The P-I-E-N-O Parkinsn's List Drug Database
diltiazem / CardizemTM , CardcalTM , CorasTM
BLOOD PRESSURE:
LOW RISK
Description: Diltiazem is a benzothiazepine calcium-channel blocking agent most similar to verapamil in its clinical use. Diltiazem increases exercise capacity and improves multiple markers of myocardial ischemia, reduces heart rate, may increase cardiac output, improves myocardial perfusion, reduces left ventricular workload, and may prevent calcium-induced reperfusion injury that occurs after procedures such as angioplasty. As such, diltiazem is used for the management of Prinzmetal's variant angina, stable angina pectoris, hypertension, paroxysmal supraventricular tachycardia, control of ventricular rate in atrial fibrillation and flutter, and prevention of injury following angioplasty. It also has been found to possibly reduce recurrent cardiac events, although not mortality, following MI in patients without left ventricular dysfunction; however, this is not an FDA-approved indication at this time. Diltiazem was approved by the FDA for general use in November 1982. The patent for Dilacor XR will expire in May 1995. The patent for Cardizem CD expired in 1994.
Mechanism of Action: Diltiazem is similar to verapamil in that it inhibits the influx of extracellular calcium across both the myocardial and vascular smooth muscle cell membranes. Serum calcium levels remain unchanged. Calcium channels in myocardial and vascular smooth muscle cell membranes are selective and allow a slow, inward flow of calcium that contributes to excitation-contraction coupling and electrical discharge (plateau phase of the action potential) of conduction cells in the heart and vasculature. Diltiazem inhibits this influx, possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum. The resultant decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, resulting in dilation of the coronary and systemic arteries and improved oxygen delivery to the myocardial tissue. In addition, total peripheral resistance, systemic blood pressure, and afterload are decreased. Diltiazem, like verapamil and nifedipine, effectively increases coronary blood flow. Therefore, calcium-channel blockers such as diltiazem are useful in managing angina and hypertension.
The electrophysiologic effects of diltiazem make it a favorable agent for the control and/or conversion of certain supraventricular arrhythmias. Diltiazem's inhibitory effects on conduction through the atrioventricular (AV) node is stronger than nifedipine's and similar to verapamil's. This is reflected on the ECG by a prolonged PR interval. Second-or third-degree heart block is possible, especially if diltiazem is given to patients receiving œ-blockers. Resting heart rate also can be decreased, especially in patients with sick sinus syndrome. Its effects on calcium channels in SA and AV nodes, and peripheral vasculature are equipotent. Diltiazem exerts fewer negative inotropic effects than either verapamil or nifedipine. Diltiazem is also less potent as a peripheral vasodilator than nifedipine and related dihydropyridine analogs.
Pharmacokinetics: Although diltiazem is well absorbed after oral administration (roughly 80%), extensive first-pass metabolism reduces bioavailability to 40-60%, with the upper range of bioavailability observed with the sustained-release products. The sustained-release capsules should be taken whole, without opening, chewing, or crushing, because this significantly alters the release characteristics of these products. The parenteral product is completely bioavailable. The onset of action occurs within minutes for the IV preparation, within 1 hour for immediate-release products, and within 2-3 hours for the sustained-release formulations of the drug. Time to peak effect is 15 minutes, 2-3 hours, and 6-11 hours for the IV, immediate-release, and sustained-release formulations, respectively.
Diltiazem is widely distributed throughout the body and into maternal breast milk in equal concentrations to those achieved in serum. Roughly 70-80% of the circulating drug is bound to plasma proteins.
About 10-35% of the absorbed dose is metabolized to deacetyldiltiazem, which has 25-50% of the coronary vasodilatory effects of diltiazem. The remaining metabolites are not pharmacologically active. Diltiazem exhibits dose-dependent kinetics, predisposing patients to accumulation with repeated dosing. The half-life of diltiazem ranges from 3.5-9 hours and is usually 4-6 hours. About 2-4% of the drug is excreted unchanged in the urine, with the remainder excreted in the bile and urine.
CONTRAINDICATIONS/PRECAUTIONS: Diltiazem should be used cautiously in patients with ventricular dysfunction, severe bradycardia, cardiogenic shock, or congestive heart failure and/or in patients taking œ-adrenergic blocking agents because diltiazem can precipitate or exacerbate heart failure in these patients, or cause excessive bradycardia or cardiac conduction abnormalities. Heart failure associated with an acute myocardial infarction may be worsened by administration of diltiazem.
Diltiazem decreases peripheral resistance and can worsen hypotension. Diltiazem should not be used in patients with systolic blood pressures of less than 90 mm Hg (i.e., severe hypotension). Diltiazem should be used with caution in patients with mild to moderate hypotension. Blood pressure should be monitored carefully in all patients receiving diltiazem.
Due to its inhibitory effects on AV node conduction, diltiazem should be used cautiously in patients with preexisting second-or third-degree AV block or previous conduction abnormalities, or in patients taking œ-adrenergic blocking agents.
Diltiazem should be used with caution in patients with sinoatrial nodal dysfunction, such as sick sinus syndrome (SSS). Use of diltiazem in patients with these conditions may lead to severe hypotension, bradycardia, or asystole. Patients with SSS with a functioning artificial ventricular pacemaker may use still use a calcium channel blocker.
Use of diltiazem for treatment of atrial fibrillation or flutter may precipitate severe ventricular arrhythmias in patients with Wolff-Parkinson-White syndrome or Lown-Ganong-Levine syndrome. Patients with these reentrant arrhythmias with a functioning artificial ventricular pacemaker may use still use a calcium channel blocker. Patients with wide-complex ventricular tachycardia are at risk of developing ventricular fibrillation after intravenous diltiazem.
The elderly, patients with renal impairment, or patients with hepatic disease, such as cirrhosis or hepatic failure, can experience a delayed clearance of diltiazem and can be at greater risk for accumulation and toxicity.
Diltiazem is contraindicated in advanced aortic stenosis because it can cause a worsening of the abnormal pressure gradient associated with this condition.
Diltiazem is classified as a pregnancy category C drug. Some fetal toxicity has benn observed in laboratory animals, but no adequate or well-controlled studies have been done in humans. Use of diltiazem in pregnancy should be restricted to cases where therapeutic benefits outeigh the potential risk to the fetus.
DRUG INTERACTIONS: Although conflicting reports exist, diltiazem can increase serum digoxin concentrations. It is believed that diltiazem decreases renal and nonrenal clearance of digoxin. Despite the fact that some reports show no effect on digoxin, plasma levels of digoxin should be monitored carefully when administered with diltiazem.
Cimetidine can increase the plasma levels of diltiazem. It is believed that cimetidine inhibits the hepatic metabolism of diltiazem, although other mechanisms are possible.
Diltiazem can inhibit the hepatic clearance of these drugs due to its effects on hepatic microsomal enzymes. Diltiazem can interfere with the metabolism of carbamazepine, cyclosporine, imipramine, midazolam, quinidine, theophylline, or valproic acid. The resultant increase in serum cyclosporine levels can lead to nephrotoxicity. The interaction with midazolam occurred with oral midazolam.ID The significance of an interaction between diltiazem and IV midazolam is uncertain but may be less significant due to absence of an effect on presystemic midazolam clearance.
Medications that possess negative inotropic effects, including procainamide, quinidine, disopyramide, flecainide, or other medications that prolong the QT interval, should be administered with caution to patients receiving concomitant therapy with diltiazem because of the risk of additive effects.
Concurrent use of amiodarone and diltiazem can result in bradycardia and depressed cardiac output by an unknown mechanism. Careful checks of blood pressure and heart rate are important monitoring parameters.
Prolongation of the effects of neuromuscular blockers is possible when they are given in combination with calcium-channel blockers, particularly diltiazem and verapamil.
The addition of diltiazem to a patient stabilized on lithium therapy will increase the potential for lithium-induced neurotoxicity.
Diltiazem is an antihypertensive agent, so its effects are additive with other antihypertensive agents. This may be desirable, but dosages should be adjusted carefully. Concomitant use of ›-blockers and diltiazem can lead to excessive bradycardia, cardiac conduction abnormalities, heart block, and congestive heart failure, however, concomitant use of diltiazem and ›-adrenergic blocking agents can reduce angina and improve exercise tolerance. Diltiazem has been shown to inhibit the metabolism of some œ-blockers to a greater degree than other calcium-channel blockers, particularly the dihydropyridines. As a result, additive effects on AV conduction (bradycardia) and blood pressure (hypotension) can occur.
Intravenous administration of calcium salts can antagonize some of the effects of calcium-channel blockers. Although the vascular effects (e.g., hypotension) can be reversed, AV nodal effects do not seem to be affected by exogenously administered calcium salts.
Rifampin, a known hepatic enzyme inducer, significantly reduces the oral bioavailability of verapamil, presumably by increasing the first-pass metabolism. Phenobarbital and phenytoin also have this effect on verapamil levels. Similar effects have been observed when rifampin, phenobarbital, or phenytoin were added to diltiazem therapy.
ADVERSE REACTIONS: Serious adverse effects of diltiazem are infrequent and rarely require discontinuation of therapy.
Skin reactions due to diltiazem are generally mild and regress with discontinuation of therapy but, in some cases, can progress to erythema multiforma, exfoliative dermatitis, or Stevens-Johnson syndrome.
More common and clinically significant cardiovascular effects that occur relatively frequently with diltiazem include first-degree AV block, sinus bradycardia, exacerbation of congestive heart failure or pulmonary edema, and excessive hypotension. Serious cardiac arrhythmias are uncommon, unless excessive doses are used or diltiazem is used in combination with other drugs that impair AV-node conduction.
Flushing and peripheral edema also occur relatively frequently during diltiazem therapy. Since diltiazem exhibits negative inotropic effects, congestive heart failure can be worsened.
About 1-3% of patients report adverse GI effects including nausea/vomiting, diarrhea, anorexia, constipation, weight gain, thirst, dyspepsia, and dysgeusia.
Moderate to marked transient elevations in liver-function tests and hepatocellular injury have been reported, usually occurring within 1-8 weeks following initiation of therapy. Elevated hepatic enzymes usually resolve after discontinuation of therapy. Overt hepatotoxicity is uncommon.
Adverse CNS effects occur in about 1-2% of patients during therapy and include headache, fatigue, nervousness, drowsiness, dizziness, depression, insomnia, and confusion. The percentage of patients reporting these symptoms increases in the population being treated for hypertension.
PATIENT INFORMATION:
What do diltiazem tablets do?
Diltiazem (CardizemTM ) 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. Diltiazem relieves different types of chest pain (angina); it is not a cure. Generic diltiazem tablets are available.
What should my doctor, dentist, or pharmacist know before I take diltiazem?
They need to know if you have any of these conditions:
How should I take this medicine?
Take diltiazem tablets by mouth. Follow the directions on the prescription label. Swallow the tablets with a drink of water. Take diltiazem tablets on an empty stomach, at least 1 hour before or 2 hours after food. 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.
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 diltiazem?
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 diltiazem?
Serious side effects with diltiazem include:
Call your doctor as soon as you can if you get any of these side effects.
Minor side effects with diltiazem 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 diltiazem?
Check your blood pressure and pulse rate regularly; this is important while you are taking diltiazem. Ask your doctor what your blood pressure and pulse rate should be and when you should contact him or her.
You may feel dizzy or lightheaded. Do not drive, use machinery, or do anything that needs mental alertness until you know how diltiazem 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. Avoid alcoholic drinks; they can make you more dizzy, increase flushing and rapid heartbeats.
If you are going to have surgery, tell your doctor or dentist that you are taking diltiazem.
Do not suddenly stop taking diltiazem. Ask your doctor how to gradually reduce the dose.
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 30C (59 and 86F). Protect from humidity. Throw away any unused medicine after the expiration date.
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