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Beta blockade and the heart
The rate of the heart and the force of its contraction are governed by careful balance of the autonomic nervous system in the human body. The sympathetic nervous system, responsible for positive stimulation of heart rate and heart beat force, is active in stressful situations or situations where the individual is physically active. Stimulation of this so called beta adrenergic pathway causes an increase in heart rate and an increase in the force of the heart beat. This is balanced in nature by the para-sympathetic nervous system which, via the vagal nerve, slows down the heart rate and modulates the heart beat force. In patients who have angina and heart failure in certain situations, the over activity of the sympathetic (adrenergic) nervous system, is detrimental both to the patients longevity and to the symptoms that the patient experiences. A patient who has angina may find considerable benefit from the heart rate blunting effects of beta blockers.
What are Beta blockers?
Beta blockers are a group of drugs. The original prototype beta blocker, such as Propranolol, had excellent effects on the heart rate, but unfortunately, were associated with significant extra cardiac side effects, such as tiredness and in the case of some of the other Beta blockers, significant problems. More modern Beta blockers are very selective for the heart (the Beta I subgroup receptor) and some are even more clever, having additional nitrate groups added to them, or some alpha blocking properties, such as Nebivolol and Carvidolol respectively & help dilate the blood vessels.
Why might a patient need Beta blockers?
In a patient with stable angina, the treatment of angina would involve a combination of revascularisation using coronary angioplasty or bypass surgery, but also the treatment of symptoms with tablets, such as Beta blockers. Beta stimulation primarily causes the heart rate to increase during exercise and stress. Accordingly, Beta blockade decreases or blunts the heart requirement for oxygen during these situations. This decreases the demand placed on the cardiac circulation and improves the patients exercise capacity and symptomatic status.
What about heart failure?
It is established in the treatment of chronic heart failure, that the addition of low dose Beta blockers, carefully titrating up the dose, not only improves patient’s symptomatic status, but moreover has a significant impact in their longevity.
Why is this the case?
In heart failure, it is not simply a case of their being abnormal pump function of the heart. It is a whole body disorder where there is a combination of physical pump dysfunction, abnormalities of the muscle blood flow, abnormalities of the vascular performance and abnormal activation of the neuro-humoral and endocrine systems with high levels of circulating adrenaline, catecholamines and abnormalities of the rennin angiotensin and aldosterone systems. Large clinical trials have shown that the addition of low dose beta blockade to standard therapy, with gradual increments, has a significant effect in all categories of heart failure ranging from mild to severe.
The effects of Beta blockers in diastolic heart failure are less well defined, but do appear to be beneficial and larger scale trials are currently underway to underline this.
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Calcium Channel Blockers
The intrinsic rhythm of the heart is governed by a number of so called “ion channels”. These ions channels allow cations, such as sodium, calcium, potassium and anions such as chloride to move in and out of the heart cell. When the heart cell is activated electrically, there is a sudden enlarged entry of sodium and calcium ions into the cell, which trigger the release of further calcium stores from inside the cell. This enables the heart cell to contract. This so called electro-mechanical coupling is very dependant on the levels of calcium within the cell and the influx of calcium triggered by the depolarisation. A certain group of drugs called calcium channel blockers decrease not only this rapid influx of calcium in the heart cells, but also in the smooth muscle cells, which ring the arteries and arterioles of the body.
Broadly speaking, there are two main types of calcium channel blockers.
- Dihydropyridine (such as Nifedipine & Amlodipine)
- Non Dihydropyridine of which these are further more divided:
In the setting of angina, there may well be patients who are unable to tolerate Beta blockers due to side effects, such as exacerbation of lung disease or asthma, tiredness or coldness with the peripheries. In these individuals, the cardiologist may often choose to use a rate limiting calcium channel blocker, such as Verapamil, to slow down the heart rate and have a similar effect to Beta blockade.
Again, in the treatment of hypertension, they are excellent drugs for use in certain individuals and commonly used agents include:
- Nifedipine (Adalat)
- Amlodipine (Istin)
Frequently, the cardiologist will use a combination of Beta blockade and Calcium channel blockers in the treatment of Angina.
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Nitrates
What are Nitrates?
The balance of tone of the coronary and peripheral circulation is dependent in a large part, on the generation of Nitric oxide (a free radical), by the endothelium of the vascular tissues. In certain disease conditions, such as hypertension and heart failure, along with coronary artery disease, the inherent generation of nitric oxide is inadequate. The main role of nitric oxide is to dilate the vessels, along with some other regulatory metabolic effects. If there is inadequate nitric oxide in the patient, for example in a scenario where there is regular exertional or angina and the patient is getting lots of symptoms, then the use of an oral nitrate tablet, such as Isosorbide Mononitrate (Imdur) is beneficial. This artificially releases nitric oxide in the blood stream and dilates the blood vessels, both of the coronary and peripheral circulation, directly and indirectly decreasing the workload of the heart and improving anginal symptoms. In certain individuals, such as those who have a low circulating renin level, they may also be beneficial when administered on a regular basis in heart failure. There are limited nitrate tolerances and should really only be given in one dose a day, allowing a nitrate free period so the bodies sensitivity to the nitrate, generated nitric oxide, is not diminished. This is often why your cardiologist will use an agent such as Imdur, which is a very well designed sustained release preparation.
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Ivabradine
Ivabradine is a newer drug, which is a very specific inhibitor of the If channel. This channel is directly responsible for the heart rate, as it occurs primarily in the sinus node, the main pacemaker of the heart. In individuals, who cannot tolerate Beta blockers, it is licensed to be used either instead of or ahead of a rate limiting calcium channel blocker. There is little experience in the United Kingdom with this drug at the moment, but widespread experience in the United States and Japan. The cardiologists in the UK have growing experience with it and the experience of this new drug is highly promising. In individuals who are unable to tolerate Beta blockers, the cardiologist may use it as their second line treatment, in addition with nitrates.
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Nicorandil
Nicorandil is a unique drug in that it has two effects on the heart.
The first, and most important, is that it inhibits a specific channel called the KATP channel, both in the cardiac sarcolemma and in the cardiac mitochondria. This is most marked in the coronary vasculature and lesser so in the peripheral vasculature. In essence, it is a coronary vasodilator, but there is also evidence that it acts in a more specific way. Independent of its ability to generate free radicals, it appears that the opening of the KATP channel in the mitochondria, is cardio protective.
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Ranolazine
Ranolazine is a new drug and is currently indicated for use in the treatment of chronic stable angina in individuals with persistent angina despite standard anti-anginal medications. Ranolazine is believed to have its effects via altering the trans-cellular late sodium current, which prevents cellular calcium overload. Unlike most other antianginal medications, ranolazine does not significantly alter either the heart rate or blood pressure. For this reason, it is of particular use in individuals with angina despite maximal tolerated doses of other anti-anginal medications.
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Aspirin
Aspirin is on the of the oldest used compounds in the clinical armamentarium. Its primary use in cardiology is that of platelet inhibitor. The platelets are a key component in the blood coagulation chain and are responsible, in a large part, for the propagation of thrombosis in acute coronary syndromes. The inhibition of platelet activity, via Aspirin, has been proven to be beneficial in a large number of clinical scenarios, most notably, in patients who have had myocardial infarction (heart attack), unstable angina, chronic stable angina; they have all been proven to be beneficial. The benefit of Aspirin in atrial fibrillation is less than that of Warfarin. However it may be adequate if you are at low risk of blood clots.
The downside of the regular use of Aspirin is that a certain proportion of patients are unable to take Aspirin due to gastric intolerance and the formation either of a gastritis, or more significantly, of gastric ulcers and bleeding of the stomach lining. We will evaluate your risk of developing this carefully before initiating Asprin and may well coat prescribe another drug to protect the lining of the stomach during the duration of your Aspirin therapy.
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Clopidogrel (Plavix)
Clopidogrel, also known as Plavix is one of the newer thienopyridine compounds, which is a very potent platelet inhibitor. In patients who are very high risk for coronary events, or those following intervention with drug eluting stents, the cardiologist will always use a combination of Aspirin and Plavix, unless there is good reason not so to do, such as previous sensitivity to the drugs or a very high risk of gastric bleeding or brain haemorrhage. Again, as with Aspirin, there is a small degree of risk of bleeding from the lining of the stomach or other areas of the body, but your cardiologist will discuss these risks and the benefit of the treatment with you in detail during the consultation.
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Prasugrel
Prasugrel, this is a new drug that is more powerful than Clopidogrel. It is used in in high risk cases, when clopidogrel alone may be inadequate or has been shown not to work. It has associated bleeding risk as it is a powerful agent.
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Statins
These agents lower cholesterol by reducing its production in the liver. They are well tolerated and have a large amount of evidence showing that they reduce heart attacks and stroke. If your risk of death, heart attack or stroke is more that 2% annually, you should be on a statin. We can calculate your risk and advise on which agent and what dose you need to be on.
| Statin | Standard dose | Maximum dose | LDL reduction |
| Pravastatin | 40 mg | 40 mg | 1.38 mmol/l |
| Simvastatin | 40 mg | 40 mg | 2.01 mmol/l |
| Atorvastatin | 40 mg | 80 mg | 2.58 mmol/l |
| Rosuvastatin | 10 mg | 40 mg | 2.64 mmol/l |
Table of statins and possible cholesterol reductions.
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Fibrates
These agents have less evidence than statins but may be useful in combination with statins or if you are intolerant of statins.
ACE Inhibitors
It is established that in systolic heart failure, there are a wide number of abnormalities in the body’s neuro-humoral balance. Ordinarily, the level of salt, and therefore free water in the body is controlled very carefully by the kidneys filtration system. This, in turn, is under the governance of the rennin, angiotensin, aldosterone axis. In heart failure, there is an abnormal set point of this axis, so the body attempts vigorously to retain fluid and sodium to maintain the forward cardiac output. This can go to far and have deleterious effects. The most sensitive part of this feedback system is the relationship of the angiotensin converting enzyme(ACE), which converts decopeptide angiotensin I, to angiotensin II under the control of renin. The ACE inhibitors very strongly inhibit this pathway and have been proven in many large clinical trials, to be beneficial in all types of heart failure from mild to severe, both in terms of the patients symptoms and moreover, in terms of the patient’s longevity.
Angiotensin Receptor Blockers (ARBs)
The downstream target of angiotensin II is the angiotensin receptor (ATII receptor). There are a number of sub-groups of this receptor, but they are located primarily on the heart muscle (myocardium) and the lining of the main arteries and blood vessels (vascular endothelium). Over activation of this occurs, in settings such as high blood pressure or heart failure. A certain group of drugs, called the angiotensin receptor blockers (ARBs) are very specific and bind this receptor to effectively switch off its down stream effects, such as thickening of the heart muscle (hypertrophy) and thickening of the arteriolar walls in hypertension. This family of drugs include agents such as Candasartan and Telmisartan, along with older agents with shorter half lives, such as Losartan.
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Alpha Blockers
Doxazosin is used as an anti-hypertension agent. It blocks alpha receptors, reducing the action of body chemicals such as adrenalin and noradrenalin, and so lowering blood pressure.
Warferin
Strong blood thinners such as warferin are needed if you have atrial fibrillation, have had blood clots, or if you have metal heart valves. Warferin requires careful monitoring that your cardiologist or your GP will be able to do. This involves regular blood tests to ensure your are getting enough drug. Too little, and it is not effective, too much and you will get bleeding problems. Do not take any over the counter or prescription medication without discussing it with your doctor- these drugs can interact with warferin and risk your health. Do not stop warferin without discussing it with your doctor. Although often avoided to prevent bleeding problems, aspirin and even clopiodgrel may be prescribed along with warferin in some circumstances.
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Digoxin
The original version of this drug was made from the plant Foxglove. In a pure form, Digoxin is used to slow the heart rate in Atrial Fibrillation, and in some patients with heart failure.
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