The P-I-E-N-O Parkinsn's List Drug Database
nifedipine / ProcardiaTM ,AdalatTM , NefecardTM ,NyefaxTM
BLOOD PRESSURE:
Description: Nifedipine is the prototype of the dihydropyridine class of calcium-channel antagonists. Nifedipine is structurally and pharmacologically similar to other dihydropyridines including amlodipine, felodipine, and nicardipine. Nifedipine and the dihydropyridine class have more prominent effects on vasodilation and coronary flow than do diltiazem and verapamil. Unlike both diltiazem and verapamil, however, nifedipine has negligible effects on AV nodal conduction. This difference is attributed to the fact that nifedipine binds to a different site in the calcium channel. Nifedipine is used in the treatment of Prinzmetal's angina, hypertension, and other vascular disorders such as Raynaud's phenomenonư. Although its actions were described in 1972, it was not approved by the FDA until 1981.
Mechanism of Action: Like other calcium-channel antagonists, nifedipine inhibits the influx of extracellular calcium through myocardial and vascular membrane pores, which are selective for specific ions. Serum calcium levels remain unchanged. It is believed that nifedipine inhibits this influx by physically plugging the channel. While verapamil and diltiazem exert balanced effects on calcium channels in the SA node, AV node, and vasculature, nifedipine and other members of the dihydropyridine group act predominantly on the vasculature, making these agents more potent peripheral vasodilators. The decrease in intracellular calcium inhibits the contractile processes of smooth muscle cells, causing dilation of the coronary and systemic arteries. This results in increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload.
Although these drugs originally were believed to improve oxygen supply, it now appears that their effectiveness as anti-ischemic agents arises from their ability to alter the systemic balance between supply and demand. Reduced afterload and reduced myocardial wall tension lead to reduced myocardial oxygen demand, which now seems to best explain the benefit of nifedipine and other dihydropyridines in the treatment of angina. Thus, nifedipine increases myocardial oxygen supply (secondary to coronary vasodilation) and decreases myocardial oxygen demand (secondary to decreased afterload). Nifedipine appears particularly effective in treating variant angina (i.e., vasospastic angina) due to this ability to increase myocardial oxygen supply by inducing coronary vasodilation. The effectiveness of nifedipine in treating chronic stable angina, on the other hand, is related to the decrease in myocardial oxygen demand secondary to decreased afterload.
Nifedipine has no clinical effect on AV conduction, which may be due to its inhibition of phosphodiesterase. This intracellular mechanism of nifedipine actually enhances calcium inflow and counteracts its own inhibitory effects on calcium influx at the membrane surface. Also, phosphodiesterase inhibition causes additional relaxation of vascular smooth muscle. Thus, nifedipine is more potent than verapamil as a peripheral vasodilator but has negligible effects on AV nodal conduction. Negative inotropic effects rarely are noted clinically, presumably due to a reflex increase in heart rate in response to nifedipine's vasodilatory activity. Nifedipine therapy usually does not affect cardiovascular parameters in patients with normal ventricular function, but patients with decreased left ventricular function can experience an increase in ejection fraction and a decrease in left ventricular filling pressures.
Pharmacokinetics: Nifedipine is rapidly and well absorbed (90%) following an oral dose but undergoes extensive first-pass metabolism, resulting in a bioavailability of 50-70%. The bioavailability of the sustained-release tablet ("gastrointestinal therapeutic system [GITS]") relative to the capsule is 86% after chronic administration. The sustained-release tablet should be swallowed whole, without breaking, crushing, or chewing, because the osmotically driven release characteristics of the sustained-release mechanism would be destroyed. The bioavailability of nifedipine does not appear to be affected by food. Bioavailability is, however, substantially increased (up to a 100% increase) in the presence of hepatic impairment. Elderly patients also appear to have an increased bioavailability of nifedipine. Decreases in gastrointestinal transit time can significantly alter the absorption characteristics of the XL formulation in a relatively unpredictable fashion by increasing the time available for the osmotically driven release to occur.
Sublingual administration of nifedipine liquid (expressed from regular-release capsules) to achieve rapid decreases in blood pressure, such as in the case of hypertensive urgency, has generated much controversy and confusion. Systemic absorption after sublingual administration is poor. Systemic effects are a result of absorption of swallowed nifedipine and, as a result, sublingual administration offers no advantage over oral administration of the immediate-release capsules (see Dosage).
Onset of hypotensive effects occurs in 30 minutes to 1 hour after administration of regular-release capsules, with peak effects occurring within 30 minutes to 2 hours. With the sustained-release tablet, serum concentrations do not peak for 6 hours, and hypotensive effects are correspondingly delayed. Duration of pharmacodynamic activity for the immediate-release preparation is approximately 8 hours. The extended-release tablet is designed to release nifedipine continuously in a zero-order process. Once-daily dosing is possible with this dosage form.
Nifedipine is relatively well distributed, including into breast milk. Nifedipine is protein-bound in a concentration-dependent way, ranging from 92-98%. Protein binding is significantly reduced in patients with hepatic or renal dysfunction.
Hepatic metabolism of nifedipine is rapid and complete, causing the formation of two inactive metabolites that, along with the parent drug, are excreted primarily in the urine and, to a lesser extent, the feces. Less than 5% of nifedipine is eliminated as unchanged drug. The elimination half-life of nifedipine is approximately 2-5 hours. In patients with clinically significant hepatic impairment, the half-life increases to an average of 7 hours. The drug's half-life is likely to be prolonged in the elderly, but the degree has not been fully characterized. Nifedipine is minimally removed by hemodialysis or hemoperfusion.
CONTRAINDICATIONS/PRECAUTIONS: Nifedipine is placed in pregnancy category C and should be used only when its benefits clearly outweigh the risks of its use to the fetus. Furthermore, nifedipine is distributed into breast milk, so clinicians should consider the risk/benefit ratio in women breast-feeding their infants.
Nifedipine should be used cautiously in patients with severe bradycardia. It also should be used cautiously following an acute myocardial infarction with concomitant pulmonary congestion, cardiogenic shock, or congestive heart failure because nifedipine can precipitate or exacerbate heart failure due to its negative inotropic effects, particularly in patients receiving concomitant œ-blocker therapy. The development or worsening of pulmonary edema is a marker for discontinuation of nifedipine.
Nifedipine decreases peripheral resistance and can worsen hypotension. Nifedipine should not be used in patients with systolic blood pressures of less than 90 mm Hg (i.e., severe hypotension). Nifedipine should be used with caution in patients with mild to moderate hypotension. Blood pressure should be monitored carefully in all patients receiving nifedipine.
Nifedipine is relatively contraindicated in patients with advanced aortic stenosis because the drug can worsen the abnormal pressure gradient associated with this condition.
The elderly, patients with renal impairment, or patients with hepatic disease, such as cirrhosis or hepatic failure, can experience a delayed clearance of nifedipine and can be at greater risk for accumulation and toxicity.
Nifedipine XL should not be used in patients with GI obstruction, constipation, or severe GI tract narrowing (i.e., esophageal stricture) because the rigid dosing form can cause obstruction.
DRUG INTERACTIONS: Digoxin levels may be increased by up to 45% with concomitant administration of nifedipine. This is believed to be due to decreased renal and nonrenal clearance of digoxin brought on by nifedipine. Despite some reports showing no effect on digoxin, plasma levels of digoxin should be monitored carefully when nifedipine is administered.
Concomitant use of calcium-channel blockers and ›-blockers or other antihypertensive agents can cause additive effects on hypotension and, possibly, orthostatic hypotension.
In general, concomitant therapy of nifedipine with œ-blockers is well tolerated and can even be beneficial in some cases (i.e., inhibition of nifedipine-induced reflex tachycardia by œ-blockade). Negative inotropic and/or chronotropic effects can be additive when these drugs are used in combination. Finally, angina has been reported when œ-adrenergic blocking agents are withdrawn abruptly and nifedipine therapy is initiated. A gradual downward titration of the œ-adrenergic blocking agent dosage during initiation of nifedipine therapy may minimize or eliminate this potential interaction.
Cimetidine and, to a lesser degree, ranitidine have been shown to increase the oral bioavailability of other dihydropyridines. These drugs potentially affect the disposition of nifedipine due to their inhibitory effects on cytochrome P-450 and, subsequently, first-pass metabolism of nifedipine, which increases nifedipine bioavailability and serum concentrations. Lower doses of nifedipine may be considered during concomitant therapy with either of these HA-antagonists.
Concomitant use of nifedipine and fentanyl, especially in combination with œ-adrenergic blocking agents during surgical procedures, has resulted in severe hypotension. It is recommended that nifedipine be withheld for at least 36 hours, if possible, prior to the use of high-dose fentanyl.
Quinidine concentrations decrease by 20-40% when nifedipine is added and rise after nifedipine is withdrawn. This appears to be an idiosyncratic reaction, although quinidine doses may need to be adjusted when nifedipine is added or withdrawn. Careful monitoring of serum quinidine concentrations is prudent following the addition or discontinuation of nifedipine.
When administered with nifedipine, highly protein-bound medications, such as warfarin, phenytoin, NSAIDs, salicylates, sulfinpyrazone, or amiodarone, have the potential to increase free or unbound concentrations of nifedipine due to displacement from protein-binding sites. Nifedipine also can displace any of these agents, although these reactions have not occurred in clinical practice.
Ethanol can increase the bioavailability of nifedipine, presumably due to P-450 inhibition.
Rifampin is a potent hepatic enzyme inducer and has been shown to exert a dramatic effect on the oral bioavailability of verapamil. Until more data are available, patients should be monitored for loss of antihypertensive effect if rifampin is added to nifedipine therapy.
The exogenous administration of calcium salts can attenuate the pharmacodynamic response to calcium-channel antagonists.
The concomitant use of nifedipine with disopyramide or flecainide is not recommended because of additive negative inotropic properties.
Estrogens can cause excess fluid retention that can increase peripheral edema as well as blood pressure. Patients receiving nifedipine should be monitored for either of these adverse effects if estrogens are added.
ADVERSE REACTIONS: Overall, the adverse effects associated with nifedipine are not serious and respond well to either dosage reduction or discontinuation of therapy. Most adverse effects during nifedipine therapy are related to vasodilatory actions, which are more significant with regular-release capsules than with the extended-release product and, in many cases, are dose-related.
The most common cardiovascular adverse effect attributed to nifedipine therapy is peripheral edema. This reaction reflects the potent vasodilatory effect of this drug because it occurs more frequently with nifedipine than with other calcium-channel blockers. Although peripheral edema may indicate a worsening of congestive heart failure, it more commonly is due to vasodilation.
Although calcium-channel blockers are effective drugs for treating angina, worsening of angina has occurred in as many as 10% of patients receiving nifedipine for angina pectoris. This reaction may be a result of excessive hypotension, coronary steal, or reflex sinus tachycardia. In rare cases, myocardial infarction has occurred, but it could not be attributed solely to the drug and may have been a reflection of disease progression. Patients with angina should be observed for worsening symptoms when nifedipine therapy is begun, particularly if œ-blocker therapy is being withdrawn.
Other common side effects, primarily related to vasodilation, include flushing, weakness, headache (more common with the XL preparation), syncope, hypotension, palpitations, dizziness, and lightheadedness.
Other less common but potentially serious adverse effects include dyspnea, wheezing (especially if underlying respiratory disease or pulmonary edema exists), asthenia, paresthesia (often associated locally with sublingual administration), immune-complex glomerulonephritis, vertigo, priapism, and visual disturbances.
PATIENT INFORMATION:
What do nifedipine capsules?
Nifedipine (AdalatTM , ProcardiaTM ) is a calcium-channel blocker. It affects the amount of calcium found in your heart and muscle cells. This results in relaxation of blood vessels, which can reduce the amount of work the heart has to do. Nifedipine reduces attacks of chest pain (angina). It is not a cure. Generic nifedipine capsules are available.
What should my doctor, dentist, or pharmacist know before I take nifedipine?
They need to know if you have any of these conditions:
How should I take this medicine?
Take nifedipine capsules by mouth. Follow the directions on the prescription label. Swallow the capsules with a drink of water. Take your doses at regular intervals. Do not take your medicine more often then directed. Do not stop taking except on your doctor's advice.
Special precautions for use in children:
This medicine is not for children.
Elderly patients over 65 years old may have a stronger reaction to this medicine and need smaller doses.
What if I miss a dose?
If you miss a dose, take it as soon as you can. If it is almost time for your next dose, take only that dose. Do not take double or extra doses.
What other medicines can interact with nifedipine?
Tell your doctor or pharmacist: about all other medicines you are taking, including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These may affect the way your medicine works. Check before stopping or starting any of your medicines.
What side effects may I notice from taking nifedipine?
Serious side effects with nifedipine include:
Call your doctor as soon as you can if you get any of these side effects.
Minor side effects with nifedipine include:
Let your doctor know about these side effects if they do not go away or if they annoy you.
What do I need to watch for while I take nifedipine?
Check your blood pressure and pulse rate regularly; this is important while you are taking nifedipine. Ask your doctor what your blood pressure and pulse rate should be and when you should contact him or her. Do not suddenly stop taking nifedipine. Ask your doctor how to gradually reduce the dose.
You may feel dizzy or lightheaded. Do not drive, use machinery, or do anything that needs mental alertness until you know how nifedipine affects you. To reduce the risk of dizzy or fainting spells, do not sit or stand up quickly, especially if you are an older patient. Alcohol can make you more dizzy, increase flushing and rapid heartbeats. Avoid alcoholic drinks.
If you are going to have surgery, tell your doctor or dentist that you are taking nifedipine.
Where can I keep my medicine?
Keep out of the reach of children in a container that small children cannot open.
Store at room temperature between 15 and 25C (59 and 77F). Protect from light and moisture. Keep container tightly closed. Throw away any unused medicine after the expiration date.
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