Angina And Calcium

What is angina?

Did you know that angina is the most common symptom of ischemic disease? Did you know about 9 million patients are affected by angina and its treatment is very expensive? Angina results when there is coronary artery disease due to an obstruction of an artery or due to a spasm in the coronary artery. The treatment for coronary artery disease includes revascularization of the artery and antianginal therapy with medications. Common medications include calcium channel blockers, calcium channel blockers like nifedipine belonging to the class of dihydropyridine calcium channel blockers, beta-blockers, short-acting nitrates or a second choice of drugs like ranolazine and ivabradine. The treatment regimen typically is to use the first choice of drugs and resort to the second choice only and if the first choice does not work without contraindications, patients are asymptomatic. Besides, there is no research or medical studies conducted that can corroborate that the first choice of drugs are indeed better at reducing complications and morbidity associated with coronary artery disease over the second choice of drugs. The second choice of drugs in fact are more contemporary. It is also to say that they might be more effective in treatment at least with the comorbid conditions over first-choice antianginal therapy with calcium channel blockers in coronary artery disease. Therefore there is a need for newer antianginal therapy based on newer algorithms and an individualized or personalized treatment for coronary artery disease patients.¹

Causes (Brief note)

Obstructive coronary artery disease is usually the cause of angina pectoris. Angina involves a deficiency of oxygen supply or ischemia and occurs after activity and physiological stress. Coronary artery disease angina pectoris is caused by coronary blood flow insufficiency leading to necrosis of myocardial cells due to the inability to meet the daily activity level requirements and thus resulting in myocardial ischemia. When this disease happens there is paroxysmal and crushing chest pain. Some other reason for coronary artery disease or heart disease is high blood pressure and this can be confirmed with computed tomography or angiography.²

Signs and symptoms (Brief note)

A discomforting chest pain that feels like someone is constricting you in the front of the chest, neck, shoulders, jaw and arms. It increases physical activity and decreases with rest. A dose of glyceryl nitrate also brings down symptoms in 5 mins. A typical angina occurs when there are two of the above symptoms. Non-anginal chest pain is when there are one or none of the symptoms. Stable angina is when non-anginal pain is not there.³

What are calcium channel blockers?

Acute coronary syndromes are effectively treated with calcium channel antagonists or calcium channel blockers (CCBs). They have been used for many indications and there are two types which are non-dihydropyridines and dihydropyridines calcium channel blockers. Cardiovascular conditions include high blood pressure, heart attack, hypertension, coronary spasm, angina pectoris, hypertrophic cardiomyopathy, and pulmonary hypertension.  The dihydropyridine calcium channel blockers are a group made of amlodipine, felodipine and lacidipine, which are a common choices for the treatment of hypertension, stable angina. This cardiovascular drug class is one of the reasons for drug-related mortality.  They are often classified into two major categories, either non-dihydropyridines or dihydropyridines. The non-dihydropyridines include verapamil, a phenylalkylamine, and diltiazem, a benzothiazepine. The dihydropyridines usually end in "pine" (i.e., amlodipine and nicardipine).⁴

Examples of calcium channel blockers

First generation calcium channel blockers like diltiazem and nifedipine and then there are second generation calcium channel blockers like amlodipine and benidipine. A acute coronary syndrome is defined as recurrent chest pain over 20 mins along with ischemic symptoms detected by ECG or cardiac markers elevation typical of heart attack. Calcium channel blockers inhibit the inflow of Ca2+ into the smooth muscle cell through voltage-sensitive Ca2 channels, thereby causing vasodilation and preventing angina. Diltiazem was the most prescribed drug (79.0%), amlodipine (11.1%), nifedipine (5.8%), and benidipine (4.1%)  for angina in acute coronary syndromes.⁵

Calcium channel antagonists are absorbed well orally. They however have low bio availability due to the drug metabolisms in the liver. The hepatic first-pass metabolism, primarily is carried out by CYP3A.⁴ Calcium channel antagonists are bound very tightly and highly to protein, and many have generous volumes of distribution in the body.

Angina and calcium channel blockers

Calcium channel blockers inhibits the flow of calcium ions into smooth muscle cells in the heart through voltage-sensitive calcium channels thereby causing vasodilation. The second generation of calcium channel blockers is effective with acute coronary syndrome and angina as they have longer sustainability and have very specific vessel targeting a property. Besides short acting calcium channel blockers are having sympathetic activity and increase nor epinephrine levels which is not good for heart attacks. It is recommended to use second generation calcium channel blockers over first generation for heart disease and angina symptoms management. Beta blockers and nondihydropyridine calcium channel blockers are anti hypertensive drugs and they decrease blood pressure. They reduce heart rate minimally on high blood pressure and angina symptoms management is ineffective. So they are sometimes and due to some research are being considered as a second option. Patients will require close monitoring of conditions and if there is an  improvement of their symptoms of angina or maintenance of their blood pressure then that could be an indication of efficacy. It is still important that a patient should undergo regular check ups with the clinician when he is prescribing these medications quickly. 

Explain how calcium channel blockers help improve the symptoms of angina

Smoking cessation, regular exercise is good to manage stable angina. Anti anginal therapy is also given with CCB and nitrates for management of disease, reducing mortality and preventing heart attack.

Calcium channel antagonists block the  movement of calcium going inside into the cell  by binding to the L-type “long-acting” voltage-gated calcium channels. These calcium channels in the heart are also present in vascular smooth muscle and in pancreas. We have already discussed the  two major categories of calcium channel antagonists: based on their primary physiologic effects they are the non-dihydropyridines and dihydropyridine. Generally non dihydropyridine have inhibitory effects on the sinoatrial (SA), and atrioventricular (AV) nodes which result in slowing of cardiac conduction and contractility of cells in the heart.vThis allows for the treatment of high blood pressure, reduces oxygen demand, and helps to control the rate in coronary artery disease like arrhythmias. The dihydropyridines, in therapeutic dosing, have more indirect effect on the myocardium and more usually as peripheral vasodilators and that is why they are useful for hypertension, and migraines.

Calcium channel blockers (CCBs) are used  in the management of high blood pressure, angina pectoris and supraventricular tachycardias. These drugs prevent the movement of calcium into the cytoplasm via  calcium channels on the cell membrane,  reduce myocardial contractility, and hence modify the activity of pacemaker cells. Myocardial ischemia is a condition in which the blood flow with oxygen is  reduced in a part of the body. Cardiac ischemia is the name given to for decrease in oxygen rich blood to the heart muscle or oxygen deprivation results and will show up clinically in ways like coronary heart disease. Calcium blockers elicit action by vasodilation, by modulating heart rate and stress levels on myocardium. Antianginal therapies also reduce myocardial work and oxygen consumption, optimize the energetic efficiency of cardiomyocytes.

When to use calcium channel blockers

Using calcium channel blockers are not useful for improving mortality and morbidity although there have been instances of these in stable angina, coronary artery disease patients. Users of calcium blockers had a higher resting heart rate and blood pressure with symptoms of angina. It may be that calcium blockers can be used for symptom relief but not for overall mortality benefit is not a guarantee. Overall, calcium blockers are prescribed for a history of myocardial infarction, blood pressure, anginal symptoms, stroke and other coronary artery disease symptoms. Short acting Nifedine is not to be used in unstable angina.

Drug interactions

Nifedipine is not to be used for acute phase myocardial infarction as calcium channel blockers are contraindicated in it. In general non dihydropyridine drugs cannot be taken with beta blockers as the negative chronotropic effects of these drugs can cause heart attack. The combination of beta blockers and calcium channel blockers is much more effective in treatment of exercise induced angina pectoris than monotherapy of beta blockers. Metroproponol ( beta blocker ) and amlodipine ( calcium channel blockers) are recommended to reduce high blood pressure, heart attack. Non dihydropyridine and beta blockers taken together however can cause increased side effects like fatigue, dizziness, heartburn.⁶

Non-dihydropyridines are not advised for those with heart failure with reduced ejection fraction, second or third-degree Artery Ventricle blockade as because of the possibility of  bradycardia and also for fears of worse cardiac output.

Calcium channel blockers are also contraindicated in patients with known hypersensitivity to the drug and it's chemical constituents. Other contraindications are severe hypotension, acute myocardial infarction, and in some cases lung or pulmonary congestion. Calcium channel blockers may also cause Arterty Ventricle blockage or sinus bradycardia. This is especially true if  taken with drugs that are known to slow cardiac conduction. There are reports of skin or dermatologic reactions and hypotension with or without syncope or fainting with or without losing consciousness when taking calcium channel blockers.  Peripheral edema or fluid build up  may occur within 2 to 3 weeks of starting calcium channel blocker drug regimen. Caution must be administered in patients with renal and hepatic issues and one must consider using these drugs at a lower dose.

Guidelines

They can be administered intravenous or through oral routes. Non-dihydropyridines may cause constipation, worsening cardiac output, and bradycardia. Dihydropyridines can cause lightheadedness, flushing, headaches, and peripheral edema. MI and stroke can be addressed with smoking cessation, management of lifestyle, regular exercise and a drug regimen. The drugs typically given as the first line are calcium channel blockers. A combination of BB and non-DHP must be avoided for episodes of bradycardia might be triggered. NonDHP are very effective in asthma and COPD patients over BB. Adding either a  CCB to Beta Blockers therapy is  useful because it reduces angina frequency, it  improves exercise tolerance and reduces myocardial infarction.

In repeated doses or  in cases of overdose, the hepatic enzymes that carries out the metabolism of drugs become saturated and reduce the effects caused by  first-pass. This results in which  increased absorption of the active part of the drug. Modifications of the release formulations and also saturation of process of absorption of these drugs will increase half-life of various the calcium channel antagonists. The drugs are excreted renally yes antagonists are primarily after metabolism.

There is the a great chance for drug-drug interactions as these  calcium channel antagonists are digested or metabolised by CYP3A.⁴ These group of hepatic enzymes are responsible for the metabolism of many other xenobiotics hence the chance of drug-drug interactions.

Side effects

The major side effects of long term usage of CCB is breast cancer risk increases two fold. This is bad news as calcium channel blockers are very effective for high blood pressure patients. The most common side effect is edema. Calcium channel blockers decrease blood pressure by hindering the influx of calcium into myocardial cells. They may also increase the diameter of blood vessels, which always results in decreased blood pressure. Both hypotension and bradycardia are side-effects in patients on calcium channel blockers and will need medical attention. Patients on these agents require meeting with doctors as long as they remain on the drugs. 

Non-dihydropyridines calcium channel blockers can cause constipation, worse  cardiac output or slower than beating heart less than 60 beats per minute or what is medically termed as bradycardia. Dihydropyridines may lead to lightheadedness, flushing, headaches, and peripheral edema. The peripheral edema is caused by redistribution of fluid from the intravascular space to the interstitium.There have also been reports of a medical condition of gingival hyperplasia or a condition of irregular growth of tissue of gum around the teeth.⁷

Summary

Calcium channel blockers are very effective in treatment of angina pectoris, stable angina. It is the sought after treatment as a first line with other drugs like beta blockers. There are two types of CCB which belong to dihydropyridine and nondihydropyridine. The drug names for dihydropyridine class of CCB include amlodipine and nifedipine. The drug names for nondihydropyridine class drugs include verapamil and diltiazem. They both reduce blood pressure but dihydropyridine calcium channel blockers are more effective in reducing blood pressures to normal ranges. They have side effects but are preferred for their ability to deal with MI and angina symptoms.