicardipine monotherapy. sure and the proportion of patients achieving a
physician-assessed good-to-excellent response
3.2.3 Comparative Trials (Murray et a1. 1986b), and to hydrochlorothiazide,
Monotherapy with nicardipine 30mg 3 times in terms of the number of patients achieving an
daily in patients with mild to moderate hyperten- 'excellent' clinical response. Nicardipine in com-
sion was shown to be as effective as treatment with bination with chlorthalidone produced similar per-
various first-line drugs such as propranolol 160mg centage reductions in blood pressure (16/16%) as a
once daily, verapamil 160mg twice daily and combination of atenolol and chlorthalidone (20/
hydrochlorothiazide 25mg twice daily in short term 18%) in patients with mild to moderate hyperten-
Supine I Standing
**
~ Time (weeks)
Fig. 6. Mean supine and standing blood pressures after administration of nicardipine 30mg 3 times a day ~; n = 26) and placebo
(II; n = 24) in patients with mild essential hypertension in a randomised double-blind parallel study. Significantly different from
pretreatment values: *= p < 0.01; ** = P < 0.001 (after Asplund 1985).
sion (Douglas-Jones & Coxhead 1986). Further- function. These findings/suggestions only apply to
more, Fagan et a1. (1986) demonstrated that a com- the dosages employed in this study (nicardipine
bination of nicardipine plus hydrochlorothiazide 30mg 3 times daily; verapamil 160mg twice daily)
further reduced blood pressure in patients with es- and need to be confirmed in patients with reduced
sential hypertension who had an incomplete re- left ventricular function.
sponse to monotherapy with these 2 drugs.
In the above studies administration of ,8-block- 3.3 Other Uses
ers caused an expected reduction in heart rate, as
did verapamil, whereas nicardipine alone pro- 3.3.1 Cardiac Failure
duced little change in heart rate (Al-I<bawaji et aI. Non-comparative studies have given indica-
1986; Douglas-Jones & Coxhead 1986; Murray et tions that the vasodilating properties of nicardi-
a1. 1986a). Additionally, AI-I<bawaja et a1. (1986) pine may be of benefit in the treatment of chronic
found that neither nicardipine nor verapamil sig- congestive heart failure (Burlew et a1. 1986). Lahiri
nificantly decreased ejection fraction or left ven- et a1. (1984) noted that after the administration of
tricular pressure/volume ratio which suggests that nicardipine IOmg intravenously to 10 patients with
neither drug produces depression ofleft ventricular New York Heart Association (NYHA) class II or
function. Indeed, nicardipine (but not verapamil) III chronic congestive heart failure, acute improve-
significantly increased the velocity of circumfer- ment in left ventricular function (as evidenced by
ential fibre shortening at rest, which is indicative increases in left ventricular ejection fraction of 23%
of improved intrinsic contractility, and may make using a Nuclear Stethoscope; p < 0.001) was as-
it a safer choice in patients with depressed cardiac sociated with significant (p < 0.001) reductions in
blood pressure and increases in heart rate. How- volume indices (Ryman et al. 1986). Thus, nicar-
ever, even though longer term treatment with oral dipine-mediated vasodilation was associated with
nicardipine 40mg 3 times daily for 4 weeks in 8 of an increased cardiac performance.
the patients did not produce significant reductions Although the above studies do provide some
in blood pressure, and no changes occurred in heart useful preliminary information regarding the
rate, a significant (p < 0.001) and sustained im- clinical efficacy of nicardipine in patients with con-
provement was maintained in both systolic and gestive heart failure, further better controlled stud-
diastolic left ventricular function, with mean in- ies in such patients are clearly needed.
creases in left ventricular ejection fraction of 23%
over that of baseline values.
3.3.2 Cerebrovascular Disorders
Similar results after oral therapy with nicardi-
Although nicardipine has been shown to possess
pine in patients with congestive heart failure were
cerebrovascular dilating properties (section 1.6), no
reported by Bellinetto and Lessem (1984). In this
adequately controlled and reported clinical studies
8-week open study, nicardipine 20 to 40mg 3 times
describing its effect in the treatment of cerebro-
daily was administered to 15 patients with con-
vascular disorders have been published.
gestive heart failure [NYHA class II (n = I) or III
Seki and Takenaka (1977) initially suggested a
(n = 14)] inadequately responsive to digitalis and
potentially therapeutic role of nicardipine as a
diuretics. After being withdrawn from previous
cerebral vasodilating agent by demonstrating that
therapy with digitalis, a dosage titration period was
intravenous nicardipine in doses of 2.5 to 20 p.g/
initiated and optimal dosages were found to be
kg effectively increased dermal forehead blood flow
20mg 3 times daily (n = 2), 30mg 3 times daily (n
= 7) and 40mg 3 times daily (n = 6). This optimal
in healthy volunteers. Fujiwara et al. (1980) ex-
dosage was continued for an additional 6 weeks. amined the efficacy of 8 weeks of oral doses of ni-
At the end of the study, significant (p < 0.001 for cardipine in 18 patients with unspecified cerebro-
each parameter) decreases in mean bodyweight, vascular disorders, and reported that after 4 and 8
right and left ankle circumference, and number of weeks of treatment slight or moderate improve-
patients with a third heart sound were reported. All ment in global evaluation scores were 67 and 71 %,
but 2 patients showed improvement in NYHA respectively. Handa et al. (1979) reported that oral
functional class, and exercise duration and total nicardipine 60 mg/day given for 4 weeks to 32
workload increased in 13 patients from 3 to 9 min- patients with cerebrovascular diseases improved
utes and 178 to 607 W/min, respectively (both p subjective complaints due to cerebrovascular is-
< 0.001). In addition, resting left ventricular ejec- chaemia, while in a double-blind parallel group
tion fraction increased from pre-treatment values study in 41 patients, Vintr6 Molins and Viaplana
in all but 2 patients by a mean of 36% (p < 0.01). Mas (1985) showed that, compared with placebo,
Importantly though, the patient group was not ho- nicardipine yielded more favourable efficacy scores
mogeneous with respect to concomitant medica- in relieving the clinical symptoms of fatigue, an-
tions, and controls to reduce bias and variation were orexia, dizziness, mood, emotional state, memory
insufficient. and self-initiative.
Finally, in 10 patients with severe, chronic con- In a retrospective study, Handa et al.(1984) re-
gestive heart failure nicardipine 30mg 3 times daily ported on 38 patients with a total of 44 ruptured
for 7 days improved both rest and exercise haemo- cerebral aneurysms of the anterior circulation
dynamic parameters: significant (p < 0.05) de- treated with intravenous nicardipine 6 mg/day for
creases in mean arterial pressure, systemic vascular 8 days, followed by oral treatment with 120 mg!
resistance, pulmonary artery pressure and pulmo- day for another 15 days. 'Excellent' clinical out-
nary artery wedge pressure were accompanied by comes were reported in 32 of the 38 patients, and
similar significant increases in cardiac and stroke this was thought to be due at least partly to the
Table VII. Randomised clinical trials comparing the efficacy of nicardlpine (NC) with alternative antihypertensive medications in patients with mild to moderate hypertension Z
5·
a
I'>
References Study No. of Study Dosage Reduction of blood pressure (mm Hg)" Overall efficacy<!
design patients· duration (mg/day) "9:
::s
supine standing exercise
(weeks)b n
>
AI-Khawaja db, co 23 6 NC 90 19"""/8"" 17""/11"" NC ==V ~
",
et al. (1986) <
(D.
V 320 16""/10""" 16··/10"· ~
Creytens & db, P 29 6 NC 90 15···/8··· 15"""/8""" NC ~ H

Saelen 30 H 50 15"·/6·" 16*uf7**.
(1986)
Douglas-Jones sb, p 14 6 NC90+C50 27""/17""· NC+C==A+C

& Coxhead 21 A 100 + C 25 36""/20""·
(1986)
Fagan et al. db,p 29' 2 NC 90 13"/9" 11"/6" NC== H

(1986) H 50 10""/8·" 14""/9""
Murray et al. db, p 15 12 NC 90 10"/14"" 15""/16"" NC== P

(1986a) 17 P 160 17""/13"" 16"/13""
Murray et al. sb, p 47g 6 NC 90 22""/17" 23·"/15" 23""/15" NC ~ Cy + Kh

(1986b) 44g Cy 0.5 + K 1200 21""/11"· 19""/10"" 19""/9""
a Number of patients included in statistical analysis.

b Duration of each period of active treatment.
c Reduction in systolic/diastolic blood pressure at end of treatment, compared with pretreatment values.
d In terms of antihypertensive efficacy; == denotes that the 2 drugs produced equivalent results, NC ~ denotes a trend in favour of nicardipine.
e Mean of 2 supine and 2 standing values after 10 minutes rest.
f Number of patients in each group not specified.
g Number of patients entering the study.
h A good to excellent overall physician assessment was recorded in 71 % of the NC group and in 55% of the Cy -K group.
Significantly different from pretreatment values: " = =
p < 0.05; "" p < 0.01; """= P < 0.001.
Abbreviations: db = double blind; sb =single-blind; co = crossover; p = parallel; A =
atenolol; C =
chlorthalidone; Cy =
cyclopenthiazide; H =
hydrochlorothiazide;
=
P propranolol; V = verapamil; K = potassium.
effects of nicardipine in protecting the brain from to note that although in one study orthostatic
ischaemia (section 1.6). hypotension required 1 patient of 47 with essential
Nakanishi et al. (1980) studied 18 patients with hypertension to withdraw after 6 weeks of therapy
vertigo and ataxia due to lesions of the peripheral (Takabatake et al. 1982), no instances of this side
labyrinth and noted that nicardipine was particu- effect were recorded in either elderly patients with
larly effective in relieving the symptoms of vertigo, hypertension or in patients with chronic renal fail-
nausea and vomiting. ure (Clair et al. 1985; Forette et al. 1985).
Other cardiovascular side effects - including in-
4. Side Effects creased angina, exercise-induced hypotension, pal-
pitations, dyspnoea and myocardial infarction -
Although the percentage of patients with hyper- have been reported to occur in as many as 27 and
tension and angina pectoris reporting any kind of 14% of patients receiving nicardipine and placebo,
adverse effect during treatment with oral doses of respectively (fig. 7). Khurmi et al. (1984) noted 1
nicardipine has ranged between 54 and 63% patient receiving nicardipine 60 mg/day who ex-
(Scheidt et al. 1985; Takabatake et al. 1982; Taylor perienced increases in unstable angina symptoms
et al. 1985a), most of these effects have been mi- and needed to have the nicardipine stopped, while
nor, transient and mild in nature (Asplund 1985; Scheidt et al. (1985) reported 4 patients who ex-
Clair et al. 1985; Deedwania et al. 1985; Gelman perienced aggravation of angina within 3 days of
et al. 1985; Gheorghiade et al. 1985; Higuchi et al. initiation of study medication 3 times daily. AI"
1980; Scheidt et al. 1985). These side effects, most though all 4 patients were withdrawn from study,
of which are extensions of the vasodilating prop- 1 of the patients was receiving placebo and not ni-
erties of nicardipine, appear to be dose related and cardipine at the time of symptom exacerbation,
more frequent within the first few weeks of therapy while 3 patients were taking nicardipine 30 or 40mg
(Taylor et al. 1985a). 3 times daily. In addition, 2 other patients who
Vasodilation-related side effects, such as flush- noted increases in their anginal symptoms while
ing, headache, peripheral oedema, lightheadedness receiving nicardipine were not withdrawn from the
and diaphoresis were noted in 37% of 63 patients study. Gheorghiade et al. (1985) found that 3
treated with oral nicardipine 30 to 40mg 3 times patients with chronic stable angina pectoris receiv-
daily over a 3-week period; however, similar effects ing nicardipine 30 to 40mg 3 times daily for 8 weeks
were also recorded in 23% of patients given pla- experienced a worsening of myocardial ischaemia;
cebo (Scheidt et al. 1985; fig. 7). While these side however, it must be pointed out that all 3 patients
effects have been reported in many clinical trials, had failed to respond to conventional maximal
they have usually been tolerable, although they were medical therapy (including ~-blockers) prior to en-
severe enough to warrant discontinuation of the try into the study, and subsequently underwent
drug in several instances (Asplund 1985; Clair et coronary artery bypass surgery.
al. 1985; Gheorghiade et al. 1985; Jones et al. 1983; This was not the case· in a patient with stable
Khurmi et al. 1984; Scheidt et al. 1985; Takabatake angina pectoris described by Lambert et al. (1985a)
et al. 1982; Taylor et al. 1985a; Thuillez et al. 1984). in whom intravenous nicardipine produced objec-
14.3% (13/91) of patients with essential hyperten- tive evidence of myocardial ischaemia at rest. Upon
sion receiving nicardipine 10 to 40mg 3 times daily discontinuation of nicardipine, the symptoms re-
experienced peripheral oedema and headache of solved completely. Investigation of coronary and
such magnitude as to necessitate their withdrawal haemodynamic indices in this patient revealed that
from study over a 12-month period (Taylor et al. anterior regional ischaemia occurred during nicar-
1985a). A similar figure (11.1 %) of drug withdraw- dipine administration, possibly due to a failure to
als due to vasodilation-related adverse effects was enhance collateral flow in response to the para-
reported by Scheidt et al. (1985). It is interesting doxical increase in myocardial oxygen demand that
Fig. 7. Reported adverse effects (percentage of patients) during treatment with oral nicardipine (30 to 40mg 3 times daily; n = 63;
0) and placebo (n = 64; II) in a multicentre randomised double blind crossover trial of 6 weeks duration in patients with stable angina
pectoris; GI = gastrointestinal; eNS = central nervous system; Total = total percentage of patients reporting any adverse effect
(after Scheidt et al. 1985).
occurred. These effects were thought to be due Other adverse reactions - few if any of which
either to increased reflex sympathetic tone, as is occur with sufficient intensity to cause discon-
seen in patients who develop angina during nifed- tinuation of the drug - include central nervous sys-
ipine administration (Jariwalla & Anderson 1978), tem (fatigue/weakness, anxiety, depression, paraes-
or to inhibition of cyclic adenosine monophos- thesiae), gastrointestinal (anorexia, nausea,
phate phosphodiesterase by nicardipine (Sakamoto vomiting, dyspepsia), musculoskeletal (myalgia,
et al. 1978). Abrupt withdrawal of nicardipine after arthralgia/arthritis) and dermatological (skin rash,
5 months on continuous treatment in patients with pruritus) effects (Asplund 1985; Clair et al. 1985;
chronic stable angina pectoris led to a rapid return Gelman et al. 1985; Gheorghiade et al. 1985; Jones
of previous anginal symptoms, but these symp- et al. 1983; Khurmi et al. 1984; Scheidt et al. 1985;
toms were not greater than those measured as base- Takabatake et al. 1982; Taylor et al.1985a; Thuil-
line values (Gheorghiade et al. 1985). lez et al. 1984). Recently, interest has centered on
the effects of antihypertensive therapy on the patients (mean age 67 years) who had been taking
patient's quality of life, especially with regard to digoxin 0.13 to 0.25 mg/day for atrial fibrillation
psychiatric side effects. Callender and associates or congestive heart failure received nicardipine
(1986) evaluated some psychological parameters in 20mg 3 times daily for 14 days. Mean plasma con-
a controlled trial involving 30 hypertensive patients centrations of digoxin were increased by about 15%
treated with nicardipine 30mg 3 times daily or pro- (p < 0.05), and returned to pretreatment values
pranolol 80mg twice daily for 12 weeks. Neither within 7 days of the discontinuation of nicardi-
treatment produced detectable impairment of psy- pine. However, in only I patient did plasma dig-
chiatric well-being or ability to fulfil normal social oxin concentrations reach the lower 'toxic' range
roles. Both drugs produced some small but statis- (greater than 2 ~g/L), and when this patient was
tically significant changes in cognitive functioning, excluded from analysis, the increases in plasma
the importance of which required further investi- digoxin concentrations did not reach statistical sig-
gation. nificance. Furthermore, although a wide variation
Nicardipine has not produced any significant of plasma nicardipine concentrations was ob-
changes in the indices of clinical haematology, served, there was no correlation between these con-
chemistry, urinalysis, bodyweight or fluid reten- centrations and changes in digoxin plasma concen-
tion (Forette et at. 1985; Gelman et at. 1985; trations.
Gheorghiade et at. 1985; Jones et at. 1983; Khurmi Donnelly and associates (1986) reported that
et at. 1984; Scheidt et at. 1985). In addition, ni- addition of nicardipine 30mg 3 times daily to the
cardipine has proven to be remarkably free from dosage regimen of patients inadequately controlled
producing adverse metabolic or endocrine effects by enalapril 20mg daily did not alter the phar-
(Feely et at. 1986). macokinetic properties of enalapril nor enalapril
Thus, oral nicardipine 30 to 40mg 3 times daily inhibition of ACE activity. Reports of increased
has been generally well tolerated. Although Khurmi cyclosporin blood concentrations due to nicardi-
et at. (1984) suggest that nicardipine appears to pine, and reductions in nicardipine volume of dis-
produce fewer side effects than nifedipine in doses tribution and total clearance due to isoflurane
up to 120 mg/day, and fewer side effects than ver- administration have also appeared in the literature
apamil and nifedipine were observed in trials in (Bourbigot et al. 1986; Merin et at. 1986). How-
angina pectoris using identical protocols (Bala Sub- ever, further investigations of these and the above
ramanian et al. 1982), further studies are necessary described nicardipine-digoxin interaction are
to investigate the short and long term comparative needed to properly assess their significance.
tolerability of nicardipine in the treatment of es-
sential hypertension and angina pectoris, particu- 6. Dosage and Administration
larly when nicardipine is used in combination with
other drugs commonly used in the treatment of In adults with essential hypertension, angina
these disorders. pectoris or cerebral vascular diseases oral nicardi-
pine should be initiated at a dose of 20mg 3 times
5. Drug Interactions a day. If the desired therapeutic response has not
been achieved after 2 weeks of treatment, the dos-
Since diltiazem, verapamil and nifedipine have age may be increased to 30 or 40mg 3 times daily.
all been implicated as agents potentially responsi-
ble for increasing plasma concentrations of digoxin 7. Place of Nicardipine in Therapy
(for reviews see Chaffman & Brogden 1985; Ha-
mann et at. 1984; Sorkin et al. 1985), Lessem and Calcium ion flux from the extracellular space
Bellinetto (1983) investigated whether nicardipine through the slow channel of the cell membrane
interacted with digoxin in a similar manner. Ten plays an important role in several fundamental
physiological processes in myocardial and vascular confirmed during long term administration, and the
smooth muscles. Nicardipine blocks this influx of absence of fluid retention and weight gain during
calcium into the cell which confers on it potent therapy may provide it with advantages over other
coronary and peripheral arteriodilator properties vasodilators used in the management of hyperten-
that are useful in different clinical areas. sion. Studies suggest that nicardipine may be used
Short and long term clinical trials to date in- as effective monotherapy in the initial treatment
dicate that nicardipine is effective and well toler- of hypertension, although additional studies are re-
ated in the treatment of chronic stable angina pec- quired for further confirmation of these initial
toris. Improvements both in symptoms and in findings. Nicardipine may also enhance the effi-
objective signs of myocardial ischaemia have been cacy of antihypertensive drug combinations in-
maintained for periods of up to 1 year during con- cluding diuretics, J3-blockers or both, and cardiac
tinuous treatment with nicardipine, with nicardi- function in patients with poor left ventricular func-
pine producing similar haemodynamic and clinical tion receiving both nicardipine and J3-blockers is
effects as nifedipine. The antianginal efficacy of ni- not further compromised. In addition, the fact that
cardipine appears to be dose-related, maximum re- nicardipine may be used without dosage modifi-
sults occurring with daily oral dosages of 90 to cation in renal failure is of special interest. Overall
l20mg. There is also evidence that nicardipine does though, as with its use in angina, the short term
not significantly affect sinoatrial or atrioventricu- nature of the controlled comparative trials pre-
lar nodal functions which would be an advantage clude a definite evaluation of the long term effec-
in the treatment of angina patients with some con- tiveness of nicardipine compared with available
comitant conduction disturbances. Furthermore, first-line treatments such as diuretics, J3-blockers
while verapamil and intravenous nifedipine have and other commonly used drugs.
produced decreases of left ventricular function, ni- Clinical trials in other therapeutic areas such as
cardipine has not, providing further obvious im- congestive heart failure and cerebrovascular dis-
plications in the treatment of angina patients with ease have been encouraging but are limited in terms
compromised cardiac function. Thus, there is fa- of the total numbers of patients studied, and here,
vourable evidence that nicardipine should be con- as with the other therapeutic areas described above,
sidered as one of the primary treatment modalities more information is needed to clarify any role ni-
of stable angina pectoris. However, additional well- cardipine may have in treating such patients.
designed comparative studies are necessary to fully Thus, while studies of nicardipine to date are
define the efficacy and safety of nicardipine in re- encouraging, and suggest it will be a very useful
lation to other available drugs such as J3-blockers addition to the drugs available to the clinician for
and nitrates, which are currently the most fre- the management of angina and/or hypertension, its
quently used drugs in this clinical setting. exact place in the treatment regimen of these dis-
Similarly, although nicardipine appears to be ease states awaits further confirmation in a few long
safe and effective for preventing angina at rest due term comparative studies.
to coronary artery spasm, and may be particularly
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Authors' address: Eugene M. Sorkin, ADIS Drug Information
pine on blood pressure, renal function and plasma aldosterone
in normotensive volunteers. British Journal of Clinical Services, Centorian Drive, Private Bag, Mairangi Bay, Auckland
Pharmacology 20 (Suppi. I): 88S-94S, 1985 10 (New Zealand).

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Drug Evaluation

Drugs 33: 296-345 (1987)

Eugene M. Sorkin and Stephen P. Clissold

Contents Summary .................................................................................................................................... 297

1.8.1 Effects on Airway Conductance ........................................................................... 315

treatment of hypertension nicardipine has been shown to be as effective as drugs such as

The administration of nicardipine to patients with coronary artery disease results in

Pharmacokinetic Although more well-designed investigations involving larger numbers of volunteers

frequency and glyceryl trinitrate (nitroglycerin) consumption, and improvements in ob-

Nicardipine Nifedipine Nitrendipine

Parameter Nicardipine Nifedipine Dlltiazem Verapamil

a Prolonged in patients given autonomic blocking agents.

Greenbaum et al. Chronic LV 10 IV (n = 3) Rest ± ± ± ± +32 -23 ± ± ±

Jackson et al. Stable AP 2.5 IV Rest - 5 -3 -6 ± +18 +17 -19 ±

Lahiri et al. Depressed LV 10lV Rest -23 -20 +28 +71

Lambert et al. CAD & 2 IV Rest -13 +17 +36 -38

Levenson et al. EH [15] 40po Rest -14 -14 -14 +8

McCredie et al. Vols [6] 20pOd Rest ± +21 +17 ± -15 ± ± ±

Visser et al. CAD 10 IV Rest -30 +26 +40 -47

patients (Corea et a1. 1981; Lederballe-Pedersen et

* 29 to 51 %, respectively (Jackson et a1. 1984; Rous-

Lambert et al. 15 2 [1V]a Resting +44 -40 ±

Rousseau et al. 10 2.5 [IV] Atrial pacing b +15 -20 ± -6 ±

Rousseau et al. 10 2.5 [IV] Resting +39 -35 -25 ±

Negative inotropic effect j Peripheral arterial

j Coronary artery spasm j Systemic vascular resistance

Positive inotropic effect

2.5 Effect of Disease on Pharmacokinetics 3. Therapeutic Trials

Di Pasquale et al. 12 r, db, co NC: 80 6w +18* +19* +20*' -67* -77* +1

McGill et al. 22 r, db, co NC: 90 4w +21*** +28** +50** -51* -67 0

Rodrigues et al. 20 r, db, co NC: 90 4w +11*

References No. of Duration Dosage Reduction of blood pressure (%)b

Fujita & Noda (1983) 10 16 60 11"/12"

Levenson et al. (1985) 11 12 60-90 12"'/10'"

Littler & Young (1985) 8 8 60-120 15"/8'

Murray et al. (1986c) 140<' up to 104 30-120 15"/17"

Takabatake et al. 31 d 8 30-60 20"'/16'"

Taylor et al. (1985a) 73 52 30-120 15/22 16/23

Young et al. (1984) 8 8 60-120 13"/8' 14'/k 13'1'

Bellet et al. (1985)m 52 4 60-90 12"'/12'" 11"'/11'"

Forette et al. (1985)m 16 4 30-90 20"'/16'"

Kolloch et al. (1985) 10 150 5'P/3

Table VI. Contd

References No. of Duration Dosage Reduction of blood pressure (%)b

Taylor et al. 6 15 1/1 15 1/1

Taylor et al. 31 12-17 30-120 17***/20"*

a Number of patients included in statistical analysis.

Creytens & db, P 29 6 NC 90 15···/8··· 15"""/8""" NC ~ H

Douglas-Jones sb, p 14 6 NC90+C50 27""/17""· NC+C==A+C

Fagan et al. db,p 29' 2 NC 90 13"/9" 11"/6" NC== H

Murray et al. db, p 15 12 NC 90 10"/14"" 15""/16"" NC== P

Murray et al. sb, p 47g 6 NC 90 22""/17" 23·"/15" 23""/15" NC ~ Cy + Kh

a Number of patients included in statistical analysis.

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Di Pasquale et al. 12 r, db, co NC: 80 6w +18* +19* +20' -67 -77* +1

McGill et al. 22 r, db, co NC: 90 4w +21* +28 +50** -51* -67 0