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Drug Therapy for Coronary Insufficiency
The problem in coronary insufficiency is an imbalance between supply and demand for oxygenated blood. The heart needs more oxygen to generate energy than can be supplied by the narrowed artery. Drug therapy in coronary insufficiency decreases the heart's demand for oxygenated blood. Drug therapy does not open up your arteries, nor does it improve the efficiency of energy metabolism, but by decreasing your heart rate, blood pressure, and the contractile vigor of the heart, oxygen demand is lessened, and with this there is a lessening of your symptoms. Let's now discuss the major classics of anti-anginal drugs:
Sublingual Nitroglycerin (NTG)
These agents are "anti-adrenalins"; they bind to and occupy the cellular receptor that would otherwise be bound to and stimulated by adrenalin. If adrenalin, our "fight or flight" hormone, is blocked, then heart rate, blood pressure, and the vigor of cardiac contraction are decreased. The heart is "placed on ice", and its demand for oxygen will be lessened. Supply : demand mismatch for oxygen will resolve, and you will experience less pain. Should you experience a heart attack, having a beta blocker on board will improve your outcome. Beta blockade is an excellent idea when a patient with coronary disease requires non-cardiac surgery. The stress of surgery is really the chemical stress of adrenaline; beta blocker therapy will block this stress and reduce your risk of an adverse cardiac event. The side effects of beta blockade is an exaggerated response, which can usually be corrected with a dosage adjustment. If I give you too much beta blockade, your heart rate and blood pressure could fall too low. Beta blockers may give you a sensation of fatigue. Some patients describe mental clouding of even depression. Erectile dysfunction is not uncommon. Patients with peripheral vascular disease may experience chilliness over their extremities, and patients with asthma may experience a worsening of their symptoms. Beta blockers are categorized as:
Cardioselective - these beta blockers bind preferentially to beta receptors in the heart, and are less likely to cause lung and nervous system side effects. Metoprolol (trade name Lopressor and Toprol XL) is the cardioselective beta blocker used most frequently.
Nonselective - these agents bind to beta receptors throughout the body. They are more effective in the treatment of migraine headache, and are typically less expensive than the cardioselective agents, but otherwise have no distinct advantage. The nonselective agents in common use are Propranolol (trade name Inderal) and Atenolol (trade name Tenormin).
ISA - these agents, which possess ISA (intrinsic sympathomimetic activity) may stimulate the beta receptor weakly while still exerting an adrenaline blocking effect. Pindolol (trade name Visken) is a member of this class, which is rarely used. These agents are less likely to compromise sugar control in diabetics, and we might also use these agents to block episodic rapid heart in patients with a tendency to low heart rate (another approach, and one that actually works better, is to place a pacemaker to allow unrestricted beta blockade).
Carvedilol (trade name Coreg, discussed in more detail in the drugs therapy for CHF section). Carvedilol is a cardioselective beta blocker that also blocks the alpha receptor, and it has an anti-oxidant effect. It has an advantage over Metoprolol in the patient with CHF who is struggling while on Metoprolol. We typically do not use Carvedilol in the treatment of angina, but will use this agent in the treatment of patients who are troubled by both angina and CHF.
Contraction of cardiovascular muscle cells is triggered biochemically by an influx of calcium ions through "calcium channels" in the cell membrane. Calcium blockers block this channel. Less calcium gets in to the cell, so it contracts with less vigor. The results is lower heart rate, lower blood pressure, and lower contractility of the heart, less demand for oxygen, and a reduction in your symptoms. The commonly used calcium blockers vary in their primary effects and side effects. Calcium blockers adversely effect heart rate variability, a characteristic not in their favor. When compared to other therapies as blood pressure control agents, long term outcome is worse when a calcium blocker is utilized. Another way to block the calcium channel is with Magnesium, a non-toxic agent that is of value in all cardiovascular conditions and syndromes. Pharmaceutical calcium channel blockers are thus not my first line agents:
Verapamil (trade names Calan, Verelan) lowers heart rate and contractility more than it does blood pressure. The major side effects of verapamil are fatigue and a tendency to constipation. Asthma does not occur and erectile dysfunction is less of an issue that with beta blockade.
Nifedipine (Procardia, Nifedipine ER) functions more as a vasodilator, so blood pressure typically falls while heart rate typically does not. Ankle edema is a common side effect. This is not due to fluid retention, kidney dysfunction, or CHF, but rather due to vasodilation at the capillary level, allowing fluid to ooze out into the extracellular space. This will not hurt you but is a nuisance.
Amlodipine (trade name Norvasc) is a never version of Nifedipine, with similar effects.
Diltiazem (trade names Cardizem, Dilacor) in sort of a cross between Verapamil and Nifedipine, producing a more balanced reduction in both blood pressure and heart rate. Diltiazem also has value in decreasing the ventricular rate in atrial fibrillation. Edema is not uncommon, and amongst the calcium blockers, Diltiazem is the most likely to produce a drug rash.
Healthy endothelial cells manufacture nitric oxide from arginine. Nitric oxide maintains our arteries in their physiologic, dilated state, blocks platelet aggregation, and resists plaque build up. Patients with symptomatic coronary insufficiency all suffer form endothelial dysfunction; they are all deficient in nitric oxide and in nitric oxide generating capacity. Sublingual (SL) NTG (nitroglycerin), in a process that uses up glutathione, our primary intracellular antioxidant and detoxifying agent, is rapidly converted into nitric oxide. If you are experiencing angina, sublingual NTG gives you a jolt of nitric oxide - your arteries dilate up and your chest pain will likely resolve. The effects of sublingual NTG are brief, but you can repeat its use throughout the day. We don't rely of sublingual NTG as a definitive, long-term therapy, but it is certainly useful in quieting down your symptoms over the short term.
These drugs represent what we don't like about drug only medicine. Long acting nitrates make you feel better, but they damage your physiology and increase your risk for an adverse event. The conversion of NTG to nitric oxide uses up glutathione, actually depleting your antioxidant reserve. As the duration of action of SL NTG is brief, glutathione wastage is brief, and this agent can be regenerated within the cell. SL NTG floods the circulation with exogenous nitric oxide. The body senses this, and appropriately shuts off production of endogenous nitric oxide within the endothelial cells. Again, the effects of SL NTG are brief, and endogenous nitric oxide production resumes shortly. Long acting nitrates are basically sustained release forms of NTG; long acting nitrate therapy can be delivered in the form of pills, a patch, or in IV format. Long acting nitrate therapy continuously dribbles NTG into the circulation. Glutathione is constantly consumed in the conversion of NTG into nitric oxide. The endothelial cells essentially halt endogenous nitric oxide production. The key enzyme of endothelial nitric oxide synthesis, nitric oxide synthase, instead begins to convert oxygen into superoxide, a potent free radical. So at this point were are continuously wasting glutathione as we are continuously overproducing superoxide. The result is free radical stress, the condition that above all other bad things is the one most likely to kill us. Remember, LDL cholesterol is harmless, while oxidized LDL cholesterol layers out readily as plaque. When we give you long acting nitrates we are turning you into a free radical factory. This is bad, but to make matters worse, the superoxide generated by nitric oxide synthase will degrade nitric oxide, the exogenous nitric oxide derived from long acting nitrate therapy, and the residual endogenous nitric oxide that your not yet fully poisoned endothelial nitric oxide synthase enzyme system is still making. As the nitric oxide is degraded, your coronary arteries will renarrow, your blood pressure may rise, and your platelets will start to get sticky again. Your symptoms that initially responded to therapy with long acting nitrates will return - we call the "nitrate tolerance". Our solution - we increase the dose of your long acting nitrate. We flood more and more exogenous nitric oxide into your circulation, and you will feel better, at least for awhile. Endothelial production of nitric oxide is now fully shut down, while superoxide production is running full steam ahead. Soon the superoxide so generated gets the upper hand, again blunting the exogenous nitric oxide effect. We can keep upping your long acting nitrate dose, but you can see the problem we are creating. The bottom line is that long acting nitrate therapy is associated with an increased future event rate - these drugs make you feel better but they are hurting you.
In our discussion of statin therapy and CoQ10, it was pointed out that statins waste CoQ10, causing us harm, while statins themselves block the generation of free radicals, causing us good. My solution is to take CoQ10 along with statin therapy, such that you get the good without the bad. Can we come up with a similar approach to the problem of long acting nitrate therapy? If you continue to experience chest pain despite beta blocker therapy I have to do something to control your symptoms. Is there a way to provide you with long acting nitrate therapy without also compromising your long term cardiovascular health?
Of course there is. The problem with long acting nitrate therapy is glutathione depletion and superoxide mediated free radical stress. Vitamin C squelches superoxide and supports glutathione production, while N-acetyl cysteine is a precursor substance that we can convert into glutathione. In theory, if we give you these agents along with long acting nitrate therapy, we can blunt "nitrate tolerance" and nitrate induced endothelial toxicity. Randomized, placebo controlled studies show that this theory works well in practice. Both agents enhance the therapeutic effects of long acting nitrate therapy and actually improve outcome (one study is presented in the Vitamin C entry in the Medical Topics section of this website). My recommendation is to take N-acetyl cysteine 500 mg/day and/or Vitamin C 500-1000 mg twice a day if you are on long acting nitrate therapy.
James C. Roberts MD FACC
1/01/07