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What is it ?
Nitrates
Nitrates have been used in the treatment of angina for over a hundred years. These drugs release nitric oxide, thereby relaxing the smooth muscles in blood vessels. Many nitrate preparations are available; the most commonly used are nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate. Nitrates can be absorbed from the gastrointestinal tract (oral tablet), skin (ointment or patch), and from under the tongue (sublingual tablet or spray).
Rapid Attacking Nitrates. Rapid-acting nitrates are used to treat acute attacks. Nitroglycerin is the most widely agent for this purpose. It can be administered under the tongue (sublingually or as a spray) or pocketed between the upper lip and gum (buccally) and can relieve angina within minutes. The procedure for taking nitroglycerine during an attack is as follows:
- At the onset of an angina attack, the patient administers one sublingual or buccal tablet or one metered dose of the spray.
- If the pain is not relieved within five minutes the patient takes a second dose; a third can be taken after another five minutes if symptoms persist.
- If pain continues after a total of three doses in 15 minutes, the patient should go to the nearest emergency room at once.
Nitroglycerin is very volatile so its potency can be easily lost. A patient should take the follow precautions:
- Keep no more than 100 tablets on hand stored in their original container.
- When first opened, the cotton filler should be discarded, and the cap screwed on tightly immediately after each use.
- A supply should always be kept close at hand in case of an attack, with the rest kept in a cool dry place.
Intermediate to Long-Term Nitrates
Sublingual tablets of isosorbide dinitrate have a somewhat slower onset of action than nitroglycerin and are useful for preventing exercise angina. They are recommended for angina attacks only in patients who do not respond to nitroglycerin.
Ointments, patches, and oral tablets are used for longer-term prevention of angina attacks:
- Transdermal patches are applied in the morning to any hair- or injury-free area on the chest, back, stomach, thigh, or upper arm. Hands should be washed after each patch or ointment application and sites of application should be rotated to avoid skin irritation.
- Nitroglycerin ointment is applied by measuring out an even amount on an applicator paper and then placing, not rubbing or massaging, it on the chest, stomach, or thigh. Any ointment that remains from the previous application should be removed.
Long-acting forms may lose their effectiveness over time, so physicians generally schedule nitrate-free breaks to prevent tolerance. Some concern exists that nitrate-free periods might increase the risk for angina and adverse heart events. One large study, however, found no increased danger when patients used a nitroglycerine patch with scheduled breaks. The use of drugs known as ACE inhibitors, normally used for high blood pressure, may help prevent tolerance to nitrates. (Some studies suggest that vitamin C or E might also may help.)
Side Effects. Side effects of nitrates include headaches, dizziness, nausea, blurred vision, fast heartbeat, and sweating. Low blood pressure and dizziness can be relieved by lying down with the legs elevated. Note: These effects can be significantly worsened by alcohol, beta-blockers, calcium channel blockers, sildenafil (Viagra), and certain antidepressants.
Withdrawal. Withdrawal from nitrates should be gradual. Abrupt termination may cause angina attacks.
Beta-Blockers
Beta-blockers reduce the oxygen demand of the heart by slowing the heart rate and lowering arterial pressure. They are now well known for reducing deaths from heart disease. Beta-blockers do not stop angina attacks, but used preventively, they reduce their frequency and the dependency on nitrates. They may also be beneficial for people with silent ischemia. (Beta-blockers are less useful for the treatment of Prinzmetal's angina.)
Specific Beta-blockers. Beta-blockers include propranolol (Inderal,Ciplar), labetalol (Normadate), acebutolol (Sectral), atenolol (Aten,Tenormin,Betacard, Tensimin), metoprolol (Betaloc,Metolar), and bisoprolol (Concor). Carvedilol (Carvedil,Carloc, Carvil), a newer agent known as a nonselective beta-blocker, appears to be as safe as the older beta-blockers and may prove to have additional advantages. A nasal spray form of propranolol appears to be very beneficial in helping to reduce exercise-induced angina attacks.
Side Effects. Some beta-blockers tend to lower HDL cholesterol (the beneficial cholesterol) by about 10%; the effect is most marked in smokers. Fatigue and lethargy are the most common psychologic side effects. Some people experience vivid dreams and nightmares, depression, and memory loss. Exercise capacity may be reduced. Other side effects may include cold extremities, asthma, decreased heart function, gastrointestinal problems, and sexual dysfunction. If side effects occur, the patient should call a physician, but it is extremely important not to stop the drug abruptly. Angina, heart attack, and even sudden death have occurred in patients who discontinued treatment without gradual withdrawal.
Aspirin and Other Anti-Clotting Agents for Unstable Angina
Anti-clotting agents, either anticoagulants (eg, heparin, warfarin) or anti-platelet drugs (aspirin, glycoprotein IIb/IIIa receptor antagonists, clopidogrel), are being used to treat unstable angina, to protect against heart attacks, and prevent blood clots during heart surgeries. Oral anticoagulants, such as warfarin, are showing promise. They may be used alone or in combinations, depending on the severity of the condition. Aspirin alone has been reported to reduce risk of death from heart attack or stroke by 25% to 50% and to cut risk of non-fatal heart attacks by 34 percent. All anti-clotting therapies carry the risk of bleeding, which can lead to dangerous situations, including stroke.
Aspirin. Aspirin inhibits blood platelets (major clotting factors). Low-dose aspirin is usually the first choice for preventing heart attacks in people with stable angina or those with risk factors for a first heart attack. Aspirin is more effective in reducing pain from unstable than stable angina. Of concern, however, is a 2000 study suggesting that low-dose aspirin may provide primary prevention only for patients with low-normal blood pressure. Prolonged use may produce gastrointestinal ulcers and bleeding.
Of further concern are reports suggesting an association between recent use of aspirin or similar drugs called NSAIDs and a higher incidence of hospitalization in heart failure patients, particularly if they are also taking diuretics or ACE inhibitors. In fact, one study suggested that anyone with a history of heart disease who is taking NSAIDs may be at higher risk for heart failure. (Low dose aspirin may not pose this danger.) Studies are needed on these important questions.
Heparin. The anticoagulant heparin, used alone or in combination with aspirin, is another standard blood-thinning drug, but it must be intravenously administered and monitored carefully for signs of bleeding. (A 1999 study indicated that adjusting the heparin dose according to the patient's weight when it is administered during acute conditions can reduce the risk for hemorrhage.)
Enoxaparin (Clexane), dalteparin (Fragmin), or reviparin(Clivarine) are drugs known as low-molecular weight heparins (LMWHs). They require injections but do not need continuous monitoring, as heparin does. Studies are finding that they are very effective for unstable angina and are outperforming standard heparin in patients with severe conditions. Patients may even be able to self-administer LMWHs as people with diabetes do insulin.
Warfarin. Warfarin (Uniwarfin) is an oral anticoagulant. It prevents clots by inhibiting vitamin K and can be taken orally. It is particularly beneficial for patients with atrial fibrillation. It, too, must be monitored. In one 1999 study, the most successful regimens in reducing risk for heart attack and stroke were moderate-to high-intensity oral anticoagulants in combination with low-dose aspirin. Low-intensity warfarin had about the same effectiveness as aspirin. Further trials are needed.
Glycoprotein IIb/IIIa Receptor Antagonists. Glycoprotein IIb/IIIa receptor antagonists thin blood by blocking platelets. Examples of these drugs include abciximab (ReoPro, Centocor), eptifibatide, lamifiban, and tirofiban. Early studies suggested that they reduced the risk for heart attack or death in many patients with unstable angina when combined with low-weight heparin or other agents. A major 2000 study on abciximab, however, reported that it offered no additional protection. In fact, patients who took it had poorer results than those on placebo, particularly after taking it for a long time. More research is needed to determine the implications of this study. Glycoprotein IIb/IIIa receptor antagonists are still helpful in relieving anginal pain in angioplasty patients, and a number of studies report significant benefits with the use of intravenous administration for unstable angina.
Certain patients (eg, thin, elderly, nonwhite, with more than one heart risk factor) may be at high risk for thrombocytopenia, a drastic reduction in platelets than can cause severe bleeding, after taking these drugs.
Platelet Inhibitors. Clopidogrel (Deplatt, Clopilet) and ticlopidine (Tyklid,Ticlop)) are platelet inhibitors. Studies indicate that clopidogrel is more effective than either aspirin or ticlopidine for reducing the incidence of a heart attack. Ticlopidine has been associated with dangerous blood disorders, particularly thrombocytopenia, and is used only in certain circumstances. Although clopidogrel has largely replaced ticlopidine because it had a better early safety profile, reports of thrombocytopenia in patients taking clopidogrel have created some concern. More research is needed to determine if the risk is as high as in ticlopidine. Platelet inhibitors may be particularly useful in preventing blood clots after angioplasty.
Hirudin. Hirudin is a substance derived from the saliva of leeches. Bivalirudin is the standard drug derived from hirudin. Studies are suggesting that hirudin agents may be more effective and safer than heparin. (Hirudin, however, can cause major bleeding episodes.)
Other Anti-Clotting Agents. Other promising anti-clotting drugs include the anticoagulant argatroban and danaparoid.
Statins
Cholesterol-lowering drugs commonly known as the statins may improve blood flow through the arteries, even after being taken for only a few months. In a 1999 review of major clinical trials of the drugs, researchers found that statins effectively reduce not only levels of LDL cholesterol but also the risk of major coronary events, including first and second heart attacks, in both women and men and in people older than sixty-five. They are even proving to reduce the risk for heart attacks in people with normal or below-normal cholesterol.
Angiotensin Converting Enzyme Inhibitors
Angiotensin converting enzyme (ACE) inhibitors are important agents. They are used in hypertension and currently recommended as first-line treatment for people with diabetes and kidney damage, for some heart attack survivors, and for patients with heart failure. Now, an important 2000 study that tested ramipril (Cardace), has suggested that other patients might benefit from it. In the study, high-risk patients who took ramipril significantly lowered their risk for heart attack, stroke, complications of diabetes, and death. Such patients had either coronary artery disease, a history of stroke, or diabetes plus at least one other heart risk factor, such as high blood pressure, unhealthy cholesterol levels, or smoking. (Ramipril had no effect on angina, however.) It is not yet known if these benefits apply to other ACE inhibitors, such as captopril (Capotril, Aceten), enalapril (Envas,Vasonorm), lisinopril (Prevace, Lipril, Zestril), and fosinopril.
Side Effects. Side effects of ACE inhibitors are uncommon but may include an irritating cough, excessive drops in blood pressure, and allergic reactions. Of great concern is research suggesting that aspirin (and other so-called NSAIDs) increases the risk for heart failure in patients taking ACE inhibitors.
Calcium Channel Blockers
Calcium channel blockers reduce heart rate and slightly dilate the blood vessels of the heart, thereby decreasing oxygen demand and increasing oxygen supply. Those approved for angina include verapamil (Calan, Isoptin), nifedipine (Adalat, Depin), nicardipine (Cardene), amlodipine (Amdepin,Corvadil), diltiazem (Cardizem, Dilzem), and bepridil (Vascor). Combinations with other agents may be beneficial. (Single use of agents, in any case, is not helpful for patients with unstable angina.) There is no evidence, in any case, that calcium channel blockers increase survival rates, and their safety in some cases is being questioned. A major 2000 study now suggests that they are inferior to other drugs (including diuretics, beta-blockers, and ACE inhibitors) in treating high blood pressure. Severe and even dangerous side effects, including an increase in heart attacks and sudden death, have occurred with short-acting forms, including short-acting nifedipine and bepridil. (A 1999 study found no worse survival rates in heart attack patients who took diltiazem, nifedipine, amlodipine, or verapamil. Bepridil, however, posed some risk and, in any case, is not recommended unless patients do not respond to other calcium blockers.) Currently the National Heart, Lung, and Blood Institute warns that short-acting nifedipine should be used with great caution (if at all), especially at higher doses, in patients with angina. No one currently taking any calcium channel blocker should stop taking it abruptly, because such action could dangerously increase the risk of high blood pressure. Overdose can cause dangerously low blood pressure and slow heart beats. It should be noted that drinking grapefruit juice with these drugs could increase their effects, sometimes to toxic levels.
Experimental Drugs
Ranolazine. Ranolazine is a unique drug under investigation that reduces the work of the cells in the heart without damaging them. Early studies are showing success in improving short-term exercise tolerance.
Nicorandil. Nicorandil, know as a potassium channel activator, has anti-ischemic and antiarrhythmic properties and may be a useful add-on for patients who need aggressive treatment. Severe mouth sores have been reported in some patients with long-term use.
Antibiotics. The antibiotics tetracyclines and quinolones, which are prescribed for Chlamydia pneumoniae and H. pylori , have been associated with a lower risk for heart attacks.
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