Benidipine Hydrochloride
Bcnidipine is a dihydropyridine calcium-channel blocker. It is given by mouth as the hydrochloride in the treatment of
hypertension.
The general properties are similar to those of nifedipine whose record is shown below :
NIFEDIPINE
CLINICAL PHARMACOLOGY
ADALATĀ® is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac muscle and smooth muscle. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. ADALATĀ® selectively inhibits calcium ion influx across the cell membrane of cardiac muscle and vascular smooth muscle without changing serum calcium concentrations.
Mechanism of Action
The precise means by which this inhibition relieves angina has not been fully determined, but includes at least the following two mechanisms:
1) Relaxation and Prevention of Coronary Artery Spasm
ADALATĀ® dilates the main coronary arteries and coronary arterioles, both in normal and ischemic regions, and is a potent inhibitor of coronary artery spasm, whether spontaneous or ergonovine-induced. This property increases myocardial oxygen delivery in patients with coronary artery spasm, and is responsible for the effectiveness of ADALATĀ® in vasospastic (Prinzmetal's or variant) angina. Whether this effect plays any role in classical angina is not clear, but studies of exercise tolerance have not shown an increase in the maximum exercise rate-pressure product, a widely accepted measure of oxygen utilization. This suggests that, in general, relief of spasm or dilation of coronary arteries is not an important factor in classical angina.
2) Reduction of Oxygen Utilization
ADALATĀ® regularly reduces arterial pressure at rest and at a given level of exercise by dilating peripheral arterioles and reducing the total peripheral resistance (afterload) against which the heart works. This unloading of the heart reduces myocardial energy consumption and oxygen requirements and probably accounts for the effectiveness of ADALATĀ® in chronic stable angina.
Pharmacokinetics and Metabolism
ADALATĀ® is rapidly and fully absorbed after oral administration. The drug is detectable in serum 10 minutes after oral administration, and peak blood levels occur in approximately 30 minutes. Bioavailability is proportional to dose from 10 to 30 mg; half-life does not change significantly with dose. There is little difference in relative bioavailability when ADALATĀ® TABLETs are given orally and swallowed whole, bitten and swallowed, or bitten and held sublingually. However, biting through the TABLET prior to swallowing does result in slightly earlier plasma concentrations (27 ng/mL 10 minutes after 10 mg) than if TABLETs are swallowed intact. It is highly bound by serum proteins. ADALATĀ® is extensively converted to inactive metabolites and approximately 80 percent of ADALATĀ® and metabolites are eliminated via the kidneys. The half-life of nifedipine in plasma is approximately two hours. Since hepatic biotransformation is the predominant route for the disposition of nifedipine, the pharmacokinetics may be altered in patients with chronic liver disease. Patients with hepatic impairment (liver cirrhosis) have a longer disposition half-life and higher bioavailability of nifedipine than healthy volunteers. The degree of serum protein binding of nifedipine is high (92-98%). Protein binding may be greatly reduced in patients with renal or hepatic impairment.
In healthy subjects, the elimination half-life of a sustained release nifedipine formulation was longer in elderly subjects (6.7 h) compared to young subjects (3.8 h) following oral administration. A decreased clearance was also observed in the elderly (348 mL/min) compared to young subjects (519 mL/min) following intravenous administration.
Co-administration of nifedipine with grapefruit juice results in up to a 2-fold increase in AUC and C max , due to inhibition of CYP3A4 related first-pass metabolism.
Hemodynamics
Like other slow channel blockers, ADALATĀ® exerts a negative inotropic effect on isolated myocardial tissue. This is rarely, if ever, seen in intact animals or man, probably because of reflex responses to its vasodilating effects. In man, ADALATĀ® causes decreased peripheral vascular resistance and a fall in systolic and diastolic pressure, usually modest (5-10mm Hg systolic), but sometimes larger. There is usually a small increase in heart rate, a reflex response to vasodilation. Measurements of cardiac function in patients with normal ventricular function have generally found a small increase in cardiac index without major effects on ejection fraction, left ventricular end diastolic pressure (LVEDP) or volume (LVEDV). In patients with impaired ventricular function, most acute studies have shown some increase in ejection fraction and reduction in left ventricular filling pressure.
Electrophysiologic Effects
Although like other members of its class, ADALATĀ® decreases sinoatrial node function and atrioventricular conduction in isolated myocardial preparations, such effects have not been seen in studies in intact animals or in man. In formal electrophysiologic studies, predominantly in patients with normal conduction system, ADALATĀ® has had no tendency to prolong atrioventricular conduction, prolong sinus node recovery time, or slow sinus rate.
INDICATIONS AND USAGE
I. Vasospastic Angina
ADALATĀ® (nifedipine) is indicated for the management of vasospastic angina confirmed by any of the following criteria: 1) classical pattern of angina at rest accompanied by ST segment elevation, 2) angina or coronary artery spasm provoked by ergonovine, or 3) angiographically demonstrated coronary artery spasm. In those patients who have had angiography, the presence of significant fixed obstructive disease is not incompatible with the diagnosis of vasospastic angina, provided that the above criteria are satisfied. ADALATĀ® may also be used where the clinical presentation suggests a possible vasospastic component but where vasospasm has not been confirmed, e.g., where pain has a variable threshold on exertion or when angina is refractory to nitrates and/or adequate doses of beta blockers.
II. Chronic Stable Angina
(Classical Effort-Associated Angina)
ADALATĀ® is indicated for the management of chronic stable angina (effort-associated angina) without evidence of vasospasm in patients who remain symptomatic despite adequate dose of beta blockers and/or organic nitrates or who cannot tolerate those agents.
In chronic stable angina (effort-associated angina) ADALATĀ® has been effective in controlled trials of up to eight weeks duration in reducing angina frequency and increasing exercise tolerance, but confirmation of sustained effectiveness and evaluation of long term safety in these patients are incomplete.
Controlled studies in small numbers of patients suggest concomitant use of ADALATĀ® and beta blocking agents may be beneficial in patients with chronic stable angina, but available information is not sufficient to predict with confidence the effects of concurrent treatment, especially in patients with compromised left ventricular function or cardiac conduction abnormalities. When introducing such concomitant therapy, care must be taken to monitor blood pressure closely since severe hypotension can occur from the combined effects of the drugs (See WARNINGS ).
CONTRAINDICATIONS
Known hypersensitivity reaction to ADALATĀ®.
WARNINGS
Excessive Hypotension
Although in most patients, the hypotensive effect of ADALATĀ® TABLETS is modest and well tolerated, occasional patients have had excessive and poorly tolerated hypotension. These responses have usually occurred during initial titration or at the time of subsequent upward dosage adjustment, and may be more likely in patients on concomitant beta blockers.
Although not approved for this purpose, ADALATĀ® TABLETS and other immediate-release nifedipine TABLETs have been used (orally and sublingually) for acute reduction of blood pressure. Several well-documented reports describe profound hypotension, myocardial infarction, and death when immediate-release nifedipine TABLETs were used in this way. ADALATĀ® TABLETS should not be used for acute reduction of blood pressure.
ADALATĀ® TABLETS and other immediate-release nifedipine TABLETs have also been used for the long-term control of essential hypertension although no properly-controlled studies have been conducted to define an appropriate dose or dose interval for such treatment. ADALATĀ® TABLETS should not be used for the control of essential hypertension.
Several well-controlled, randomized trials studied the use of immediate-release nifedipine TABLETs in patients who had just sustained myocardial infarctions. In none of these trials did immediate-release nifedipine appear to provide any benefit. In some of the trials, patients who received immediate-release nifedipine had significantly worse outcomes than patients who received placebo. ADALATĀ® TABLETS should not be administered for 1 week after myocardial infarction, and it should also be avoided in the setting of acute coronary syndrome (when infarction may be imminent).
Severe hypotension and/or increased fluid volume requirements have been reported in patients receiving ADALATĀ® together with a beta blocking agent who underwent coronary artery bypass surgery using high dose fentanyl anesthesia. The interaction with high dose fentanyl appears to be due to the combination of ADALATĀ® and a beta blocker, but the possibility that it may occur with ADALATĀ® alone, with low doses of fentanyl, in other surgical procedures, or with other narcotic analgesics cannot be ruled out. In ADALATĀ® treated patients where surgery using high dose fentanyl anesthesia is contemplated, the physician should be aware of these potential problems and, if the patient' condition permits, sufficient time (at least 36 hours) should be allowed for ADALATĀ® to be washed out of the body prior to surgery.
Increased Angina and/or Myocardial Infarction
Rarely, patients, particularly those who have severe obstructive coronary artery disease, have developed well documented increased frequency, duration, and/or severity of angina or acute myocardial infarction on starting ADALATĀ® or at the time of dosage increase. The mechanism of this effect is not established.
Beta Blocker Withdrawal
Patients recently withdrawn from beta blockers may develop a withdrawal syndrome with increased angina, probably related to increased sensitivity to catecholamines. Initiation of ADALATĀ® treatment will not prevent this occurrence and might be expected to exacerbate it by provoking reflex catecholamine release. There have been occasional reports of increased angina in a setting of beta blocker withdrawal and ADALATĀ® initiation. It is important to taper beta blockers if possible, rather than stopping them abruptly before beginning ADALATĀ®.
Congestive Heart Failure
Rarely, patients (usually those receiving a beta blocker) have developed heart failure after beginning ADALATĀ®. Patients with tight aortic stenosis may be at greater risk for such an event since the unloading effect of ADALATĀ® would be expected to be of less benefit to these patients, owing to the fixed impedance to flow across the aortic valve.
PRECAUTIONS
General: Hypotension: Because ADALATĀ® decreases peripheral vascular resistance, careful monitoring of blood pressure during the initial administration and titration of ADALATĀ® is suggested. Close observation is especially recommended for patients already taking medications that are known to lower blood pressure (See WARNINGS ).
Peripheral Edema: Mild to moderate peripheral edema, typically associated with arterial vasodilation and not due to left ventricular dysfunction, occurs in about one in ten patients treated with ADALATĀ® (nifedipine). This edema occurs primarily in the lower extremities and usually responds to diuretic therapy. With patients whose angina is complicated by congestive heart failure, care should be taken to differentiate this peripheral edema from the effects of increasing left ventricular dysfunction.
Laboratory Tests: Rare, usually transient, but occasionally significant elevations of enzymes such as alkaline phosphatase, CPK, LDH, SGOT, and SGPT have been noted. The relationship to ADALATĀ® therapy is uncertain in most cases, but probable in some. These laboratory abnormalities have rarely been associated with clinical symptoms, however, cholestasis with or without jaundice has been reported. Rare instances of allergic hepatitis have been reported.
ADALATĀ®, like other calcium channel blockers, decreases platelet aggregation in vitro . Limited clinical studies have demonstrated a moderate but statistically significant decrease in platelet aggregation and increase in bleeding time in some ADALATĀ® patients. This is thought to be a function of inhibition of calcium transport across the platelet membrane. No clinical significance for these findings has been demonstrated.
Positive direct Coombs test with/without hemolytic anemia has been reported.
Although ADALATĀ® has been used safely in patients with renal dysfunction and has been reported to exert a beneficial effect in certain cases, rare reversible elevations in BUN and serum creatinine have been reported in patients with pre-existing chronic renal insufficiency. The relationship to ADALATĀ® therapy is uncertain in most cases but probable in some.
Drug Interactions: Beta-adrenergic blocking agents : (See INDICATIONS and WARNINGS ). Experience in over 1400 patients in a non-comparative clinical trial has shown that concomitant administration of ADALATĀ® and beta blocking agents is usually well tolerated, but there have been occasional literature reports suggesting that the combination may increase the likelihood of congestive heart failure, severe hypotension or exacerbation of angina.
Long acting nitrates: ADALATĀ® may be safely co-administered with nitrates, but there have been no controlled studies to evaluate the antianginal effectiveness of this combination.
Digitalis: Since there have been isolated reports of patients with elevated digoxin levels, and there is a possible interaction between digoxin and nifedipine, it is recommended that digoxin levels be monitored when initiating, adjusting and discontinuing nifedipine to avoid possible over- or under-digitalization.
Coumarin anticoagulants: There have been rare reports of increased prothrombin time in patients taking coumarin anticoagulants to whom ADALATĀ® was administered. However, the relationship to ADALATĀ® therapy is uncertain.
Cimetidine A study in six healthy volunteers has shown a significant increase in peak nifedipine plasma levels (80%) and area-under-the-curve (74%) after a one week course of cimetidine at 1000 mg per day and nifedipine at 40 mg per day. Ranitidine produced smaller, non-significant increases. The effect may be mediated by the known inhibition of cimetidine on hepatic cytochrome P-450, the enzyme system probably responsible for the first-pass metabolism of nifedipine. If nifedipine therapy is initiated in a patient currently receiving cimetidine, cautious titration is advised.
Quinidine There have been rare reports of an interaction between quinidine and nifedipine (with a decreased plasma level of quinidine).
Other Interactions:
Grapefruit Juice: Co-administration of nifedipine with grapefruit juice results in up to a 2-fold increase in AUC and C max , due to inhibition of CYP3A4 related first-pass metabolism. Co-administration of nifedipine with grapefruit juice is to be avoided.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Nifedipine was administered orally to rats for two years and was not shown to be carcinogenic. When given to rats prior to mating, nifedipine caused reduced fertility at a dose approximately 30 times the maximum recommended human dose. There is a literature report of reversible reduction in the ability of human sperm obtained from a limited number of infertile men taking recommended doses of nifedipine to bind to and fertilize an ovum in vitro. In vivo mutagenicity studies were negative.
Pregnancy: Pregnancy Category C. In rodents, rabbits, and monkeys, nifedipine has been shown to have a variety of embryotoxic, placentoxic, and fetotoxic effects, including stunted fetuses (rats, mice, and rabbits), digital anomalies (rats and rabbits), rib deformities (mice), cleft palate (mice), small placentas and underdeveloped chorionic villi (monkeys), embryonic and fetal deaths (rats, mice, and rabbits), prolonged pregnancy (rats; not evaluated in other species), and decreased neonatal survival (rats; not evaluated in other species). On a mg/kg or mg/m 2 basis, some of the doses associated with these various effects are higher than the maximum recommended human dose and some are lower, but all are within one order of magnitude of it.
The digital anomalies seen in nifedipine-exposed rabbit pups are strikingly similar to those seen in pups exposed to phenytoin, and these are in turn similar to the phalangeal deformities that are the most common malformation seen in human children with in utero exposure to phenytoin.
There are no adequate and well-controlled studies in pregnant women. ADALATĀ® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers: Nifedipine is excreted in human milk. Therefore, a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Geriatric Use: Although small pharmacokinetic studies have identified an increased half-life and increased C max and AUC (See CLINICAL PHARMACOLOGY : Pharmacokinetics and Metabolism ), clinical studies of nifedipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
ADVERSE REACTION
In multiple-dose U.S. and foreign controlled studies in which adverse reactions were reported spontaneously, adverse effects were frequent but generally not serious and rarely required discontinuation of therapy or dosage adjustment. Most were expected consequences of the vasodilator effects of ADALATĀ®.
Adverse Effect ADALATĀ® (%) (N = 226) Placebo (%) (N = 235)
-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Dizziness, lightheadedness, giddiness 27 15
Flushing, heat sensation 25 8
Headache 23 20
Weakness 12 10
Nausea, heartburn 11 8
Muscle cramps, tremor 8 3
Peripheral edema 7 1
Nervousness, mood changes 7 4
Palpitation 7 5
Dyspnea, cough, wheezing 6 3
Nasal congestion, sore throat 6 8
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
There is also a large uncontrolled experience in over 2100 patients in the United States. Most of the patients had vasospastic or resistant angina pectoris, and about half had concomitant treatment with beta-adrenergic blocking agents. The most common adverse events were:
Incidence Approximately 10%
Cardiovascular peripheral edema
Central Nervous System: dizziness or lightheadedness
Gastrointestinal nausea
Systemic headache and flushing, weakness.
Incidence Approximately 5%
Cardiovascular transient hypotension.
Incidence 2% or Less:
Cardiovascular: palpitation
Respiratory: nasal and chest congestion, shortness of breath
Gastrointestinal: diarrhea, constipation, cramps, flatulence
Musculoskeletal: inflammation, joint stiffness, muscle cramps
Central Nervous System: shakiness, nervousness, jitteriness, sleep disturbances, blurred vision, difficulties in balance
Other: dermatitis, pruritus, urticaria, fever, sweating, chills, sexual difficulties.
Incidence Approximately 0.5%
Cardiovascular syncope. Syncopal episodes occurred mostly with initial dose and/or increase of dosage.
Incidence Less Than 0.5%
Hematologic: thrombocytopenia, anemia, leukopenia, purpura
Gastrointestinal: allergic hepatitis
Face and Throat: angioedema (mostly oropharyngeal edema with breathing difficulty in a few patients), gingival hyperplasia
CNS: depression, paranoid syndrome
Musculoskeletal: myalgia
Special Senses: transient blindness at the peak of plasma level
Urogenital: nocturia, polyuria
Other: erythromelalgia, arthritis with ANA (+), gynecomastia, exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis.
Several of these side effects appear to be dose related. Peripheral edema occurred in about one in 25 patients at doses less than 60 mg per day and in about one patient in eight at 120 mg per day or more. Transient hypotension, generally mild to moderate severity and seldom requiring discontinuation of therapy, occurred in one of 50 patients at less than 60 mg per day and in one of 20 patients at 120 mg per day or more. Very rarely, introduction of ADALATĀ® therapy was associated with an increase in anginal pain, possibly due to associated hypotension.
In addition, more serious adverse events were observed, not readily distinguishable from the natural history of the disease in these patients. It remains possible, however, that some or many of these events were drug related. Myocardial infarction occurred in about 4% of patients and congestive heart failure or pulmonary edema in about 2%. Ventricular arrhythmias or conduction disturbances each occurred in fewer than 0.5% of patients.
In a subgroup of over 1000 patients receiving ADALATĀ® with concomitant beta blocker therapy, the pattern and incidence of adverse experiences were not different from that of the entire group of ADALATĀ® (nifedipine) treated patients (See PRECAUTIONS ).
In a subgroup of approximately 250 patients with a diagnosis of congestive heart failure as well as angina, dizziness or lightheadedness, peripheral edema, headache or flushing each occurred in one in eight patients. Hypotension occurred in about one in 20 patients. Syncope occurred in approximately one patient in 250. Myocardial infarction or symptoms of congestive heart failure each occurred in about one patient in 15. Atrial or ventricular dysrhythmias each occurred in about one patient in 150.
VASCULAR ENDOTHELIUM: ROLE IN HEALTH
"Endothelial dysfunction leads to atherosclerosis, which
eventually leads to clinical syndrome of angina.
Hypertension along with vasoconstriction and thrombosis
precipitates unstable angina resulting into myocardial
infarction or sudden cardiac death."
"A prospectively defined subgroup analysis of ACTION
study delivers convincing evidence that patients with
symptomatic stable angina and hypertension greatly
benefit from the addition of nifedipine GITS to their
therapy."
"Nifedipine-treated patients were also less likely to
have diabetes or secondary events (a composite of all-
cause mortality, death from a vascular cause, and death
from a non-vascular cause)than co-amilozide recipients. The results
suggested that nifedipine could be considered as a
first-line therapy for hypertensive diabetics."
"Nifedipine retard and enalapril had a similar effect on
nephropathy in hypertensive type 2 diabetic patients
without overt proteinuria."
The endothelium controls tone, growth and structure of blood
vessels. It secretes metabolically active substances such as nitric
oxide (NO), prostacyclin, endothelin I, angiotensin II, adhesion mole-
cules, etc. It is an interface where anti-coagulant and anti-thrombotic
activity takes place in the blood stream and importantly acts as a
barrier between the blood vessels and blood elements, and thus
prevents the development of atherosclerosis. Prostacyclins and NO are
involved in dilatory and anti-proliferating effect whereas, endothelin I
(a powerful vasoconstrictor),angiotensin II and thromboxane all
are involved in vasoconstriction and proliferation.
NO inhibits platelet aggregation, smooth muscle cell proliferation
and blocks leukocyte adhesion. It keeps endothelium non-sticky,
non-leaky and helps in blood vessel dilatation.
ENDOTHELIAL DYSFUNCTION
Damaged endothelium is leaky, sticky and unable to relax.
Endothelial dysfunction promotes atherosclerosis through the follow-
ing mechanisms: vasoconstriction, monocyte and platelet adhesion,
thrombogenesis; cytokines with growth-stimulating factor initiate
smooth muscle cell proliferation.
Clinical importance
Endothelial dysfunction leads to atherosclerosis, which eventually
leads to clinical syndrome of angina. Hypertension along with vasocon-
striction and thrombosis precipi-
tates unstable angina resulting into
myocardial infarction or sudden
cardiac death.
Modulation
Endothelial dysfunction can be
improved by risk factor modifica-
tion and drug therapy. Risk factor
modification includes:
ā¢ Quitting tobacco
ā¢ Lowering cholesterol level
ā¢ Exercising
ā¢ Modification of lifestyle
Various drugs that can reverse
endothelial dysfunction are
calcium-channel blockers particu-
larly nifedipine and ACE-inhibitors
such as quinapril and ramipril,
statins and oestrogen supplementa-
tions.
CALCIUM-CHANNEL BLOCKERS
Nifedipine improves endothelial
NO availability, antagonizes endo-
thelin I, and restores endothelial
permeability.
Nifedipine, apart from its well-
known Ca" antagonistic properties
in vascular smooth muscle cells,
stimulates the release of significant
concentration of NO in endothelium
and preserves NO concentration.
Both these effects may be beneficial
in the treatment of hypertension.6
Nifedipine upregulates man-
ganese superoxide dismutase
expression in vascular smooth
muscle cells via endothelial cell-
dependent pathways, normalizes
endothelial dysfunction and
improves the clinical outcome in
patients with hypertension'
In fact, large studies such as the
International Nifedipine Trial on
Anti-atherosclerotic Therapy
(INTACT)* and Regression Growth
Evaluation Statin Study (REGRESS)
have clearly established the athero-
protective role of nifedipine, when
used either alone or with other
vasculoprotective drugs such as
statins and/or ACE-inhibitors.
Further, it has also been established
through large studies such as
the Shanghai Trial of Nifedipine in
Elderly (STONE)" and Internatio-
nal Nifedipine GITS Study of Inter-
vention as a Goal in Hypertension
Treatment (INSIGHT)" that this
vasculoprotective action of nifedip-
ine results into very significant
reduction in long-term cardiovascu-
lar complications in hypertensives.
Interestingly, it has been seen
that the beneficial effect of nifedip-
ine on endothelial function is not
shared by other calcium-channel
blockers, e.g. amiodipine."
Nifedipine versus amiodipine
The efficacy and safety profiles of
nifedipine retard (20-40 mg twice
daily) and amiodipine (5-10 mg
once daily) were compared in III
hypertensive patients (sitting DBF
95-115 mmHg) during eight weeks
of treatment in a randomized, dou-
ble-blind, parallel group study. BP
was measured 22-24 hours after the
daily dose of amiodipine and 10-12
hours after a dose of nifedipine
retard. Baseline sitting BP of
175/105 mmHg and 168/104
mmHg were significantly reduced
(p<0.05) to 157/93 mmHg and
151/92 mmHg at the end of treat-
ment in response to mean daily dos-
es of amiodipine 7.3 mg and
nifedipine retard 58.9 mg. There
were no clinically significant
changes in heart rate with either
treatment. Three patients in the
amiodipine group and five in the
nifedipine retard group could not be
considered in the analysis. The total
number of adverse events (consid-
ered related or possibly related to
treatment) (42 vs. 36) as well as the
numbers of patients experiencing
such events (22 vs. 22) were similar
in the amiodipine and nifedipine
retard treated groups, respectively,
but with a greater incidence of
headaches in response to nifedipine
retard and of oedema in response to
amiodipine. Five patients in each
treatment group discontinued thera-
py due to such events."
A randomized, multicentre, open
trial over 12 weeks, was conducted
to compare the effectiveness, safety
and tolerability of once-daily
nifedipine and amiodipine treat-
ment in patients with mild-to-mod-
erate essential hypertension. 155
patients with essential hypertension
(diastolic blood pressure 95-109
mmHg) were included in the study.
Initial treatment (step 1) consisted of
30 mg nifedipine CITS (n=76) or 5
mg amiodipine (n=79), either
administered once daily as a morn-
ing dose, or if the blood pressure
was not below 140/90 mmHg or the
reduction in diastolic blood pressure
was lower than 10 mmHg after a
treatment period of 6 weeks, the
dose was increased (step 2) to 60 mg
once daily in the nifedipine group,
or 10 mg once daily in the amiodip-
ine group. The main efficacy param-
eter was diastolic blood pressure at
trough after 12 weeks of active com-
pound therapy adjusted to baseline.
After 12 weeks of treatment, the
mean diastolic blood pressure was
83.1 and 81.9 mmHg, in the nifedip-
ine and amiodipine groups, respec-
tively (p=0.436). The mean decrease
in systolic blood pressure (28.5 Ā±
11.9 and 28.2 Ā± 11.2 mmHg in the
nifedipine and amiodipine groups,
respectively) and the mean decrease
in diastolic blood pressure (16.4 Ā±
7.0 and 17.5 Ā± 6.9 mmHg in the
nifedipine and amiodipine groups,
respectively), as well as the respon-
der rates (88.1% and 92.1% in the
nifedipine and amiodipine groups,
respectively) were comparable at the
end of the study. No significant dif-
ferences between groups were
detected in the efficacy parameters
assessed in this study. Both drugs
were well tolerated. The overall
incidence of adverse events was
7.9% in the nifedipine group and
10.1% in the amiodipine group.
However, more patients discontin-
ued treatment prematurely in the
amiodipine group (13 patients;
19.7%) than in the nifedipine group
(four patients; 5.6%).'4
All calcium-channel blockers do
not offer same benefit of reversal of
endothelial dysfunction. Amiodi-
pine does not seem to be as effective
as nifedipine in terms of atheropro-
tection. With nifedipine, the overall
risk of cardiovascular events
decreased siginificantly."
There are many landmark
studies like ACTION, INSIGHT, J-
MIND and PRESERVE involving
large number of patients highlight-
ing benefits of long-acting nifedip-
ine preparation.
ACTION TRIAL
In this study, the effects of nifedipine
CITS on clinical outcome in patients
with concurrent stable angina and
hypertension were examined. Data
from the double-blind, placebo-
controlled ACTION trial were strati-
fied for hypertension (blood pres-
sure ~ 140/90 mmHg), at baseline. A
total of 52% of 7665 ACTION
patients were hypertensive. Some
80% were on a beta-blocker; hyper-
tensives were more often treated
with other blood pressure-lowering
drugs. Mean baseline blood pressure
was 122/74 mmHg among nor-
motensives and 151/85 mmHg
among hypertensives. Follow-up
blood pressures were reduced by
nifedipine (p<0.001) on the average
by 3.9/2.4 and 6.6/3.5 mmHg
among normotensives and hyper-
tensives, respectively.
Action Hypertension Subgroup
Analysis"
A prospectively defined subgroup
analysis of ACTION study delivers
convincing evidence that patients
with symptomatic stable angina and
hypertension greatly benefit from
the addition of nifedipine CITS to
their therapy.
Reduction of death and cardiovascular
events
ā¢ 52% of the nearly 8,000 patients
enrolled in the ACTION study
were found to be hypertensive,
although 88% of these were
already on blood pressure-lower-
ing therapy.
ā¢ The analysis of this large sub-
group demonstrates that adding
nifedipine GITS to existing best
practice therapy results in a sig-
nificant 13% reduction in the
combined rate of death from any
cause and cardiovascular events.
Reduction in heart failure and stroke
ā¢ There is a 38% reduction in the
incidence of new overt heart fail-
ure, a 33% reduction in debilitat-
ing stroke and a 16% reduction
in the need for coronary
angiography.
ā¢ Since these patients were already
receiving best practice therapy
(aspirin, (3-blockers, ACE-
inhibitors, ARBs, diuretics or
statins), the findings strongly
suggest that current manage-
ment of these patients can be
improved.
Primary and secondary endpoints met
ā¢ Patients enrolled in the ACTION
study suffered from stable
angina pectoris and were ran-
domized to two groups receiv-
ing, in addition to their best
practice therapies, either nifedip-
ine GITS or a placebo.
ā¢ The patients in the hypertension
analysis were followed-up in the
trial for at least four years.
ā¢ In addition to the significant
reduction in the primary
endpoint (combined incidence of
all-cause mortality, myocardial
infarction, refractory angina,
heart failure, stroke and periph-
eral revascularization) in this
subgroup analysis, and the
proven safety, nifedipine GITS
also significantly reduced the
secondary endpoint "any CV
event" by 17% in the hyperten-
sive population. Death and any
CV event or procedure was
reduced by 10% and any vascu-
lar event or procedure was
reduced by 11%.
INSIGHT CALCIFICTION STUDY'
In the INSIDE calcification study, the overall treatment effect of
nifedipine demonstrated significant
inhibition of coronary calcification
progression over a three-year
period.
INSIGHT STUDY: BENEFITS IN
DIABETICS"
ā¢ The aim of this study was to
investigate the impact of treat-
ment on cardiovascular mortali-
ty and morbidity, the outcomes
in patients with hypertension
and diabetes who received
co-amilozide (25 mg hydrochi-
orothiazide and 2.5 mg
amiloride) or nifedipine.
ā¢ Participants were aged 55 to 80
years of age, with hypertension
(BP > 150/95 or > 160 mmHg)
and at least one additional car-
diovascular risk factor.
> Patients received 30 mg nifedip-
ine once daily or co-amilozide
daily.
> There was no significant differ-
ence in the incidence of primary
outcomes between nifedipine-
treated and co-amilozide-treated
patients with diabetes at baseline
(n=1302) (8.3% versus 8.4%; rela-
tive risk 0.99; 95% Cl 0.69-1.42).
> A significant benefit for nifedip-
ine-treated patients was seen for
the composite secondary out-
come (14.2% versus 18.7%;
relative risk, 0.76, 95% Cl 0.59-
0.97).
> Among patients without dia-
betes at baseline (n=5019), there
was a significant difference in
the incidence of new diabetes
(nifedipine 4.3% versus
co-amilozide 5.6%).
ā¢ Nifedipine GITS once daily is as
effective as diuretic therapy in
reducing cardiovascular compli-
cations in hypertensive diabetes.
ā¢ Nifedipine-treated patients were
also less likely to have diabetes
or secondary events ( a compos-
ite of all-cause mortality, death
from a vascular cause, and death
from a non-vascular cause) than
co-amilozide recipients.
ā¢ The results suggested that
nifedipine could be considered
as first-line therapy for hyper-
tensive diabetics.
J-MIND STUDY: PREVENTION OF PRO-
GRESSION OF NEPHROPATHY"
The Japan Multicenter Investigation
of Antihypertensive Treatment for
Nephropathy in Diabetics (J-MIND)
study was conducted to evaluate
the effect of nifedipine retard or
enalapril on nephropathy in hyper-
tensive patients with type 2
diabetes.
A total of 436 patients with nor-
moalbuminuria (urinary albumin
excretion rate [AER] <30 mg/day)
or microalbuminuria (AER: 30-300
mg/day) were randomized to
receive nifedipine retard or
enalapril and were followed for 24
months.
ā¢ There were no differences in
baseline characteristics between
the two groups (the mean AER
was 45 and 42 mg/day).
ā¢ Intent-to-treat analysis showed
no significant difference in AER
after 2 years, although the mean
AER increased to 64 and 74
mg/day in the nifedipine
retard and enalapril groups,
respectively.
ā¢ The AER increased in patients
with normoalbuminuria, where-
as it did not change in those with
microalbuminuria.
ā¢ There were no differences
between the two groups with
respect to progression from
normoalbuminuria to microal-
buminuria, progression from
microalbuminuria to overt
proteinuria, and regression from
microalbuminuria to normoal-
buminuria.
ā¢ The incidence of cardiovascular
events was also similar in both
groups.
In conclusion, nifedipine retard
and enalapril had a similar effect on
diabetic patients without overt
proteinuria.
PRESERVE STUDY
The PRESERVE (prospective ran-
domized enalapril study evaluating
regression of ventricular enlarge-
ment) study was designed to test
whether enalapril achieves greater
LV mass reduction than does a
nifedipine GITS by a prognostically
meaningful degree on a population
basis (10 g/m').
ā¢ No significant between-treat-
ment difference was detected in
population subsets defined by
monotherapy treatment, sex,
age, race, or severity of baseline
hypertrophy.
ā¢ Similarly, there was no between-
treatment difference in change
in velocities of early diastolic or
atrial phase transmitral blood
flow.
ā¢ More enalapril-treated than
nifedipine-treated patients
required supplemental treat-
ment with hydrochlorothiazide
(59% versus 34%, p<0.001).
ā¢ It was concluded that treatment
with long-acting nifedipine was
equally effective as compared to
enalapril in regressing the LV-
hypertrophy (LV-mass index
was reduced by 15 gm2 with
enalapril and by 17 gm2 with
long-acting nifedipine). Both
treatments achieved equivalent
BP control, however, significant-
ly more enalapril-treated
patients required addition of
diuretic to achieve the control.
CONCLUSION
Long-acting nifedipine favourably
modulates endothelial dysfunction.
The reversal of endothelial dysfunc-
tion found with nifedipine is not
found with other calcium antago-
nists. It is as effective as amiodipine
in controlling blood pressure with
fewer side effects. Nifedipine is the
drug of choice in elderly hyperten-
sives (with isolated systolic new
hypertension and a high risk of
stroke), for patients with COPD and
bronchial asthma, those with
Raynaud's syndrome, Prinzmetal-
angina, patients with diastolic func-
tion disturbances including dias-
tolic heart failure, hypertensives
with massive LVH in combination
with ACE or angiotensin -
inhibitors. It is an effective add-on
to other drugs in hypertension
management. Nifedipine is safe in
pregnancy. Thus, nifedipine
appears to be a versatile and multi-
faceted drug with numerous bene-
fits in patients with CAD.